Lori A.

Erickson

Atlas of
Endocrine Pathology

123
Atlas of Anatomic Pathology

Series Editor
Liang Cheng

For further volumes:

http://www.springer.com/series/10144
Lori A. Erickson

Atlas of Endocrine Pathology

Lori A. Erickson, MD
Mayo Clinic College of Medicine
Rochester, MN
USA

ISBN 978-1-4939-0442-6 ISBN 978-1-4939-0443-3 (eBook)

DOI 10.1007/978-1-4939-0443-3
Springer New York Heidelberg Dordrecht London

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Series Preface

One Picture is Worth Ten Thousand Words

Frederick Barnard, 1927

Remarkable progress has been made in anatomic and surgical pathology during the last 10
years. The ability of surgical pathologists to reach a definite diagnosis is now enhanced by
immunohistochemical and molecular techniques. Many new clinically important histopatho-
logic entities and variants have been described using these techniques. Established diagnostic
entities are more fully defined for virtually every organ system. The emergence of personalized
medicine has also created a paradigm shift in surgical pathology. Both promptness and preci-
sion are required of modern pathologists. Newer diagnostic tests in anatomic pathology, how-
ever, cannot benefit the patient unless the pathologist recognizes the lesion and requests the
necessary special studies. An up-to-date Atlas encompassing the full spectrum of benign and
malignant lesions, their variants, and evidence-based diagnostic criteria for each organ system
is needed. This Atlas is not intended as a comprehensive source of detailed clinical information
concerning the entities shown. Clinical and therapeutic guidelines are served admirably by a
large number of excellent textbooks. This Atlas, however, is intended as a first knowledge
base in the quest for definitive and efficient diagnosis of both usual and unusual diseases.
The Atlas of Anatomic Pathology is presented to the reader as a quick reference guide for
diagnosis and classification of benign, congenital, inflammatory, nonneoplastic, and neoplastic
lesions organized by organ systems. Normal and variations of normal histology are illus-
trated for each organ. The Atlas focuses on visual diagnostic criteria and differential diagnosis.
The organization is intended to provide quick access to images and confirmatory tests for each
specific organ or site. The Atlas adopts the well-known and widely accepted terminology,
nomenclature, classification schemes, and staging algorithms.
This book Series is intended chiefly for use by pathologists in training and practicing surgi-
cal pathologists in their daily practice. It is also a useful resource for medical students, cyto-
technologists, pathologist assistants, and other medical professionals with special interest in
anatomic pathology. We hope that our trainees, students, and readers at all levels of expertise
will learn, understand, and gain insight into the pathophysiology of disease processes through
this comprehensive resource. Macroscopic and histological images are aesthetically pleasing
in many ways. We hope that the new Series will serve as a virtual pathology museum for the
edification of our readers.

Indianapolis, IN, USA Liang Cheng, MD

v
Preface

The Atlas of Endocrine Pathology provides a comprehensive compendium of photomicro-

graphs of common and uncommon entities in endocrine pathology. Histologic features of nor-
mal features, reactive conditions, hyperplasia, and tumors are included. The most helpful
diagnostic features are illustrated to provide direction and clues to the diagnosis of endocrine
tumors. The photomicrographs highlight the most pertinent diagnostic features in problematic
diagnoses in endocrine pathology. This Atlas serves as a learning tool for those becoming
familiar with the diverse entities encountered in endocrine pathology and a reference for prac-
ticing pathologists faced with challenging diagnoses in endocrine pathology.

Rochester, MN, USA Lori A. Erickson, MD

vii
Contents

1 Thyroid Histology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Normal Thyroid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Solid Cell Nests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Radiation Changes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Minocycline and Amiodarone Thyroid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Palpation Thyroiditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Thyroid Needle-Biopsy Site . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Ectopic Thyroid Tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Thyroglossal Duct Cyst . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Struma Ovarii . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2 Thyroiditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Acute Thyroiditis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Granulomatous (de Quervain) Thyroiditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Fibrous (Riedel) Thyroiditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Hashimoto Thyroiditis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Focal Lymphocytic Thyroiditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
3 Graves Disease (Diffuse Hyperplasia) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
4 Thyroid Goiter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
Multinodular Goiter. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Dyshormonogenetic Goiter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Amyloid Goiter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
5 Papillary Thyroid Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Classic PTC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Papillary Thyroid Microcarcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
FVPTC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Cribriform-Morular Variant of PTC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
Warthin-Like Variant of PTC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
Diffuse Sclerosing Variant of PTC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Oxyphilic (Oncocytic/Hurthle Cell) Variant of PTC . . . . . . . . . . . . . . . . . . . . . . . . 44
Solid Variant of PTC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Tall Cell Variant of PTC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
Columnar Variant of PTC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Hobnail Variant of PTC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
6 Hyalinizing Trabecular Tumor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

ix
x Contents

7 Follicular Thyroid Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

Follicular Adenoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Follicular Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
8 Hurthle Cell Thyroid Neoplasms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
Hurthle Cell Adenoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
Hurthle Cell Carcinoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
9 Poorly Differentiated Thyroid Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
10 Anaplastic Thyroid Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
11 Tumors of C Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
C-Cell Hyperplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
Medullary Thyroid Microcarcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
Medullary Thyroid Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
12 Unusual Thyroid Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Sclerosing Mucoepidermoid Carcinoma with Eosinophils . . . . . . . . . . . . . . . . . . . 87
Squamous Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
Langerhans Cell Histiocytosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Solitary Fibrous Tumor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Angiosarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
Synovial Sarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Low-Grade Fibromyxoid Sarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Rhabdomyosarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
Carcinoma Showing Thymus-Like Differentiation . . . . . . . . . . . . . . . . . . . . . . . . . 94
Teratoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
Paraganglioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
13 Metastases to Thyroid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
14 Parathyroid Histology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Normal Parathyroid Histology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
Parathyroid Cysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
Parathyroiditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
15 Parathyroid Hyperplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
Primary Parathyroid Hyperplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
Primary Clear Cell Hyperplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
Lipoadenomatous Hyperplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
Secondary Parathyroid Hyperplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
Tertiary Parathyroid Hyperplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
16 Parathyroid Adenoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
Chief Cell Parathyroid Adenoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
Oxyphil Cell Parathyroid Adenoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
Contents xi

Clear Cell Parathyroid Adenoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126

Parathyroid Lipoadenoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
Atypical Parathyroid Adenoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
17 Parathyroid Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
18 Parathyromatosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
19 Metastases to Parathyroid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
20 Adrenal Gland Histology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
Normal Adrenal Histology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
Heterotopia of Adrenal Tissue. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
Adrenal Infection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
21 Adrenal Cysts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
22 Adrenal Cortical Hyperplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Adrenal Cortical Hyperplasia, Diffuse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
Adrenal Cortical Hyperplasia, Nodular . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
Primary Pigmented Nodular Adrenocortical Disease . . . . . . . . . . . . . . . . . . . . . . . 162
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
23 Adrenal Cortical Adenoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
24 Adrenal Cortical Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
25 Adrenal Myelolipoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
26 Pheochromocytoma and Adrenal Medullary Hyperplasia . . . . . . . . . . . . . . . . . 187
Adrenal Medullary Hyperplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188
Pheochromocytoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189
Composite Pheochromocytoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
27 Ganglioneuroma and Neuroblastoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
28 Unusual Adrenal Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
Angiosarcoma of the Adrenal Gland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
Leiomyosarcoma of the Adrenal Gland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
Schwannoma of the Adrenal Gland. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
Teratoma of the Adrenal Gland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
Adenomatoid Tumor of the Adrenal Gland. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
29 Metastases to the Adrenal Gland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
 Thyroid Histology
The thyroid gland weighs 1525 g and is composed of two
lobes joined by the isthmus, with approximately 40 % of
people having a pyramidal lobe [1]. The thyroid is com-
posed of lobules, each of which is composed of 2040 fol-
licles. Each follicle is surrounded by a basement membrane
and lined by follicular cells. Colloid is present in the lumen
of the follicles. The presence of calcium oxalate crystals in
the colloid is a helpful feature differentiating it from para-
thyroid. Thyrocytes also may be distinguished from para-
thyroid cells by reactivity to thyroid transcription factor 1
(TTF1) and thyroglobulin and the absence of parathyroid
hormone and the neuroendocrine markers chromogranin
and synaptophysin in thyrocytes. C cells are calcitonin-
producing cells in the thyroid. They are present in interfol-
licular areas but are difficult to identify in normal thyroid
tissue with hematoxylin and eosin (H&E) alone. The
immunohistochemical stains calcitonin, chromogranin,
synaptophysin, somatostatin, calcitonin gene-related pep-
tide, and bombesin will highlight these neuroendocrine
cells of the thyroid. Thyroid follicular cells produce thy-
roxine (T4) and triiodothyronine (T3), and C cells produce
calcitonin. C cells migrate from the neural crest to the
L.A. Erickson, Atlas of Endocrine Pathology, Atlas of Anatomic Pathology,
DOI 10.1007/978-1-4939-0443-3_1, Springer Science+Business Media New York 2014
1
ultimobranchial bodies, which are derived from branchial
pouch complexes IV and V and develop in the first five to
seven fetal weeks [2, 3]. C cells have clear cytoplasm and
oval to round nuclei; they are positive for calcitonin, chro-
mogranin, synaptophysin, calcitonin, calcitonin gene-
related peptide, somatostatin, and bombesin [4]. Calcitonin
mRNA has been localized in C cells by in situ hybridization
studies [5]. Calcitonin is present in both 280-nm type I and
130-nm type II secretory granules; it is produced by C
cells. Calcitonin interacts with bone, kidney, and the gas-
trointestinal tract to lower serum calcium [6]. Thyroid fol-
licular cells and tumors are immunopositive for
thyroglobulin, TTF1, and keratin. Thyroid C cells and
tumors are immunopositive for calcitonin, chromogranin,
synaptophysin, keratin (Cam5.2), and TTF1, although the
intensity of TTF1 immunostaining often is less than in fol-
licular thyroid cells and tumors. Interesting histologic fea-
tures occasionally may be recognized in thyroid tissue,
including solid cell nests, fatty metaplasia, radiation
changes, drugs such as minocycline and amiodarone, and
palpation thyroiditis. Thyroid tissue also may occur ectopi-
cally, and tumors may develop in this tissue.
1
2 1 Thyroid Histology

Normal Thyroid

Fig. 1.1 Normal thyroid. Gross image of a normal thyroid gland show-
ing the bilobed gland joined by the isthmus in the center. The isthmus
lies anterior to the trachea and inferior to the cricoid cartilage. The thy-
roid is in front of the larynx and trachea. The thyroid descends with the
thyroglossal duct into the neck and expands after the thyroglossal duct
atrophies. The pyramidal lobe, present in approximately 40 % of peo-
ple, is a vestige of the thyroglossal duct. The anlage is visible in the
pharynx in association with the heart by day 17 of fetal life [7, 8].
Follicles develop from 9 to 12 fetal weeks, and well-developed colloid
follicles are seen at 14 weeks gestation [7, 8]
Fig. 1.2 Normal thyroid. Gross image of a cut section of a normal
thyroid gland, showing the bilobed gland joined by the isthmus in the
center. Normal thyroid glands in adults weigh 1525 g and may vary
with constitutional factors, age, sex, size of the individual, and func-
tional status. The thyroid may be larger in women and may change with
hormonal effects such as pregnancy and the menstrual cycle [9, 10]. An
enlarged thyroid gland is referred to as a goiter
Normal Thyroid
Fig. 1.3 Normal thyroid. The thyroid gland is made up of lobules of 2040
follicles. The follicles have an average size of 200 m (range of 50500 m)
and have colloid in their lumens, which is made up mostly of thyroglobulin.
Calcium oxalate crystals are present in normal colloid and allow a distinc-
tion from colloid-like material in parathyroid tissue that lacks calcium oxa-
late [11]. Normal thyroid tissue may be present in soft tissues next to the
thyroid as ectopic thyroid tissue [12]. The follicular cells have round nuclei
with a diffuse chromatin pattern and amphophilic to eosinophilic cytoplasm.
Thyroglobulin mRNA has been identified in follicular cells by in situ
hybridization studies [13]. Follicular cells are positive for the immunohisto-
chemical markers thyroglobulin, keratin, and TTF1
Fig. 1.4 Normal thyroid. Thyroid follicles are present with a central
lumen containing colloid. Thyroid follicular cells are polygonal, with
central nuclei and round nuclei with diffuse chromatin and moderate
amounts of amphophilic to eosinophilic cytoplasm. The follicular cells
produce thyroxine (T4) and triiodothyronine (T3) from exogenous
iodine, which is oxidized and catalyzed by thyroid peroxidase. Thyroid-
stimulating hormone (TSH) regulates the release of thyroglobulin,
stored as colloid, endocytosed, and hydrolyzed with release of T3 and
T4. Thyroglobulin breakdown and release of T3 and T4 are inhibited by
iodine by inhibiting TSH stimulation of thyroid adenylate cyclase
3
Fig. 1.5 Normal thyroid. Immunopositivity for thyroglobulin is pres-
ent in thyroid tissues and folliculogenic thyroid tumors. The thyrocytes
stain with thyroglobulin, as does the colloid. Medullary thyroid tumors
are negative for thyroglobulin. Thyroglobulin is helpful in identifying
tissues and tumors as thyroid and differentiating them from tumors
from other sites
Fig. 1.6 Normal thyroid. Thyroid follicular cells are immunopositive
for TTF1, which is helpful in differentiating thyroid from parathyroid
and other tissues. TTF1 is not specific for thyroid follicular cells or fol-
liculogenic tumors as it also stains, although with less intensity, medul-
lary thyroid carcinoma. TTF1 also stains most adenocarcinomas of the
lung and papillary adenocarcinoma of the sinuses. High-grade neuroen-
docrine tumors from the lung and some other sites may stain from
TTF1. Thus, this marker is not specific for thyroid, although it is very
helpful in determining the differentiation or primary site of difficult
tumors, particularly when used as part of a panel of immunostains
4 1 Thyroid Histology
Fig. 1.7 Normal thyroid. This chromogranin immunostain highlights
scattered C cells in interfollicular areas in normal thyroid. C cells of the
thyroid are difficult to identify in normal thyroid tissue with H&E stain-
ing. C cells have clear cytoplasm and oval to round nuclei. They are
positive for calcitonin, chromogranin, synaptophysin, calcitonin, calci-
tonin gene-related peptide, somatostatin, and bombesin [4]
Fig. 1.8 Normal thyroid. Foci of fat cells can be seen in the thyroid
parenchyma. Fat also may be seen in thyroid neoplasms. This finding of
adipocytes in the thyroid is not known to be of pathologic significance
Solid Cell Nests
Fig. 1.9 Solid cell nests. Solid cell nests are small nests of oval cells
with fine chromatin identified in 3 % of thyroid glands. They are
thought to be ultimobranchial body rests [14]
Fig. 1.10 Solid cell nests. Solid cell nests may be mistaken for papil-
lary thyroid carcinomas (PTCs) and for squamous metaplasia. They
stain for low molecular weight keratin and polyclonal carcinoembry-
onic antigen, and may show variable staining for calcitonin [15]
Minocycline and Amiodarone Thyroid 5

Radiation Changes Minocycline and Amiodarone Thyroid

Fig. 1.13 Minocycline thyroid. Drugs may have various effects on the
Fig. 1.11 Radiation changes. Radiation to the thyroid, neck, or tonsils
thyroid. Minocycline is a tetracycline antibiotic that produces a black
may affect the thyroid. The effects depend on the dose and isotope [16
pigment in the thyroid, which may be related to its interaction with
18]. Historical irradiation of the tonsils was associated with nodular
thyroid peroxidase [24]. Minocycline pigmentation also may affect the
hyperplasia of the thyroid. Radiation for acne also was associated with
skin, sclera, teeth, bone, heart valves, oral mucosa, and atherosclerotic
thyroid carcinoma [19]. More extensive irradiation, as with lymphoma
plaques [2530]. The antithyroid compounds thiocyanate (both in its
treatment, is associated with increased cellularity, increased nodular
chemical form and in cabbage and turnips) and perchlorate can inhibit
size, fibrosis, chronic thyroiditis, and cytologic atypia [16]
thyroid iodine transport, whereas propothiouracil, methimazole, phen-
ylbutazone, and lithium can inhibit binding reactions and thyroid hor-
mone release [4, 31]

Fig. 1.12 Radiation changes. Acute radiation changes include hemor-

rhage, neutrophilic infiltration, necrosis, and follicular disruption [18].
Radiation may be associated with cytologic atypia, pleomorphism, and
Fig. 1.14 Minocycline thyroid. Minocycline pigment in the colloid and
an increased incidence of thyroid carcinoma, predominantly PTCs [20,
localized within the cytoplasm of thyroid follicular epithelial cells.
21]. The latency may vary from decades to a short latency, as in child-
Lipofuscin and hemosiderin also may localize in the cytoplasm but are light
hood cancers after the Chernobyl accident [17, 22]. It is speculated that
brown and brown yellow, respectively. Minocycline is dark brown/black
dietary iodine levels may have implications in radiation-associated thy-
roid carcinogenesis, and iodine deficiency might increase incidence,
reduce latency, and influence tumor morphology and aggressiveness [23]
6 1 Thyroid Histology

Fig. 1.15 Minocycline thyroid. Minocycline is present in the follicular
lumen and as pigmented granules in the follicular cells. In addition to
pigments, other substances, such as calcium oxalate crystals, may be
seen in colloid and are highlighted with polarization. Crystals are not
specific for a particular disorder but are helpful in separating thyroid
from parathyroid, which lacks calcium oxalate crystals
Fig. 1.17 Amiodarone thyroid. Amiodarone is a class III antiarrhyth-
mic agent associated with changes in thyroid function tests due to inhi-
bition of 5-deiodinase, resulting in decreased T3 generation from T4
with an associated increase in reverse T3 [33]. Amiodarone is associ-
ated with amiodarone-induced thyrotoxicosis related to excess iodine-
induced thyroid hormone synthesis in an abnormal thyroid or is the
result of destructive thyroiditis [33]. Amiodarone-induced hypothyroid-
ism is thought to result from escape from the acute Wolff-Chaikoff
effect, from defects in thyroid hormonogenesis, or from concomitant
Hashimoto thyroiditis [33]

Fig. 1.16 Amiodarone thyroid. Histologic features of amiodarone thy-

roid disease include involutional changes, degenerative and destructive
follicular lesions, and zones of fibrosis [32]. Small groups of involuted
follicles may have damage varying from changes in a few lining cells to
total follicular destruction and follicular cell injury with swelling and
granular or vacuolated cytoplasm [32]. The follicular damage and
release of hormones may contribute to the associated thyrotoxicosis [32]
Thyroid Needle-Biopsy Site
Palpation Thyroiditis
Fig. 1.18 Palpation thyroiditis. Multiple foci of small groups or single
follicles are disrupted and associated with a mixed inflammatory infil-
trate with prominent histiocytes, appearing as multiple small granulo-
matous foci in this case of palpation thyroiditis. Palpation thyroiditis is
a common finding in surgically resected thyroids from palpation of the
thyroid gland
Fig. 1.19 Palpation thyroiditis. Palpation thyroiditis with disrupted fol-
licles with mixed inflammatory infiltrate forming a small granulomatous
focus. Palpation folliculitis is believed to be caused by traumatic rupture
of isolated thyroid follicles as a result of palpation of the gland [34]
7
Thyroid Needle-Biopsy Site
Fig. 1.20 Thyroid needle-biopsy site. Shown is an area of fibrosis
where prior fine-needle aspiration was performed. Needle-biopsy sites
are not an uncommon finding in the thyroid. The fibrosis in these cases
may entrap follicular cells and be mistaken for infiltrative growth.
Inflammation and hemosiderin in these fibrous foci are helpful in
identification
Fig. 1.21 Thyroid needle biopsy site. Inflamed focus with associated
fibrosis and histiocytic reaction in a fine-needle aspiration site. Cells
associated with inflammation may have cytologic clearing and irregu-
larity and should not be mistaken for PTC. Also, in follicular neo-
plasms, identifying the perpendicular and linear appearance of the
needle-biopsy site with associated inflammation and hemosiderin pre-
vents misinterpretation of capsular invasion
8 1 Thyroid Histology

Ectopic Thyroid Tissue

Fig. 1.24 Ectopic thyroid tissue. This ectopic thyroid tissue is in the
wall of the gallbladder. Although this is a rare location for ectopic thy-
roid tissue, it is important to recognize that ectopic thyroid tissue may
Fig. 1.22 Ectopic thyroid tissue. This is an unusual example of ectopic occur in unusual locations and not to mistake it for another tissue type
thyroid tissue in the adrenal gland. Ectopic thyroid tissue has been of a metastasis
reported from a variety of sites; however, historic reference to ectopic
thyroid tissue involving lymph nodes now is thought most likely to rep-
resent metastatic PTC, particularly if lateral to the jugular vein
[3537]

Fig. 1.23 Ectopic thyroid tissue. This ectopic thyroid tissue in the
heart was identified along the left ventricular outflow tract. Ectopic thy-
roid tissue has been reported along the thyroglossal tract and in unusual
locations such as the heart and pericardium, chest wall, porta hepatis,
and vagina [3840]
Struma Ovarii
Thyroglossal Duct Cyst
Fig. 1.25 Thyroglossal duct cyst. Thyroglossal duct cyst developmen-
tal anomalies due to a persistent connection between the foramen
cecum and the thyroid gland. The cystic structures, lined by ciliated
respiratory epithelium, may show squamous metaplasia, particularly if
inflamed, and may have thyroid follicles in the wall. Complications
include infections with fistula formation; rarely, carcinoma, usually
papillary carcinoma, may develop in these lesions
9
Struma Ovarii
Fig. 1.26 Struma ovarii. Struma ovarii are uncommon mature terato-
mas in which thyroid tissue is present exclusively or predominantly. In
this photomicrograph, the thyroid tissue is identified adjacent to ovarian
tissue. No other components are present. Struma ovarii usually present
in adults in the fifth or sixth decade as an ovarian mass and may have
unusual clinical manifestations, such as hyperthyroidism, ascites, and
Meigs syndrome [41]. Strumal carcinoids are uncommon, comprising
approximately 1 % of ovarian tumors and 2.7 % of teratomas [41]
Fig. 1.27 Struma ovarii. Struma ovarii with thyroid tissue adjacent to
ovarian tissue. The thyroid tissue is present in follicles with eosino-
philic colloid. The follicular cells are cuboid to slightly flattened cells
with round nuclei and lack nuclear atypia. In this case, other tissue com-
ponents are not present. When struma ovarii have a component of car-
cinoid tumor, they are referred to as strumal carcinoid. Carcinoid
elements are not identified in this patients tumor
10
Fig. 1.28 Struma ovarii with papillary thyroid carcinoma. PTC, clas-
sic type, is identified in these struma ovarii. Malignant struma ovarii are
quite uncommon and most often associated with a PTC, but they may
be associated with follicular tumors. In this case, the features of PTC
are classic; however, the follicular variant of PTC also occurs in struma
ovarii [42]. Diagnosing this variant may be difficult. A study found
BRAF mutation in four of six PTCs in struma ovarii and in none of the
nine benign struma ovarii in the study [43]. RAS mutation has been
identified in the follicular variant of PTC [44]
Fig. 1.29 Struma ovarii with papillary thyroid carcinoma. This classic
type of PTC in struma ovarii has numerous papillae with fibrovascular
cores lined by atypical epithelial cells, with nuclear enlargement,
nuclear clearing, nuclear groves, and intranuclear holes. Malignant
struma usually are treated surgically, and radioactive iodine may be
effective in treating metastatic struma [44]. Although most patients
with malignant struma do well, some have died from the disease, par-
ticularly if there was metastasis [45]. In a study of 88 cases of malignant
struma ovarii, the survival rate was 89 % at 10 years and 84 % at
25 years [46]
1 Thyroid Histology
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thyroiditis sharing features with papillary thyroid microcarcinoma.
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diation for Hodgkins and non-Hodgkins lymphoma. Cancer.
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17. Favus MJ, et al. Thyroid cancer occurring as a late consequence of
head-and-neck irradiation. Evaluation of 1056 patients. N Engl
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18. Holten I. Acute response of the thyroid to external radia-
tion. Acta Pathol Microbiol Immunol Scand Suppl. 1983;283:
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23. Williams ED, et al. Morphologic characteristics of Chernobyl-
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32. Smyrk TC, et al. Pathology of the thyroid in amiodarone-associated
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 Thyroiditis
2

Thyroiditis, or inflammation of the thyroid, encompasses a
great variety of entities, such as acute thyroiditis, granulo-
matous (de Quervain) thyroiditis, fibrous (Riedel) thyroid-
itis, Hashimoto thyroiditis, and focal lymphocytic
thyroiditis. These entities are associated with varying
degrees and types of inflammation and different underlying
causes. Patients with acute thyroiditis often have symptoms
including a painful thyroid gland with acute inflammation,
which usually is caused by an infection, often a systemic
bacterial infection that involves the thyroid secondarily [1].
Patients with de Quervain granulomatous thyroiditis also
commonly are symptomatic and have a painful thyroid
gland. The thyroid shows nonsuppurative, granulomatous
thyroiditis that often is viral and related to a prior upper
respiratory infection [2, 3]. Fibrous (Riedel) thyroiditis
generally is painless and presents as an enlarged, hard
thyroid replaced by fibrosis, which may cause compressive
symptoms and be worrisome for malignancy as the fibrosis
extends beyond the thyroid [4]. Hashimoto thyroiditis
(struma lymphomatosa) is an autoimmune disorder associ-
ated with antimicrosomal (antithyroid peroxidase) antibod-
ies. The thyroid in Hashimoto thyroiditis may be diffusely
involved or fibrotic and shows a marked lymphoid infiltrate
with follicles with germinal centers and prominent Hurthle
cells. The fibrous variant of Hashimoto thyroiditis may be
difficult to separate from fibrous (Riedel) thyroiditis. Focal
lymphocytic thyroiditis is quite common and likely an inci-
dental finding in thyroids, often from women and elderly
people, showing foci of lymphoid aggregates in the
thyroid.

L.A. Erickson, Atlas of Endocrine Pathology, Atlas of Anatomic Pathology, 13

DOI 10.1007/978-1-4939-0443-3_2, Springer Science+Business Media New York 2014
14
Acute Thyroiditis
Fig. 2.1 Acute thyroiditis. Patients with acute thyroiditis usually are
symptomatic, with a painful thyroid, chills, and fever. Histologically,
acute thyroiditis is characterized by an acute inflammatory infiltrate and
microabscesses, and focal necrosis may be seen
Fig. 2.2 Acute thyroiditis. Special stains may be helpful in identifying
causative organisms. Patients usually have a systemic infection, with
secondary involvement of the thyroid [1]. Bacteria are the most com-
mon cause of acute thyroiditis, but fungi and viruses also may be etiolo-
gies. Patients may present with symptoms mimicking acute thyroiditis
from trauma, emboli, and malignancies [57]
2 Thyroiditis
Granulomatous (de Quervain) Thyroiditis
Fig. 2.3 Granulomatous (de Quervain) thyroiditis. Granulomatous
thyroiditis also is known as de Quervain thyroiditis, subacute thyroid-
itis, giant cell thyroiditis, and nonsuppurative thyroiditis. Patients usu-
ally have pain and systemic symptoms and often have had a recent
upper respiratory infection [2, 3]. Patients may have transiently elevated
antithyroid antibodies and hyperthyroid, hypothyroid, and recovery
phases. Patients are treated symptomatically and usually recover in a
few months
Fig. 2.4 Granulomatous (de Quervain) thyroiditis. Early granuloma-
tous thyroiditis has patchy areas of neutrophils and microabscesses
and becomes more granulomatous with time. The etiology of granu-
lomatous thyroiditis is unknown, but it may be the result of a viral
infection. Patients may have circulating antibodies to viruses such as
influenza, adenovirus, mononucleosis, Coxsackievirus, and Epstein
Barr virus, among others [811]. The term subacute thyroiditis has
been applied to a painful form of thyroiditis likely of viral etiology (de
Quervain) and also has been used in subacute lymphocytic thyroiditis
[12]. Additionally, the term granulomatous is somewhat problematic as
granulomatous inflammation may occur from a variety of etiologies in
the thyroid, including palpation, infection (tuberculosis, fungi, syphilis,
Echinococcus), sarcoid, trauma, and other inflammatory reactions
Granulomatous (de Quervain) Thyroiditis 15

Fig. 2.5 Granulomatous (de Quervain) thyroiditis. Granulomatous
inflammation with multinucleated giant cells and a prominent lympho-
plasmacytic infiltrate is present in this thyroid involved by granuloma-
tous (de Quervain) thyroiditis. In the early acute phase, giant cells are
present with microabscess formation. Later, there is inflammatory infil-
trate of lymphocytes and plasma cells. In well-developed cases, the thy-
roid shows noncaseating granulomas, lymphoid follicles, and
aggregates, and a loss of follicular epithelium [13]
Fig. 2.7 Granulomatous (de Quervain) thyroiditis. A focus of multi-
nucleated giant cells among remaining follicles is present in this thyroid
in the late phase of granulomatous (de Quervain) thyroiditis. As the
follicles rupture, there is a giant cell response to the released colloid. In
the late phase of granulomatous (de Quervain) thyroiditis, the inflam-
matory infiltrate is composed predominantly of lymphocytes and
plasma cells

Fig. 2.6 Granulomatous (de Quervain) thyroiditis. Noncaseating gran-

ulomas in a fibrotic background are seen in this late phase of granulo-
matous (de Quervain) thyroiditis. Lymphocytes and plasma cells are
present, as well as multinucleated giant cells and noncaseating granulo-
mas in the late phase of granulomatous thyroiditis
16
Fibrous (Riedel) Thyroiditis
Fig. 2.8 Fibrous (Riedel) thyroiditis. This is fibrous (Riedel) thyroid-
itis, a rare inflammatory condition in which the thyroid is grossly
enlarged, hard, and fibrotic as it is replaced by fibrosis. The fibrosis may
extend beyond the thyroid and cause compressive symptoms clinically
worrisome for anaplastic thyroid carcinoma or lymphoma [4]. Riedel
thyroiditis usually is painless and is more common in women. Patients
may be normothyroid, hypothyroid, or hyperthyroid and may have ele-
vated antithyroglobulin antibodies and antimicrosomal antibodies.
Patients may be treated with corticosteroids and tamoxifen (which
induces transforming growth factor-, inhibiting proliferation of fibro-
blasts) [14]. Surgery may decompress the structures of the neck, and the
prognosis generally is good after the involved area of the thyroid is
removed. An autoimmune etiology has been suggested [15]. Fibrous
(Riedel) thyroiditis may be part of multiorgan fibrosclerosis and IgG4-
related disease [16, 17]. Hashimoto thyroiditis and Graves disease also
have been associated with IgG4 disease [18, 19]. Some have thought of
IgG4 thyroiditis as a unique concept or entity [20]
2 Thyroiditis
Fig. 2.9 Fibrous (Riedel) thyroiditis. In fibrous (Riedel) thyroiditis,
normal thyroid parenchyma is replaced by fibrosis and inflammatory
cells. The sclerotic fibrous tissue may extend beyond the thyroid into
the extrathyroidal soft tissue. Unlike the fibrous variant of Hashimoto
thyroiditis, patients with Riedel thyroiditis lack the high antibody titers
of Hashimoto thyroiditis and the pressure symptoms. In the fibrous
variant of Hashimoto thyroiditis, some of the lobular architecture usu-
ally is preserved and Hurthle cells often are identified. The fibrous vari-
ant of Hashimoto thyroiditis usually is confined to the thyroid, whereas
Riedel thyroiditis often infiltrates into the soft tissue. Clinically,
fibrous (Riedel) thyroiditis can mimic anaplastic thyroid carcinoma.
Histologically, anaplastic carcinoma usually is readily distinguishable
from fibrous (Riedel) thyroiditis because of the undifferentiated malig-
nant cells of anaplastic thyroid carcinoma. However, the paucicellular
variant of anaplastic carcinoma may be difficult to differentiate from
Riedel thyroiditis in small biopsies. Cytologic atypia, angiolymphatic
invasion, and lymph node metastases are helpful in differentiating ana-
plastic carcinoma from Riedel thyroiditis
Hashimoto Thyroiditis
Hashimoto Thyroiditis
Fig. 2.10 Hashimoto thyroiditis. Hashimoto thyroiditis showing a
marked lymphoid infiltrate, follicles with germinal centers, and promi-
nent Hurthle cells. Hashimoto thyroiditis is an autoimmune disorder with
a marked female predominance that occurs around age 60 but may occur
over a wide age range, including in children, in whom it accounts for a
substantial number of pediatric goiters. Antimicrosomal (antithyroid per-
oxidase) antibodies are identified in 95 % and antithyroglobulin antibod-
ies in at least 60 % of cases. Patients may have or develop other
autoimmune disorders. In Hashimoto thyroiditis, the thyroid is grossly
enlarged and the cut surface may be diffusely involved or fibrotic and pale
Fig. 2.11 Hashimoto thyroiditis. This image shows a thyroid involved
by Hashimoto thyroiditis, and a lymphoid follicle is seen at the bottom
of the photograph. The thyroid parenchyma shows prominent Hurthle
cell change, with cells with abundant eosinophilic cytoplasm
17
Fig. 2.12 Hashimoto thyroiditis. Prominent lymphoid follicles with
germinal centers are seen in this case of Hashimoto thyroiditis. The
thyroid parenchyma has atrophic follicles and Hurthle cell change. Foci
of squamous metaplasia and fibrosis may be identified in some cases.
The prominent lymphocytic and lymphoplasmacytic infiltrate in
Hashimoto thyroiditis must be differentiated from lymphoma involving
the thyroid, as thyroid lymphomas may arise in the setting of Hashimoto
thyroiditis
Fig. 2.13 Hashimoto thyroiditis. A follicle with a germinal center is
present on the right side of this image of Hashimoto thyroiditis. The
thyroid parenchyma on the left side of the photograph shows the exten-
sive Hurthle cell change, a characteristic histologic feature in Hashimoto
thyroiditis
18 2 Thyroiditis

Focal Lymphocytic Thyroiditis

Fig. 2.14 Hashimoto thyroiditis with solid cell nests. A focus of solid
cell nests is seen in the center of this image of Hashimoto thyroiditis.
Solid cell nests may have prominent nuclear grooves, enlarged overlap-
ping nuclei, and nuclear clearing that must be differentiated from papil- Fig. 2.16 Focal lymphocytic thyroiditis. Focal lymphocytic thyroiditis
lary thyroid microcarcinoma [21]. Of 1,420 Hashimoto thyroiditis is a relatively common condition, more frequent in women and elderly
cases, 12 had more than 10 solid cell nests per slide [21]. In addition to people, and is identified in up to 20 % of autopsied thyroids. A postmor-
the atypical cytologic features, solid cell nests are surrounded by a dis- tem review of 197 thyroid glands identified varying degrees of focal
tinct eosinophilic basement membrane [21]. Solid cell nests show lymphocytic thyroiditis in 54 % of women and 24 % of men, but this
strong staining for p63 and weak staining for thyroid transcription fac- study found no association with age [22]. Histologically, foci of dense
tor 1 (TTF1), and are negative for thyroglobulin, HBME-1, and calcito- lymphoid aggregates, with or without germinal centers, are seen
nin [21]. Papillary thyroid microcarcinomas are strongly positive for
thyroglobulin, TTF1, and HBME-1; show variable staining for p63; and
are negative for calcitonin and chromogranin [21]

Fig. 2.15 Hashimoto thyroiditis, fibrous variant. The fibrous variant of Fig. 2.17 Focal lymphocytic thyroiditis. Focal lymphoid aggregates in
Hashimoto thyroiditis in this image shows dense fibrous bands and a thyroid with focal lymphocytic thyroiditis, a condition thought likely
parenchymal atrophy. This variant must be differentiated from Riedel to be an incidental finding in thyroids removed for other causes or iden-
(fibrosing) thyroiditis. Both the fibrous variant of Hashimoto thyroiditis tified in thyroid glands at autopsy
and Riedel thyroiditis may be adherent to adjacent structures, but the
fibrous variant of Hashimoto thyroiditis usually does not show the
marked extrathyroidal extension that may be seen in Riedel thyroiditis.
Also, the fibrous variant of Hashimoto thyroiditis generally maintains
its normal lobular thyroid architecture. Other variants of Hashimoto
thyroiditis include fibrous atrophy, juvenile, and cystic variants
References 19

References 11. Dimos G, Pappas G, Akritidis N. Subacute thyroiditis in the course

of novel H1N1 influenza infection. Endocrine. 2010;37(3):
4401.
1. Andres JC, Nagalla R. Acute bacterial thyroiditis secondary to uro-
12. Volpe R. Subacute thyroiditis. Prog Clin Biol Res. 1981;74:11534.
sepsis. J Am Board Fam Pract. 1995;8(2):1289.
13. Volpe R. The pathology of thyroiditis. Hum Pathol. 1978;
2. Meachim G, Young MH. De Quervains subacute granulomatous
9(4):42938.
thyroiditis: histological identification and incidence. J Clin Pathol.
14. Few J, et al. Riedels thyroiditis: treatment with tamoxifen. Surgery.
1963;16:18999.
1996;120(6):9938; discussion 9989.
3. Woolner LB, McConahey WM, Beahrs OH. Granulomatous thy-
15. Heufelder AE, Hay ID. Further evidence for autoimmune mecha-
roiditis (De Quervains thyroiditis). J Clin Endocrinol Metab.
nisms in the pathogenesis of Riedels invasive fibrous thyroiditis.
1957;17(10):120221.
J Intern Med. 1995;238(1):856.
4. Beahrs OH, McConahey WM, Woolner LB. Invasive fibrous thyroid-
16. Dahlgren M, et al. Riedels thyroiditis and multifocal fibrosclerosis
itis (Riedels struma). J Clin Endocrinol Metab. 1957;17(2):20120.
are part of the IgG4-related systemic disease spectrum. Arthritis
5. Chen HW, et al. Secondary infection and ischemic necrosis after
Care Res (Hoboken). 2010;62(9):13128.
fine needle aspiration for a painful papillary thyroid carcinoma: a
17. Pusztaszeri M, et al. Riedels thyroiditis with increased IgG4
case report. Acta Cytol. 2006;50(2):21720.
plasma cells: evidence for an underlying IgG4-related sclerosing
6. Jimenez-Heffernan JA, et al. Massive thyroid tumoral embolism
disease? Thyroid. 2012;22(9):9648.
from a breast carcinoma presenting as acute thyroiditis. Arch Pathol
18. Deshpande V, et al. Fibrosing variant of Hashimoto thyroiditis is an
Lab Med. 2004;128(7):8046.
IgG4 related disease. J Clin Pathol. 2012;65(8):7258.
7. Lin KD, et al. Acute suppurative thyroiditis and aggressive malig-
19. Nishihara E, et al. IgG4 thyroiditis in a Graves disease patient
nant thyroid tumors: differences in clinical presentation. J Surg
with large goiter developing hypothyroidism. Thyroid. 2013;
Oncol. 1998;67(1):2832.
23(11):14967.
8. Brouqui P, Raoult D, Conte-Devolx B. Coxsackie thyroiditis. Ann
20. Watanabe T, et al. Clinical features of a new disease concept, IgG4-
Intern Med. 1991;114(12):10634.
related thyroiditis. Scand J Rheumatol. 2013;42(4):32530.
9. Swann NH. Acute thyroiditis. Five cases associated with adenovi-
21. Asioli S, Erickson LA, Lloyd RV. Solid cell nests in Hashimotos
rus infection. Metabolism. 1964;13:90810.
thyroiditis sharing features with papillary thyroid microcarcinoma.
10. Cunha BA, Berbari N. Subacute thyroiditis (de Quervains) due to
Endocr Pathol. 2009;20(4):197203.
influenza A: presenting as fever of unknown origin (FUO). Heart
22. Mitchell JD, Kirkham N, Machin D. Focal lymphocytic thyroiditis
Lung. 2013;42(1):778.
in Southampton. J Pathol. 1984;144(4):26973.
 Graves Disease (Diffuse Hyperplasia)
3

Graves disease, an autoimmune disorder, is the most com-
mon cause of hyperthyroidism. Graves disease is associated
with antibodies against the thyrotropin receptor that stimu-
late the receptor and promote synthesis and secretion of thy-
roglobulin and follicular cell proliferation. Patients present
with goiter and symptoms of hyperthyroidism, including
anxiety, tachycardia, palpitations, tremor, heat sensitivity,
and weight loss, and may develop ophthalmopathy and der-
mopathy. Patients may be treated symptomatically with
-blockers and with antithyroid medications (propothioura-
cil and methimazole), radioactive iodine, and surgery.
Complications of untreated Graves disease are thyroid storm,
muscle catabolism with myopathy, and bone catabolism with
osteoporosis, among others. Graves disease occurs in 1 in
2,000 people in the United States. A study from Olmstead
County, Minnesota, reports an incidence of 30 cases per
100,000 person years [1]. Graves disease is more common in
women than in men. There is a marked increase risk of
Graves disease in the postpartum period. In men, Graves dis-
ease occurs at an older age and frequently is more severe and
associated with greater ophthalmopathy. Graves disease
occasionally occurs in children and has a high concordance
in identical twins. Smoking is associated with an increased
risk of Graves disease and Graves ophthalmopathy [2].
Patients have elevated serum thyroxine and low thyroid-
stimulating hormone levels. There is an association with
HLA-B8 and DR3, and patients may have a familial predis-
position to autoimmune disease, including thyroid disease.
Thyroid carcinomas occasionally occur in thyroids involved
by Graves disease [3]. In a retrospective review of 61 thyroid
carcinomas with concurrent Graves disease, 58 papillary car-
cinomas, 1 follicular carcinoma, 1 Hurthle cell carcinoma,
and 1 medullary carcinoma were identified [4]. Most (80 %)
of the tumors were 1 cm or smaller [4]. Incidental thyroid
carcinomas are less prevalent in Graves disease than in mul-
tinodular goiter [5].

L.A. Erickson, Atlas of Endocrine Pathology, Atlas of Anatomic Pathology, 21

DOI 10.1007/978-1-4939-0443-3_3, Springer Science+Business Media New York 2014
22 3 Graves Disease (Diffuse Hyperplasia)

Fig. 3.3 Graves disease (diffuse hyperplasia). This low-power photo-

micrograph shows the diffuse hyperplasia characteristic of Graves dis-
ease. Papillae with fibrovascular cores are prominent and diffusely
involve the thyroid gland

Fig. 3.1 Graves disease (diffuse hyperplasia). This diffusely enlarged

thyroid is affected by Graves disease. Thyroids in Graves disease weigh
50150 g. Toxic nodular goiters also may be associated with hyperthy-
roidism but have a multinodular appearance and focal histologic
involvement, unlike the diffuse hyperplasia and diffuse involvement of
the thyroid histologically in Graves disease. Hyper functioning thyroid
tumors may be associated with hyperthyroidism, but they are single
nodules rather than the diffusely enlarged thyroid of Graves disease

Fig. 3.4 Graves disease (diffuse hyperplasia). The thyroid parenchyma

is diffusely involved by hyperplasia in Graves disease. Fibrosis gener-
ally is absent or only focal, unlike Hashimoto thyroiditis, which may
have prominent fibrosis. Although focal chronic inflammation may be
seen in Graves disease in the stroma, it is quite limited, unlike the prom-
inent chronic inflammatory infiltrate in Hashimoto thyroditis, which
has lymphoid follicles with germinal centers. Also, Hurthle cells/onco-
cytic metaplasia are more prominent in Hashimoto thyroiditis than
Graves disease

Fig. 3.2 Graves disease (diffuse hyperplasia). Shown is a cut section from
a thyroid affected by Graves disease. The thyroid shows diffuse enlarge-
ment and has a red cut surface. Untreated Graves may be a very deep red,
whereas glands treated preoperatively are lighter in color with less vascu-
larity. Note the diffusely homogenous appearance of the parenchyma in this
cut section, which differs from the multinodular appearance of multinodu-
lar goiter. The cut surface of Hashimoto thyroiditis is lobulated and may
appear yellow-tan as a result of prominent lymphoid infiltrate
Graves Disease (Diffuse Hyperplasia)
Fig. 3.5 Graves disease (diffuse hyperplasia). Diffuse hyperplasia of
Graves disease enveloping skeletal muscle. The hyperplasia in Graves
disease is extensive and appears similar throughout the thyroid
Fig. 3.6 Graves disease (diffuse hyperplasia). The cells in Graves dis-
ease are tall columnar cells with basally located round nuclei ampho-
philic to eosinophilic cytoplasm. Occasional oncocytic cells may be
seen in Graves disease, particularly with preoperative treatment, but the
oncocytic change is very focal compared with the extensive oncocytic
change in Hashimoto thyroiditis
23
Fig. 3.7 Graves disease (diffuse hyperplasia). Papillae with fibrovas-
cular cores in Graves disease may be mistaken for papillary thyroid
carcinoma. The overall appearance of the thyroid diffusely involved by
the hyperplasia is helpful in recognizing Graves disease. Cytologic fea-
tures of papillary thyroid carcinoma with cytoplasmic clearing, large
nuclei with irregular nuclear membranes, nuclear clearing, nuclear
grooves, and intranuclear holes are helpful in differentiating papillary
thyroid carcinoma from Graves disease. In difficult cases, p27 protein
and HBME-1 may be used to separate these two lesions. p27 shows
higher expression in Graves disease compared with papillary thyroid
carcinoma [6]. HBME-1 usually is positive in papillary thyroid carci-
noma and negative in papillary hyperplasia [7]
Fig. 3.8 Graves disease (diffuse hyperplasia). This thyroid involved by
Graves disease shows some scalloping of colloid, and the cells are still
fairly columnar, compatible with hyperthyroidism. However, the
increased colloid and decreased vascularity are compatible with the
thyroid having been treated preoperatively with iodine
24 3 Graves Disease (Diffuse Hyperplasia)

References
1. Furszyfer J, et al. Graves disease in Olmsted County, Minnesota,
1935 through 1967. Mayo Clin Proc. 1970;45(9):63644.
2. Balazs C, Stenszky V, Farid NR. Association between Graves oph-
thalmopathy and smoking. Lancet. 1990;336(8717):754.
3. Brandle M, et al. Medullary thyroid carcinoma in Graves disease.
Clin Endocrinol. 1999;50(4):5456.
4. Chao TC, Lin JD, Chen MF. Surgical treatment of thyroid cancers
with concurrent Graves disease. Ann Surg Oncol. 2004;11(4):
40712.
5. Pascual Corrales E, et al. Incidental differentiated thyroid carcinoma
is less prevalent in Graves disease than in multinodular goiter.
Endocrinol Nutr. 2012;59(3):16973.
6. Erickson LA, et al. p27kip1 expression distinguishes papillary
hyperplasia in Graves disease from papillary thyroid carcinoma.
Mod Pathol. 2000;13(9):10149.
7. Casey MB, Lohse CM, Lloyd RV. Distinction between papillary thy-
roid hyperplasia and papillary thyroid carcinoma by immunohisto-
Fig. 3.9 Graves disease (diffuse hyperplasia). The follicular epithe- chemical staining for cytokeratin 19, galectin-3, and HBME-1.
lium in this thyroid appears cuboidal, and colloid is increased, findings Endocr Pathol. 2003;14(1):5560.
that indicate preoperative treatment of Graves disease. The decreased
vascularity in this photograph compared with the previous images also
indicates that this thyroid was treated preoperatively with radioactive
iodine

Fig. 3.10 Graves disease (diffuse hyperplasia). This thyroid involved

by Graves disease is from a patient extensively treated with iodine
before surgery. Patients treated preoperatively with iodine show involu-
tion of the epithelium with cuboidal rather than columnar cells,
increased colloid, and decreased vascularity. In this thyroid, the involu-
tional changes are marked
 Thyroid Goiter
A goiter is an enlarged thyroid gland. Goiters may be simple
or multinodular, dyshormonogenetic, toxic, endemic, or
composed of amyloid. Simple nontoxic goiters usually are
sporadic but may be endemic in areas of iodine deficiency.
Endemic goiters are uncommon in modern times, with the
use of iodized table salt. In the United States and other non-
endemic areas, sporadic nontoxic goiters affect approxi-
mately 5 % of the population, are more common in women,
and rarely affect young children. Although the etiology of
sporadic nontoxic goiter is unknown, it likely is multifacto-
rial. It may be associated with medications such as lithium,
aminoglutethimide, propylthiouracil, and perchlorate; cer-
tain substances and foods (cassava, aniline derivatives, thio-
cyanates, perchlorates, and cyanoglucosides); and disruption
of the hypothalamic pituitary axis, resulting increase of thy-
roid stimulating hormone. It also may have a hereditary
component, particularly in women [1, 2]. Goiters also may
occur in Cowden syndrome (germline PTEN mutation).
Goiters usually are slow growing and may be associated
with compressive and obstructive symptoms of dyspnea,
stridor, hoarseness, and dilated neck veins. Goiters are
treated with thyroxine, radioactive iodine, and surgery. A
new nodule or sudden increase in growth is worrisome for
malignancy [3]. In a surgical series of 270 goiters, 7.7 % of
which were suspected of being malignant, malignancy was
identified in 33 cases (12.2 %) [4]. Nineteen were classic
papillary thyroid carcinomas, two were a follicular variant
L.A. Erickson, Atlas of Endocrine Pathology, Atlas of Anatomic Pathology,
DOI 10.1007/978-1-4939-0443-3_4, Springer Science+Business Media New York 2014
4
of papillary carcinoma, three were lymphomas, three were
medullary carcinomas, three were anaplastic carcinomas,
two were follicular carcinomas, and one was a Hurthle cell
carcinoma [4]. An Italian study identified carcinoma in
13.7 % of goiters [5]. A meta-analysis of 14 studies found
that multinodular goiters were associated with a lower risk
of cancer than single nodules, but a subgroup analysis sug-
gested this difference depends on the inclusion of studies
outside the United States [6]. Unlike sporadic goiters, dys-
hormonogenetic goiters may develop in childhood, often are
associated with hypothyroidism, and usually are the result
of an autosomal recessive defect in thyroid hormone synthe-
sis [7]. Pendred syndrome includes congenital goiters and
congenital sensorineural deafness and accounts for 10 % of
hereditary deafness [8, 9]. The Pendred syndrome gene
(7q22-31.1) encodes pendrin, an iodide/choride transporter
[8]. Toxic multinodular goiters are associated with thyro-
toxicosis, which may develop insidiously. An autonomously
hyperfunctioning nodule in a multinodular goiter has been
referred to as Plummer disease. Amyloid goiters present as
diffuse thyroid enlargement or a mass lesion. Patients often
are asymptomatic but may have compressive symptoms and
usually are euthyroid [10]. Amyloid goiter also may occur
in primary systemic amyloidosis and occasionally second-
ary amyloidosis, but secondary amyloidosis usually shows
only focal involvement rather than diffuse replacement of
the gland.
25
26 4 Thyroid Goiter

Multinodular Goiter

Fig. 4.3 Multinodular goiter. The nodules in this multinodular goiter

vary in size, and some appear encapsulated. The cellularity also varies
among the nodules. The cells are follicular and lack cytologic features
of papillary thyroid carcinoma

Fig. 4.1 Multinodular goiter. Shown is the cut section of a multinodu-

lar goiter. Normal thyroid glands weigh 1520 g, whereas goiters may
weigh greater than 1,000 g. Multinodular goiters show multiple nod-
ules, whereas simple goiters have diffuse thyroid enlargement. The his-
tologic features of endemic goiters are similar to those of multinodular
goiters. This sporadic multinodular goiters nodules distort the thyroid.
Palpable nodules increase with age. These are not uncommon pathol-
ogy specimens, as sporadic goiters affect 5 % of the population.
Additional sampling of suspicious areas is recommended, because car-
cinomas are identified in up to 13.7 % of goiters [5]

Fig. 4.4 Multinodular goiter. Multinodular goiter with nodules and

variably sized follicles and colloid. The nodules in multinodular goiters
compress the adjacent thyroid parenchyma. The follicles vary in size.
The smaller follicles are cuboidal follicular lining cells, whereas the
larger follicles have flattening of the follicular lining cells

Fig. 4.2 Multinodular goiter. Multiple nodules are seen characteristi-

cally in multinodular goiters. Multinodular goiters may show degenera-
tive features such as fibrosis, hemosiderin deposition, and cystic
degeneration, but the nodules do not show invasive growth. Also, cyto-
logic features of papillary thyroid carcinoma are not identified
Dyshormonogenetic Goiter
Fig. 4.5 Multinodular goiter. This is one of multiple nodules in a mul-
tinodular goiter. Multiple encapsulated nodules are referred to as ade-
nomatoid nodules. It may be difficult to differentiate a follicular
adenoma from a dominant nodule in a multinodular goiter. Interestingly,
nodules in multinodular goiters may be clonal. Diagnosing follicular
carcinoma in multinodular goiter requires definitive capsular or vascu-
lar invasion
Fig. 4.6 Multinodular goiter. Colloid cyst is identified in this multi-
nodular goiter. The cyst contains colloid and may distort the adjacent
thyroid parenchyma. Multinodular goiters show various nodules of dif-
ferent sizes, including adenomatous nodules, hyperplastic nodules, and
colloid cysts
27
Dyshormonogenetic Goiter
Fig. 4.7 Dyshormonogenetic goiter. This dyshormonogenetic goiter
shows characteristic features of multinodularity and marked cellularity
[7, 11]. Dyshormonogenetic goiters usually are autosomal recessive
disorders of thyroid hormone synthesis and generally affect children
[7]. In Dr. Ghosseins study of 56 cases [7], the age ranged from new-
born to 52 years (median, 16 years), with 75 % of patients younger than
24 years. All thyroid glands were enlarged (up to 600 g) and multinodu-
lar [7]. In this series, goiter was identified clinically in 54 of 56 cases,
and hypothyroidism was documented in 36 (64 %) before the histologic
diagnosis was made [7]
Fig. 4.8 Dyshormonogenetic goiter. Nodules in dyshormonogenetic
goiters may show a variety of patterns, of which solid and microfollicu-
lar are the most common [7, 11]. Other features are papillary prolifera-
tions; insular growth; fibrosis, which may be conspicuous and simulate
capsular invasion; marked nuclear atypia; and minimal colloid [7].
Three of the 56 cases in Dr. Ghosseins study [7], were associated with
papillary thyroid microcarcinomas. Papillary, follicular, and anaplastic
carcinomas and metastases also have been reported [12, 13]. This is a
significant issue, as 10 of the 56 cases (18 %) in Ghosseins study [7]
had hyperplasia, atypia, and irregular growth due to fibrosis that were
so marked that a mistaken diagnosis of malignancy (follicular, papil-
lary, medullary, and undifferentiated carcinoma) was considered
28
Fig. 4.9 Dyshormonogenetic goiter. Cytologic atypia, present in this
dyshormonogenetic goiter, often involves the thyroid parenchyma
between the nodules. The multinodularity, minimal colloid, fibrosis,
and atypia are quite characteristic of dyshormonogenetic goiter, but iat-
rogenic goiter due to administration of antithyroidal agents may have
similar features [7]. Thus, correlation with the clinical information and
history is helpful
4 Thyroid Goiter
Amyloid Goiter
Fig. 4.10 Amyloid goiter. This amyloid goiter has diffuse amyloid
deposition throughout the parenchyma. Foci of amyloid in thyroid
parenchyma are not uncommon, but the extensive deposition of amy-
loid in amyloid goiter is uncommon. Amyloid may surround follicles
diffusely or form nodules distorting and compressing the thyroid [10].
Amyloid goiters may present as diffuse enlargement or a mass lesion.
Patients often are asymptomatic but may have a nontender, rapidly
enlarging neck mass with compressive symptoms of dysphagia, dys-
pnea, or hoarseness [10]. In a series of 14 amyloid goiters, 9 were iden-
tified at autopsy [10]. Although the thyroid is extensively infiltrated by
amyloid, patients usually are euthyroid. Rare cases of hypothyroidism
and hyperthyroidism occur [14, 15]. Papillary thyroid carcinoma has
been reported with amyloid goiter [16]. Medullary thyroid carcinoma
often has amyloid, but the amyloid is stromal and stains with calcitonin.
Hematolymphoid malignancies also may be associated with amyloid
and must be excluded
Fig. 4.11 Amyloid goiter. Focal lymphocytic inflammation and foreign
bodytype giant cells are seen in this amyloid goiter. Focal lymphocytic
thyroiditis with or without foreign bodytype giant cells and mature adi-
pose tissue are seen in about one third of amyloid goiters [10]. Amyloid
goiter may occur in primary systemic amyloidosis and secondary amy-
loidosis [17, 18]. Although amyloid is not uncommon in the thyroid in
secondary amyloidosis, amyloid goiters are uncommon [19]
References 29

References
1. Brix TH, Kyvik KO, Hegedus L. Major role of genes in the etiology
of simple goiter in females: a population-based twin study. J Clin
Endocrinol Metab. 1999;84(9):30715.
2. Bignell GR, et al. Familial nontoxic multinodular thyroid goiter
locus maps to chromosome 14q but does not account for familial
nonmedullary thyroid cancer. Am J Hum Genet. 1997;61(5):
112330.
3. Sakorafas GH, et al. Microscopic papillary thyroid cancer as an
incidental finding in patients treated surgically for presumably
benign thyroid disease. J Postgrad Med. 2007;53(1):236.
4. Prades JM, et al. Multinodular goiter: surgical management and
histopathological findings. Eur Arch Otorhinolaryngol.
2002;259(4):21721.
5. Gandolfi PP, et al. The incidence of thyroid carcinoma in multi-
nodular goiter: retrospective analysis. Acta Biomed. 2004;75(2):
1147.
6. Brito JP, et al. Prevalence of thyroid cancer in multinodular goiter
Fig. 4.12 Amyloid goiter, Congo red stain. Congo red staining shows versus single nodule: a systematic review and meta-analysis.
apple-green birefringence under polarized light microscopy in an amy- Thyroid. 2013;23(4):44955.
loid goiter. Unlike the amyloid in medullary thyroid carcinoma, which 7. Ghossein RA, Rosai J, Heffess C. Dyshormonogenetic goiter: a
is stromal and positive for calcitonin, the amyloid in amyloid goiters clinicopathologic study of 56 cases. Endocr Pathol. 1997;8(4):
diffusely involves the gland or is in large masses and is negative for 28392.
calcitonin. Immunohistochemical or mass spectrometry evaluation may 8. Kopp P. Pendreds syndrome: identification of the genetic defect a
help determine the subtype of amyloid century after its recognition. Thyroid. 1999;9(1):659.
9. Borck G, et al. Mutations in the PDS gene in German families with
Pendreds syndrome: V138F is a founder mutation. J Clin
Endocrinol Metab. 2003;88(6):291621.
10. Hamed G, et al. Amyloid goiter. A clinicopathologic study of 14
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30612.
11. Kennedy JS. The pathology of dyshormonogenetic goitre. J Pathol.
1969;99(3):25164.
12. Yashiro T, et al. Papillary carcinoma of the thyroid arising from
dyshormonogenetic goiter. Endocrinol Jpn. 1987;34(6):95564.
13. Medeiros-Neto G, et al. Metastatic thyroid carcinoma arising from
congenital goiter due to mutation in the thyroperoxidase gene. J
Clin Endocrinol Metab. 1998;83(11):41626.
14. Kanoh T, et al. Amyloid goiter with hypothyroidism. Arch Pathol
Lab Med. 1989;113(5):5424.
15. Tokyol C, et al. Amyloid goiter with hyperthyroidism. Endocr
Pathol. 2004;15(1):8990.
16. Nessim S, Tamilia M. Papillary thyroid carcinoma associated with
amyloid goiter. Thyroid. 2005;15(4):3825.
17. Sinha RN, Plehn JF, Kinlaw WB. Amyloid goiter due to primary
systemic amyloidosis: a diagnostic challenge. Thyroid.
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18. Cohan P, et al. Amyloid goiter in a case of systemic amyloidosis
secondary to ankylosing spondylitis. J Endocrinol Invest.
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19. DAntonio A, et al. Amyloid goiter: the first evidence in secondary
amyloidosis. Report of five cases and review of literature. Adv Clin
Path. 2000;4(2):99106.
 Papillary Thyroid Carcinoma
Papillary thyroid carcinoma (PTC) is the most common
endocrine malignancy, accounting for 80 % of thyroid carci-
nomas in adults and 90 % in children [1]. PTC is a malignant
epithelial tumor showing follicular differentiation and dis-
tinctive nuclear features [2]. Patients usually are 2050 years
old, but those of any age may be affected [2]. PTC is more
common in women than men. Most PTCs are sporadic but
may occur with syndromes such as Gardner syndrome,
Cowden syndrome, and ataxia telangiectasia [3, 4]. PTC may
arise in ectopic thyroid tissue such as struma ovarii, adrenal
glands, and trachea [57]. Radiation exposure is a risk factor
for PTC [8]. Histologic variants of PTC are important to rec-
ognize prognostically and for association with other diseases.
Aggressive variants include tall cell, columnar cell, solid, and
the recently described hobnail variant. The cribriform-moru-
lar variant often is associated with familial adenomatous pol-
yposis. PTCs are positive for thyroglobulin, thyroid
transcription factor 1 (TTF1), and keratins and are negative
for calcitonin, chromogranin, and synaptophysin. Markers
useful in confirming a diagnosis of PTC are HBME-1, keratin
19, galectin-3, and CITED1. BRAF mutations occur in about
60 % of PTCs, and RET/PTC rearrangements occur in
2030 % of adult PTCs. BRAF mutation and RET/PTC rear-
rangement are mutually exclusive abnormalities in PTCs.
L.A. Erickson, Atlas of Endocrine Pathology, Atlas of Anatomic Pathology,
DOI 10.1007/978-1-4939-0443-3_5, Springer Science+Business Media New York 2014
5
RET/PTC1 is more common in papillary microcarcinomas
and PTCs with classic architectural features, whereas RET/
PTC3 is more common in the solid variant. BRAF mutations
occur in classic, Warthin-like, and oncocytic PTCs; microcar-
cinomas; and aggressive variants such as tall cell, columnar,
and hobnail PTCs. Poorly differentiated and anaplastic thy-
roid carcinomas also may show BRAF mutation, particularly
if associated with or dedifferentiated from a PTC. BRAF
mutation is not common in pediatric or radiation-associated
PTCs. The follicular variant of PTC (FVPTC) is associated
with RAS mutations (as are follicular neoplasms), thus RAS is
not useful in separating FVPTC from follicular neoplasms.
PTCs usually metastasize to cervical nodes, particularly ipsi-
lateral nodes, before spreading to the lung and other sites [1].
Unfavorable prognostic features are older age, male sex, large
tumor size, multicentricity, angiolymphatic invasion, necro-
sis, mitoses, extrathyroid extension, distant metastases, high
grade, marked nuclear atypia, and progression to poorly or
undifferentiated carcinoma [1, 9]. PTCs are treated by thy-
roidectomy and removal of involved lymph nodes. Radioactive
iodine may be used to ablate any remaining tumor, including
metastatic sites. Overall, PTC has an excellent prognosis,
with >90 % survival, and most patients survive even with
metastatic disease.
31
32
Classic PTC
Fig. 5.1 Classic papillary thyroid carcinoma. This thyroid has multi-
ple ill-defined firm masses of PTC with a granular white cut surface.
Tumors may be single or multifocal and bilateral. The mean tumor size
is 23 cm, although size may vary greatly
Fig. 5.2 Classic papillary thyroid carcinoma. Invasive PTC is shown
with a lymphocytic infiltrate at the periphery. The stroma in PTC often
is abundant, fibrous, and sclerotic
5 Papillary Thyroid Carcinoma
Fig. 5.3 Classic papillary thyroid carcinoma. Prominent papillae with
fibrovascular cores lined by epithelial cells with characteristic cytologic
features are seen in this PTC. The differential diagnosis includes papil-
lary hyperplasia, both focal and diffuse, as seen in Graves disease.
Nuclear features are used to differentiate PTC from papillary hyperpla-
sia and Graves disease. Also, Graves disease diffusely involves the
entire thyroid rather than forming a distinct mass, as often is seen in
PTC. In difficult cases, p27 protein expression has shown some promise
in separating these entities, as it has shown significantly higher expres-
sion in papillary hyperplasia of Graves disease than in PTC [10]
Fig. 5.4 Classic papillary thyroid carcinoma. This classic PTC shows
papillae with fibrovascular cores and lined by cells with cytologic fea-
tures of PTC. The cells show nuclear enlargement, irregular nuclear
membranes, nuclear clearing (Orphan Annie nuclei), nuclear grooves,
intranuclear holes, and cytoplasmic clearing. Although Graves disease
may show papillary fronds, the cells lining the papillae in Graves lack
cytologic features of PTC. PTC usually is positive for HBME-1, galec-
tin-3, CITED-1, and keratin 19. These immunohistochemical markers
may be helpful in difficult cases
Classic PTC 33

Fig. 5.5 Classic papillary thyroid carcinoma. Classic PTC with papil- Fig. 5.7 Classic papillary thyroid carcinoma. Psammoma bodies are
lae with fibrovascular cores and cystic change. Focal areas of more calcifications with concentric lamellations that are seen in 50 % of PTCs,
solid growth and squamous metaplasia may be seen in some cases. The particularly those with prominent papillary architectural features [1]
proportion of papillary structures in PTC may vary

Fig. 5.6 Classic papillary thyroid carcinoma. This partially cystic PTC Fig. 5.8 Classic papillary thyroid carcinoma. The characteristic cyto-
has prominent papillae. Cystic areas are not uncommon in PTC logic features of PTC are seen in this image. The nuclei are enlarged,
overlap, and show clearing, irregularity, grooves, and intranuclear
holes. Mitotic figures are uncommon
34
Fig. 5.9 Classic papillary thyroid carcinoma. Intranuclear holes are
eosinophilic invaginations of the cytoplasm. They are well defined,
round to ovoid, and eosinophilic. Intranuclear holes, when present, are
characteristic of PTC; however, they are not specific for PTC because
they may be seen in parathyroid tissue, occasionally in Hurthle cell
tumors, and in medullary thyroid carcinoma
Fig. 5.10 Classic papillary thyroid carcinoma. The cells in PTC are
enlarged, with irregular nuclei, nuclear clearing, nuclear grooves,
nuclear overlap, and intranuclear holes. The cytologic features are diag-
nostic in PTC. Colloid in PTC often is darker than in the benign thyroid,
although this feature is variable
5 Papillary Thyroid Carcinoma
Fig. 5.11 Classic papillary thyroid carcinoma. Growth patterns in
PTC are variable. In this image, there is an area of follicular growth in
a PTC that shows papillae in other areas of the tumor. If a PTC has both
a papillary and follicular growth pattern, it is classified as a classic PTC
rather than an FVPTC, which would require the tumor to have cytologic
features of PTC and the entire tumor to have a follicular growth
pattern
Fig. 5.12 Classic papillary thyroid carcinoma. The colloid in PTC
often is darker than that of the surrounding thyroid parenchyma. The
cytologic features are characteristic of PTC, with enlarged, irregular
nuclei; nuclear clearing; intranuclear pink holes; and longitudinal
nuclear grooves. The intranuclear holes are cytoplasmic invaginations
of the cytoplasm that are eosinophilic, comprise >50 % of the nucleus,
and show condensation around the periphery of the hole
Classic PTC
Fig. 5.13 Classic papillary thyroid carcinoma. Shown is a cystic PTC.
PTCs often are white-tan, firm masses grossly and may be gritty as the
result of psammoma bodies. However, a cystic gross appearance or a
cystic PTC with a mural nodule of tumor is not uncommon. This cystic
PTC is multiloculated, with the bulk of the tumor cells in the center
Fig. 5.14 Classic papillary thyroid carcinoma. Low-power photomi-
crograph of multiple cystic spaces in a PTC. These tumors often have
prominent papillary architectural features. Cystic PTC must be differ-
entiated from an adenomatous or a hyperplastic nodule with papillary
hyperplasia
35
Fig. 5.15 Classic papillary thyroid carcinoma. The papillae in this cys-
tic PTC have fibrovascular cores and are lined by cells with characteris-
tic features of PTC, including enlarged, irregular nuclei; nuclear
clearing; intranuclear pink holes; and longitudinal nuclear grooves
Fig. 5.16 Classic papillary thyroid carcinoma. PTC metastatic to a
lymph node. Cervical and ipsilateral lymph nodes are the most common
sites of metastasis for classic PTC. Patients with lymph node metastases
of PTC still may have long-term survival and be cured of their disease
36 5 Papillary Thyroid Carcinoma

Papillary Thyroid Microcarcinoma

Fig. 5.17 Classic papillary thyroid carcinoma. Cystic metastases of

PTC to regional lymph nodes. Cystic change in lymph node metastases
is not uncommon in PTC

Fig. 5.20 Papillary thyroid microcarcinoma. Two papillary thyroid

microcarcinomas are seen in this gross photograph. Papillary thyroid
microcarcinoma is defined as measuring 1 cm or less. This tumor often
is an incidental finding in thyroid glands removed for benign disease
[11]. Autopsy and surgical series identify these tumors in 735 % and
7 % of cases, respectively [1215]. Incidental, clinically occult tumors
are less aggressive than those presenting clinically. If a tumor is clini-
cally apparent, regardless of size, it is a clinical carcinoma and usually
treated as such. Clinically overt microcarcinomas are larger than occult
tumors and more often show multifocality, extrathyroid extension, vas-
cular invasion, recurrence, and metastases and usually are treated as
clinical cancer [1618]. A meta-analysis of 1,586 microcarcinomas
found multifocality related to nodal metastases [19]. Microcarcinomas
may be aggressive and may present as distant metastases [20, 21].
Familial occurrence has been noted in 5.9 % of papillary microcarcino-
mas, and these tumors may be aggressive [22]

Fig. 5.18 Classic papillary thyroid carcinoma. An area of solid growth

is present in a cystic-appearing lymph node metastasis of PTC

Fig. 5.19 Classic papillary thyroid carcinoma. In some cases, lymph node
metastases of PTC may be difficult to diagnose, as they do not always show
the prominent features of classic PTC. In difficult cases, immunoperoxidase
studies may be helpful, as PTC is positive for TTF1 and thyroglobulin
FVPTC
Fig. 5.21 Papillary thyroid microcarcinoma. This papillary thyroid
microcarcinoma was discovered incidentally in a patient undergoing
surgery for benign thyroid disease. Cases presenting clinically usually
are treated as clinical cancer [11]; however, treatment of incidental
microcarcinoma is more controversial. Another focus of microcarci-
noma is identified in the contralateral lobe in 1520 % of cases, and
20 % of patients may have long-term recurrent disease without com-
plete resection. Capsular invasion or distant metastases occur in up to
5 % of microcarcinomas [23]. Of 115 clinically overt and 75 occult
papillary microcarcinomas, the overt tumors were larger and more often
had extrathyroid extension, multifocality, vascular invasion, and nodal
metastases, and recurrence occurred only in the overt microcarcinomas
[18]. However, clinically incidental papillary microcarcinomas also
may behave aggressively; thus, treatment remains controversial
Fig. 5.22 Papillary thyroid microcarcinoma. Although papillary
microcarcinomas have an excellent prognosis overall, they have 1 %
mortality, 2.5 % local recurrence, 1 % nodal recurrence, and 1 % distant
metastatic rates [24]. Comparing subtypes of papillary microcarcino-
mas, tall cell microcarcinomas are larger (7.1 mm) than the classic type
(5.3 mm) and have higher rates of multifocality and extrathyroid exten-
sion than classic microcarcinomas (47.2 % vs. 34 %) [25]. Diffuse scle-
rosing microcarcinomas have higher rates of nodal metastases (57 % vs.
33 %) and extrathyroid extension than classic papillary microcarcino-
mas (13 % vs. 6 %) [25]. However, no differences in survival were
found among the three groups [25]
37
FVPTC
Fig. 5.23 Follicular variant of papillary thyroid carcinoma, gross. This
FVPTC appears circumscribed. Encapsulated tumors with vascular or
capsular invasion may behave more aggressively than those without
invasion [26, 27]. Encapsulated FVPTCs with no invasion have mini-
mal metastatic potential, and FVPTCs that are not fully encapsulated or
infiltrative but are partially encapsulated or well circumscribed also
have very low metastatic potential/recurrence risk, unlike more aggres-
sive infiltrative FVPTC [28]. Both encapsulated and partially encapsu-
lated FVPTCs often have RAS mutations (46 %) and lack BRAF
mutations (which are found in some infiltrative FVPTCs) [29]
Fig. 5.24 Follicular variant of papillary thyroid carcinoma. FVPTC has a
follicular growth pattern and cytologic features of PTC. Classic cytologic
features may not be present throughout the tumor; thus, differentiation from
follicular neoplasms may be difficult. FVPTC is the second most common
PTC and one of the most difficult to diagnose. Ten thyroid pathologists
evaluated 87 FVPTCs, and all ten made a concordant diagnosis of FVPTC
in 39 % [30]. Seven of the pathologists made a diagnosis of FVPTC in all
cases associated with metastases, but the cumulative diagnosis of all ten
reviewers in these cases was 66.7 % [30]. Comparing FVPTC with classic
PTC, patient age (4648 years) and female predominance (7779 %) are
similar [3133]. These tumors do not differ in size, multifocality, or capsu-
lar, lymphovascular, or perineural invasion, but FVPTCs have fewer lymph
node metastases and less extrathyroid extension than classic PTC [31].
Older age, male sex, high T stage, extrathyroid extension, and nodal disease
are associated with decreased survival [32, 33]. Ten-year survival (96
98 %) is similar for FVPTC and classic PTC [3133]
38
Fig. 5.25 Follicular variant of papillary thyroid carcinoma. FVPTC
may not have classic features of PTC throughout the tumor. Foci of
characteristic features may be identified along the periphery of the
tumor. Unlike classic PTC, FVPTC does not show papillary growth. If
this tumor showed areas of papillary growth, it would be classified as
classic PTC
Fig. 5.26 Follicular variant of papillary thyroid carcinoma. This pho-
tomicrograph shows features of FVPTC, with variably sized follicles
lined by cells with large, irregular, back-to-back nuclei; nuclear groves;
and chromatin clearing. Less nuclear overlap is seen in FVPTC than in
classic PTC. Although dark colloid may be seen, it is not diagnostic for
malignancy
5 Papillary Thyroid Carcinoma
Fig. 5.27 Follicular variant of papillary thyroid carcinoma. Numerous
patterns have been identified in FVPTC, including microfollicular,
macrofollicular, diffuse, and adenoid cystic patterns, as well as combi-
nations of these. From low to medium power, a pattern of small follicles
intermixed with larger follicles is a clue to the diagnosis of FVPTC
Fig. 5.28 Follicular variant of papillary thyroid carcinoma. The elon-
gated follicles in this thyroid tumor are a clue to the diagnosis of
FVPTC. Elongated follicles in parallel cords also may be seen in the
columnar and tall cell variants of PTC
FVPTC
Fig. 5.29 Follicular variant of papillary thyroid carcinoma. The cells
in FVPTC have large, irregular, back-to-back nuclei; grooves; and chro-
matin clearing and show less nuclear overlap than classic PTC. The
nuclei in FVPTC appear somewhat rectangular and squared off.
Although dark colloid may be seen, it is not diagnostic of malignancy.
Giant cells may be seen in PTC, including FVPTC, but are nonspecific
Fig. 5.30 Follicular variant of papillary thyroid carcinoma.
Intranuclear pink holes are helpful in the diagnosis of FVPTC, but they
are seen in only a minority of the cases. Intranuclear pink holes are less
common in FVPTC than in classic PTC. These intracytoplasmic invagi-
nations into the nuclei must comprise >50 % of the nucleus, are eosino-
philic, and have condensation around the periphery. Intranuclear pink
holes are not specific for FVPTC or PTC, as they also are seen in med-
ullary thyroid carcinoma, some Hurthle cell neoplasms, and parathy-
roid tissue
39
Fig. 5.31 Follicular variant of papillary thyroid carcinoma. Low-
power photomicrograph of an FVPTC showing infiltrative/diffuse
growth. This growth pattern is more common in younger patients, often
multicentric, and associated with extrathyroid extension, nodal metas-
tases, and vascular invasion [34, 35]. Encapsulated FVPTCs have less
intratumor fibrosis (18 %), extrathyroid extension (5 %), positive mar-
gins (2 %), and lymph node metastases (5 %) than nonencapsulated
FVPTCs with diffuse/infiltrative growth (88, 65 , 50, and 65 %, respec-
tively) [27]. Encapsulated tumors with vascular or capsular invasion
may be more aggressive than those without invasion [26, 27].
Encapsulated FVPTCs with no capsular or vascular invasion have mini-
mal metastatic potential, and FVPTCs that are not fully encapsulated or
infiltrative but are partially encapsulated or well circumscribed also
have a very low metastatic potential/recurrence risk, unlike more
aggressive infiltrative FVPTC [28]. Both encapsulated and partially
encapsulated FVPTCs often have RAS mutations (46 %) and lack BRAF
mutations (which occur in some infiltrative FVPTCs) [29]
Fig. 5.32 Follicular variant of papillary thyroid carcinoma. This is an
encapsulated, noninvasive FVPTC. The surrounding thyroid paren-
chyma shows thyroiditis, which often is seen in cases of PTC. From low
power, the tumor cells appear lighter in color, likely because of the
nuclear clearing and the areas of scalloped-appearing colloid. Note that
the colloid in this example does not appear darker than in the surround-
ing thyroid parenchyma
40
Fig. 5.33 Follicular variant of papillary thyroid carcinoma. HBME-1
immunostain is positive in the FVPTC on the right side of the photomi-
crograph. This is a helpful feature to confirm a diagnosis of FVPTC.
Notice that in the surrounding thyroid parenchyma, there is focal non-
specific staining of colloid and a few cells around areas of inflamma-
tion. It is important to recognize that this occurs, so these inflamed foci
are not diagnosed as PTC
Fig. 5.34 Follicular variant of papillary thyroid carcinoma. HBME-1
shows membranous and some cytoplasmic staining of the tumor cells in
this FVPTC. The colloid also shows staining, but this is not specific.
Several immunohistochemical markers, such as HBME-1, galectin-3,
CITED-1, and keratin 19, may be helpful in confirming a diagnosis of
FVPTC [36]. Although a panel of immunostains may be most helpful,
HBME-1 is probably the best single marker to assist in differentiating
FVPTC from a follicular neoplasm or adenomatous nodule
5 Papillary Thyroid Carcinoma
Cribriform-Morular Variant of PTC
Fig. 5.35 Cribriform-morular variant of papillary thyroid carcinoma.
The cribriform-morular variant of PTC has unique histologic features
and is associated with familial adenomatous polyposis (FAP) and germ-
line APC mutations [3741]. Although sporadic cases of cribriform-
morular PTC occur, this variant often occurs in FAP, an autosomal
dominant syndrome of gastrointestinal adenomas and carcinomas,
endometrial cancer, and medulloblastomas [39]. Patients with FAP may
present with the cribriform-morular variant of PTC [38]; thus, patients
diagnosed with cribriform-morular PTC should be evaluated for FAP
Fig. 5.36 Cribriform-morular variant of papillary thyroid carcinoma.
The cribriform areas in the cribriform-morular variant of PTC have
arches and anastomosing bars of cells. The arches and bars of cells lack
intervening fibrovascular stroma [40]. These tumors have cytologic fea-
tures of PTC, and areas of follicular and papillary growth may be seen.
The architectural features are the most distinguishing in separating
cribriform-morular PTC from other types of PTC. These tumors occur
most commonly in women, they may be single or multifocal, and their
prognosis is similar to that of classic PTC
Cribriform-Morular Variant of PTC 41

Fig. 5.37 Cribriform-morular variant of papillary thyroid carcinoma.
Shown is an area of prominent morules in a cribriform-morular PTC.
The morules are composed of spindle/oval tumor cells, which are posi-
tive for TTF1 and sometimes thyroglobulin. The tumor cells show aber-
rant nuclear and cytoplasmic expression of -catenin. The morular
areas may show absent or focal keratin expression [42]. Nuclear expres-
sion of estrogen and progesterone receptors and Bcl-2 also has been
reported [43]
Fig. 5.39 Cribriform-morular variant of papillary thyroid carcinoma.
Aberrant nuclear and cytoplasmic staining for -catenin is present in
cribriform-morular PTC. The follicular cells in the surrounding thyroid
may show membranous staining for -catenin, but aberrant cytoplasmic
and nuclear staining for -catenin is seen in cribriform-morular PTC

Fig. 5.38 Cribriform-morular variant of papillary thyroid carcinoma. Fig. 5.40 Cribriform-morular variant of papillary thyroid carcinoma.
High-power view of morules in the cribriform-morular variant of PTC. Cribriform-morular variant of PTC shows nuclear staining for TTF1
The morules are a helpful diagnostic feature but must be distinguished
from those of squamous metaplasia [42]. Unlike in squamous metapla-
sia, the morules may lack or show decreased staining for keratin [42]
42 5 Papillary Thyroid Carcinoma

Warthin-Like Variant of PTC

Fig. 5.43 Warthin-like variant of papillary thyroid carcinoma. In addi-

Fig. 5.41 Warthin-like variant of papillary thyroid carcinoma. The
Warthin-like variant of PTC shows papillary nuclear features, oxyphilic
cytoplasm, and lymphocytic infiltrates filling papillary cores lined by
the tumor cells. In 1995, Dr. LiVolsi described this tumor as a peculiar
thyroid tumor of follicular epithelial differentiation with distinctly pap-
illary architecture, oxyphilic cytology, and lymphocytic infiltrates in
papillary stalks [44]. This Warthin-like variant of PTC resembles
Warthin tumor of the salivary glands [44]. These tumors occur in adults,
have a female predominance, and usually are solitary, circumscribed
small tumors. The prognosis is similar to that of classic PTC
tion to the characteristic low-power architecture of the Warthin-like
variant of PTC, the nuclear features are classic for PTC. The cells have
eosinophilic cytoplasm. The tall cell variant of PTC also shows fairly
eosinophilic cytoplasm, but the cells in the Warthin-like variant of PTC
are not elongated as those of the tall cell variant, in which the cells are
twice as tall as they are wide. The papillary cores filled with lympho-
cytic infiltrates lined by epithelial cells help separate the Warthin-like
variant from the oxyphilic/Hurthle variant of PTC. The architectural
and nuclear features separate the Warthin-like variant of PTC from
Hurthle cell thyroid neoplasms

Fig. 5.42 Warthin-like variant of papillary thyroid carcinoma. This

low-power view of Warthin-like variant PTC shows papillary cores
filled with lymphocytic infiltrates and lined by epithelial cells with
eosinophilic cytoplasm. This low-power appearance is quite character-
istic and helpful in identifying this tumor. The surrounding thyroid
parenchyma often shows lymphocytic or Hashimoto thyroiditis
Diffuse Sclerosing Variant of PTC 43

Diffuse Sclerosing Variant of PTC

Fig. 5.46 Diffuse sclerosing variant of papillary thyroid carcinoma.

Diffuse sclerosing variant of PTC with fibrosis, lymphocytic infiltrate
including lymphoid follicles with germinal centers, and extensive
Fig. 5.44 Diffuse sclerosing variant of papillary thyroid carcinoma. angiolymphatic invasion
The diffuse sclerosing variant of PTC has prominent calcifications,
numerous psammoma bodies, fibrosis, squamous metaplasia, and a
marked lymphocytic infiltrate. This variant, described in 1985, is more
common in females and young patients [45]. This tumor often has
aggressive features of large size, diffuse involvement of both lobes,
prominent angiolymphatic invasion throughout the thyroid, and
increased lymph node and lung metastases [46, 47]. Ultrastructurally,
the dissemination in the thyroid is the result of lymphatic invasion [48].
The prognosis varies in the literature, with some studies showing a
worse prognosis than that of conventional PTC [46, 49]. Other studies
report distinctive and unfavorable features but an outcome similar to
that of conventional PTC [47, 50]

Fig. 5.45 Diffuse sclerosing variant of papillary thyroid carcinoma.

Diffuse sclerosing PTC showing widespread intrathyroidal angiolym-
phatic permeation, which may appear as micropapillary formations in
cleft-like spaces [46]. Although an earlier study did not identify thyro-
globulin staining in the squamous metaplasia [51], a subsequent study
reported that both PTC and squamous metaplasia cells stain strongly
with keratin 19, thyroglobulin, and TTF1 [50]. Prominent S100 den-
dritic cells also are seen in these tumors [50, 51]
44 5 Papillary Thyroid Carcinoma

Oxyphilic (Oncocytic/Hurthle Cell)

Variant of PTC

Fig. 5.47 Oxyphilic (oncocytic/Hurthle cell) variant of papillary thy-
roid carcinoma. Low-power photomicrograph of the papillary architec-
ture in an oxyphilic variant of PTC. This is an uncommon variant of PTC
and one of the most difficult to diagnose. Oxyphilic PTC has cytologic
features of PTC and abundant eosinophilic cytoplasm. Because of the
abundant cytoplasm, the nuclei do not show the prominent overlapping
often seen in other types of PTC. Oxyphilic PTC must be differentiated
from Hurthle cell neoplasms and papillary hyperplasia with oxyphilic
change, both of which lack the characteristic nuclear features of PTC
Fig. 5.49 Oxyphilic (oncocytic/Hurthle cell) variant of papillary thy-
roid carcinoma. Oxyphilic variant of PTC with papillae lined by a sin-
gle layer of epithelial cells with abundant eosinophilic cytoplasm and
nuclear features of PTC, including large nuclei with irregular nuclear
membranes, focal nuclear grooves, and eosinophilic intranuclear inclu-
sions (holes). The oxyphilic variant of PTC shows an immunopheno-
type similar to that of classic PTC, but the immunostains may be
difficult to interpret because there may be nonspecific staining in the
cytoplasm

Fig. 5.48 Oxyphilic (oncocytic/Hurthle cell) variant of papillary thyroid

carcinoma. The papillae in this oxyphilic variant of PTC are lined by a
single layer of oxyphilic cells with cytologic features of PTC, including
intranuclear inclusions. These tumors may behave similarly to classic
PTC, although some studies have reported more aggressive behavior [52].
Tumors with features of both oxyphilic and tall cell PTC may behave more
aggressively [53]. In a study of 42 oxyphilic PTCs, the tumors ranged
from 1 to 9 cm (median, 3 cm), 19 tumors had extrathyroid extension, 13
tumors had lymph node metastases, 2 tumors had distant metastases, 4
patients had locoregional recurrence, 1 patient had disseminated disease,
and 3 patients died from the disease [54]. The 5- and 10-year survival rates
were 94 and 87 %, respectively [54]. Prognostic factors were age, extra-
thyroid extension, primary tumor stage, and regional and distant metasta-
ses [54]. In this study, extrathyroid tumor growth was common (45 %), but
the tumors still had a favorable prognosis with radical resection, radioio-
dine ablation of the thyroid remnant, and external irradiation [54]
Solid Variant of PTC 45

Solid Variant of PTC

Fig. 5.50 Solid variant of papillary thyroid carcinoma. The solid vari-
ant of PTC is uncommon, accounting for 23 % of PTCs, but is more
common in children [55]. In a study from the Mayo Clinic, the solid
variant of PTC was defined as having predominantly (>70 %) solid
growth, a lack of necrosis, and the presence cytologic features of PTC
[55]. This variant must be differentiated from poorly differentiated thy-
roid carcinoma. Both may show solid growth, but the solid variant of
PTC has cytologic features of PTC and lacks necrosis. The solid variant
has a less favorable prognosis than classic PTC but higher survival than
poorly differentiated carcinoma [55]. In a study of 121 PTCs, the solid
cell variant had the highest proportion (75 %) of high-risk tumors clas-
sified by AMES (age, metastases, extent, and size) criteria (75 %), fol-
lowed by the tall cell variant (33.3 %), with only 8.3 % of classic PTC
being high risk [56]
Fig. 5.52 Solid variant of papillary thyroid carcinoma. The solid vari-
ant of PTC has a solid growth pattern and nuclear features of PTC. This
tumor is more common in children, particularly those exposed to radia-
tion [57]. The solid variant was the most common PTC in Belarus chil-
dren after the Chernobyl disaster [57]. This variant is associated with
BRAF mutation, but the radiation-associated tumors have a low inci-
dence of BRAF mutation and commonly have RET/PTC rearrange-
ments [58]. The pediatric post-Chernobyl PTCs were associated with
RET/PTC1 and RET/PTC3 rearrangements. RET/PTC1 occurs with
classic and diffuse sclerosing PTCs and RET/PTC3 with the solid/fol-
licular variant [59]. These tumors occur in young children and have a
high frequency of solid growth, an equal female-to-male ratio, a short
latency, intraglandular spread, and capsular and soft tissue invasion and
metastases [57, 60]

Fig. 5.51 Solid variant of papillary thyroid carcinoma. The solid vari-
ant of PTC has a solid growth pattern, as demonstrated in this image;
however, a trabecular growth pattern also may be seen. The tumor cells
are in solid sheets or nests or trabeculae, and psammoma bodies and
fibrosis may be seen in some cases. These tumors generally lack a
fibrous capsule and necrosis, and have few mitoses. A thyroid tumor
with solid growth, prominent mitotic activity, and necrosis more likely
would be classified as a poorly differentiated carcinoma
46 5 Papillary Thyroid Carcinoma

Tall Cell Variant of PTC

Fig. 5.53 Tall cell variant of papillary thyroid carcinoma. The tall cell
variant of PTC is characterized by cells twice as tall as they are wide
and by nuclear features of PTC [61]. Tall cell PTC, described in 1976
by Hawk and Hazard [62], is aggressive and occurs more often in males
and elderly people. These tumors often are large (>6 cm) and have
aggressive features of extrathyroid extension, vascular invasion, metas-
tases, and shorter disease-free survival than that of classic PTC [63, 64].
Up to 2025 % of patients with this tumor die from the disease [64].
Recent studies suggest it may not be the histologic subtype of the tumor
that is prognostic but other factors, such as tumor size, age, and extra-
thyroid extension, among others. A study of 62 tall cell and 83 classic
PTCs without extrathyroid extension found no difference between tall
cell and classical PTC with regard to age, gender, size, risk stratifica-
tion, type of therapy, or length of follow-up, but found the tall cell vari-
ant without extrathyroid extension more aggressive than classic PTC
without extrathyroid extension, independent of age, gender, or tumor
size [65]
Fig. 5.54 Tall cell variant of papillary thyroid carcinoma. The papil-
lary structures in tall cell PTC are lined by cells with abundant eosino-
philic cytoplasm, basally oriented nuclei, and nuclear features of PTC.
The tumor cells are at least twice as tall as they are wide. It has been
proposed that the tall cell variant be diagnosed if the tumor is composed
of 50 % or more of tall cells that have a height at least twice the width,
eosinophilic cytoplasm, and nuclear features of PTC [61]. Regardless
of the exact proportion of tall cells or whether they are twice or three
times as tall as wide, this entity reportedly is underdiagnosed [61]. This
is important because this tumor accounts for 20 % of incurable flude-
oxyglucose positron emission tomographypositive thyroid carcinomas
refractory to radioactive iodine therapy [61]
Columnar Variant of PTC
Columnar Variant of PTC
Fig. 5.55 Columnar variant of papillary thyroid carcinoma. The
columnar variant of PTC is a rare, aggressive tumor that occurs over a
wide age range, metastasizes widely, and does not respond to radioac-
tive iodine or chemotherapy [66]. This tumor has a prominent papillary
architecture and elongated cells with nuclear stratification and scant
cytoplasm. The tumor appears basophilic and histologically resembles
endometrial or colon cancer. Others may have more cytoplasmic clear-
ing, similar to secretory endometrium. Solid growth with spindle cells
and follicular and microfollicular growth may be seen [67, 68]. Tumors
may have both tall cell and columnar features [69, 70]. The prognosis
for encapsulated tumors is better than that of highly invasive unencap-
sulated tumors [68]. The columnar variant may be a distinct morpho-
logic type of PTC but not necessarily a distinct clinical subtype, as the
behavior may be associated with clinical stage and extrathyroid inva-
sion rather than the morphologic subtype [71]. This variant of PTC has
a high proliferation index with MIB1 [72, 73]
47
Fig. 5.56 Columnar variant of papillary thyroid carcinoma. This
image of the columnar variant of PTC shows a focally microfollicular
growth pattern, prominent nuclear stratification, and scant cytoplasm.
The cells are twice as tall as they are wide, but unlike the tall cell variant
of PTC, the columnar cells are more elongated than tall cells and show
prominent nuclear stratification. Psammoma bodies usually are not
seen. Although colloid may be seen, it is not prominent. These tumors
often show angiolymphatic invasion, extrathyroid extension, and nodal
and distant metastases. The mortality rate is high. The columnar variant
of PTC is positive for TTF1, estrogen and progesterone receptor, and
-catenin (membranous); is negative for carcinoembryonic antigen and
calcitonin; and may stain for CDX2, although reports are variable
[7375]
48 5 Papillary Thyroid Carcinoma

Hobnail Variant of PTC

Fig. 5.58 Hobnail variant of papillary thyroid carcinoma. The cells

lining the papillae and follicles in this hobnail variant of PTC show loss
of polarity with apically placed nuclei and clusters of atypical cells. The
Fig. 5.57 Hobnail variant of papillary thyroid carcinoma. Hobnail papillae lack fibrovascular cores and follicular structures that, when
PTC is a rare, recently described aggressive variant of PTC that has present, lack colloid. The papillary structures vary in size and are lined
prominent hobnail (micropapillary) features. The tumor is composed of by atypical cells with increased nuclear-to-cytoplasmic ratios and api-
prominent papillae that lack fibrovascular cores, follicles with little col- cal nuclei producing a surface bulge (hobnail) [76]. These tumors are
loid, and clusters of atypical cells with increased nuclear-to-cytoplasmic positive for thyroglobulin, TTF1, HBME-1, p53, -catenin (membra-
ratios and apical nuclei that appear hobnailed [76]. In the original eight nous), and E-cadherin [76]. Mitotic figures are common, and the Ki67
cases from the Mayo Clinic, six were in women aged 2878 years proliferative index is 220 % (mean, 10 %) [76]. BRAF mutation is
(mean, 58 years) [76]. The tumors were 14 cm (mean, 2.5 cm) and present in 57 % of cases [76]
often multifocal. Four of the eight patients died of disease, and two
were alive with disease [76]. In a subsequent series of 24 cases, 18 of 24
were women aged 2878 years (mean, 57 years), the average follow-up
was 106 months (range, 4274 months), and tumor sizes ranged from 1
to 5.8 cm (mean, 3 cm) [77]. Of the 24 cases, 12 had <30 % and 12 had
>30 % hobnail component. Six of the 12 with >30 % hobnail compo-
nent died of disease, and 3 were alive with extensive disease with a
mean follow-up of 32 months. Of the 12 with <30 % hobnail compo-
nent, 2 died of disease [77]. These tumors are aggressive, particularly if
>30 % of the tumor is hobnail; however, even in those with less hobnail
component, aggressive behavior may occur [77]

Fig. 5.59 Hobnail variant of papillary thyroid carcinoma. Hobnail

PTC with prominent hobnail features, with papillae without fibrovascu-
lar cores lined by atypical epithelial cells with loss of polarity and api-
cal nuclei, giving the tumor a hobnail (micropapillary) appearance. An
intranuclear pink hole is identified in the center of the photomicrograph.
The tumor cells also show a loss of cohesiveness. These tumors metas-
tasize to the lymph nodes, liver, lung, bone, brain, muscle, and pancreas
[76]. The metastases appear histologically similar to the primary tumor
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 Hyalinizing Trabecular Tumor
6

The hyalinizing trabecular tumoror adenoma, as it
originally was described by Carney [1] in 1987, can mimic
medullary and papillary thyroid carcinoma. This unique
tumor occurs more commonly in females and over a broad
age range (2772 years; mean, 46 years). These tumors
originally were diagnosed as carcinoma, adenoma, para-
ganglioma, or indeterminate [1]. None of the tumors in
the original series metastasized during 10 years of follow-
up. Additional case reports and small series followed, with
a few tumors showing capsular or vascular invasion [2, 3].
These tumors generally are not associated with BRAF or
RAS mutations, but RET alterations have been reported [4
6]. Whether this is sufficient for these tumors to be regarded
as variants of papillary thyroid carcinoma (PTC) has been
controversial, as RET/PTC rearrangements are not specific
for PTC [7]. Some of the hyalinizing trabecular tumors
with RET rearrangements were from thyroids that also had
PTCs [4, 5]. Also, some have reported RET/PTC rearrange-
ments in Hashimoto thyroiditis [8, 9], although this is not
corroborated by others [10]. A subsequent report from
Carneys group [11] found that of 119 hyalinizing trabecu-
lar tumors studied over a 20-year period, with follow-up for
96 %, 118 tumors had no evidence of aggressive behavior
(capsular, vascular, or parenchymal invasion), recurrence,
or metastasis. One of the 119 tumors showed capsular and
vascular invasion and pulmonary metastasis [11]. Although
these neoplasms now are usually referred to as hyalinizing
trabecular tumors, their behavior generally is benign and
they treated as such. Although malignant hyalinizing tra-
becular tumors have occurred, they generally are regarded
as benign or, at most, neoplasms of extremely low malig-
nant potential [12]. They probably should be considered
malignant only if there is obvious capsular or vascular
invasion or metastasis [7].

L.A. Erickson, Atlas of Endocrine Pathology, Atlas of Anatomic Pathology, 51

DOI 10.1007/978-1-4939-0443-3_6, Springer Science+Business Media New York 2014
52
Fig. 6.1 Hyalinizing trabecular tumor. This hyalinizing trabecular
tumor shows encapsulation and separation from the adjacent thyroid.
Hyalinizing trabecular tumors measure 0.34 cm, are yellow-tan
grossly, and are circumscribed [1]. The tumors are solid, and the cells
are arranged in trabeculae and clusters, which may be oriented vertical
to capillaries [1]
Fig. 6.2 Hyalinizing trabecular tumor. The tumor cells in this hyalin-
izing trabecular tumor are sharply outlined, elongated oval cells with
finely granular cytoplasm that is eosinophilic or amphophilic. The
nuclei are elongated and oval and have fine grooves, perinucleolar vacu-
oles, and intranuclear holes [1]. The cells are arranged perpendicular to
the major axis of the trabecula or nest. These tumors may have cyto-
plasmic yellow bodies [7]. Mitotic figures are uncommon
6 Hyalinizing Trabecular Tumor
Fig. 6.3 Hyalinizing trabecular tumor. Extracellular eosinophilic hya-
line fibrosis may be seen, especially around vessels, in hyalinizing tra-
becular tumors, and this fibrosis is negative for Congo red [1].
Differentiating hyalinizing trabecular tumor from PTC or medullary
thyroid carcinoma or paraganglioma usually is not difficult. Hyalinizing
trabecular tumors are circumscribed and have hyalinized stroma, tra-
beculae or solid nests of elongated tumor cells oriented perpendicular to
the long axis of the trabeculae, nuclear pseudoinclusions (in nearly
every field), and prominent nuclear grooves. They show unusual cyto-
plasmic and cell membrane staining for Ki67 with MIB1 antibody [13],
although this may be temperature or technically dependent. Hyalinizing
trabecular tumors are positive for thyroid transcription factor 1 (TTF1)
and thyroglobulin and negative for chromogranin and synaptophysin.
They also are negative for HBME-1, which is helpful as PTCs often are
positive for HBME-1 [14]
Fig. 6.4 Hyalinizing trabecular tumor. Prominent eosinophilic intra-
nuclear inclusions are characteristic in hyalinizing trabecular tumor.
Similar eosinophilic intranuclear inclusions may be seen in PTCs and
medullary thyroid carcinomas, occasionally in Hurthle cell tumors, and
in the parathyroid gland [2, 15]. In hyalinizing trabecular tumors, the
eosinophilic intranuclear inclusions are prominent and present in nearly
every microscopic field, unlike those seen in other thyroid and parathy-
roid lesions
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structures and intranuclear inclusions in Hurthle-cell neoplasms of
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the thyroid. Diagn Cytopathol. 1999;20(4):1859.
papillary carcinoma? Adv Anat Pathol. 2002;9(1):711.
8. Sheils O, et al. RET/PTC rearrangements in Hashimotos thyroid-
itis. Int J Surg Pathol. 2002;10(2):1678; author reply 1689.
 Follicular Thyroid Neoplasms
Follicular thyroid neoplasms are solitary nodules that pres-
ent as a mass. Follicular adenomas are benign, encapsulated
tumors with follicular differentiation that are more common
in women, usually occur in adults, and are more common in
areas of iodine deficiency [1]. Follicular adenomas measure
13 cm and usually are smaller than follicular carcinomas,
although size may overlap. Follicular neoplasms lack cyto-
logic features of papillary thyroid carcinoma (PTC).
Malignancy in follicular neoplasms requires capsular or
vascular invasion. The capsule in follicular carcinomas
often is thicker and more irregular than that of adenomas.
Various histologic patterns, including microfollicular, mac-
rofollicular, normofollicular, and trabecular growth, may be
seen in follicular neoplasms. Areas of papillary architecture
may be seen. Follicular neoplasms may have different cyto-
morphologies, including mucinous, signet ring cell, and
clear cell, and may have intratumoral fat. Follicular neo-
plasms show immunopositivity for thyroid transcription
factor 1 (TTF1), thyroglobulin, and keratin and are negative
for chromogranin, synaptophysin, and calcitonin. Follicular
neoplasms often show RAS mutations, and a few have t(2;3)
(q13;p25) involving PAX8 and peroxisome proliferator-
activated receptor- encoding a fusion protein [24].
Follicular adenomas show increased expression of p27 cell
cycle inhibitory protein and decreased Ki67 proliferative
indices (LI) compared with follicular carcinomas, and
L.A. Erickson, Atlas of Endocrine Pathology, Atlas of Anatomic Pathology,
DOI 10.1007/978-1-4939-0443-3_7, Springer Science+Business Media New York 2014
7
carcinomas with metastases have higher Ki67 LI levels than
those without [5]. However, in an individual lesion, these
and other immunohistochemical or molecular markers can-
not separate benign from malignant follicular neoplasms
definitively. Cytologic specimens cannot distinguish benign
from malignant follicular neoplasms, as diagnosis of malig-
nancy requires invasive growth. Follicular adenomas are
treated with lobectomy and have an excellent prognosis.
Follicular carcinomas show capsular and/or vascular inva-
sion. Vascular invasion must occur within or beyond the
capsule. Tumors with capsular invasion only (no vascular
invasion) have more indolent behavior than those with vas-
cular invasion [6]. Follicular carcinomas with focal capsular
and/or vascular invasion have been designated as minimally
invasive, whereas those with more extensive invasion have
been characterized as widely invasive, although this classi-
fication is being used less often. Tumors with extensive vas-
cular invasion often are referred to as angioinvasive
follicular carcinomas. Unlike PTC, which has frequent
lymph node metastases, follicular carcinomas usually
metastasize directly to viscera. Minimally invasive follicu-
lar carcinomas have a low mortality rate (35 % in some
studies), and those with only capsular invasion (no vascular
invasion) have a particularly good prognosis [1, 6]. Widely
invasive carcinomas are aggressive, with a long-term
mortality rate of 50 % [1].
55
56
Follicular Adenoma
Fig. 7.1 Follicular adenoma. Shown is a thyroid follicular adenoma
with a thin capsule. Follicular adenomas are benign, solitary, encapsu-
lated tumors showing follicular differentiation. They generally occur in
adults and are more common in females and in iodine-deficient areas.
These tumors may vary in size, but generally measure 13 cm. The
capsule generally is thin, unlike that of follicular carcinomas, which
tends to be thicker and more irregular. Follicular adenomas lack the
cytologic features of the follicular variant of PTC. Differentiating fol-
licular adenoma from follicular carcinoma is based on invasion; follicu-
lar adenomas do not show capsular or vascular invasion. Thus, thorough
evaluation of the capsule is required to differentiate follicular adenoma
from carcinoma
Fig. 7.2 Follicular adenoma. Follicular adenomas have a capsule sepa-
rating the tumor from the adjacent thyroid parenchyma. The capsule is
thin and no capsular or vascular invasion is identified, as would be
required for a diagnosis of follicular carcinoma. Follicular adenomas
usually are solitary and have a well-defined capsule, features separating
them from adenomatous and hyperplastic nodules. Differentiating fol-
licular adenoma from the follicular variant of PTC may be difficult
because both tumors have a follicular growth pattern. However, follicu-
lar adenomas lack the cytologic features characteristic of PTC. These
features, however, may be subtle and more prominent at the peripheral
aspect of the lesion. Thus, careful evaluation of the cytologic features is
needed. In difficult cases, immunoperoxidase markers, such as
HBME-1, may be helpful, as this marker often is positive in the follicu-
lar variant of PTC and negative in follicular adenoma
7 Follicular Thyroid Neoplasms
Fig. 7.3 Follicular adenoma. This follicular adenoma has a mixed
microfollicular and macrofollicular architectural pattern. It is a single
encapsulated lesion in the thyroid. When multiple noninvasive encapsu-
lated and nonencapsulated lesions are identified in the thyroid, they
usually are classified as adenomatous and hyperplastic nodules
Fig. 7.4 Follicular adenoma. This follicular adenoma shows promi-
nent clear cell change. Clear cell change may be seen in many thyroid
neoplasms (follicular, papillary, and medullary), parathyroid neo-
plasms, and metastases to the thyroid, such as those from renal cell
carcinoma [711]. A review of 38 primary thyroid neoplasms with
extensive clear cell change included 10 Hurthle cell tumors, 17 follicu-
lar tumors, 7 papillary thyroid carcinomas, and 4 undifferentiated carci-
nomas [12]. Factors associated with cytoplasmic clear cell change were
vesicle formation (some of mitochondrial derivation) in Hurthle cell
and follicular tumors; glycogen accumulation in papillary, undifferenti-
ated, and metastatic tumors; and intracellular thyroglobulin in follicular
tumors with a signet ring or lipoblast-like appearance [12]
Follicular Adenoma
Fig. 7.5 Follicular adenoma. This follicular adenoma has marked clear
cell change. This tumor appears quite vascular, a feature often seen in
endocrine tissues and tumors but also in metastatic renal cell carci-
noma. In difficult cases, immunostains may be helpful in differentiating
a primary thyroid neoplasm from a metastasis, such as that from renal
cell carcinoma. Thyroid folliculogenic neoplasms are positive for kera-
tin, TTF1, and thyroglobulin. Renal cell carcinoma is negative for TTF1
and thyroglobulin
Fig. 7.6 Follicular adenoma. This follicular adenoma shows mucinous
change. Mucinous change may be seen in thyroid neoplasms, although
it is uncommon. Follicular thyroid neoplasms with mucinous features
must be differentiated from metastatic carcinoma to the thyroid. In dif-
ficult cases, immunoperoxidase studies may be helpful, as folliculo-
genic thyroid tumors show immunopositivity for TTF1, thyroglobulin,
and keratin
57
Fig. 7.7 Follicular adenoma. Mucin is identified in follicular/acinar
spaces in this thyroid follicular adenoma. Mucin appears in the follicu-
lar lumina in this tumor; however, it may be seen in other tumors. Thus,
differentiation from other thyroid tumors and metastases to the thyroid
is needed
Fig. 7.8 Follicular adenoma. Foci of adipocytes are identified in this
follicular adenoma. When extensive lipomatous metaplasia is identified
in a follicular adenoma, the term lipoadenoma may be used. Overall,
this is an interesting histologic feature, albeit one with no known clini-
cal significance
58 7 Follicular Thyroid Neoplasms

Fig. 7.9 Follicular adenoma. This follicular adenoma shows promi- Fig. 7.11 Follicular adenoma. This follicular adenoma shows exten-
nent spindle cell change. Spindle cell proliferations in the thyroid occur sive signet ring cell change. The tumor is encapsulated and lacks capsu-
in reactive and neoplastic processes, including some aggressive tumors. lar or vascular invasion. Signet ring cell change may be seen in other
Follicular adenomas with spindle cell proliferations usually show bland thyroid tumors and in metastases to the thyroid
spindle cells with fine chromatin, subtle nucleoli, and rare mitoses [13].
In addition to folliculogenic neoplasms, mesenchymal tumors also may
show spindle cell change. Also, whenever one faces a thyroid tumor
with spindle cell change, particularly one that does not show colloid,
medullary thyroid carcinoma must be excluded. In difficult cases,
immunostains may be helpful, as medullary carcinomas are positive for
TTF1, chromogranin, synaptophysin, carcinoembryonic antigen
(CEA), and calcitonin and negative for thyroglobulin

Fig. 7.10 Follicular adenoma. This follicular adenoma shows promi-
nent spindle cells. Spindle cell change may constitute a minor part of a
tumor, be present at the periphery, or diffusely involve the entire tumor
[13]. In addition to follicular neoplasms, spindle cell change may be
seen in PTCs and aggressive thyroid neoplasms, including anaplastic
carcinoma [13]
Fig. 7.12 Follicular adenoma. Signet ring cell change is prominent in
this follicular adenoma. Signet ring cell change may occur in benign
and malignant thyroid neoplasms and metastases to the thyroid. Thus,
in difficult cases, immunoperoxidase studies may be helpful
Follicular Adenoma 59

Fig. 7.13 Follicular adenoma. Follicular adenoma with degenerative Fig. 7.15 Follicular adenoma. Medium-power view showing meta-
features and hyalinization. Degenerative features may be seen in fol- plastic bone with associated giant cell reaction in the thyroid
licular adenomas and in adenomatous nodules

Fig. 7.14 Follicular adenoma. Metaplastic bone or ossification occurs

in the thyroid. However, metaplastic bone with marrow elements or
extramedullary hematopoiesis is quite uncommon and has been
reported in multinodular goiter and follicular adenoma [14, 15]
60
Follicular Carcinoma
Fig. 7.16 Follicular carcinoma. This follicular carcinoma has capsular
invasion. Follicular carcinomas are malignant epithelial tumors show-
ing follicular differentiation and lacking nuclear features of PTC.
Follicular carcinomas comprise 1015 % of clinical thyroid carcino-
mas, present as a mass, occur most commonly in the fifth decade, affect
women more than men, and have an increased incidence in iodine-
deficient areas. Unlike PTC, ipsilateral lymph node metastases are rela-
tively uncommon in follicular carcinomas, occurring in 5 % of cases.
Follicular carcinomas are cellular tumors with a follicular or solid pat-
tern of growth and often have thicker and more irregular capsules com-
pared with follicular adenomas. Capsular and/or vascular invasion is
required for a diagnosis of malignancy in a follicular thyroid neoplasm
Fig. 7.17 Follicular carcinoma. This follicular carcinoma has a
mushroom-like area of invasion of the capsule. This is a common pat-
tern of capsular invasion in follicular carcinoma. Differentiating capsu-
lar invasion from a prior needle aspiration site may be difficult in some
cases. Needle tracks generally are perpendicular to the capsule, have a
linear pattern, and often have inflammation, hemorrhage, and reactive
stromal changes. Follicular carcinomas often have thicker and more
irregular capsules compared with adenomas. Follicular carcinomas
with only capsular invasion and no vascular invasion have a better prog-
nosis than those with vascular invasion [6]
7 Follicular Thyroid Neoplasms
Fig. 7.18 Follicular carcinoma. This follicular carcinoma shows vas-
cular invasion. Vascular invasion must occur within or beyond the cap-
sule in follicular carcinoma. Follicular carcinomas have been classified
as minimally invasive and widely invasive. Minimally invasive carcino-
mas show focal capsular and/or vascular invasion. Tumors with vascu-
lar invasion behave more aggressively than those with capsular invasion
only [6]. Recently, tumors with extensive angioinvasion have been
referred to as angioinvasive thyroid carcinomas by some pathologists
Fig. 7.19 Follicular carcinoma. Vascular invasion, a feature diagnostic
of malignancy, is seen in this follicular carcinoma. Vascular invasion
must occur within or beyond the capsule in follicular carcinoma.
Follicular carcinomas have been classified as minimally invasive or
widely invasive. Minimally invasive carcinomas show focal capsular
and/or vascular invasion. Tumors with vascular invasion behave more
aggressively than those with capsular invasion only [6]. Recently, some
pathologists have referred to tumors with extensive angioinvasion as
angioinvasive thyroid carcinomas
Follicular Carcinoma
Fig. 7.20 Follicular carcinoma. This follicular carcinoma shows inva-
sion in a vessel located beyond the capsule. Vascular invasion must
occur within or beyond the capsule
Fig. 7.21 Follicular carcinoma. This follicular carcinoma has a throm-
bus of follicular thyroid carcinoma in a vessel. Both capsular and vas-
cular invasions are diagnostic of malignancy in a follicular neoplasm.
Tumors with vascular invasion generally are more aggressive than those
that show capsular invasion only and no vascular invasion
61
Fig. 7.22 Follicular carcinoma. This follicular carcinoma shows clear
cell change, an uncommon finding. Clear cell change may occur in
many thyroid neoplasms, including follicular adenoma, PTC, Hurthle
cell neoplasms, and medullary thyroid carcinomas, as well as in the
parathyroid gland and metastases to the thyroid [712]. The architec-
tural and cytologic features in follicular neoplasms otherwise are simi-
lar to those of conventional neoplasms. In difficult cases, immunostains
may be helpful in separating these tumors
Fig. 7.23 Follicular carcinoma. This follicular carcinoma has marked
clear cell change and appears quite vascular, a feature often seen in
endocrine tissues and tumors but also in metastatic renal cell carci-
noma. In difficult cases, immunostains may be helpful in differentiating
a primary thyroid neoplasm from a metastasis
62
Fig. 7.24 Follicular carcinoma. In difficult or unusual tumors, such as
this follicular carcinoma with clear cell change, immunoperoxidase
studies may be helpful. This photomicrograph shows a clear cell fol-
licular carcinoma showing nuclear staining for TTF1. These tumors
also are positive for thyroglobulin and keratin
Fig. 7.25 Follicular carcinoma. This follicular carcinoma shows spin-
dle cell change. Spindle cell proliferations may occur in reactive and
neoplastic thyroid lesions, PTC, anaplastic thyroid carcinoma, and mes-
enchymal thyroid tumors [13]. This follicular carcinoma shows capsu-
lar and vascular invasion. Whenever spindling is identified in a thyroid
lesion, medullary thyroid carcinoma must be excluded. In difficult
cases, immunostains may be helpful, as medullary thyroid carcinomas
are positive for TTF1, chromogranin, synaptophysin, CEA, and calcito-
nin and negative for thyroglobulin
References
1. DeLellis RA, Lloyd RV, Heitz PU, Eng C. Pathology and genetics
of tumours of endocrine organs, World Health Organization classi-
fication of tumours. Lyon: IARC Press; 2004. p. 320.
2. Kroll TG, et al. PAX8-PPARgamma1 fusion oncogene in human
thyroid carcinoma [corrected]. Science. 2000;289(5483):135760.
7 Follicular Thyroid Neoplasms
Fig. 7.26 Follicular carcinoma. This follicular carcinoma shows sig-
net ring cell change. Occasionally, unusual cytologic features, such as
signet ring cell change, mucinous features, and clear cell change may
be seen in follicular neoplasms, including follicular carcinomas
3. Marques AR, et al. Expression of PAX8-PPAR gamma 1 rearrange-
ments in both follicular thyroid carcinomas and adenomas. J Clin
Endocrinol Metab. 2002;87(8):394752.
4. Nikiforova MN, et al. RAS point mutations and PAX8-PPAR gamma
rearrangement in thyroid tumors: evidence for distinct molecular
pathways in thyroid follicular carcinoma. J Clin Endocrinol Metab.
2003;88(5):231826.
5. Erickson LA, et al. Expression of p27kip1 and Ki-67 in benign and
malignant thyroid tumors. Mod Pathol. 1998;11(2):16974.
6. van Heerden JA, et al. Follicular thyroid carcinoma with cap-
sular invasion alone: a nonthreatening malignancy. Surgery.
1992;112(6):11306; discussion 11368.
7. Variakojis D, et al. Papillary clear cell carcinoma of the thyroid
gland. Hum Pathol. 1975;6(3):38490.
8. Landon G, Ordonez NG. Clear cell variant of medullary carcinoma
of the thyroid. Hum Pathol. 1985;16(8):8447.
9. Schroder S, Bocker W. Clear-cell carcinomas of thyroid
gland: a clinicopathological study of 13 cases. Histopathology.
1986;10(1):7589.
10. Ropp BG, et al. Follicular carcinoma of the thyroid with extensive
clear-cell differentiation: a potential diagnostic pitfall. Diagn
Cytopathol. 2000;23(3):2223.
11. Heffess CS, Wenig BM, Thompson LD. Metastatic renal cell carci-
noma to the thyroid gland: a clinicopathologic study of 36 cases.
Cancer. 2002;95(9):186978.
12. Carcangiu ML, Sibley RK, Rosai J. Clear cell change in pri-
mary thyroid tumors. A study of 38 cases. Am J Surg Pathol.
1985;9(10):70522.
13. Vergilio J, Baloch ZW, LiVolsi VA. Spindle cell metaplasia of the
thyroid arising in association with papillary carcinoma and follicu-
lar adenoma. Am J Clin Pathol. 2002;117(2):199204.
14. Harsh M, Dimri P, Nagarkar NM. Osseous metaplasia and
mature bone formation with extramedullary hematopoiesis in
follicular adenoma of thyroid gland. Indian J Pathol Microbiol.
2009;52(3):3778.
15. Pontikides N, et al. Extramedullary hemopoiesis in a thyroid nodule
with extensive bone metaplasia and mature bone formation.
Thyroid. 2003;13(9):87780.
 Hurthle Cell Thyroid Neoplasms
Hurthle cell adenomas and carcinomas are thyroid neo-
plasms that are composed predominantly (>75 %) or exclu-
sively of Hurthle cells and lack cytologic features of
papillary thyroid carcinoma (PTC). Hurthle cell neoplasms
are classified by the World Health Organization as onco-
cytic variants of follicular neoplasms [1]. Hurthle cell neo-
plasms present as a thyroid mass, affect women more often
than men, and usually occur in adults [2]. The mean patient
age for a Hurthle cell adenoma is 45 years, which is
510 years younger than that for Hurthle cell carcinomas
[2]. Hurthle cell adenomas are benign and lack the capsular
and/or vascular invasion seen in Hurthle cell carcinomas.
Hurthle cell adenomas usually are smaller than carcinomas
but may overlap in size [3]. Hurthle cell adenomas have a
lower Ki67 proliferative labeling index and less often have
diffuse nuclear cyclin D1 staining compared with Hurthle
cell carcinomas [3]. However, in evaluating an individual
lesion, no immunohistochemical or genetic marker can
separate Hurthle cell adenoma from carcinoma definitively.
Hurthle cell tumors show a low prevalence of RAS mutation
or PAX8peroxisome proliferator-activated receptor-
translocation [4, 5]. Many chromosomal abnormalities
have been identified, and chromosomal gains are more
common than losses in both benign and malignant Hurthle
cell neoplasms [6]. Hurthle cell carcinomas tend to have
L.A. Erickson, Atlas of Endocrine Pathology, Atlas of Anatomic Pathology,
DOI 10.1007/978-1-4939-0443-3_8, Springer Science+Business Media New York 2014
8
more chromosome losses than adenomas, and among carci-
nomas, losses, particularly of chromosome 22, are more
frequent in tumors associated with death from disease [6].
GRIM-19 (gene associated with retinoic-interferon
induced mortality 19) point mutations, thought to be
involved in tumorigenesis via mitochondrial metabolism
and cell death, have been identified in Hurthle cell tumors
and are more specific than other markers for Hurthle cell
neoplasms [7, 8]. Unlike hyperplastic or adenomatous nod-
ules, Hurthle cell neoplasms generally are solitary encapsu-
lated lesions. Hurthle cell neoplasms with papillary growth
are differentiated from oxyphilic PTC by the lack of char-
acteristic nuclear features of PTC. Hurthle cell adenomas
are benign, treated by lobectomy, and have an excellent
prognosis. Hurthle cell carcinomas invade soft tissue and
show nodal involvement more often than conventional fol-
licular carcinomas [9, 10]. Hurthle cell carcinoma accounts
for 23 % of thyroid carcinomas and 20 % of follicular car-
cinomas [10]. Hurthle cell carcinomas are thought to be
somewhat more aggressive than follicular carcinomas and
have a 5-year survival rate of 5060 %. Features associated
with aggressive behavior include large tumor size and vas-
cular invasion. Tumors with only capsular invasion and no
vascular invasion usually behave less aggressively than
those with vascular invasion [3].
63
64
Hurthle Cell Adenoma
Fig. 8.1 Hurthle cell adenoma. This gross photograph shows a Hurthle
cell adenoma, a solitary, encapsulated, round to oval neoplasm.
Infarction is not uncommon following fine-needle aspiration of Hurthle
cell adenomas. A feature diagnostic of malignancy in Hurthle cell neo-
plasms is capsular and/or vascular invasion. Carcinomas often have
thicker and more irregular capsules compared with adenomas
Fig. 8.2 Hurthle cell adenoma. A thin capsule separates the Hurthle
cell adenoma from the adjacent thyroid parenchyma. These are solitary,
encapsulated tumors with a solid, follicular, or trabecular growth pat-
tern, and they may show foci of papillary architecture
8 Hurthle Cell Thyroid Neoplasms
Fig. 8.3 Hurthle cell adenoma. Hurthle cell adenomas lack capsular or
vascular invasion, as would be required for a diagnosis of carcinoma.
This Hurthle cell adenoma has a mixed macro- and microfollicular
growth pattern. The constituent cells have abundant granular eosino-
philic cytoplasm reflecting mitochondria and large nuclei with promi-
nent nucleoli [1, 9]
Fig. 8.4 Hurthle cell adenoma. This Hurthle cell adenoma shows areas
of clear cell cytoplasmic change. Hurthle cell neoplasms show an
immunostaining pattern similar to that of conventional follicular neo-
plasms. In difficult cases, immunostains may be helpful in separating
Hurthle cell adenomas from other tumors, such as parathyroid tumors
or medullary thyroid carcinomas showing oxyphilic or clear cell
change. Hurthle cell follicular neoplasms are positive for thyroid tran-
scription factor 1 (TTF1) and thyroglobulin and negative for chromo-
granin, synaptophysin, and calcitonin
Hurthle Cell Carcinoma
Hurthle Cell Carcinoma
Fig. 8.5 Hurthle cell carcinoma. Shown is a Hurthle cell carcinoma, a
solid, encapsulated tumor that may show gross invasion in widely inva-
sive tumors. The capsule in Hurthle cell carcinomas usually is thicker
and more irregular than that of Hurthle cell adenomas. Hurthle cell car-
cinomas usually are larger than adenomas [3]
Fig. 8.6 Hurthle cell carcinoma. Multiple areas of vascular and capsu-
lar invasion are identified in this Hurthle cell carcinoma, which is
widely invasive. These tumors have a worse prognosis than those with
only focal invasion, particularly those with only focal capsular invasion
and no vascular invasion [3]. Capsular invasion may have a mushroom-
like growth pattern. Vascular invasion must occur within or beyond the
tumor capsule
65
Fig. 8.7 Hurthle cell carcinoma. Hurthle cell carcinomas usually are
cellular tumors with a solid, microfollicular, or trabecular growth pat-
tern and have little colloid. Hurthle cell carcinomas are composed pre-
dominantly or entirely of Hurthle cells with abundant granular
eosinophilic cytoplasm and usually have vesicular nuclei and promi-
nent nucleoli. Cytologically, Hurthle cell carcinoma cannot be differen-
tiated from Hurthle cell adenoma. This requires the identification of
capsular and/or vascular invasion
Fig. 8.8 Hurthle cell carcinoma. This widely invasive Hurthle cell car-
cinoma has multiple nodules of tumor infiltrating the thyroid. Hurthle
cell carcinomas are distinguished from the oxyphilic variant of PTC by
the lack PTC cytologic features. Because Hurthle cell carcinomas often
show little to no colloid, they must be differentiated from the oxyphilic/
oncocytic variant of medullary thyroid carcinoma. In difficult cases,
immunoperoxidase studies may be helpful, as Hurthle cell tumors are
positive for thyroglobulin whereas the oncocytic/oxyphilic variant of
medullary thyroid carcinoma is positive for chromogranin, synaptophy-
sin, calcitonin, and carcinoembryonic antigen. Both are positive for
TTF1
66 8 Hurthle Cell Thyroid Neoplasms

References 6. Erickson LA, et al. Analysis of Hurthle cell neoplasms of the thy-
roid by interphase fluorescence in situ hybridization. Am J Surg
Pathol. 2001;25(7):9117.
1. DeLellis RA, Lloyd RV, Heitz PU, Eng C. Pathology and genetics
7. Fusco A, Viglietto G, Santoro M. Point mutation in GRIM-19: a
of tumours of endocrine organs, World Health Organization classi-
new genetic lesion in Hurthle cell thyroid carcinomas. Br J Cancer.
fication of tumours. Lyon: IARC Press; 2004. p. 320.
2005;92(10):18178.
2. Chen HY, Benjamin LB, Chen MF. Hurthle cell tumor. Int Surg.
8. Maximo V, et al. Somatic and germline mutation in GRIM-19, a
1996;81(2):16870.
dual function gene involved in mitochondrial metabolism and cell
3. Erickson LA, et al. Pathologic features, proliferative activity, and
death, is linked to mitochondrion-rich (Hurthle cell) tumours of the
cyclin D1 expression in Hurthle cell neoplasms of the thyroid. Mod
thyroid. Br J Cancer. 2005;92(10):18928.
Pathol. 2000;13(2):18692.
9. Rosai J, Carcangiu ML, DeLellis RA. Tumors of the thyroid gland,
4. Volante M, et al. Galectin-3 and HBME-1 expression in oncocytic
Atlas of tumor pathology, vol. 5. 3rd ed. Washington, DC: Armed
cell tumors of the thyroid. Virchows Arch. 2004;445(2):1838.
Forces Institute of Pathology; 1992. p. 343.
5. Nikiforova MN, et al. RAS point mutations and PAX8-PPAR gamma
10. Watson RG, et al. Invasive Hurthle cell carcinoma of the thyroid: nat-
rearrangement in thyroid tumors: evidence for distinct molecular
ural history and management. Mayo Clin Proc. 1984;59(12):8515.
pathways in thyroid follicular carcinoma. J Clin Endocrinol Metab.
2003;88(5):231826.
 Poorly Differentiated Thyroid
Carcinoma
Poorly differentiated thyroid carcinomas are diagnostically
controversial, as there is a lack of consensus regarding diag-
nostic criteria [13]. Poorly differentiated thyroid carcino-
mas usually occur in older patients (>50 years) and are more
common in Italy and Latin America (47 % of thyroid car-
cinomas) and less common in the United States [4]. These
tumors are morphologically and prognostically intermediate
between well-differentiated and anaplastic thyroid carci-
noma [2, 5]. An operational pathologic definition offered in
2007 included insular and trabecular variants, but not solid
lesions or more differentiated tumors that may have a poor
prognosis, such as tall cell, columnar, diffuse sclerosing, and
oncocytic lesions [2]. At a consensus conference in Turin in
2006, 12 thyroid pathologists evaluated 83 tumors without
knowledge of clinical parameters and devised a diagnostic
algorithm for the diagnosis of poorly differentiated thyroid
carcinoma to include (1) presence of a solid/trabecular/
insular pattern of growth, (2) absence of the conventional
nuclear features of papillary carcinoma, and (3) presence
of at least one of the following features: convoluted nuclei;
mitotic activity 3 10 HPF [high-power fields]; and tumor
necrosis [5]. A subsequent study of 56 cases from the Mayo
Clinic and 96 from the University of Turin in northern Italy
validated the Turin criteria [6]. The prevalence of poorly
differentiated carcinoma in the United States was 1.8 and
6.7 % in the northern Italy cases. Tumor characteristics were
L.A. Erickson, Atlas of Endocrine Pathology, Atlas of Anatomic Pathology,
DOI 10.1007/978-1-4939-0443-3_9, Springer Science+Business Media New York 2014
9
similar, except extensive vascular invasion and prevalent
insular growth was less common in the US cases than the
Italian cases [6]. The Turin criteria work well for cases from
mountain areas such as northern Italy, where most thyroid
carcinomas with high-grade features also have a solid/trabec-
ular/insular growth pattern [3]. However, this algorithm may
not work as well for cases from other geographic areas that
may have tumors with more heterogeneous architectural and
cytologic features, and some pathologists base their diagno-
sis on only high-grade features, mitotic index, and necrosis,
irrespective of the growth pattern [3]. Tumor necrosis and
high mitotic activity, rather than growth pattern or histologic
subtype, may be prognostic in thyroid tumors [1]. Poorly
differentiated tumors have lower relapse-free and cause-spe-
cific survival rates than well-differentiated tumors, and poor
differentiation and age affect survival [7]. Extrathyroidal
infiltration also affects disease-free survival [7]. Aggressive
surgery for tumors with gross extrathyroidal extension has
resulted in satisfactory locoregional control [8]. Although
the benefit of iodine-131 is unclear, it has been recommended
for all patients postoperatively because of its lack of morbid-
ity and potential for benefit [2]. External-beam radiotherapy
has been suggested for T3 tumors without distant metastasis,
all T4 tumors, and all tumors with regional node metastases
[2]. The 5-year overall survival rate for poorly differentiated
thyroid carcinoma is 47 % [8].
67
68
Fig. 9.1 Poorly differentiated thyroid carcinoma. This poorly differen-
tiated thyroid carcinoma has a characteristic insular growth pattern.
Growth patterns vary, but the most common are insular, trabecular, and
solid [5]. A peritheliomatous pattern admixed with fibrosis and/or
necrosis also may occur [9]
Fig. 9.2 Poorly differentiated thyroid carcinoma. Areas of necrosis are
seen in this poorly differentiated thyroid carcinoma. The differential
diagnosis of poorly differentiated thyroid carcinoma includes medul-
lary thyroid carcinoma, follicular carcinoma, the solid variant of papil-
lary thyroid carcinoma (PTC), and carcinoma metastatic to the thyroid.
Follicular carcinomas lack necrosis and show a lower grade of cytomor-
phology and less prominent mitotic activity compared with poorly dif-
ferentiated carcinomas. The solid variant of PTC has nuclear PTC
cytomorphology. Medullary thyroid carcinoma has neuroendocrine
nuclei with stippled chromatin and is positive for chromogranin, synap-
tophysin, and calcitonin. Poorly differentiated carcinomas stain with
thyroid transcription factor 1 (TTF1) and thyroglobulin, although thy-
roglobulin may be focal [10]. Carcinoma metastatic to the thyroid usu-
ally is negative for TTF1, except for lung adenocarcinomas
9 Poorly Differentiated Thyroid Carcinoma
Fig. 9.3 Poorly differentiated thyroid carcinoma. This poorly differen-
tiated thyroid carcinoma has focal necrosis, hyperchromatic tumor
cells, and mitotic activity. These tumors show a high Ki67 proliferative
index; p53 staining, when present, may be focal [10]. TP53 mutations
are identified in 2030 % and aberrant p53 overexpression in 4050 %
of cases [11]. BRAF, RET/PTC, and NTRK1 abnormalities occur in a
small percentage of patients [11]. H-, K-, and N-RAS mutations are
identified in about 50 % of cases [12]. In a series of 65 poorly differenti-
ated thyroid carcinomas, RAS mutations in codon 61 were the most
common genetic abnormality (23 %), whereas no KRAS, RET/PTC, or
PAX8/peroxisome proliferator-activated receptor- alterations and only
a single BRAF mutation were found (in a tumor with residual tall cell
PTC) [13]. RAS mutation was a negative prognostic parameter in these
tumors [13]
Fig. 9.4 Poorly differentiated thyroid carcinoma. This poorly differen-
tiated thyroid carcinoma has uniform tumor cells with hyperchromatic
nuclei containing small nucleoli. Vesicular nuclei are focally present.
Although the nuclei are atypical, extensive anaplastic nuclear features,
as seen in anaplastic thyroid carcinoma, are not identified
References 69

References 8. Ibrahimpasic T, et al. Poorly differentiated thyroid carcinoma

presenting with gross extrathyroidal extension: 19862009
Memorial Sloan-Kettering Cancer Center experience. Thyroid.
1. Tallini G. Poorly differentiated thyroid carcinoma. Are we there
2013;23(8):9971002.
yet? Endocr Pathol. 2011;22(4):1904.
9. Papotti M, et al. Poorly differentiated thyroid carcinomas with
2. Sanders Jr EM, et al. An evidence-based review of poorly differen-
primordial cell component. A group of aggressive lesions shar-
tiated thyroid cancer. World J Surg. 2007;31(5):93445.
ing insular, trabecular, and solid patterns. Am J Surg Pathol.
3. Volante M, Papotti M. Poorly differentiated thyroid carcinoma:
1993;17(3):291301.
5 years after the 2004 WHO classification of endocrine tumours.
10. Volante M, et al. Poorly differentiated carcinomas of the thyroid
Endocr Pathol. 2010;21(1):16.
with trabecular, insular, and solid patterns: a clinicopathologic
4. DeLellis RA, Lloyd RV, Heitz PU. WHO classification of tumours
study of 183 patients. Cancer. 2004;100(5):9507.
pathology and genetics. In: DeLellis RA, Lloyd RV, Heitz PU, edi-
11. Nikiforov YE. Genetic alterations involved in the transition from
tors. Tumours of endocrine organs. Lyon: IARC Press; 2004.
well-differentiated to poorly differentiated and anaplastic thyroid
5. Volante M, et al. Poorly differentiated thyroid carcinoma: the Turin
carcinomas. Endocr Pathol. 2004;15(4):31927.
proposal for the use of uniform diagnostic criteria and an algorith-
12. Albores-Saavedra J, Carrick K. Where to set the threshold between
mic diagnostic approach. Am J Surg Pathol. 2007;31(8):125664.
well differentiated and poorly differentiated follicular carcinomas
6. Asioli S, et al. Poorly differentiated carcinoma of the thyroid: vali-
of the thyroid. Endocr Pathol. 2004;15(4):297305.
dation of the Turin proposal and analysis of IMP3 expression. Mod
13. Volante M, et al. RAS mutations are the predominant molecu-
Pathol. 2010;23(9):126978.
lar alteration in poorly differentiated thyroid carcinomas
7. Tanaka K, et al. Analysis of clinical outcome of patients with
and bear prognostic impact. J Clin Endocrinol Metab. 2009;
poorly differentiated thyroid carcinoma. ISRN Endocrinol. 2011;
94(12):473541.
2011:308029.
 Anaplastic Thyroid Carcinoma
Anaplastic (undifferentiated) thyroid carcinoma is a highly
aggressive malignancy that usually presents with a rapidly
growing neck mass in older patients, with hoarseness, dys-
phasia, and vocal cord paralysis. This tumor accounts for
12 % of thyroid malignancies [1]. The annual incidence
of anaplastic thyroid carcinoma is 12 in 1,000,000 people,
and the overall incidence is higher in Europe and areas of
endemic goiter than in the United States [2]. These tumors
are composed of undifferentiated cells with immunohisto-
chemical and ultrastructural features supporting epithelial
differentiation [3]. One third of anaplastic carcinomas are
associated with a better-differentiated thyroid carcinoma
and may represent dedifferentiation [4]. Anaplastic carcino-
mas must be differentiated from poorly differentiated car-
cinoma metastatic to the thyroid, lymphoma, and sarcoma.
The paucicellular variant of anaplastic thyroid carcinoma
must be differentiated from Riedel (fibrous) thyroiditis. In
small biopsy samples, the differential diagnoses may be dif-
ficult. Anaplastic thyroid carcinomas usually are positive for
keratin, but most show only focal staining for thyroglobu-
lin. Thyroid transcription factor 1 (TTF1) may be present
focally, but strong diffuse staining of TTF1 throughout the
tumor is not seen. These tumors are positive for vimentin and
show a high Ki67 proliferative index and p53 overexpres-
sion. Decreased p27 expression, cyclin D1 overexpression,
L.A. Erickson, Atlas of Endocrine Pathology, Atlas of Anatomic Pathology,
DOI 10.1007/978-1-4939-0443-3_10, Springer Science+Business Media New York 2014
10
and inactivation of PTEN and p16 are reported [5]. TP53 and
CTNNB1 (-catenin) mutations and complex chromosomal
alterations with allelic losses of 1q, 1p, 5, 8, 9p, 11, 17p, 19p
occur [3, 68]. Anaplastic carcinomas are highly destructive
locally with invasion of adjacent structures and metastases
to lung, bone, and brain [3]. Distant metastases are present
at diagnosis in almost half of patients. These tumors often
are not amenable to surgical resection and may be diagnosed
on biopsy and treated with radiation and chemotherapy [3].
A recent study suggested that select patients with anaplas-
tic thyroid cancer with extrathyroid extension and no distant
metastases on CT or positron emission tomography who do
not have tumor extending lateral to the carotid arteries may
be candidates for complete surgical resection [9]. From a
multicenter registry, 677 anaplastic thyroid carcinomas from
38 institutions were subtyped; the incidental type had the
best outcome, followed by anaplastic transformation at the
neck, common type, and anaplastic transformation at a dis-
tant site [1]. Although the survival rate at 1 year in this study
was only 18 %, 84 patients (15 %) survived longer than 1
year. Features associated with decreased survival include age
70 years, acute symptoms, leukocytosis, size greater than
5 cm, T4b stage, and distant metastases [1]. Anaplastic thy-
roid carcinomas are very aggressive, with a median survival
of 2.56 months and a 5-year survival of 014 % [3, 10, 11].
71
72
Fig. 10.1 Anaplastic thyroid carcinoma. This anaplastic thyroid carci-
noma has areas of hemorrhage and necrosis. These tumors are large,
often white to gray, and firm or hard, and infiltrate adjacent soft tissue
and structures
Fig. 10.2 Anaplastic thyroid carcinoma. Anaplastic thyroid carcino-
mas often invade adjacent structures, such as skeletal muscle, as dem-
onstrated in this photograph. Invasion of adjacent structures in the neck,
including skeletal muscle, laryngeal nerve, trachea, esophagus, and
larynx, is common
10 Anaplastic Thyroid Carcinoma
Fig. 10.3 Anaplastic thyroid carcinoma. An area of necrosis is present
in this anaplastic thyroid carcinoma. Necrosis is not uncommon in ana-
plastic thyroid carcinoma. These are undifferentiated carcinomas that
are highly malignant and composed of undifferentiated cells, usually
with immunohistochemical features of epithelial differentiation
Fig. 10.4 Anaplastic thyroid carcinoma. Vascular invasion, as demon-
strated in this photograph, and other aggressive histologic features,
such as necrosis, prominent mitotic activity, and extrathyroid extension,
are common in anaplastic thyroid carcinoma
Anaplastic Thyroid Carcinoma
Fig. 10.5 Anaplastic thyroid carcinoma. This anaplastic thyroid carci-
noma is composed of undifferentiated epithelioid and spindle cells with
prominent mitotic activity. Anaplastic thyroid carcinomas often are
composed of a variety of cell types, including epithelial, spindle, and
pleomorphic multinucleated cells
Fig. 10.6 Anaplastic thyroid carcinoma. This anaplastic thyroid carci-
noma is composed of undifferentiated spindle cells and multinucleated
epithelioid cells. Prominent mitotic activity is seen. Anaplastic carcino-
mas often are composed of a variety of cell types. In some cases, a dif-
ferentiated thyroid carcinoma may be present in association with the
anaplastic carcinoma, which is helpful in recognizing the undifferenti-
ated component as anaplastic thyroid carcinoma rather than a metasta-
sis to the thyroid
73
Fig. 10.7 Anaplastic thyroid carcinoma. Markedly atypical spindle
cells are seen in this anaplastic thyroid carcinoma. Prominent mitotic
activity is present. Anaplastic thyroid carcinomas with prominent spin-
dle cells must be differentiated from high-grade sarcomas. Anaplastic
thyroid carcinomas usually show at least focal staining for keratin and
may show focal staining for thyroid transcription factor 1 (TTF1),
which is helpful in identifying these tumors
Fig. 10.8 Anaplastic thyroid carcinoma. This sclerotic cell-poor
anaplastic thyroid carcinoma might be mistaken for Riedel (fibrous)
thyroiditis
74
Fig. 10.9 Anaplastic thyroid carcinoma. This anaplastic thyroid carci-
noma shows rhabdoid features. Rhabdoid features, as well as rhabdo-
myosarcomatous differentiation, may be seen in anaplastic thyroid
carcinoma
Fig. 10.10 Anaplastic thyroid carcinoma arising with Hurthle cell car-
cinoma. Anaplastic thyroid carcinoma is seen on the left arising in asso-
ciation with Hurthle cell carcinoma on the right. It is not unusual for a
better-differentiated thyroid carcinoma to be identified in association
with an anaplastic thyroid carcinoma, which suggests dedifferentiation.
This finding also is helpful in identifying the undifferentiated tumor as
anaplastic thyroid carcinoma rather than a metastasis to the thyroid
10 Anaplastic Thyroid Carcinoma
Fig. 10.11 Anaplastic thyroid carcinoma. The anaplastic thyroid car-
cinoma on the left appears to have dedifferentiated from the Hurthle cell
carcinoma seen on the right
Fig. 10.12 Anaplastic thyroid carcinoma. Papillary thyroid carcinoma
(PTC) is identified in the lower portion of the photomicrograph and
is surrounded by anaplastic thyroid carcinoma. Approximately one
third of anaplastic thyroid carcinomas are identified with a differenti-
ated thyroid carcinoma [4]
References
Fig. 10.13 Anaplastic thyroid carcinoma. This anaplastic carcinoma
is highly vascular and may be mistaken for angiosarcoma, which may
occur in the thyroid. In the center is a PTC. The presence of the differ-
entiated tumor (PTC) associated with the undifferentiated carcinoma
also would support a diagnosis of anaplastic thyroid carcinoma. Recent
studies show that PTC with mutant BRAF or RAS may progress to
poorly differentiated and anaplastic carcinoma, but additional muta-
tions likely would be needed [12]. Similarly, RAS mutation in follicular
carcinoma may predispose tumors to dedifferentiation with the addition
of other mutations, such as TP53 and -catenin [12]
75
References
1. Sugitani I, et al. Prognostic factors and treatment outcomes for ana-
plastic thyroid carcinoma: ATC Research Consortium of Japan
cohort study of 677 patients. World J Surg. 2012;36(6):124754.
2. Taccaliti A, et al. Anaplastic thyroid carcinoma. Front Endocrinol.
2012;3:84.
3. DeLellis RA, Lloyd RV, Heitz PU. WHO classificaiton of tumours
pathology and genetics. In: DeLellis RA, Lloyd RV, Heitz PU, edi-
tors. Tumours of endocrine organs. Lyon: IARC Press; 2004.
4. Carcangiu ML, et al. Anaplastic thyroid carcinoma. A study of 70
cases. Am J Clin Pathol. 1985;83(2):13558.
5. Gimm O, et al. Differential nuclear and cytoplasmic expression of
PTEN in normal thyroid tissue, and benign and malignant epithelial
thyroid tumors. Am J Pathol. 2000;156(5):1693700.
6. Fagin JA, et al. High prevalence of mutations of the p53 gene in
poorly differentiated human thyroid carcinomas. J Clin Invest.
1993;91(1):17984.
7. Farid NR. P53 mutations in thyroid carcinoma: tidings from an old
foe. J Endocrinol Invest. 2001;24(7):53645.
8. Garcia-Rostan G, et al. Frequent mutation and nuclear localization
of beta-catenin in anaplastic thyroid carcinoma. Cancer Res.
1999;59(8):18115.
9. Brown RF, Ducic Y. Aggressive surgical resection of anaplastic
thyroid carcinoma may provide long-term survival in selected
patients. Otolaryngol Head Neck Surg. 2013;148(4):56471.
10. Giuffrida D, Gharib H. Anaplastic thyroid carcinoma: current diag-
nosis and treatment. Ann Oncol. 2000;11(9):10839.
11. Ordonez NG, et al. Anaplastic thyroid carcinoma. Immuno-
cytochemical study of 32 cases. Am J Clin Pathol. 1991;96(1):
1524.
12. Nikiforov YE. Genetic alterations involved in the transition from
well-differentiated to poorly differentiated and anaplastic thyroid
carcinomas. Endocr Pathol. 2004;15(4):31927.
 Tumors of C Cells
Medullary thyroid carcinoma (MTC) comprises 510 % of
thyroid carcinomas [1]. About 25 % of cases are familial; thus,
patients are offered RET mutation analysis [2]. MTC occurs
in multiple endocrine neoplasia 2A (MEN2A), MEN2B, and
familial MTC (FMTC), autosomal dominant disorders due
to RET mutations [37]. MEN2A and FMTC are associated
with RET mutations of codons 609, 611, 618, 620, and 634
[8, 9]. In FMTC, mutations of codons 768, 790, 791, 804,
844, and 891 are associated with less aggressive disease and
a later onset. Most MEN2B RET mutations are at codon 918
(>95 %) or 883 (23 %). MEN2A is associated with MTC,
pheochromocytoma, and parathyroid disease. MEN2B is
associated with MTC, pheochromocytoma, mucocutane-
ous neuromas, ganglioneuromatosis, and marfanoid habitus.
MTC usually occurs before pheochromocytoma in MEN2A
and MEN2B, and preoperative calcitonin levels may help
identify MTC and prevent a hypertensive crisis during sur-
gery [10, 11]. FMTC is not associated with other abnormali-
ties. If a patient is found to have RET mutation, relatives are
offered testing [12]. Prophylactic thyroidectomy may be
performed by age 6 years for MEN2A and by 6 months for
MEN2B [10, 13, 14]. Prophylactic thyroidectomy specimens
are serially sectioned and immunoperoxidase studies used to
evaluate for C-cell hyperplasia, medullary microcarcinomas,
and carcinomas. Particular attention is given to the junction
L.A. Erickson, Atlas of Endocrine Pathology, Atlas of Anatomic Pathology,
DOI 10.1007/978-1-4939-0443-3_11, Springer Science+Business Media New York 2014
11
of the upper and middle lobes, as this is the area of the high-
est concentration of C cells. C-cell hyperplasia is not specific
for syndrome-associated MTC, as it may be seen in other
thyroid tumors and thyroiditis [15, 16]. Sporadic MTC often
presents around age 50, whereas syndromic MTC presents
earlier. MEN2B MTC may present in infancy or childhood
and has been diagnosed in neonates [17]. MEN2A MTC
often presents in early adulthood, and FMTC presents at an
older age than other syndromic MTCs. Patients diagnosed
by biochemical or molecular methods have a better prog-
nosis than those not screened [18]. MTC is radioresistant
and chemotherapy resistant, does not take up iodine, and
usually is treated by thyroidectomy and node dissection
[2]. Diarrhea, bone pain, and flushing often are associated
with widely metastatic disease, with a 5-year survival rate
of 33.3 % [18]. Patients with persistent or recurrent MTC
have a life expectancy of 3.6 years [18]. Compared with less
extensive surgery, total or subtotal thyroidectomy is associ-
ated with less persistent or recurrent disease and total thy-
roidectomy with cervical node dissection is associated with
fewer reoperations for persistent or recurrent disease [18].
Negative prognostic factors are older age, male sex, clini-
cal (vs. biochemical or molecular) presentation, TNM stage,
distant metastases, sporadic (vs. hereditary) occurrence, and
less extensive surgery [18].
77
78
C-Cell Hyperplasia
Fig. 11.1 C-cell hyperplasia. C-cell hyperplasia is highlighted with
calcitonin immunostain in a prophylactic thyroidectomy. C cells are
identified most readily with immunostaining for chromogranin, synap-
tophysin, or calcitonin. C-cell hyperplasia may be physiologic or neo-
plastic [15, 19, 20]. Physiologic C-cell hyperplasia may be seen in
neonates and elderly people and may be associated with follicular
tumors, Hashimoto thyroiditis, hypergastrinemia, or hyperparathyroid-
ism, among other entities [2022]. Neoplastic C-cell hyperplasia is
associated with familial cases of MTC. The presence or absence of
C-cell hyperplasia is not used to determine whether a patient with MTC
has familial or sporadic disease. This determination is made by clinical
evaluation, patient and family history, and RET mutation testing
Fig. 11.2 C-cell hyperplasia. C-cell hyperplasia is highlighted with
calcitonin immunostain in this prophylactic thyroidectomy specimen.
Extensive sectioning, often with immunoperoxidase, with special
emphasis in the middle to upper portions of the lobes is recommended
to identify C-cell hyperplasia and medullary microcarcinomas. The
growth pattern may be diffuse or nodular; nodular growth is more com-
mon and more prominent with neoplastic C-cell hyperplasia [15, 19
23]. The definition of C-cell hyperplasia varies, but the term generally
refers to an increase in the total mass of C cells in the thyroid. One defi-
nition of diffuse hyperplasia is at least 50 C cells per low-power field
bilaterally [19, 20]. Nodular C-cell hyperplasia has been described as
bilateral clusters of more than six C cells in several foci [1]
11 Tumors of C Cells
Medullary Thyroid Microcarcinoma
Fig. 11.3 Medullary thyroid microcarcinoma. Medullary thyroid
microcarcinomas are defined as measuring 1 cm or less. In a compari-
son of 16 familial and 34 sporadic medullary microcarcinomas, familial
tumors occurred at a younger age (mean 32 vs. 58 years) and were more
often bilateral (68.8 % vs. 8.8 %), multifocal (81.3 % vs. 8.8 %), and
accompanied by C-cell hyperplasia (100 % vs. 71 %) than sporadic
tumors [24]. In that study, only tumors with desmoplastic stroma had
lymph node metastases (8 of 50) [24]. The smallest tumor with lymph
node metastasis was 3 mm [24]. From a national database of 357 spo-
radic medullary carcinomas larger than 1 cm, 149 familial microcarci-
nomas, and 80 sporadic medullary microcarcinomas, nodal metastases
were more frequent with multifocal than unifocal tumors [25]. When
126 hereditary and 107 sporadic medullary microcarcinomas were
stratified by tumor diameter in 2-mm increments and by biochemical
cure, the incidence of nodal metastasis increased with increasing tumor
size and biochemical cure rates declined [26]. The strongest predictors
of a failure to achieve normal serum calcitonin were positive nodes
(79 % vs. 11 % in hereditary and 79 % vs. 12 % in sporadic cases) and
the number of involved nodes (6.6 vs. 0.3 in hereditary and 8.8 vs. 0.4
nodes in sporadic cases) [26]
Medullary Thyroid Carcinoma 79

Medullary Thyroid Carcinoma

Fig. 11.4 Medullary thyroid microcarcinoma. Medullary thyroid

microcarcinoma from a prophylactic thyroidectomy. In a study of 42
prophylactic thyroidectomies, C-cell hyperplasia was identified in 36
cases (multifocal in 30 and bilateral in 23), medullary microcarcinoma
in 29 cases (1 had node metastasis), and medullary macrocarcinoma in
1 case [27]. Most of the microcarcinomas (83 %) had a solid growth
pattern with round, polygonal, spindled, or plasmacytoid cells and des-
moplastic stroma (100 %), and a subset (41 %) had focal amyloid [27].
Among 310 medullary microcarcinomas from the Surveillance, Fig. 11.5 Medullary thyroid carcinoma. This MTC forms a firm white
Epidemiology, and End Results database from 1988 to 2007, the mean mass in the thyroid. In sporadic cases, these tumors often are single
tumor size was 5.7 mm, 31 % of tumors were multifocal, 7.8 % of tumors. Although MTCs in MEN2B, MEN2A, and FMTC are histo-
tumors had extrathyroid extension, and 37 % of patients (65 of 176) logically identical to sporadic tumors, syndrome-associated tumors
with lymph nodes removed had metastases [28]. Ten-year survival rates often are bilateral and multicentric [1, 29]. Syndromic MTCs often are
with localized, regional, and distant disease were 96, 87, and 50 %, associated with C-cell hyperplasia, but C-cell hyperplasia may occur
respectively [28]. Extrathyroid extension and tumor size were associ- with other thyroid tumors and with lymphocytic thyroiditis [15, 16].
ated with lymph node metastases. The probability of lymph node Thus, determining whether MTC is syndrome associated is done by
metastases in tumors 5 mm was 23 %, increasing for tumors larger germline genetic testing for RET mutation
than 5 mm [28]

Fig. 11.6 Medullary thyroid carcinoma, amyloid. This MTC has epi-
thelial and spindle tumor cells and prominent amyloid. Although amy-
loid is a helpful feature in recognizing MTC, it may be seen in the
thyroid incidentally, as a secondary finding, in systemic amyloidosis, in
association with lymphoproliferative and plasmacytic disorders, and in
amyloid goiters. The amyloid in MTC shows apple-green birefringence
with Congo red and is positive for calcitonin. The absence of colloid is
helpful in identifying MTC
80
Fig. 11.7 Medullary thyroid carcinoma. Spindle cells are prominent in
this MTC. MTCs may have a variety of cytomorphologies (spindle, epi-
thelioid, oxyphilic, clear), and awareness of these possibilities enables
the diagnosis. Spindle cells are particularly important. Whenever spin-
dle cells are identified in a thyroid tumor, MTC must be ruled out.
Spindle cells in the thyroid always raise the suspicion of MTC
Fig. 11.8 Medullary thyroid carcinoma. Epithelioid cells predominate
in this MTC. The cells have amphophilic cytoplasm and neuroendo-
crine nuclear features with stippled chromatin
11 Tumors of C Cells
Fig. 11.9 Medullary thyroid carcinoma. A nested pattern of growth
predominates in this MTC. Various growth patterns may be seen in
these tumors. The lack of colloid is a clue to MTC
Fig. 11.10 Medullary thyroid carcinoma. Intranuclear pink holes may
be seen in MTC. This feature often is emphasized in papillary thyroid
carcinoma (PTC), but it is not specific. Intranuclear pink holes may be
seen in MTC, PTCs, occasional Hurthle cell thyroid neoplasms, and the
parathyroid
Medullary Thyroid Carcinoma 81

Fig. 11.11 Medullary thyroid carcinoma. A solid, nested, and some- Fig. 11.13 Medullary thyroid carcinoma. This MTC is composed of
what insular growth pattern may be seen in MTC. Any thyroid tumor epithelial cells with epithelioid and spindle morphology. Areas of amy-
lacking colloid should raise the possibility of MTC loid deposition also are present

Fig. 11.12 Medullary thyroid carcinoma. Solid growth is seen in this Fig. 11.14 Medullary thyroid carcinoma. Calcifications may be seen
MTC with an area of necrosis. Recognizing the neuroendocrine differ- in MTC; they often are stromal and may be associated with amyloid
entiation of the tumor is important to avoid mistaking it for a follicular
thyroid carcinoma or a poorly differentiated carcinoma
82
Fig. 11.15 Medullary thyroid carcinoma. Recognizing MTC with a
follicular or glandular growth pattern may be very difficult. A high
index of suspicion is needed, and immunostains may be helpful in dif-
ficult cases, as MTCs are positive for chromogranin, synaptophysin,
and calcitonin and negative for thyroglobulin
Fig. 11.16 Medullary thyroid carcinoma. This MTC has a glandular
or acinar growth pattern. Recognizing the wide spectrum of histologic
patterns that may be seen in MTC is important in recognizing these
tumors
11 Tumors of C Cells
Fig. 11.17 Medullary thyroid carcinoma. Oxyphilic MTCs may be
mistaken for Hurthle cell neoplasms of the thyroid. The large polygonal
cells with abundant eosinophilic cytoplasm may be indistinguishable
from Hurthle cells. Ultrastructural studies identified mitochondrion-
rich cells containing round neurosecretory granules [30]. The lack of
colloid is a clue to the diagnosis of this histologic variant of MTC
Fig. 11.18 Medullary thyroid carcinoma. The oxyphilic variant of
MTC may be difficult to recognize if one is not familiar with this histo-
logic subtype. Mistaking the oxyphilic variant of MTC for a Hurthle
cell neoplasm is particularly problematic because MTC is a radioresis-
tant tumor and is familial in 25 % of cases
Medullary Thyroid Carcinoma
Fig. 11.19 Medullary thyroid carcinoma. The papillary architectural
pattern in MTC may present a difficult diagnostic problem. Both papil-
lary carcinomas and MTC may have intranuclear pink holes. Other than
the pink holes, MTCs have nuclear features different from those of pap-
illary carcinomas, as the nuclei of MTCs have stippled neuroendocrine
chromatin and may show areas of spindling and amyloid
Fig. 11.20 Medullary thyroid carcinoma. Recognizing that MTCs
may have papillary growth is crucial to considering it in the differential
diagnosis of thyroid tumor with papillary architecture. Both MTC and
PTC may have pink holes, but MTC lacks colloid and has stippled neu-
roendocrine chromatin. In difficult cases, immunoperoxidase studies
may be helpful, as MTCs are positive for chromogranin, synaptophysin,
and calcitonin and negative for thyroglobulin, whereas PTCs express
thyroglobulin and are negative for chromogranin, synaptophysin, and
calcitonin
83
Fig. 11.21 Medullary thyroid carcinoma. Neuroendocrine markers
such as chromogranin, as in this photograph, and synaptophysin are
helpful in identifying neuroendocrine differentiation in a tumor. These
markers are helpful in separating MTC from folliculogenic thyroid car-
cinomas, which do not express these markers. Of the commonly used
neuroendocrine markers, chromogranin is the most specific. Parathyroid
tumors are positive for neuroendocrine markers but also are positive for
parathyroid hormone and negative for thyroid transcription factor 1
(TTF1). Neuroendocrine lung tumors are positive for neuroendocrine
markers and TTF1 but usually are negative for calcitonin
Fig. 11.22 Medullary thyroid carcinoma. Calcitonin is positive in
MTC, and patients with MTC usually have elevated serum calcitonin
levels. Atypical laryngeal carcinoids also express calcitonin, chromo-
granin, and synaptophysin, although calcitonin staining may be focal.
Atypical laryngeal carcinoid is negative for TTF1. Atypical laryngeal
carcinoid may be associated with elevated serum calcitonin levels, but
the levels generally are lower than those in patients with MTC. Other
tumors may express calcitonin aberrantly
84
Fig. 11.23 Medullary thyroid carcinoma. Carcinoembryonic antigen
(CEA) is positive in MTC. Atypical laryngeal carcinoids also are posi-
tive for CEA, chromogranin, synaptophysin, and calcitonin, but they
are negative for TTF1 and calcitonin staining often is focal
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11 Tumors of C Cells
Fig. 11.24 Medullary thyroid carcinoma. MTCs are positive for
TTF1, although the staining is weaker than in the subjacent thyroid
parenchyma. It is unclear why medullary carcinomas are positive for
TTF1, as embryologically they are distinctly different from folliculo-
genic tumors. The TTF1 immunopositivity, although weaker than in
follicular neoplasms, is helpful in differentiating MTC from parathy-
roid and other neuroendocrine tumors. Neuroendocrine lung tumors
usually are positive for TTF1 but generally are negative for calcitonin
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13. Frilling A, et al. Prophylactic thyroidectomy in multiple endocrine
neoplasia: the impact of molecular mechanisms of RET proto-
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14. Ogilvie JB, Kebebew E. Indication and timing of thyroid surgery
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21. Libbey NP, Nowakowski KJ, Tucci JR. C-cell hyperplasia of the
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22. LiVolsi VA, et al. Demonstration by immunoperoxidase staining of
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23. Eng C, et al. Mutation of the RET proto-oncogene is correlated
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103944.
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27. Etit D, et al. Histopathologic and clinical features of medullary
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28. Kazaure HS, Roman SA, Sosa JA. Medullary thyroid microcarci-
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118(3):6207.
29. Lee NC, Norton JA. Multiple endocrine neoplasia type 2Bgenetic
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30. Dominguez-Malagon H, et al. Oxyphil and squamous variants of
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 Unusual Thyroid Tumors
12

A variety of unusual tumors involve the thyroid, including Sclerosing Mucoepidermoid Carcinoma
sclerosing mucoepidermoid carcinoma with eosinophils, with Eosinophils
which has an unusual appearance with infiltrating glandu-
lar cells and squamoid cells. Squamous cell carcinoma may
involve the thyroid by direct extension from a tumor in the
neck or as a metastasis, but primary squamous cell carcino-
mas of the thyroid also occur. Malignant lymphoma may be
primary to the thyroid, or the thyroid may be affected in sys-
temic disease. When limited to the thyroid, Langerhans cell
histiocytosis tends to be quite indolent and to remain local-
ized. A variety of mesenchymal tumors affect the thyroid,
including solitary fibrous tumor, angiosarcoma, synovial
sarcoma, leiomyosarcoma, low-grade fibromyxoid sarcoma,
and rhabdomyosarcoma, but angiosarcomas are among
the most common and most aggressive sarcomas affecting
the thyroid. Other unusual tumors in the thyroid are carci-
noma showing thymus-like differentiation, teratoma, and
paraganglioma.

Fig. 12.1 Sclerosing mucoepidermoid carcinoma with eosinophils.

Sclerosing mucoepidermoid carcinoma with eosinophils is a rare thy-
roid malignancy that occurs predominantly in adult women [13]. The
tumor usually is slow growing and appears cold or hypofunctioning on
radionucleotide scans. Grossly, the tumors are well circumscribed, but
many extend to involve the soft tissues. The tumors are firm with a
white to yellow cut surface. The tumor, as the name implies, has a scle-
rotic stroma and is associated with eosinophils. The infiltrating cells
appear both squamoid and glandular. The tumor cells may become dis-
cohesive and appear pseudoangiomatous

L.A. Erickson, Atlas of Endocrine Pathology, Atlas of Anatomic Pathology, 87

DOI 10.1007/978-1-4939-0443-3_12, Springer Science+Business Media New York 2014
88 12 Unusual Thyroid Tumors

Fig. 12.2 Sclerosing mucoepidermoid carcinoma with eosinophils.
Sclerosing mucoepidermoid carcinoma with eosinophils may be diffi-
cult to diagnose because the squamoid areas may be mistaken for squa-
mous metaplasia; therefore, recognizing invasive growth is important.
Perineural invasion is not uncommon. The tumor cells are positive for
keratin and negative for thyroglobulin and calcitonin. Thyroid tran-
scription factor 1 (TTF1) immunoreactivity is seen in approximately
50 % of cases [4]. Sclerosing mucoepidermoid carcinoma with eosino-
phils is treated surgically; approximately 50 % of patients do well,
whereas others show regional or distant metastases [4]
Fig. 12.4 Sclerosing mucoepidermoid carcinoma with eosinophils.
The eosinophils usually are fairly prominent in sclerosing mucoepider-
moid carcinoma with eosinophils. Eosinophils, sclerosis, and squamous
metaplasia in a thyroid neoplasm are features that suggest sclerosing
mucoepidermoid carcinoma. On further evaluation of this tumor,
mucous cells are identified

Fig. 12.3 Sclerosing mucoepidermoid carcinoma with eosinophils.

Mucous cells are present but not always prominent in sclerosing muco-
epidermoid carcinoma with eosinophils. The background of eosino-
phils and surrounding squamous areas are clues in looking for mucous
cells
Squamous Cell Carcinoma
Squamous Cell Carcinoma
Fig. 12.5 Squamous cell carcinoma. Squamous cell carcinoma pri-
mary to the thyroid is an uncommon, rapidly growing tumor that usu-
ally occurs in adult patients and has a female predominance [58].
Primary squamous cell carcinoma of the thyroid has been reported in an
adolescent with Hashimoto thyroiditis [9]. Presenting features include
signs and symptoms of airway or esophageal obstruction or compres-
sion and neck swelling [5]. Grossly, these tumors are firm, are 28 cm,
and may show areas of necrosis [10]. In a series of 16 patients, 12 had
locoregional disease at presentation and 4 had distant metastases [6].
The median survival was 16 months, but there were three long-term
survivors [6]. These tumors are aggressive and generally have a poor
prognosis; however, long-term survival is possible in localized disease
treated aggressively with surgery and radiotherapy [6]
Fig. 12.6 Squamous cell carcinoma. This primary squamous cell car-
cinoma of the thyroid has squamous cells with keratinization. Other
tumors, such as the tall cell variant of papillary thyroid carcinoma, may
be identified in association with squamous cell carcinoma of the thyroid
[10]. Areas of squamous differentiation also may be seen in undifferen-
tiated carcinomas. Others have raised the possibility that some cases
diagnosed solely as squamous cell carcinoma with a prognosis similar
to undifferentiated carcinoma might represent extensive squamous dif-
ferentiation in an undifferentiated carcinoma rather than true squamous
cell carcinoma of the thyroid [11]
89
Fig. 12.7 Squamous cell carcinoma. Squamous cell carcinoma is
composed of cells showing pure squamous differentiation. Other thy-
roid tumors may show focal squamous differentiation and should not be
mistaken for the pure squamous differentiation throughout the tumor in
primary squamous cell carcinoma of the thyroid. The tumor cells in
thyroid squamous cell carcinoma are variably positive for keratins,
including CK19, CK18, and CK7, and negative for CK1, CK4,
CK10/13, and CK20 [5, 8]. Thyroglobulin usually is negative. The
tumors show decreased staining for p21, and p53 expression occurs par-
ticularly in poorly differentiated cases [5, 10]. Ki67 labeling index is
30 % [10]. Differentiating primary squamous cell carcinoma of the thy-
roid from secondary involvement of the thyroid may be difficult histo-
logically, and imaging studies often are helpful. TTF1 is reported to be
focally positive in 37.5 % of primary squamous cell carcinomas of the
thyroid, a feature, along with focal thyroglobulin staining, that may be
helpful in differentiating it from squamous cell carcinoma involving the
thyroid secondarily [8]
90 12 Unusual Thyroid Tumors

Lymphoma

Fig. 12.10 Lymphoma. This high-power photomicrograph shows a

diffuse large B-cell lymphoma of thyroid. These large cells have vesic-
Fig. 12.8 Lymphoma. This gross photograph shows a follicular lym-
ular nuclei, nucleoli, and mitotic activity
phoma involving the thyroid. Lymphomas constitute approximately
5 % of thyroid tumors and usually are identified in older individuals.
Thyroid lymphomas often are identified in patients with a history of
Hashimoto thyroiditis. Mucosa-associated lymphoid tissue (MALT)
lymphomas are among the most common. The microscopic features are
quite variable, ranging from small cells with sparse cytoplasm of extra-
nodal marginal zone B-cell lymphomas to much larger cells and diffuse
large B-cell lymphomas. Follicular lymphomas of the thyroid are rare.
Plasmacytomas and MALT lymphomas with prominent plasma cell dif-
ferentiation also occur in the thyroid

Fig. 12.9 Lymphoma. This low-power photomicrograph shows a dif-

fuse large B-cell lymphoma of thyroid. In a retrospective review of 108
primary thyroid lymphomas, the average age was 64 years and patients
presented with a thyroid mass [12]. Of the 108 primary thyroid lympho-
mas, 30 were marginal zone B-cell lymphomas of MALT or marginal
zone B-cell lymphomas, 36 were diffuse large B-cell lymphomas with
marginal zone lymphomas, 41 were diffuse large B-cell lymphomas,
and 1 was follicular lymphoma. Lymphocytic thyroiditis was identified
in 94 % of cases, and 69 % had perithyroidal soft tissue extension [12]
Solitary Fibrous Tumor
Langerhans Cell Histiocytosis
Fig. 12.11 Langerhans cell histiocytosis. Langerhans cell histiocyto-
sis is a rare tumor of the thyroid that occurs most often in children and
young adults, although it may affect a wide age spectrum. The thyroid
may be involved in systemic disease; however, Langerhans cell histio-
cytosis localized to the thyroid is associated with good prognosis and
usually does not develop into systemic disease [13]. Histologically, the
thyroid may be involved focally or diffusely by Langerhans cells with
intermixed eosinophils [13]
Fig. 12.12 Langerhans cell histiocytosis. CD1a immunostain high-
lights the Langerhans cells in this case of Langerhans cell histiocytosis
of the thyroid. The Langerhans cells have grooved or folded vesicular
nuclei and are positive for S100 and CD1a. Ultrastructurally, Langerhans
cells have characteristic Birbeck or Langerhans granules. The sur-
rounding thyroid may show a variety of changes, from chronic lympho-
cytic thyroiditis to papillary thyroid carcinoma
91
Solitary Fibrous Tumor
Fig. 12.13 Solitary fibrous tumor. Solitary fibrous tumors are rare
tumors in the thyroid and usually are associated with indolent behavior
in this location. They form a solitary circumscribed mass, 28 cm, in
the thyroid of middle-aged adults [14, 15]
Fig. 12.14 Solitary fibrous tumor. Solitary fibrous tumors are rare.
They are composed of spindle cells and have a storiform, hemangio-
pericytoma, or desmoid-like architecture and hypo- and hypercellular
areas. The lesional cells are positive for CD34. Follicles may appear
trapped at the periphery of the tumor, and the tumor cells have an infil-
trative pattern among the follicles
92 12 Unusual Thyroid Tumors

Angiosarcoma

Fig. 12.17 Angiosarcoma. Angiosarcomas of the thyroid must be dif-

ferentiated from metastasis to the thyroid and carcinomas and angioma-
toid features, although they are all aggressive tumors with a poor
Fig. 12.15 Angiosarcoma. Angiosarcoma is the most common malig- prognosis [18]
nant mesenchymal tumor involving the thyroid gland [16, 17]. The
tumors are large and often occur in a background of nodular goiter.
They are more common in the Alpine regions of central Europe than
elsewhere

Fig. 12.16 Angiosarcoma. Angiosarcomas of the thyroid are solid and

cystic and may be hemorrhagic and show necrosis. They are composed
of anastomosing channels of atypical endothelial cells, often epithelioid
when these tumors affect the thyroid. The tumors stain for vascular
markers CD31, CD34, factor VIII, and FLI-1. Angiosarcomas with epi-
thelioid features also often show keratin expression [16, 17].
Angiosarcomas are highly aggressive tumors, and survival often is less
than 6 months
Low-Grade Fibromyxoid Sarcoma
Synovial Sarcoma
Fig. 12.18 Synovial sarcoma. Synovial sarcoma of the thyroid is pres-
ent on the right, with normal thyroid parenchyma on the left. Like other
uncommon mesenchymal tumors, synovial sarcoma rarely may involve
the thyroid [19, 20]
Fig. 12.19 Synovial sarcoma. This synovial sarcoma of the thyroid
has a monophasic pattern. These tumors may be biphasic, with both
epithelial and spindle components, or monophasic, with a pure spindle
pattern. The spindle cells have stippled chromatin, indistinct cell mar-
gins, and scant cytoplasm and grow in sheets or fascicles. These tumors
often have thick ropy collagen bundles, hemangiopericytoma-like ves-
sels, and calcifications. They show keratin positivity and have a charac-
teristic translocation t(X;18/p11;q11), resulting in an SYT/SSX fusion
transcript that has been used to confirm the diagnosis of synovial sar-
coma of the thyroid [19]
93
Low-Grade Fibromyxoid Sarcoma
Fig. 12.20 Low-grade fibromyxoid sarcoma. Low-grade fibromyxoid
sarcoma rarely affects the thyroid and is quite uncommon, and the lit-
erature is limited to case reports [21, 22]. These tumors appear decep-
tively benign and often are indolent, but they can metastasize. This
tumor shows bland fibroblasts in a linear arrangement and alternating
areas or less cellular myxoid and more cellular areas
Fig. 12.21 Low-grade fibromyxoid sarcoma. The cells in this low-
grade fibromyxoid sarcoma have weakly eosinophilic cytoplasm and
ovoid nuclei with indistinct nucleoli and lack significant nuclear atypia.
Mitotic figures are absent or sparse. These tumors have a characteristic
balanced translocation, resulting in a FUS/CREB3L2 fusion gene [23]
94
Rhabdomyosarcoma
Fig. 12.22 Rhabdomyosarcoma. Rhabdomyosarcoma is a rare sar-
coma, particularly with regard to the thyroid. Shown is a primitive
embryonal rhabdomyosarcoma with an area of residual thyroid follicles
in the center of the field
Fig. 12.23 Rhabdomyosarcoma. Poorly differentiated primitive, pre-
dominantly embryonal rhabdomyosarcoma in the thyroid gland.
Rhabdomyosarcomatous differentiation also may be seen in anaplastic
carcinoma in the thyroid [24]
12 Unusual Thyroid Tumors
Carcinoma Showing Thymus-Like
Differentiation
Fig. 12.24 Carcinoma showing thymus-like differentiation
(CASTLE). CASTLE is a rare malignant neoplasm postulated to arise
from intrathyroidal thymic rests or thymic rests within the thyroid or
remnants of the branchial pouch. It may show thymic differentiation,
including solid cell nests [2528]. This tumor also is known as intrathy-
roidal epithelial thymoma/carcinoma showing thymus-like differentia-
tion, intrathyroidal epithelial thymoma, thymic carcinoma of thyroid,
and lymphoepithelioma-like carcinoma of thyroid. CASTLE resembles
thymic lymphoepithelioma-like carcinoma and squamous cell carci-
noma and is positive for CD5, which is negative in thyroid carcinomas,
including those with squamous differentiation [26]. Lymph node metas-
tases are found at surgery in 40 % of cases; other metastatic sites are
bones, liver, and lungs. The overall survival rate is 71 % [27]
Fig. 12.25 Carcinoma showing thymus-like differentiation. The cells
of this CASTLE tumor are epithelial and have distinct nucleoli. Three
histologic subtypes may occur: keratinizing squamous cell carcinoma,
nonkeratinizing basaloid cell carcinoma (lymphoepithelioma-like), and
neuroendocrine carcinoma. These subtypes correspond to those of the
mediastinal thymic carcinomas [27]
Teratoma
Fig. 12.26 Carcinoma showing thymus-like differentiation. This
CASTLE tumor is growing in solid sheets. Immunopositivity for CD5,
p63, and KIT (and negative staining for TTF1, thyroglobulin, and calci-
tonin) is helpful in differentiating CASTLE from undifferentiated or
poorly differentiated carcinoma, medullary thyroid carcinoma, and
squamous cell carcinoma of the thyroid [27]. CD5, high molecular
weight kininogen (HMWK), carcinoembryonic antigen (CEA), and p63
may be used to help distinguish CASTLE from other thyroid neo-
plasms, as CASTLE and most thymic carcinomas are positive for these
markers and other thyroid tumors usually are negative [28]. Solid cell
nests, thymomas, and normal thymus stain for p63, HMWK, and CEA,
which supports the hypothesis that CASTLE may be of thymic origin
and may arise from branchial pouch remnants, such as solid cell nests
in the thyroid [28]
95
Teratoma
Fig. 12.27 Teratoma. This is an immature teratoma from the thyroid
of an infant. Thyroid teratomas are rare tumors with trilineage (ecto-
derm, mesoderm, and endoderm) differentiation and show varying
degrees of maturity [29]. In a study of 30 thyroid teratomas, males and
females were affected equally, patient age ranged from newborns to 56
years (mean age, 12.4 years), and all presented as a thyroid mass mea-
suring 213 cm (mean, 6 cm) [29]. The tumors in this study were
divided into benign (7), immature (14), and malignant (9) by an increas-
ing proportion of primitive mesenchymal or neural-type tissue and
found outcome depending on age, tumor size, and proportion of imma-
ture tissue [29]. The authors suggested the tumors be excised surgically,
with adjuvant therapy reserved for malignant cases [29]
Fig. 12.28 Teratoma. This immature teratoma is from the thyroid of
an infant. In a study of 11 cervical teratomas containing thyroid tissue,
8 were thought to be of thyroid origin because of an intimate admixture
of thyroid and other tissues with or without a surrounding fibrous pseu-
docapsule [30]. All these tumors were congenital, measured 3.5
13.5 cm (median, 6.9 cm), were excised surgically, and had a follow-up
of 145 years (median, 17 years) with no recurrence in any patient [30].
The authors concluded that histologic immaturity in congenital thy-
roid teratomas is not the harbinger of adverse behavior as seen in ado-
lescents and adults [30]
96
Paraganglioma
Fig. 12.29 Paraganglioma. Paraganglioma of the thyroid is an
extremely rare entity. These tumors have a female predominance, occur
in young adults, and present as a neck mass. They are slow-growing
neuroendocrine tumors that, in the thyroid, are thought to represent a
subset of laryngeal paraganglioma [31]. Patients may have associated
carotid body tumors or glomus vagale [32]. Multiple paragangliomas
often are associated with syndromes with corresponding succinate
dehydrogenase mutations. Less than 10 % of paragangliomas are
malignant. Locally aggressive thyroid paragangliomas have been
reported [33, 34], but metastases have not been reported. Paragangliomas
are treated by surgical excision
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carcinoma and sclerosing mucoepidermoid carcinoma with eosino-
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2. Cavazza A, et al. Sclerosing mucoepidermoid carcinoma with
eosinophilia of the thyroid: description of a case. Pathologica.
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3. Chan JK, et al. Sclerosing mucoepidermoid thyroid carcinoma with
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6. Cook AM, Vini L, Harmer C. Squamous cell carcinoma of the thy-
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12 Unusual Thyroid Tumors
Fig. 12.30 Paraganglioma. Paraganglioma of the thyroid histologi-
cally resembles paraganglioma of other sites. Paragangliomas charac-
teristically have a zellballen or nested growth pattern but may have
alveolar or lobular growth patterns and are highly vascular.
Paragangliomas are composed of chief cells that are polygonal and have
eosinophilic cytoplasm and round nuclei. Sustentacular cells are deli-
cate spindle cells best seen with S100 immunostain. The main problem
in diagnosing thyroid paraganglioma is considering it in the differential
diagnosis of tumors such as medullary thyroid carcinoma, hyalinizing
trabecular tumor, and thyroid adenomas with unusual growth patterns.
Paragangliomas are positive for synaptophysin and chromogranin, with
sustentacular cells staining for S100. Thyroid paragangliomas are nega-
tive for keratin, thyroglobulin, TTF1, calcitonin and CEA [35]
8. Booya F, et al. Primary squamous cell carcinoma of the thyroid:
report of ten cases. Thyroid. 2006;16(1):8993.
9. Sanchez-Sosa S, et al. Primary squamous cell carcinoma of the thy-
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10. Kleer CG, Giordano TJ, Merino MJ. Squamous cell carcinoma of
the thyroid: an aggressive tumor associated with tall cell variant of
papillary thyroid carcinoma. Mod Pathol. 2000;13(7):7426.
11. Katoh R, et al. Squamous differentiation in thyroid carcinoma.
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12. Derringer GA, et al. Malignant lymphoma of the thyroid gland: a
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14. Cameselle-Teijeiro J, et al. Lipomatous hemangiopericytoma of the
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15. Deshmukh NS, et al. Solitary fibrous tumour of the thyroid gland.
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16. Hedinger C. Geographic pathology of thyroid diseases. Pathol Res
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17. Eusebi V, et al. Keratin-positive epithelioid angiosarcoma of thy-
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with aspiration cytology findings and gene analysis. Acta Cytol.
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21. Dong W, Zhang H. Low-grade fibromyxoid sarcoma of the thyroid:
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22. Merchant SH. Low grade fibromyxoid sarcoma: report of a case
with epithelioid cell morphology, masquerading as a papillary thy-
roid carcinoma. Acta Cytol. 2009;53(6):68992.
23. Mertens F, et al. Clinicopathologic and molecular genetic char-
acterization of low-grade fibromyxoid sarcoma, and cloning of a
novel FUS/CREB3L1 fusion gene. Lab Invest. 2005;85(3):40815.
24. Carda C, et al. Anaplastic carcinoma of the thyroid with rhabdo-
myosarcomatous differentiation: a report of two cases. Virchows
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noma showing thymus-like differentiation (CASTLE): CD5-
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 Metastases to Thyroid
13

Metastases to the thyroid from tumors of other sites are not
uncommon in patients with disseminated cancer, as metasta-
ses are identified in approximately 25 % of autopsies in this
setting. The most common primary tumors to metastasize to
the thyroid are renal cell carcinoma, lung cancer, breast can-
cer, malignant melanoma, esophageal cancer, and gyneco-
logic malignancies [15]. The tumors may form a single
mass or show multifocal disease. Patients may present with a
mass, hoarseness, pain, or dysphagia [2, 3]. Squamous cell
carcinoma of the head and neck may involve the thyroid sec-
ondarily by direct extension. Metastases to the thyroid gen-
erally retain the histologic features of the primary tumor, and
many are known to have metastatic disease elsewhere at the
time of presentation of the thyroid metastasis. A review of
the 19932003 pathology files from two Italian pathology
units identified 36 cases, with thyroid metastases accounting
for 0.13 % of thyroidectomies ad 0.07 % of fine-needle aspi-
ration biopsies [5]. It also found that thyroidectomy did not
contribute to prolonged survival [5]. In a series of 15 cases at
Royal Marsden Hospital, the interval from diagnosis of the
primary tumor to the thyroid metastasis ranged from 0
months to 15 years, and the thyroid metastasis was the initial
manifestation of metastatic disease in five patients [4].
Resection of solitary metastasis may be helpful, and chemo-
therapy and radiotherapy may be useful in specific situations,
but overall survival remains quite poor [4].

L.A. Erickson, Atlas of Endocrine Pathology, Atlas of Anatomic Pathology, 99

DOI 10.1007/978-1-4939-0443-3_13, Springer Science+Business Media New York 2014
100
Fig. 13.1 Renal cell carcinoma metastatic to thyroid. The thyroid
gland shown here is affected by metastatic renal cell carcinoma. Renal
cell carcinoma is one of the most common metastases identified at the
thyroid. Metastases may appear as a single lesion or be multifocal in the
thyroid. Renal cell carcinoma, clear cell type, has prominent cytoplas-
mic clearing and usually appears highly vascular
Fig. 13.2 Renal cell carcinoma metastatic to thyroid. Clear cell renal
cell carcinoma (lower) must be differentiated from clear cell tumors of
the thyroid. In difficult cases, immunostains may be helpful, as both
follicular and papillary thyroid neoplasms are positive for thyroid tran-
scription factor 1 (TTF1) and thyroglobulin, both of which are negative
in renal cell carcinoma
13 Metastases to Thyroid
Fig. 13.3 Breast cancer metastatic to thyroid. Breast cancer metasta-
ses to the thyroid often show multiple small foci of tumor and may form
nodules or irregularly infiltrating areas of tumor. Often, there is a known
history of breast cancer; however, in difficult cases, immunostains may
be helpful in confirming the diagnosis. Breast cancer is positive for
keratin 7, BRST-2, and mammaglobin and negative for TTF1 and
thyroglobulin
Fig. 13.4 Breast cancer metastatic to thyroid. Breast cancer metastatic
to the thyroid often appears to encircle follicular structures or appear as
an expanded area of epithelioid cells around an area of colloid. This is
a common pattern in breast cancer metastases to the thyroid
References 101

References
1. Cichon S, et al. Metastases to the thyroid gland: seventeen cases
operated on in a single clinical center. Langenbecks Arch Surg.
2006;391(6):5817.
2. Nakhjavani MK, et al. Metastasis to the thyroid gland. A report of
43 cases. Cancer. 1997;79(3):5748.
3. Heffess CS, Wenig BM, Thompson LD. Metastatic renal cell carci-
noma to the thyroid gland: a clinicopathologic study of 36 cases.
Cancer. 2002;95(9):186978.
4. Wood K, Vini L, Harmer C. Metastases to the thyroid gland: the
Royal Marsden experience. Eur J Surg Oncol. 2004;30(6):5838.
5. Papi G, et al. Metastases to the thyroid gland: prevalence, clinico-
pathological aspects and prognosis: a 10-year experience. Clin
Endocrinol. 2007;66(4):56571.

Fig. 13.5 Melanoma metastatic to thyroid. Malignant melanoma often

has a nodular pattern of metastases in the thyroid. Metastases may be
identified readily as melanoma if the patient has a history of metastatic
disease and the tumor shows prominent melanin pigment

Fig 13.6 Metastatic melanoma to thyroid. This metastatic melanoma

is pigmented, but not all cases show such prominent pigment. In diffi-
cult cases, immunostains may be helpful. Melanoma is positive for
S100, MelanA/MART1, and HMB-45 and negative for keratin, TTF1,
and thyroglobulin
 Parathyroid Histology
14

Parathyroid glands are derived from the endodermal third
and fourth branchial pouches and are involved in the regula-
tion of serum calcium and bone metabolism. Calcium-
sensing receptors on the surface of parathyroid cells sense
serum calcium levels. When serum calcium levels are low,
parathyroid hormone (PTH) is secreted. Most individuals
have four parathyroid glands, but 513 % have five or more
and 2 % have fewer than four parathyroid glands [13].
Normal parathyroid glands measure 36 mm in length,
24 mm in width, and 0.52 mm in thickness [4]. Normal
parathyroid glands each weigh 2040 mg; those weighing
more than 5060 mg usually are abnormal. Parathyroid
glands are composed of parathyroid parenchymal cells and
adipocytes. Stromal fat constitutes 1030 % of normal para-
thyroid glands. Parathyroid glands are composed of chief
cells, transitional cells, oxyphilic cells, and adipose tissue.
Normal and pathologic parathyroid tissue may show one or
more parenchymal cell types. Parathyroid cysts and inflam-
mation also are important to recognize in diagnostic parathy-
roid pathology. Parathyroid tissue is immunoreactive with
parathyroid hormone, chromogranin, synaptophysin, and
keratin (Cam5.2).

L.A. Erickson, Atlas of Endocrine Pathology, Atlas of Anatomic Pathology, 103

DOI 10.1007/978-1-4939-0443-3_14, Springer Science+Business Media New York 2014
104
Normal Parathyroid Histology
Fig. 14.1 Normal parathyroid histology. Normal parathyroid glands
are composed of parathyroid parenchymal cells, which predominantly
are chief cells but may be mixtures of chief, oxyphilic, transitional, and
clear cells. Stromal fat also is present
Fig. 14.2 Normal parathyroid histology. Understanding the variability
in cellularity of normal parathyroid tissue is helpful, particularly in
evaluating small biopsies. The cellularity of normal parathyroid glands
is quite variable within and among glands in an individual, as well as
among individuals. Stromal fat constitutes 1030 % of normal parathy-
roid glands. The cellularity may be distributed unevenly, and there may
be more stromal fat in the polar regions of a parathyroid gland than
centrally [2]. Cellularity also varies with age and is high in infants and
children, with adipocytes appearing in puberty and increasing in num-
ber until 2540 years of age [1, 4]. Constitutional factors also affect
cellularity [1]
14 Parathyroid Histology
Fig. 14.3 Normal parathyroid histology. Chief cells are polyhedral
and measure approximately 8 m, with round central nuclei comprising
more than half the cell, eosinophilic to amphophilic cytoplasm, and
well-defined cytoplasmic membranes [1, 4]. The well-defined cytoplas-
mic membranes are helpful in differentiating parathyroid from thyroid.
Fat droplets are identified in parathyroid chief cells in adults and are
helpful in differentiating parathyroid from thyroid
Fig. 14.4 Normal parathyroid histology. Oxyphilic cells measure
1220 m and are larger than chief cells [1, 5]. Oxyphilic cells have
abundant eosinophilic cytoplasm reflecting numerous mitochondria.
Oxyphilic cells are not present at birth or seen in parathyroid glands in
small children; they appear at puberty and increase with age [1, 4]
Parathyroid Cysts 105

Parathyroid Cysts

Fig. 14.5 Normal parathyroid histology. In older patients, oxyphilic

cells may appear as nodular aggregates and be mistaken for parathyroid
disease
Fig. 14.7 Parathyroid cyst. Parathyroid cysts are uncommon, repre-
senting only 0.51 % of parathyroid lesions and less than 1 % of neck
masses [6]. Among 6,621 patients undergoing neck ultrasound, five
parathyroid cysts were identified [6]. The mean diameter was 3.6 cm
and ranged from 2.5 to 8.1 cm [6]. Serum PTH was elevated in all five
cysts (mean, 221 pg/mL), but serum calcium was elevated in only three
of the five cases (9.212.9 mg/mL) [6]. In a study of 325 patients under-
going parathyroid operations, 11 parathyroid cysts were identified,
ranging in size from 1.6 to 10 cm and occurring in men and women over
a broad age range [7]

Fig. 14.6 Normal parathyroid histology. Clear (water-clear/

Wasserhalle) cells measure 1015 m and have clear cytoplasm and
pyknotic nuclei [4, 5]. The clear cytoplasm has been attributed to pos-
sible vacuolization of other cells, and in some types of parathyroid dis-
ease, such as clear cell parathyroid hyperplasia, a technical artifact has
been suggested

Fig. 14.8 Parathyroid cyst. Parathyroid cysts occur in the neck, within
the thyroid, or in the mediastinum. Cysts may be functional or nonfunc-
tional. Nonfunctional cysts may present as a mass, but clinically appar-
ent cysts are quite rare. A study of 12 nonfunctional symptomatic
parathyroid cysts, diagnosed on the basis of whether the aspirated fluid
was colorless and clear and had elevated PTH, reported that aspiration
was successful in treating four cysts; the eight recurrent cysts were
ablated with ethanol [8]. Functional cysts also may be multiple [9].
Parathyroid adenoma or hyperplasia also may be associated with a cyst
or cystic degeneration
106
Fig. 14.9 Parathyroid cyst. Parathyroid cysts may be lined by epithe-
lium but often have fibrotic walls. Different elements may be present in
the wall, including parathyroid tissue, muscle, lymphoid, thymic tissue,
and adipose tissue
14 Parathyroid Histology
Parathyroiditis
Fig. 14.10 Parathyroiditis. This parathyroid gland affected by chronic
parathyroiditis shows atrophic nests of remaining parathyroid paren-
chyma and extensive fibrosis, which has replaced much of the paren-
chyma. Chronic parathyroiditis is considered an autoimmune condition
that may result in hypoparathyroidism or hyperparathyroidism,
although most cases are asymptomatic [10, 11]. A lymphocytic infil-
trate is found in parathyroid glands at autopsy in patients without
known clinical parathyroid dysfunction, but clinically evident parathy-
roiditis is extremely rare. Chronic parathyroiditis also may be associ-
ated with adenomas and hyperplasia [12, 13]
Fig. 14.11 Parathyroiditis. Histologic features of chronic parathyroid-
itis are variable and range from focal lymphocytic infiltrate to promi-
nent lymphoid follicles with germinal center formation involving one
or multiple parathyroid glands. The parathyroid parenchyma in this
example has been extensively replaced by fibrous tissue and adipose,
with only small nests and islands of parathyroid parenchymal cells
remaining
References
Fig. 14.12 Parathyroiditis. This parathyroid gland shows a diffuse and
fairly dense infiltrate of lymphocytes. Prominent lymphoid follicles
with germinal centers also may be present. Involvement may be diffuse
or patchy and affect one or more glands in parathyroiditis. Autopsy
studies have shown focal lymphocytic infiltrate in up to 16 % of cases
[14]. Multiple glands may be involved, particularly in patients with
autoimmune disorders. When the lymphoid infiltrate is marked, it must
be distinguished from involvement by malignant lymphoma, which
may occur but is extraordinarily rare
Fig. 14.13 Parathyroiditis. This parathyroid gland parenchyma
affected by chronic parathyroiditis shows nodular infiltrates of chronic
inflammatory cells and a few nests of residual parathyroid parenchymal
cells
107
References
1. DeLellis RA. Tumors of the parathyroid gland. In: Rosai J, Sobin
LH, editors. Atlas of tumor pathology, vol. 6. Washington, DC:
Armed Forces Institute of Pathology; 1993. p. 102.
2. Akerstrom G, Malmaeus J, Bergstrom R. Surgical anatomy of
human parathyroid glands. Surgery. 1984;95(1):1421.
3. Lappas D, et al. Location, number and morphology of parathyroid
glands: results from a large anatomical series. Anat Sci Int.
2012;87(3):1604.
4. Castleman B, Mallory TB. The pathology of the parathyroid gland
in hyperparathyroidism. A study of 25 cases. Am J Pathol.
1935;X(1):172.
5. Castleman B, Roth SI. Tumors of the parathyroid glands, Atlas of
tumor pathology, vol. 14. Washington, DC: Armed Forces Institute
of Pathology; 1978.
6. Cappelli C, et al. Prevalence of parathyroid cysts by neck ultrasound
scan in unselected patients. J Endocrinol Invest. 2009;32(4):3579.
7. Calandra DB, et al. Parathyroid cysts: a report of eleven cases
including two associated with hyperparathyroid crisis. Surgery.
1983;94(6):88792.
8. Sung JY, et al. Symptomatic nonfunctioning parathyroid cysts:
role of simple aspiration and ethanol ablation. Eur J Radiol.
2013;82(2):31620.
9. Glynn N, et al. Multiple functional parathyroid cysts. J Clin
Endocrinol Metab. 2013;98(7):26412.
10. Bondeson AG, Bondeson L, Ljungberg O. Chronic parathyroiditis
associated with parathyroid hyperplasia and hyperparathyroidism.
Am J Surg Pathol. 1984;8(3):2115.
11. Boyce BF, Doherty VR, Mortimer G. Hyperplastic parathyroid-
itisa new autoimmune disease? J Clin Pathol. 1982;35(8):8124.
12. Kovacs K, et al. Parathyroid chief cell adenoma associated with
massive chronic parathyroiditis in a woman with hyperparathyroid-
ism. Endocr Pathol. 2007;18(1):425.
13. Sinha SN, McArdle JP, Shepherd JJ. Hyperparathyroidism with
chronic parathyroiditis in a multiple endocrine neoplasia patient.
Aust N Z J Surg. 1993;63(12):9812.
14. Talat N, Diaz-Cano S, Schulte KM. Inflammatory diseases of the
parathyroid gland. Histopathology. 2011;59(5):897908.
 Parathyroid Hyperplasia
Parathyroid hyperplasia accounts for 15 % of primary
hyperparathyroidism cases, with parathyroid adenoma
accounting for 8085 % and carcinoma 0.52 %. The inci-
dence of primary hyperparathyroidism increased in the
early 1970s with the introduction of automatic screening
serum calcium [1]. Patients today may be asymptomatic or
have weakness or lethargy, but nephrocalcinosis and osteo-
penia are much less common. Primary parathyroid hyper-
plasia is an absolute increase in parathyroid parenchymal
mass involving multiple parathyroid glands in the absence
of a recognized stimulus for parathyroid hormone (PTH)
secretion [2]. The etiology of sporadic primary parathy-
roid hyperplasia is unclear. The most common causes of
hereditary hyperparathyroidism include multiple endocrine
neoplasia (MEN) types 1 and 2A, familial hypocalciuric
hypercalcemia, hyperparathyroidismjaw tumor syndrome
(HP-JT), neonatal severe primary hyperparathyroidism, and
familial isolated hyperparathyroidism. Parathyroid hyper-
plasia is the most common manifestation of MEN1, and
up to 20 % of patients with parathyroid hyperplasia have
MEN1. Unlike sporadic hyperparathyroidism, which occurs
in the fifth decade of life with a 2:1 female predominance,
syndrome-associated cases often occur in the patients early
20s and affects females and males equally. The most com-
mon cause of secondary hyperparathyroidism is chronic
renal failure. Patients with secondary hyperparathyroid-
ism have increased PTH due to low serum calcium caused
by disorders of vitamin D (rickets, vitamin D deficiency
L.A. Erickson, Atlas of Endocrine Pathology, Atlas of Anatomic Pathology,
DOI 10.1007/978-1-4939-0443-3_15, Springer Science+Business Media New York 2014
15
or malabsorption), disorders of phosphate metabolism
(malnutrition, malabsorption, renal disease, aluminum tox-
icity), tissue resistance to vitamin D, pseudohypoparathy-
roidism, hypomagnesemia, and calcium deficiency. Tertiary
hyperparathyroidism occurs in patients with secondary
hyperparathyroidism who develop an autonomously func-
tioning parathyroid. Grossly, parathyroid hyperplasia shows
enlargement of multiple glands. Not all glands necessar-
ily are equally enlarged. Asymmetric enlargement may be
mistaken for a parathyroid adenoma. Evaluating parathy-
roid glands in relation to size and cellularity may be prob-
lematic, because these may vary even within an individual
with hyperplasia. Histologically, it is not possible to differ-
entiate sporadic from familial hyperplasia. It has been sug-
gested that parathyroid glands in primary hyperplasia have
a more nodular growth pattern, whereas those of secondary
hyperplasia have more diffuse growth. But it is extremely
difficult to determine this in an individual case because the
features may overlap. Cases of secondary hyperplasia due
to renal failure often are quite nodular and may appear simi-
lar to primary and tertiary hyperplasia. A diffuse increase
in clear cells in multiple glands is referred to as primary
water-clear cell hyperplasia (Wasserhalle cell hyperplasia),
which is rare. Lipohyperplasia is another rare type of pri-
mary hyperplasia with multiple enlarged glands with an
admixture of large amounts of mature fat, myxoid stroma,
and focal parenchymal cell nests. Parathyroid hyperplasia
is an interesting and complex area of endocrine pathology.
109
110 15 Parathyroid Hyperplasia

Primary Parathyroid Hyperplasia

Fig. 15.2 Primary parathyroid hyperplasia. This hypercellular para-

thyroid gland in primary parathyroid hyperplasia shows nodular
enlargement with nodules of chief, oxyphilic, and transitional cells.
Fig. 15.1 Primary parathyroid hyperplasia. Primary parathyroid This hypercellular parathyroid gland shows nodular enlargement.
hyperplasia is an absolute increase in parathyroid parenchymal mass Primary hyperplasia may show nodular or diffuse growth, with nodular
involving multiple parathyroid glands in the absence of a recognized growth being more common [2]. Nodular growth is more common in
stimulus for PTH secretion [2]. The etiology of sporadic primary para- older patients, who also have more asymmetric hyperplasia and more
thyroid hyperplasia is unclear. The most common cause of hereditary oxyphilic cells [3]. Younger patients may show more diffuse growth
hyperparathyroidism is MEN1, an autosomal dominant disorder with and have moderately enlarged and more symmetric parathyroids and
high penetrance involving germline mutation of the MEN1 tumor sup- moderate hypercalcemia [3]. Parathyroid hyperplasia in MEN1 often is
pressor gene (11q13). Hyperparathyroidism is the most common mani- asymmetric and may show nodular or diffuse growth and a
festation of MEN1, occurring in 90 % of cases. Around 20 % of normocellular-appearing rim [4]
hyperplasias are associated with MEN1; thus, genetic testing is sug-
gested. This also is a manifestation of MEN2a in 2030 % of cases.
Other causes of hereditary hyperparathyroidism include familial iso-
lated hyperparathyroidism, familial hypocalciuric hypercalcemia,
HP-JT, and neonatal severe primary hyperparathyroidism. This photo-
micrograph shows a parathyroid gland affected by sporadic primary
hyperparathyroidism. It is not possible to differentiate sporadic from
hereditary hyperparathyroidism histologically (although MEN1-
associated hyperplasia often is asymmetric)

Fig. 15.3 Primary parathyroid hyperplasia. Single and small groups of

adipocytes are scattered throughout this hyperplastic parathyroid; the
amount of adipocytes varies. Parathyroid hyperplasia shows enlarge-
ment of multiple parathyroid glands, but not all glands are necessarily
equally enlarged. Asymmetric enlargement of a parathyroid gland may
be mistaken for an adenoma. Evaluating parathyroids in relation to size
and cellularity may be problematic as these may vary, even within an
individual with parathyroid hyperplasia
Primary Parathyroid Hyperplasia
Fig. 15.4 Primary parathyroid hyperplasia. Nodule of chief cells
(lower) and nodule of clear cells (upper). Although chief cells usually
predominate in parathyroid hyperplasia, multiple cell types may be
seen. In nodular hyperplasia, each nodule may be composed of a single
cell type
Fig. 15.5 Primary parathyroid hyperplasia. A nodule of clear cells is
present in this primary parathyroid hyperplasia. The cells have abun-
dant clear cytoplasm containing glycogen, ovoid nuclei, and distinct
cell membranes. The nuclei often are at the pole of the cell in apposition
to the vessels. Foci of clear cells are not uncommon in hyperplasia.
When parathyroid hyperplasia is composed entirely of clear cells, the
term clear cell hyperplasia is used for this rare entity
111
Fig 15.6 Primary parathyroid hyperplasia. A nodule of oxyphilic cells
is seen in this primary parathyroid hyperplasia. Oxyphilic cells are not
seen in normal parathyroids of small children. Oxyphilic cells increase
with age. In normal parathyroids of older patients, oxyphilic cells may
form nodular aggregates and be mistaken for parathyroid disease.
Nodules or sheet-like areas of oxyphilic cells may be seen in parathy-
roid adenoma, hyperplasia, and carcinoma. The oxyphilic cytoplasm is
the result of mitochondria
Fig. 15.7 Primary parathyroid hyperplasia. Although primary para-
thyroid hyperplasia may have nodular or diffuse growth, nodular growth
may be more common. This is an example of diffuse chief cell hyper-
plasia. The cells may show foci of pleomorphism and hyperchromasia,
referred to as endocrine atypia
112 15 Parathyroid Hyperplasia

Fig. 15.8 Primary parathyroid hyperplasia. Sheet-like diffuse growth Fig. 15.10 Primary parathyroid hyperplasia. Nuclear palisading, often
of parathyroid chief cells is seen in this primary parathyroid hyperpla- around vascular structures, may be seen in parathyroid hyperplasia
sia. Although no adipocytes are in this field, single and small groups of
adipocytes often are seen in hyperplasia. Mitotic figures are present in
up to 80 % of parathyroid hyperplasias, but most show fewer than one
mitotic figure per 10 high-power fields (HPF) [5]. MEN2A cases may
show increased mitotic activity [5]; fibrosis also may occur, but hyper-
plasia does not show invasive growth. Degenerative changes of hemo-
siderin deposition, fibrosis, and cystic change may occur [2]. Cystic
change is common in HP-JT parathyroids

Fig. 15.11 Primary parathyroid hyperplasia. A rim of normal-

Fig. 15.9 Primary parathyroid hyperplasia. A glandular growth pat-
tern is one of many patterns that may be seen in parathyroid
hyperplasia
appearing parathyroid tissue, characteristically seen in parathyroid
adenomas, occasionally may be seen in hyperplastic parathyroid glands.
All four parathyroid glands are symmetrically enlarged in only 50 % of
hyperplasias, thus differentiating adenoma from hyperplasia may be
extremely difficult based only on the histologic evaluation of a single
gland
Primary Clear Cell Hyperplasia
Fig. 15.12 Parathyroid hyperplasia, brown tumor of bone. Brown
tumors of bone (osteitis fibrosa cystica) are an uncommon and late
manifestation of hyperparathyroidism, usually in severe disease. Brown
tumors look like giant cell reparative granulomas, which also often
affect the jaw. Differentiating these entities may be nearly impossible
histologically. Brown tumors are more common in women and occur in
bones of the head, spine, femur, tibia, clavicle, scapula, and humerus
113
Primary Clear Cell Hyperplasia
Fig. 15.13 Primary clear (water-clear, Wasserhalle) cell hyperplasia.
This is one of multiple parathyroid glands showing an absolute increase
in parathyroid parenchymal cells with abundant clear cytoplasm in the
absence of a known stimulus for PTH secretion [2]. Clear (water-clear,
Wasserhalle) cell hyperplasia is an extremely rare form of hyperpara-
thyroidism today, with most cases having been described in historical
literature with patients presenting with classic signs and symptoms of
hyperparathyroidism (bone disease and nephrolithiasis) [68]. Primary
clear cell hyperplasia is not associated with familial hyperparathyroid-
ism and rarely is identified today. Usually, all four glands are involved,
but the disease may involve fewer than four glands [2]
Fig. 15.14 Primary (water-clear, Wasserhalle) cell hyperplasia. Another
parathyroid gland involved by primary clear cell parathyroid hyperplasia.
Clear cell hyperplasia involves multiple glands, unlike clear cell ade-
noma, which involves only a single gland. The differential diagnosis also
includes lipohyperplasia, which shows an increase in cells with clear
cytoplasm, but they are adipocytes. Lipohyperplasia often has small nests
of parenchymal chief or oxyphilic cells, as well as foci of myxoid stroma.
Thyroid tumors also may show clear cell change but lack increased serum
calcium and PTH. In difficult cases, immunostains might be used to dis-
tinguish clear cell parathyroid hyperplasia or adenoma, particularly intra-
thyroidal disease, from a thyroid tumor with clear cell change. Clear cell
parathyroid lesions are positive for PTH, chromogranin, and synaptophy-
sin and negative for TTF1 and thyroglobulin
114
Fig. 15.15 Primary clear (water-clear, Wasserhalle) cell hyperplasia.
The glands in clear cell parathyroid hyperplasia show a diffuse increase
in polyhedral cells, 1520 m in size, with distinct cell membranes.
Tubular and glandular patterns, as well as occasional cystic structures,
may be seen
Fig. 15.16 Primary clear (water-clear, Wasserhalle) cell hyperplasia.
There is a diffuse increase in parathyroid parenchymal cells in multiple
parathyroid glands in this primary clear cell hyperplasia. The cells have
clear cytoplasm, well-defined cell membranes, and small pyknotic
nuclei. Electron microscopic studies show the cytoplasm to have vacu-
oles thought to be Golgi vessels. The nuclei often are eccentric and may
be located basally at the pole of cells adjacent to the stroma. The nuclei
are hyperchromatic and often multiple
15 Parathyroid Hyperplasia
Lipoadenomatous Hyperplasia
Fig. 15.17 Lipoadenomatous hyperplasia (lipohyperplasia).
Parathyroid lipohyperplasia is an extremely rare form of parathyroid
hyperplasia. Usually, three or four glands are enlarged. This parathy-
roid gland is one of four affected by lipoadenomatous hyperplasia. In a
description by Straus et al. [9] of five cases of lipohyperplasia, women
between the ages of 3662 years were affected. The glands ranged from
100 to 200 mg, with the largest being 820 mg [9]. The glands were five
times the normal size and showed the 50 % fat/50 % parenchyma pat-
tern of normal glands, amounting to a 500 % increase in parathyroid
tissue [9]. Involved glands showed an increase in adipocytes and scat-
tered nests of chief or oxyphilic cells in multiple parathyroids. Foci of
myxoid change are identified in the background stroma. Parathyroid
lipoadenoma and lipoadenomatous hyperplasia cannot be differentiated
based on the histologic evaluation of a single gland. The only feature
differentiating lipoadenoma from lipoadenomatous hyperplasia is the
number of glands involved
Secondary Parathyroid Hyperplasia 115

Secondary Parathyroid Hyperplasia

Fig. 15.20 Secondary parathyroid hyperplasia. Although nodular

growth may be more common in primary hyperplasia, it also may be
identified in secondary hyperplasia. Over time, glands may become
Fig. 15.18 Secondary parathyroid hyperplasia. This parathyroid gland more nodular and larger and show degenerative features such as cystic
is affected by secondary parathyroid hyperplasia with an increase in the change, fibrosis, and hemorrhage [2]
size and cellularity and a decrease in adipocytes of involved glands.
Parathyroid glands in secondary hyperplasia show an adaptive increase
in parenchymal mass due to proliferation of chief, oxyphilic, and tran-
sitional cells in multiple glands as the result of a known stimulus for
PTH secretion [2]. The most common cause is chronic renal failure.
The secondary increase in PTH is the result of low serum calcium levels
and hyperphosphatemia. Disorders of vitamin D (rickets, vitamin D
deficiency or malabsorption), disorders of phosphate metabolism (mal-
nutrition or malabsorption, renal disease, aluminum toxicity), tissue
resistance to vitamin D, hypomagnesemia, pseudohypoparathyroidism,
and calcium deficiency are other causes. The severity of hyperplasia
may correlate with the severity of the underlying disease

Fig. 15.21 Secondary parathyroid hyperplasia. Nodular hyperplasia in

parathyroid hyperplasia, with each nodule composed of a separate cell
type

Fig. 15.19 Secondary parathyroid hyperplasia. In secondary parathy-

roid hyperplasia, multiple parathyroid glands are enlarged, may appear
yellow to gray, and weigh 1206,000 mg [2]. The cells often show a
diffuse growth pattern with sheets of parenchymal cells and scattered
adipocytes, as seen in this photomicrograph. Secondary parathyroid
hyperplasia may show diffuse or nodular growth, although diffuse
growth is more common, at least early in the disease [2]. Particularly in
advanced disease, it may be impossible to differentiate primary from
secondary hyperplasia histologically
116
Fig. 15.22 Secondary parathyroid hyperplasia. Chief cells are one of
the most common cells in hyperplasia, both primary and secondary
Fig. 15.23 Secondary parathyroid hyperplasia. Sheets of chief and
oxyphilic cells in an area of diffuse growth in parathyroid hyperplasia
15 Parathyroid Hyperplasia
Fig. 15.24 Secondary parathyroid hyperplasia. Oxyphilic cells with
abundant eosinophilic cytoplasm. In the normal parathyroid gland, oxy-
philic cells may increase with age and in older patients may form nodu-
lar aggregates and be mistaken for parathyroid disease. Oxyphilic cells
may be seen in parathyroid hyperplasia, both primary and secondary,
and in adenomas and carcinomas
Fig. 15.25 Secondary parathyroid hyperplasia. An area of clear cells
in parathyroid hyperplasia. These cells have ovoid nuclei, abundant
clear cytoplasm, and distinct cell membranes. The nuclei often are in
apposition to vessels
Secondary Parathyroid Hyperplasia 117

Fig. 15.26 Secondary parathyroid hyperplasia. Fibrosis and fibrous Fig. 15.28 Secondary parathyroid hyperplasia. A prominent area of
bands may be seen in parathyroid adenomas and hyperplasias, as well hemosiderin deposition is seen in this hyperplastic parathyroid gland.
as carcinomas. Areas of fibrosis must be differentiated from invasion, Hemosiderin may be seen in association with other parathyroid disor-
which is diagnostic of carcinoma. Mitotic figures may be seen in up to ders. It usually is a degenerative finding
80 % of parathyroid hyperplasia cases, but most show less than one
mitotic figure per 10 HPF [5]. Foci of endocrine atypia also may be
seen as microscopic areas of pleomorphism and hyperchromasia.
However, unlike parathyroid carcinoma, hyperplasia does not show
capsular, vascular, or perineural invasion or invasion into adjacent
structures

Fig. 15.29 Secondary parathyroid hyperplasia. This implant of para-

thyroid tissue in the forearm continued to grow and show hyperplastic
changes

Fig. 15.27 Secondary parathyroid hyperplasia. Diffuse hyperplasia

with focal hemosiderin deposition is seen in this parathyroid affected
by secondary hyperplasia. Larger glands and chronicity often are asso-
ciated with degenerative features such as fibrosis and hemosiderin
118 15 Parathyroid Hyperplasia

Tertiary Parathyroid Hyperplasia

Fig. 15.30 Secondary parathyroid hyperplasia. This implant of para-

thyroid tissue in the forearm continued to grow and show hyperplastic
changes in this case of secondary parathyroid hyperplasia
Fig. 15.32 Tertiary parathyroid hyperplasia. This is an example of a
tertiary parathyroid hyperplasia, an autonomously functioning parathy-
roid gland(s) that usually occurs in the setting of or in a patient with
secondary hyperplasia. Up to 8 % of patients with secondary parathy-
roid hyperplasia develop tertiary hyperplasia. The etiology is unknown,
but the disease may occur as a lack of resolution of secondary hyper-
parathyroidism after renal transplantation. Different ideas have been
postulated, including a change in the set point of the calcium-sensing
receptor and resistance to calcimimetic agents. The calcium-sensing set
point may change. Patients may become resistant to calcimimetic
agents

Fig. 15.31 Secondary parathyroid hyperplasia. A focus of amyloid is

seen in this hyperplastic parathyroid gland. Foci of amyloid may be
seen in parathyroid tissues. They may be interesting incidental findings,
but amyloid also may involve the parathyroid in systemic amyloidosis

Fig. 15.33 Tertiary parathyroid hyperplasia. Hyperplastic parathyroid

glands may have nodular or diffuse growth, and growth patterns cannot
distinguish primary from secondary or secondary from tertiary hyper-
plasia. The involved gland(s) shows an increase in parenchymal chief
and oxyphilic cells and a decrease in adipocytes. Tertiary hyperplasia
may affect only one gland, but multiple glands often are involved. It
also is not uncommon for ectopic glands to be involved
References 119

References 5. Snover DC, Foucar K. Mitotic activity in benign parathyroid

disease. Am J Clin Pathol. 1981;75(3):3457.
6. Castleman B, Mallory TB. The pathology of the parathyroid gland
1. Wermers RA, et al. Incidence of primary hyperparathyroidism in
in hyperparathyroidism. A study of 25 cases. Am J Pathol.
Rochester, Minnesota, 1993-2001: an update on the changing epide-
1935;XI(1):172.
miology of the disease. J Bone Miner Res. 2006;21(1):1717.
7. Castleman B, Roth SI. Tumors of the parathyroid glands, Atlas of
2. DeLellis RA. Tumors of the parathyroid gland. In: Rosai J, Sobin
tumor pathology, vol. 14. Washington, DC: Armed Forces Institute
LH, editors. Atlas of tumor pathology, vol. 6. Washington, DC:
of Pathology; 1978.
Armed Forces Institute of Pathology; 1993. p. 102.
8. Castleman B, Schantz A, Roth S. Parathyroid hyperplasia in pri-
3. Tominaga Y, et al. Histological and clinical features of non-familial
mary hyperparathyroidism: a review of 85 cases. Cancer.
primary parathyroid hyperplasia. Pathol Res Pract.
1976;38(4):166875.
1992;188(12):11522.
9. Straus 2nd FH, et al. Five cases of parathyroid lipohyperplasia.
4. DeLellis RA. Parathyroid tumors and related disorders. Mod Pathol.
Surgery. 1983;94(6):9015.
2011;24 Suppl 2:S7893.
 Parathyroid Adenoma
Parathyroid adenoma is a benign neoplasm of chief, onco-
cytic, transitional cells; water-clear cells; or a mixture of cell
types affecting a single parathyroid gland [1]. Parathyroid
adenoma is the most common cause of primary hyperpara-
thyroidism, accounting for 8085 % of cases, with hyperpla-
sia accounting for 15 % and carcinoma 0.51 %. Parathyroid
adenomas most commonly are sporadic, are more common
in women than men (3:1), and occur at any age, although
most occur at ages 5060 years [1]. Parathyroid adenomas
may occur in familial disorders such as multiple endocrine
neoplasia type 1 (MEN1), MEN2A, hyperparathyroidism
jaw tumor (HP-JT) syndrome, and familial isolated hyper-
parathyroidism. Familial cases affect females and males
equally and occur at a younger age than sporadic adenomas.
Unlike patients in the past who had symptoms, namely neph-
rolithiasis and bone disease, patients today often are asymp-
tomatic, with adenomas detected by screening calcium. The
increased incidence of hyperparathyroidism since the 1970s
correlates with the implementation of screening calcium [2].
Serum calcium levels are elevated but usually not as mark-
edly elevated (>13 mg/dL) as in parathyroid carcinoma.
Parathyroid adenomas usually are smaller than carcinomas
and are not palpable. Both may show fibrous bands.
Occasional mitotic figures may be identified in adenomas,
but carcinomas usually have more mitotic figures and higher
Ki67 labeling indices (>4 %) than adenomas (<4 %).
Parathyroid adenomas also have more variety in growth pat-
terns, unlike the monotonous or trabecular growth of carci-
L.A. Erickson, Atlas of Endocrine Pathology, Atlas of Anatomic Pathology,
DOI 10.1007/978-1-4939-0443-3_16, Springer Science+Business Media New York 2014
16
nomas. Most importantly, parathyroid adenomas do not
show invasive growth. Atypical parathyroid adenomas have
some features of carcinoma (adherence to adjacent struc-
tures, mitotic activity, fibrosis, trabecular growth, tumor cells
in capsule) but do not show definitive invasion. Separating
parathyroid adenoma from hyperplasia often requires corre-
lation between the pathologist and surgeon. Parathyroid
hyperplasia is an increase in parathyroid parenchyma mass
involving multiple glands. Traditionally, distinguishing para-
thyroid adenoma from hyperplasia required examination of
at least one additional gland; however, the increasing use of
preoperative localization and imaging and intraoperative
parathyroid hormone (PTH) monitoring have been helpful in
identifying the appropriate gland(s). Subtypes of parathyroid
adenomas (conventional chief cell, oxyphil, and clear cell
adenomas, and lipoadenomas) must be recognized to avoid
confusion with other tumors. The molecular basis of para-
thyroid adenomas is understood better in familial than spo-
radic cases. Inactivating mutations of HRPT2 tumor
suppressor gene (1q21-q32), involved in HP-JT syndrome
and some cases of familial isolated hyperparathyroidism,
have been implicated in a large proportion of familial
parathyroid carcinomas and adenomas and in a subset of
sporadic parathyroid carcinomas but are very uncommon in
sporadic adenomas [36]. Cyclin D1 [7, 8], retinoblastoma
tumor suppressor gene [9, 10], p53 [9, 10], and numeric
chromosomal abnormalities [11, 12] also may be involved in
parathyroid tumorigenesis.
121
122 16 Parathyroid Adenoma

Chief Cell Parathyroid Adenoma

Fig. 16.3 Parathyroid adenoma. At low power, the rim of this parathy-
roid adenoma appears to show normal parathyroid tissue composed of a
mixture of parathyroid parenchyma cells and adipocytes. On closer
inspection, however, the cells in the rim often appear smaller and have
more and larger fat droplets, reflecting suppression, compared with the
cells of the adenoma [1]

Fig. 16.1 Parathyroid adenoma. This parathyroid adenoma weighed more

than 900 mg. Parathyroid adenomas are tan to red-orange in color and
encapsulated [1]. Occasionally, a rim of light brown normal parathyroid
tissue may be seen grossly. Adenomas may vary from 0.2 g to more than
1 g. Bone disease may be more common with larger adenomas. Parathyroid
adenomas generally are smaller than carcinomas, but their size may vary.
Parathyroid adenoma generally involves a single gland, but extraordinarily
rare double and even triple adenomas have been reported. However,
asymmetric hyperplasia is much more likely than multiple adenomas, so
extreme caution is suggested before even considering a diagnosis of mul-
tiple adenomas. Parathyroid adenoma may be ectopic (mediastinum, intra-
thyroidal, thymus, soft tissue) in around 10 % of cases [1]

Fig. 16.4 Parathyroid adenoma. This parathyroid adenoma has a rim

of normal-appearing parathyroid tissue separated from the adenoma by
a fibrous connective tissue capsule. Parathyroid adenomas may be com-
posed of chief, oxyphil, transitional, or clear cells or a mixture of cell
types. The cells in the rim may be smaller than those in the adenoma,
but they may have large lipid droplets, reflecting suppression

Fig. 16.2 Parathyroid adenoma. This chief cell adenoma shows dif-
fuse cellularity in the adenoma and a rim of normal-appearing parathy-
roid tissue. The rim often is separated from the adenoma by a thin
connective tissue capsule [1]. Rims are identified in 5060 % of adeno-
mas and more often in smaller adenomas [1]. A rim is not specific for
parathyroid adenoma, as a rim of normal-appearing parathyroid tissue
occasionally may be seen in parathyroid hyperplasia
Chief Cell Parathyroid Adenoma
Fig. 16.5 Parathyroid adenoma. Parathyroid adenomas are composed
of chief, oxyphilic, transitional, or clear cells, or a mixture of cell types.
Parathyroid adenomas have little stromal fat. This parathyroid adenoma
shows two cell types: oxyphil cells are identified on the left and chief
cells on the right. Unlike thyroid cells, parathyroid cells have well-
demarcated cytoplasmic membranes, cytoplasmic lipid, and round
nuclei with dense chromatin and lack calcium oxalate crystals and col-
loid. These features are helpful in separating parathyroid from thyroid
Fig. 16.6 Parathyroid adenoma. Degenerative edema in the center of a
parathyroid adenoma. Parathyroid adenomas, especially large ones,
may show fibrosis, cystic change, hyalinization, edema, and hemosid-
erin deposition
123
Fig. 16.7 Parathyroid adenoma. Edematous change is seen in the cen-
ter of this parathyroid adenoma
Fig. 16.8 Parathyroid adenoma. Hyalinization and metaplastic bone
are seen in this large parathyroid adenoma. Degenerative features are
more common in large adenomas. Fibrosis may occur in parathyroid
adenomas and must be differentiated from infiltrative growth of para-
thyroid carcinoma. Parathyroid carcinomas usually show more mitotic
figures than adenomas, but there may be overlap. Mitotic figures occur
in up to 71 % of adenomas [13]. Unlike parathyroid carcinoma, adeno-
mas do not show capsular, vascular, or perineural invasion or invasion
of adjacent structures
124
Fig. 16.9 Parathyroid adenoma. This parathyroid adenoma has cystic
change. Cystic change is more common in large adenomas and cases of
HP-JT syndrome
Fig. 16.10 Parathyroid adenoma. This parathyroid adenoma shows
glandular growth, a pattern that may be confused with follicular growth
of the thyroid. In difficult cases, immunostains may be helpful in sepa-
rating parathyroid from thyroid. Parathyroid is positive for chromo-
granin, synaptophysin, and PTH, markers that are negative in
folliculogenic thyroid tumors. Follicular thyroid tumors are positive for
thyroid transcription factor 1 and thyroglobulin, markers negative in
parathyroid
16 Parathyroid Adenoma
Fig. 16.11 Parathyroid adenoma. Endocrine atypia usually is focal
with pleomorphic nuclear features and hyperchromasia. Foci of endo-
crine atypia are not uncommon in benign parathyroid disease and do
not indicate malignancy. Foci of endocrine atypia are seen in up to 25 %
of adenomas [1]. This atypia is different from the monotonous growth
and high nuclear-to-cytoplasmic ratios often seen in parathyroid
carcinoma
Fig. 16.12 Parathyroid adenoma. Signet ring cell change is an uncom-
mon finding in parathyroid adenomas, but recognizing that a variety of
growth patterns may occur in the parathyroid may help identify tissue
as parathyroid
Oxyphil Cell Parathyroid Adenoma 125

Oxyphil Cell Parathyroid Adenoma

Fig. 16.13 Parathyroid adenoma. Spindle cell change, as seen in this

parathyroid adenoma, is an uncommon finding but one that needs to be
recognized and separated from epithelial and mesenchymal nonpara-
thyroid tumors

Fig 16.15 Oxyphil cell parathyroid adenoma. This oxyphil parathy-

roid adenoma weighed 2,800 mg. Oxyphil adenomas are fairly uncom-
mon, comprising 36 % of parathyroid adenomas [14, 15]. Oxyphil
adenomas historically were thought to be nonfunctional, but they now
are recognized as a cause of hyperparathyroidism [14, 15]. The weight
of oxyphil adenomas ranges from 0.2 to 4.0 g [15]. Oxyphil adenomas
are composed of at least 90 % oxyphil cells [14]. Patients range in age
from 28 to 82 years, and women are affected more commonly [15].
These lesions occur in a clinical setting and with elevated serum cal-
cium levels similar to those of chief cell adenomas

Fig. 16.14 Parathyroid adenoma. Large dilated follicular-like spaces

occasionally are seen in parathyroid adenomas. The eosinophilic mate-
rial within the lumen may be mistaken for thyroglobulin, and this fol-
licular growth pattern may easily be mistaken for follicular thyroid
tissue or tumors

Fig. 16.16 Oxyphil cell parathyroid adenoma. This oxyphil cell ade-
noma has a rim of normal parathyroid tissue with fat and nests of oxy-
phil and chief cells. Oxyphil adenomas are composed of at least 90 %
oxyphil cells. This oxyphil adenoma shows an abundance of fat in the
rim, but oxyphil adenomas often have less fat in the rim than chief cell
adenomas
126 16 Parathyroid Adenoma

Clear Cell Parathyroid Adenoma

Fig. 16.17 Oxyphil cell parathyroid adenoma. Oxyphil parathyroid

adenomas are functional tumors that must be separated from oxyphil
carcinomas. Compared with patients with oxyphil or chief cell carcino-
mas, those with oxyphil or chief cell adenomas had elevated serum cal- Fig. 16.19 Clear cell parathyroid adenoma. Clear (water-clear,
cium levels; however, the serum calcium of the carcinomas was higher Wasserhalle) cell parathyroid adenoma is an extremely rare cause of
than that of the adenomas. Patients with oxyphil or chief cell carcinoma hyperparathyroidism [1]. Clear cell parathyroid hyperplasia is more
presented with high levels of serum calcium (n = 15.5 and 13.7 mg/dL, common (at least historically) than clear cell adenoma
respectively), and approximately half the patients in each carcinoma
group died of disease [16]. Primary oxyphil adenomas had a lower Ki67
labeling index than oxyphil carcinomas (1.9 vs. 4.9). Oxyphil adeno-
mas had a higher p27 index than oxyphil carcinomas (66 vs. 23) [16].
Most oxyphil adenomas (35 of 38 cases) expressed keratin 14, but none
of oxyphil carcinomas (0 of 10 cases) expressed keratin 14 [16]. Glut-4
was expressed more commonly in oxyphil and chief cell adenomas than
in oxyphil and chief cell carcinomas [16]

Fig. 16.20 Clear cell parathyroid adenoma. This clear cell parathyroid
adenoma is composed of large polygonal cells with clear cytoplasm and
well-defined cytoplasmic membranes. The clearing may represent vac-
uolization or glycogenation of cytoplasm or artifact

Fig. 16.18 Oxyphil cell parathyroid adenoma. The cells in this oxy-
phil adenoma show nuclear palisading around vessels. Oxyphil cells
have abundant eosinophilic cytoplasm, reflecting an abundance of mito-
chondria. Oxyphil adenomas may have occasional mitotic figures and
foci of endocrine atypia. Unlike oxyphil carcinomas, however, oxyphil
adenomas do not show definitive invasion. No capsular, vascular, or
perineural invasion or invasion into adjacent organs is identified.
Oxyphil adenomas also must be separated from Hurthle cell tumors of
the parathyroid. Lipid in parathyroid cells and colloid and crystals in
the thyroid are helpful differentiating features. In difficult cases, immu-
noperoxidase studies may be used
Parathyroid Lipoadenoma 127

Parathyroid Lipoadenoma

Fig. 16.23 Parathyroid lipoadenoma. Oxyphil lipoadenoma is a

lipoadenoma with small nests of oxyphil cells and abundant adipose
tissue (>50 %). In the series of five cases of lipoadenomas from the
Fig. 16.21 Parathyroid lipoadenoma. Parathyroid lipoadenoma is a Mayo Clinic, only one was an oxyphil lipoadenoma [17]. The stroma
rare lesion composed of abundant adipose tissue (>50 %) and scattered of lipoadenomas may have myxoid change, calcium, and fibrosis
small nests of parathyroid parenchyma cells and hyperparathyroidism [18]. A variant of lipoadenoma with thymic elements is referred to as
[1, 17]. The clinical setting is similar to that of conventional adenomas, thymolipoadenoma
but these are such rare entities that few cases have been studied. In a
series of five cases from the Mayo Clinic from 1971 to 2001, three were
in women and two in men [17]. The mean serum calcium was 11.1 mg/
dL, and all patients had elevated serum PTH [17]. Only one patient had
hypercalcemia-related symptoms of nephrolithiasis and hip fracture [17]

Fig. 16.24 Parathyroid lipoadenoma. Oxyphil lipoadenoma with

abundant adipose and small nests of oxyphil cells. The abundant adi-
pose makes lipoadenomas difficult to identify with imaging, but lipoad-
enomas were identified in two of three patients evaluated by neck
ultrasound in the series from the Mayo Clinic [17]. Technetium (Tc
Fig. 16.22 Parathyroid lipoadenoma. Parathyroid lipoadenomas may 99m) sestamibi scanning also may be helpful in these cases
contain small irregular nests of chief cells or oxyphil cells. In this exam-
ple, the lipoadenoma contains scattered nests of chief cells. If more than
one gland is involved, the disease would be diagnosed as parathyroid
lipohyperplasia (lipoadenomatous hyperplasia)
128 16 Parathyroid Adenoma

Atypical Parathyroid Adenoma

Fig. 16.27 Atypical parathyroid adenoma. This atypical parathyroid

adenoma was adherent to adjacent thyroid tissue. Intraoperatively, it
may be difficult to differentiate atypical parathyroid adenoma from car-
Fig. 16.25 Atypical parathyroid adenoma. Atypical parathyroid ade- cinoma, because both may adhere to adjacent structures [22]. Of 16
noma is a parathyroid neoplasm composed of chief, oxyphil, or transi- atypical parathyroid adenomas and 11 carcinomas, the clinical presen-
tional cells, or a mixture of cell types, that has atypical features (mitotic tation and operative findings were indistinguishable [22]. Although
activity, trabecular growth, fibrosis, tumor cells within the capsule, or atypical adenomas have atypical features, they are generally associated
adherence to adjacent structures) but does not show definitive invasion with indolent behavior
[1, 19, 20]. The lack of invasive growth separates atypical parathyroid
adenoma from carcinoma. Atypical adenomas are usually functional
tumors with hypercalcemia. Serum calcium levels may be intermediate
between conventional adenomas and carcinomas [20, 21]. Parathyroid
adenomas are more common in women, but atypical parathyroid adeno-
mas affect women and men similarly. Atypical adenomas, unlike 32 %
of parathyroid carcinomas, are not associated with a palpable neck
mass [20]

Fig. 16.28 Atypical parathyroid adenoma. This atypical parathyroid

adenoma is adherent to the thyroid (upper left). If the tumor invaded the
thyroid parenchyma, it would be regarded as a parathyroid carcinoma.
Invasive growth, capsular or vascular invasion, or invasion of adjacent
structures is diagnostic of malignancy. Although this is a difficult case,
the tumor appears to adhere to, rather than invade, the thyroid

Fig. 16.26 Atypical parathyroid adenoma. This atypical parathyroid

adenoma is hypercellular and has a thick capsule, fibrosis, and entrapped
tumor cells, but no definitive capsular, vascular, or perineural invasion
or invasion of adjacent structures. Atypical parathyroid adenoma often
has fibrosis but lacks definitive capsular or vascular invasion and inva-
sion of adjacent structures [1, 19]. In a study by Guiter and DeLellis
[21] of 24 atypical adenomas, 87 % had tumor cells trapped in the cap-
sule, 75 % had fibrosis, 58 % had prominent hemosiderin, 50 % had
cystic change, 30 % had mitoses, and 25 % had peritumoral fibrosis
Atypical Parathyroid Adenoma
Fig. 16.29 Atypical parathyroid adenoma. This atypical parathyroid
adenoma has fibrosis and cells entrapped in the fibrosis, which must be
distinguished from true invasion
Fig. 16.30 Atypical parathyroid adenoma. The irregular growth and
fibrous bands in this atypical parathyroid adenoma are concerning for
malignancy. Definitive invasion, however, is not identified as would be
required for a diagnosis of parathyroid carcinoma
129
Fig. 16.31 Atypical parathyroid adenoma. Monotonous growth is
seen in this atypical parathyroid adenoma. Occasional mitotic figures
may be seen in atypical parathyroid adenomas, but atypical mitoses
generally are seen only in parathyroid carcinomas
Fig. 16.32 Atypical parathyroid adenoma. The Ki67 labeling index
highlights proliferating cells in this atypical parathyroid adenoma. Ki67
has a higher labeling index in parathyroid carcinoma than in adenoma,
but there may be overlap. Thus, markers such as Ki67 need to be evalu-
ated in the setting of the other features
130 16 Parathyroid Adenoma

References 11. Agarwal SK, et al. Comparative genomic hybridization analysis of

human parathyroid tumors. Cancer Genet Cytogenet. 1998;106(1):
306.
1. DeLellis RA. Tumors of the parathyroid gland. In: Rosai J, Sobin
12. Erickson LA, et al. Analysis of parathyroid neoplasms by inter-
LH, editors. Atlas of tumor pathology, vol. 6. Washington, DC:
phase fluorescence in situ hybridization. Am J Surg Pathol. 2004;
Armed Forces Institute of Pathology; 1993. p. 102.
28(5):57884.
2. Wermers RA, et al. Incidence of primary hyperparathyroidism in
13. Snover DC, Foucar K. Mitotic activity in benign parathyroid dis-
Rochester, Minnesota, 19932001: an update on the changing epi-
ease. Am J Clin Pathol. 1981;75(3):3457.
demiology of the disease. J Bone Miner Res. 2006;21(1):1717.
14. Wolpert HR, Vickery Jr AL, Wang CA. Functioning oxyphil cell
3. DeLellis RA. Parathyroid carcinoma: an overview. Adv Anat
adenomas of the parathyroid gland. A study of 15 cases. Am J Surg
Pathol. 2005;12(2):5361.
Pathol. 1989;13(6):5004.
4. Howell VM, et al. HRPT2 mutations are associated with malig-
15. Bedetti CD, Dekker A, Watson CG. Functioning oxyphil cell adenoma
nancy in sporadic parathyroid tumours. J Med Genet.
of the parathyroid gland: a clinicopathologic study of ten patients
2003;40(9):65763.
with hyperparathyroidism. Hum Pathol. 1984;15(12):11216.
5. Shattuck TM, et al. Somatic and germ-line mutations of the HRPT2
16. Erickson LA, et al. Oxyphil parathyroid carcinomas: a clinicopath-
gene in sporadic parathyroid carcinoma. N Engl J Med.
ologic and immunohistochemical study of 10 cases. Am J Surg
2003;349(18):17229.
Pathol. 2002;26(3):3449.
6. Krebs LJ, Shattuck TM, Arnold A. HRPT2 mutational analysis of
17. Chow LS, et al. Parathyroid lipoadenomas: a rare cause of primary
typical sporadic parathyroid adenomas. J Clin Endocrinol Metab.
hyperparathyroidism. Endocr Pract. 2006;12(2):1316.
2005;90(9):50157.
18. Gabbert H, Rothmund M, Hohn P. Myxoid lipoadenoma of the
7. Hsi ED, et al. Cyclin D1/PRAD1 expression in parathyroid adeno-
parathyroid gland. Pathol Res Pract. 1980;170(4):4205.
mas: an immunohistochemical study. J Clin Endocrinol Metab.
19. DeLellis RA. Parathyroid tumors and related disorders. Mod
1996;81(5):17369.
Pathol. 2011;24 Suppl 2:S7893.
8. Hemmer S, et al. Deletion of 11q23 and cyclin D1 overexpression
20. Fernandez-Ranvier GG, et al. Parathyroid carcinoma, atypical para-
are frequent aberrations in parathyroid adenomas. Am J Pathol.
thyroid adenoma, or parathyromatosis? Cancer. 2007;110(2):25564.
2001;158(4):135562.
21. Guiter GE, DeLellis RA. Risk of recurrence or metastases in atypi-
9. Cryns VL, et al. Loss of the retinoblastoma tumor-suppressor gene
cal parathyroid adenomas [abstract]. Mod Pathol. 2002;15:115A.
in parathyroid carcinoma. N Engl J Med. 1994;330(11):75761.
22. Ippolito G, et al. Intraoperative diagnosis and treatment of parathy-
10. Cryns VL, et al. p53 abnormalities in human parathyroid carci-
roid cancer and atypical parathyroid adenoma. Br J Surg. 2007;
noma. J Clin Endocrinol Metab. 1994;78(6):13204.
94(5):56670.
 Parathyroid Carcinoma
Parathyroid carcinoma accounts for 1 % of hyperparathy-
roidism cases, affects men and women equally, and occurs
over a wide age range, although most patients are in their
mid-40s to mid-50s. Symptoms are polyuria, polydipsia,
nephrolithiasis, fatigue, nausea, bone disease, and a palpable
neck mass. Serum calcium often is markedly elevated (13.2
15.5 mg/dL), as is parathyroid hormone (PTH) and alkaline
phosphatase. Most carcinomas are sporadic but may occur in
hyperparathyroidismjaw tumor syndrome (HP-JT) and
familial isolated hyperparathyroidism (FIH). FIH, an autoso-
mal dominant disorder associated with HRPT2, MEN1, and
a 1.7-Mb region on 2p13.3-14, involves only the parathyroid
[15]. HP-JT is an autosomal dominant disorder caused by
inactivating mutations of the HRPT2 tumor suppressor gene
(1q21-q32) [1, 6]. The incidence of parathyroid carcinoma in
HJ-PT is 15 % [6]. HP-JT includes parathyroid, jaw tumors,
kidney cysts, Wilms tumors, and uterine tumors. Sporadic
carcinomas may have acquired HRPT2 inactivation, but spo-
radic adenomas do not [79]. Ten of 15 carcinomas in
patients with no family history had HRPT2 mutations, and 3
were germline [7]. Some apparently sporadic carcinomas
may have germline HRPT2 mutations and HP-JT or a variant
[7]. The diagnosis of carcinoma requires vascular or perineu-
ral invasion, invasion of adjacent structures, or metastases
[10, 11]. Carcinomas often have sheet-like or trabecular
growth and are cytologically monotonous with high nuclear-
to-cytoplasmic ratios, prominent nucleoli, mitotic activity,
fibrous bands, and necrosis. Parathyroid carcinomas are pos-
itive for chromogranin, synaptophysin, keratin (Cam 5.2),
and PTH and negative for thyroid transcription factor 1
(TTF1), and thyroglobulin. Carcinomas have higher Ki67
labeling indices (LIs) than adenomas (>68.4 % vs.
L.A. Erickson, Atlas of Endocrine Pathology, Atlas of Anatomic Pathology,
DOI 10.1007/978-1-4939-0443-3_17, Springer Science+Business Media New York 2014
17
<25.3 %) [1215]. A Ki67 LI greater than 6 % and galectin-
3 expression also favor malignancy [16]. Carcinomas show
decreased p27 expression [1417]. Normal parathyroids
have the highest p27 LI (89.6), followed by hyperplasia
(69.6), adenomas (56.8), and carcinomas (13.9) [14]. A
study found p27+Bcl-2+Ki67mdm2+ in 76 % of adenomas,
29 % of atypical adenomas, and 0 % of carcinomas [15]. p53
[18], cyclin D1/PRAD1 [18, 19], retinoblastoma [13], and
numeric chromosomal abnormalities [20, 21] have been
evaluated but are not used diagnostically. Parafibromin is a
protein encoded by HRPT2, and HRPT2 inactivation is asso-
ciated with loss of parafibromin nuclear staining.
Parafibromin expression may help differentiate adenoma
from carcinoma [2224]. Tan et al. [24] found loss of nuclear
parafibromin has 96 % sensitivity and 99 % specificity in
definite carcinomas. However, others reported a loss of
parafibromin in 61.6 % of carcinomas if they included weak
staining or staining of a portion of the cells as loss of
parafibromin. [25]. Carcinomas in secondary or tertiary
hyperplasia may not show parafibromin loss [26]. Parathyroid
carcinomas are treated by en bloc resection of the tumor and
ipsilateral thyroid lobe, which carries the best chance for
cure [2729]. However, clinical and operative findings can-
not distinguish atypical adenoma from carcinoma reliably,
thus less extensive surgery often is performed [30]. Poor
prognostic factors are male sex, older age, local excision
rather than extensive surgery, margin involvement, and dis-
tant metastases [29, 31]. Postoperative radiation improves
survival and decreases locoregional progression and recur-
rent disease [31]. Five- and 10-year relative survival rates are
85.5 and 49.1 %, respectively [29]. Uncontrollable
hypercalcemia is the usual cause of death.
131
132 17 Parathyroid Carcinoma

Fig. 17.3 Parathyroid carcinoma. Invasive growth is seen in this para-

thyroid adenoma. Differentiating invasive growth in a parathyroid car-
cinoma from fibrous bands and fibrosis, which may be seen in
parathyroid carcinoma and adenoma, may be difficult

Fig. 17.1 Parathyroid carcinoma. This is a parathyroid carcinoma.

Parathyroid carcinomas usually are larger than adenomas, but may
overlap in size. Carcinomas may vary in size, but most weigh 1.527 g,
measure 1.56 cm, and often are adherent to adjacent structures [10,
29]. Clinical and operative findings cannot distinguish atypical ade-
noma from carcinoma reliably [30]. Unlike parathyroid adenoma, para-
thyroid carcinoma may be associated with a palpable neck mass. A
recent study found 9 of 28 parathyroid carcinomas (32 %) were associ-
ated with a palpable neck mass, whereas none of the seven atypical
parathyroid adenomas had a palpable neck mass [32]

Fig. 17.4 Parathyroid carcinoma. This parathyroid carcinoma is

invading the skeletal muscle in the neck. Invasion of adjacent structures
in the neck indicates malignancy in parathyroid carcinoma

Fig. 17.2 Parathyroid carcinoma. This parathyroid carcinoma is

invading the perithyroidal soft tissue. This infiltrative growth is diag-
nostic of malignancy in a parathyroid tumor
Parathyroid Carcinoma
Fig. 17.5 Parathyroid carcinoma. Invasion of the skeletal muscle in
the neck, as seen in this parathyroid carcinoma, indicates malignancy.
Differentiating fibrous bands from infiltrative growth may be difficult,
but invasion of adjacent structures in the neck is more readily diagnostic
of malignancy
Fig. 17.6 Parathyroid carcinoma. This parathyroid carcinoma (right)
has invaded the thyroid (left). Invasion of the thyroid is diagnostic of
malignancy. However, this must be differentiated from parathyroid tis-
sue adherent to the thyroid, which may occur in benign parathyroid
disease. Also, parathyroid adenomas may be intrathyroidal in rare cases
133
Fig. 17.7 Parathyroid carcinoma. A vascular thrombus of parathyroid
carcinoma cells is seen in this photograph. Vascular invasion is diag-
nostic of malignancy in the parathyroid. Often, areas of irregular nests
of parathyroid tissue may be seen in fibrosis with retraction artifact,
which must be differentiated from true vascular invasion
Fig. 17.8 Parathyroid carcinoma. This parathyroid carcinoma has
fibrous bands, which are a worrisome feature but are not diagnostic of
malignancy because they also may be seen in parathyroid adenoma and
hyperplasia
134
Fig. 17.9 Parathyroid carcinoma. This low-power view shows the
monotonous growth pattern often seen in parathyroid carcinoma, with
sheets of cells with high nuclear-to-cytoplasmic ratios. Although this
monotonous pattern of growth is worrisome, it is not diagnostic of
malignancy in itself
Fig. 17.10 Parathyroid carcinoma. Monotonous growth of chief cells
is seen in this parathyroid carcinoma. Parathyroid carcinomas often
show a monotonous or trabecular growth pattern rather than a mixture
of growth patterns. However, this feature alone is not sufficient for a
diagnosis of malignancy. A diagnosis of malignancy in the parathyroid
requires invasive growth or metastatic disease
17 Parathyroid Carcinoma
Fig. 17.11 Parathyroid carcinoma. This parathyroid carcinoma has
hemosiderin deposition and mitotic activity. Mitotic figures are not
definitive of malignancy in the parathyroid, as they may be seen in both
benign and malignant parathyroid lesions. However, parathyroid carci-
nomas generally have more mitoses compared with adenomas, and
atypical mitoses usually are seen only in parathyroid carcinomas
Fig. 17.12 Parathyroid carcinoma. Multiple mitotic figures are pres-
ent in this parathyroid carcinoma. This tumor also shows nuclear
pleomorphism
Parathyroid Carcinoma
Fig. 17.13 Parathyroid carcinoma. A glandular growth pattern is seen
in this parathyroid carcinoma. Although parathyroid carcinomas may
show different growth patterns, the pattern usually is very monotonous
Fig. 17.14 Parathyroid carcinoma. This unusual parathyroid carci-
noma has an area of dilated follicular structures with proteinaceous
material that easily could be mistaken for thyroid tissue. In difficult
cases, immunoperoxidase studies may be helpful in separating parathy-
roid from thyroid. Parathyroid is positive for chromogranin, synapto-
physin, and PTH, whereas folliculogenic thyroid tissues and tumors are
positive for thyroglobulin and TTF1
135
Fig. 17.15 Parathyroid carcinoma. This is an oxyphilic parathyroid
carcinoma. Oxyphilic parathyroid carcinomas have clinical features
similar to those of chief cell carcinomas. Oxyphilic carcinomas are
functional tumors associated with hypercalcemia and hyperparathy-
roidism [33]. In a comparison of oxyphilic parathyroid adenomas with
oxyphilic parathyroid carcinomas and chief cell adenomas and carcino-
mas, patients with oxyphilic and chief cell carcinoma presented with
high serum levels of calcium (n = 15.5 and 13.7 mg/dL, respectively),
and approximately half the patients in each group died of disease [33].
Like chief cell carcinomas, oxyphilic parathyroid carcinomas are func-
tional tumors associated with recurrence and death from disease [33]
Fig. 17.16 Parathyroid carcinoma. This oxyphilic parathyroid carci-
noma has numerous mitotic figures. Mitotic activity is more prominent
and Ki67 LIs are higher in oxyphilic parathyroid carcinomas than oxy-
philic adenomas (4.9 vs. 1.9) [33]. Oxyphilic carcinomas have a lower
p27 index compared with oxyphilic adenomas (23 vs. 66) [33]. Most
oxyphilic adenomas express keratin 14, a marker generally not
expressed in oxyphilic carcinomas [33]. Glut-4 also is expressed more
commonly in oxyphilic and chief cell adenomas than in oxyphilic and
chief cell carcinomas [33]
136
Fig. 17.17 Parathyroid carcinoma. This oxyphilic parathyroid carci-
noma has mitotic figures and an intranuclear pink hole. Although intra-
nuclear pink holes are common in papillary thyroid carcinoma, they are
not specific. Intranuclear pink holes also may be seen in medullary thy-
roid carcinoma as well as in parathyroid tissues and tumors
Fig. 17.18 Parathyroid carcinoma. This oxyphilic parathyroid carci-
noma shows vascular invasion as well as invasion of the adjacent thy-
roid. Similar to chief cell parathyroid carcinomas, invasive growth is
required for a diagnosis of oxyphilic parathyroid carcinoma
17 Parathyroid Carcinoma
Fig. 17.19 Parathyroid carcinoma. Trabecular growth pattern is seen
in this chief cell parathyroid carcinoma. Although trabecular growth is
common in parathyroid carcinoma, this growth pattern alone is not suf-
ficient for a diagnosis of malignancy
Fig. 17.20 Parathyroid carcinoma. Palisading of parathyroid cells
around vessels is a common growth pattern in benign and malignant
parathyroid tumors
Parathyroid Carcinoma
Fig. 17.21 Parathyroid carcinoma. Prominent palisading of tumor
cells around a vessel is seen in this parathyroid carcinoma
Fig. 17.22 Parathyroid carcinoma. Sheet-like growth is seen in this
functioning clear cell parathyroid carcinoma. Clear cell parathyroid
carcinomas are quite rare. In difficult cases, immunostains may be help-
ful in differentiating these tumors from other tumors in the neck as well
as metastases to the neck. Diagnosis of malignancy in a clear cell para-
thyroid neoplasm is similar to that of conventional parathyroid carci-
noma: it requires invasive growth or metastases
137
Fig. 17.23 Parathyroid carcinoma. Nuclear atypia and mitotic activity
are seen in this clear cell parathyroid carcinoma. Although these fea-
tures are worrisome for malignancy, invasive growth or metastasis is
required for a definitive diagnosis of carcinoma in a parathyroid tumor
Fig. 17.24 Parathyroid carcinoma. This parathyroid carcinoma has
metastasized to the lung, a common site of metastases for parathyroid
carcinoma, along with the lymph nodes, bones, and liver [28, 29].
These tumors often recur before they metastasize. The average time to
recurrence is 33 months but may be longer (range, 1228 months) [27].
Poor prognostic features are male sex, older age, local excision rather
than extensive surgery, the institution in which the surgery was per-
formed, margin involvement, and distant metastases [29, 31]. The best
surgical chance for cure is en bloc resection of the tumor and associated
structures, such as the ipsilateral thyroid lobe [2729]. Patients treated
with extensive surgery have longer survival and relapse-free survival
[27]. Postoperative radiation may decrease the risk of locoregional dis-
ease progression, improve cause-specific survival, and provide locore-
gional control of recurrent disease [31]
138
References
1. Warner JV, et al. Familial isolated hyperparathyroidism is linked to
a 1.7 Mb region on chromosome 2p13.3-14. J Med Genet. 2006;
43(3):e12.
2. Guarnieri V, et al. Diagnosis of parathyroid tumors in familial iso-
lated hyperparathyroidism with HRPT2 mutation: implications for
cancer surveillance. J Clin Endocrinol Metab. 2006;91(8):282732.
3. Teh BT, et al. Familial isolated hyperparathyroidism maps to the
hyperparathyroidism-jaw tumor locus in 1q21-q32 in a subset of
families. J Clin Endocrinol Metab. 1998;83(6):211420.
4. Villablanca A, et al. Germline and de novo mutations in the HRPT2
tumour suppressor gene in familial isolated hyperparathyroidism
(FIHP). J Med Genet. 2004;41(3):e32.
5. Villablanca A, et al. Involvement of the MEN1 gene locus in familial
isolated hyperparathyroidism. Eur J Endocrinol. 2002;147(3):31322.
6. Marx SJ, et al. Hyperparathyroidism in hereditary syndromes: spe-
cial expressions and special managements. J Bone Miner Res.
2002;17 Suppl 2:N3743.
7. Shattuck TM, et al. Somatic and germ-line mutations of the HRPT2
gene in sporadic parathyroid carcinoma. N Engl J Med. 2003;
349(18):17229.
8. Howell VM, et al. HRPT2 mutations are associated with malignancy
in sporadic parathyroid tumours. J Med Genet. 2003;40(9):65763.
9. Krebs LJ, Shattuck TM, Arnold A. HRPT2 mutational analysis of
typical sporadic parathyroid adenomas. J Clin Endocrinol Metab.
2005;90(9):50157.
10. DeLellis RA. Tumors of the parathyroid gland. In: Rosai J, Sobin
LH, editors. Atlas of tumor pathology, vol. 6. Washington: Armed
Forces Institute of, Pathology; 1993. p. 102.
11. DeLellis RA. Parathyroid tumors and related disorders. Mod
Pathol. 2011;24 Suppl 2:S7893.
12. Abbona GC, et al. Proliferative activity in parathyroid tumors as
detected by Ki-67 immunostaining. Hum Pathol. 1995;26(2):1358.
13. Lloyd RV, et al. Immunohistochemical analysis of the cell cycle-
associated antigens Ki-67 and retinoblastoma protein in parathy-
roid carcinomas and adenomas. Endocr Pathol. 1995;6(4):27987.
14. Erickson LA, et al. Parathyroid hyperplasia, adenomas, and carci-
nomas: differential expression of p27Kip1 protein. Am J Surg
Pathol. 1999;23(3):28895.
15. Stojadinovic A, et al. Parathyroid neoplasms: clinical, histopatho-
logical, and tissue microarray-based molecular analysis. Hum
Pathol. 2003;34(1):5464.
16. Bergero N, et al. Galectin-3 expression in parathyroid carcinoma:
immunohistochemical study of 26 cases. Hum Pathol.
2005;36(8):90814.
17. Erickson LA. p27(kip1) and other cell-cycle protein expression in
normal and neoplastic endocrine tissues. Endocr Pathol. 2000;
11(2):10922.
17 Parathyroid Carcinoma
18. Cryns VL, et al. p53 abnormalities in human parathyroid carcinoma.
J Clin Endocrinol Metab. 1994;78(6):13204.
19. Hemmer S, et al. Deletion of 11q23 and cyclin D1 overexpression
are frequent aberrations in parathyroid adenomas. Am J Pathol.
2001;158(4):135562.
20. Erickson LA, et al. Analysis of parathyroid neoplasms by inter-
phase fluorescence in situ hybridization. Am J Surg Pathol. 2004;
28(5):57884.
21. Agarwal SK, et al. Comparative genomic hybridization analysis of
human parathyroid tumors. Cancer Genet Cytogenet. 1998;106(1):
306.
22. Gill AJ, et al. Loss of nuclear expression of parafibromin distin-
guishes parathyroid carcinomas and hyperparathyroidism-jaw
tumor (HPT-JT) syndrome-related adenomas from sporadic para-
thyroid adenomas and hyperplasias. Am J Surg Pathol. 2006;30(9):
11409.
23. Juhlin CC, et al. Parafibromin immunoreactivity: its use as an addi-
tional diagnostic marker for parathyroid tumor classification.
Endocr Relat Cancer. 2007;14(2):50112.
24. Tan MH, et al. Loss of parafibromin immunoreactivity is a distin-
guishing feature of parathyroid carcinoma. Clin Cancer Res.
2004;10(19):662937.
25. DeLellis RA, Mazzaglia P, Mangray S. Primary hyperparathyroidism:
a current perspective. Arch Pathol Lab Med. 2008;132(8):125162.
26. Tominaga Y, et al. Expression of parafibromin in distant metastatic
parathyroid tumors in patients with advanced secondary hyperpara-
thyroidism due to chronic kidney disease. World J Surg.
2008;32(5):81521.
27. Sandelin K, et al. Prognostic factors in parathyroid cancer: a review
of 95 cases. World J Surg. 1992;16(4):72431.
28. Talat N, Schulte KM. Clinical presentation, staging and long-term
evolution of parathyroid cancer. Ann Surg Oncol. 2010;17(8):
215674.
29. Hundahl SA, et al. Two hundred eighty-six cases of parathyroid
carcinoma treated in the U.S. between 19851995: a National
Cancer Data Base Report. The American College of Surgeons
Commission on Cancer and the American Cancer Society. Cancer.
1999;86(3):53844.
30. Ippolito G, et al. Intraoperative diagnosis and treatment of parathy-
roid cancer and atypical parathyroid adenoma. Br J Surg.
2007;94(5):56670.
31. Munson ND, et al. Parathyroid carcinoma: is there a role for adju-
vant radiation therapy? Cancer. 2003;98(11):237884.
32. Fernandez-Ranvier GG, et al. Parathyroid carcinoma, atypical para-
thyroid adenoma, or parathyromatosis? Cancer. 2007;110(2):
25564.
33. Erickson LA, et al. Oxyphil parathyroid carcinomas: a clinicopath-
ologic and immunohistochemical study of 10 cases. Am J Surg
Pathol. 2002;26(3):3449.
 Parathyromatosis
18

Parathyromatosis is a rare cause of persistent or recurrent
hyperparathyroidism. It is characterized by small nodules
and nests of hyperfunctioning parathyroid tissue in soft tis-
sue caused by seeding or implantation of parathyroid tissue
during surgical removal or by overgrowth of embryologic
nests of parathyroid tissue left behind in development.
Parathyromatosis is more common in females, in the fifth to
sixth decade, and in end-stage renal disease [1].
Differentiating parathyromatosis from parathyroid carci-
noma may be difficult, but patients with parathyroid carci-
noma usually have higher serum calcium levels (14 mg/dL)
and may have a palpable neck mass [2]. Serum calcium lev-
els may overlap in benign and malignant parathyroid dis-
ease; thus, careful histologic examination is required to
separate these entities. Although nests and nodules of para-
thyroid cells are identified in soft tissue in parathyromatosis,
they usually do not appear to have an infiltrative growth pat-
tern. This lack of invasive growth is helpful in separating
parathyromatosis from parathyroid carcinoma. Treating
parathyromatosis may be difficult because surgical treatment
may fail or not be feasible, and calcimimetic agents may be
used [1].

L.A. Erickson, Atlas of Endocrine Pathology, Atlas of Anatomic Pathology, 139

DOI 10.1007/978-1-4939-0443-3_18, Springer Science+Business Media New York 2014
140
Fig. 18.1 Parathyromatosis. Parathyromatosis is characterized by
small nodules and nests of hyperfunctioning parathyroid tissue in soft
tissue. This may be caused by seeding or implantation of parathyroid
tissue during surgical removal or by overgrowth of parathyroid rests left
behind in development
Fig. 18.2 Parathyromatosis. Nodules of hypercellular parathyroid tis-
sue are seen in the soft tissue in this case of parathyromatosis.
Parathyromatosis, although rare, is a cause of recurrent or persistent
hyperparathyroidism. Parathyromatosis is more common with end-
stage renal disease, in females, and in the fifth to sixth decade of life [1].
Treating parathyromatosis may be difficult because surgical treatment
may fail or not be feasible, and calcimimetic agents may be used [1]
18 Parathyromatosis
Fig. 18.3 Parathyromatosis. The nests and nodules of parathyroid
cells in parathyromatosis are within soft tissue but do not appear to have
an infiltrative growth pattern. Rather, they appear to be expansive but
not infiltrating. This lack of invasive growth is helpful in separating
parathyromatosis from parathyroid carcinoma
Fig. 18.4 Parathyromatosis. This nodule of parathyromatosis is adja-
cent to skeletal muscle in this photograph. Note the lack of infiltrative
growth. Comparing 13 cases of parathyromatosis with 7 atypical ade-
nomas and 28 carcinomas, a palpable neck mass and hoarseness were
identified almost exclusively in carcinoma [2]. Patients with parathy-
roid carcinoma usually have a higher serum calcium level, with 16 of 26
patients with levels 14 mg/dL, whereas only 1 of 6 patients with
atypical adenoma and none of the 13 patients with parathyromatosis
were associated with this degree of hypercalcemia [2]. However, serum
calcium levels may overlap; thus, careful histologic evaluation is
required
References 141

References
1. Hage MP, Salti I, El-Hajj Fuleihan G. Parathyromatosis: a rare yet
problematic etiology of recurrent and persistent hyperparathyroid-
ism. Metabolism. 2012;61(6):76275.
2. Fernandez-Ranvier GG, et al. Parathyroid carcinoma, atypical
parathyroid adenoma, or parathyromatosis? Cancer. 2007;110(2):
25564.
 Metastases to Parathyroid
19

Although metastases or secondary direct extension of tumor to
parathyroid tissues and tumors is rare, it is known to occur. In
a series of 911 papillary thyroid carcinomas, 20 involved the
parathyroid by direct invasion from the main tumor with infil-
trative growth, invasion of the parathyroid with an expansive
growth with pseudocapsule between the carcinoma and the
parathyroid, and metastatic tumor within the parathyroid gland
[1]. Of the 20 cases, 6 (30 %) had primary thyroid tumors
measuring 1 cm or less and 14 (70 %) had primary tumors
measuring more than 1 cm, indicating that parathyroid
involvement may occur in papillary thyroid carcinomas even
in the early stage of the disease [1]. A study of 1,770 thyroid
carcinomas identified 10 (6 papillary, 3 follicular, and 1 ana-
plastic thyroid carcinoma) with parathyroid metastases (0.5 %)
[2]. Other tumors in the neck may involve the parathyroid sec-
ondarily. Hepatocellular carcinoma, breast carcinoma, and
tumors from other visceral sites may occasionally metastasize
to the parathyroid or even to a parathyroid adenoma [3, 4].

L.A. Erickson, Atlas of Endocrine Pathology, Atlas of Anatomic Pathology, 143

DOI 10.1007/978-1-4939-0443-3_19, Springer Science+Business Media New York 2014
144
Fig. 19.1 Medullary thyroid carcinoma invading adjacent parathyroid.
This medullary thyroid carcinoma is invading the parathyroid. Thyroid
tumors, most often papillary thyroid carcinoma, may involve the para-
thyroid secondarily. This may occur by direct extension or by
metastasis
Fig. 19.2 Medullary thyroid carcinoma invading adjacent parathyroid.
This medullary thyroid carcinoma has invaded the adjacent parathyroid
gland. In difficult cases, immunoperoxidase studies may be helpful in
differentiating primary parathyroid tumors from tumors involving the
parathyroid secondarily. In a case such as this, both the medullary thy-
roid carcinoma and the parathyroid tissue would be positive for the neu-
roendocrine markers synaptophysin and chromogranin and positive for
keratin (Cam5.2). However, medullary thyroid carcinoma would be
positive for thyroid transcription factor 1 and calcitonin, and parathy-
roid tissue would be positive for parathyroid hormone
19 Metastases to Parathyroid
Fig. 19.3 Carcinoma metastatic to the parathyroid. Tumors may
involve the parathyroid secondarily by direct extension or metastatic
spread. This is a carcinoma, thought to be of breast origin, metastatic to
the parathyroid. Parathyroid tissue is identified in the lower half of the
photograph. The metastatic carcinoma is in the upper portion of the
photograph
Fig. 19.4 Carcinoma metastatic to the parathyroid. This is a tumor
thrombus of carcinoma metastatic to the parathyroid gland. It was
thought likely to be from a breast primary. Although immunopheno-
typic findings may not be specific with regard to the primary site,
immunostains are helpful in differentiating parathyroid tissues and
tumors from those from other sites
References 145

References 3. Lee HE, et al. Tumor-to-tumor metastasis: hepatocellular carcinoma

metastatic to parathyroid adenoma. Pathol Int. 2011;61(10):
5937.
1. Tang W, et al. Parathyroid gland involvement by papillary carcinoma
4. Fulciniti F, et al. Metastatic breast carcinoma to parathyroid
of the thyroid gland. Arch Pathol Lab Med. 2002;126(12):15114.
adenoma on fine needle cytology sample: report of a case. Diagn
2. Chrisoulidou A, et al. Parathyroid involvement in thyroid cancer: an
Cytopathol. 2011;39(9):6815.
unforeseen event. World J Surg Oncol. 2012;10:121.
 Adrenal Gland Histology
The adrenal glands are composed of two distinct types of tis-
sue: adrenal cortical tissue and adrenal medullary tissue. The
adrenal cortex is approximately 2 mm thick and surrounds
the adrenal medulla [1]. The adrenal cortex shows zonation
with the thin discontinuous zona glomerulosa most periph-
erally, the zona fasciculata comprising most of the cortex,
and the innermost zona reticularis cells, which are adjacent
to the adrenal medulla. The adrenal cortex synthesizes min-
eralcorticoids, glucocorticoids, and sex steroids. These ste-
roids have been associated with different zones of the adrenal
cortex, with aldosterone produced by the zona glomerulosa,
cortisol produced by the zona fasciculata and somewhat by
the zona reticularis, and dehydroepiandrosterone sulfate syn-
thesized by the zona reticularis and somewhat by the zona
fasciculata [1]. This simplified characterization is proving
more complex as more is learned about the adrenal cortex.
Various abnormalities and pathogenic processes may involve
the adrenal gland and cortex, including agenesis, hypopla-
sia, malformations, primary adrenocorticotropic hormone
(ACTH)-independent cortical hyperplasia (sporadic or in
Carney complex), ACTH-dependent hyperplasia (in congeni-
tal adrenal hyperplasia), secondary hyperplasia (from pituitary
ACTH adenoma or ectopic ACTH production), cytomegaly
(from Beckwith-Wiedemann syndrome, X-linked congenital
L.A. Erickson, Atlas of Endocrine Pathology, Atlas of Anatomic Pathology,
DOI 10.1007/978-1-4939-0443-3_20, Springer Science+Business Media New York 2014
20
adrenal hypoplasia, and infections), adrenal cortical adenomas
and carcinomas, and unusual tumors in the adrenal glands. The
chromaffin cells of the medulla produce catecholamines such
as epinephrine. The medulla appears gray-white grossly and
comprises 10 % of the gland. Adrenal medullary hyperplasia
may occur in multiple endocrine neoplasia 2A and 2B, in cys-
tic fibrosis, in Beckwith-Wiedemann syndrome, or sporadi-
cally. Adrenal medullary hyperplasia often is associated with
clinical and biochemical findings similar to those of pheochro-
mocytoma. Medullary hyperplasia usually affects both adre-
nals, unlike most sporadic pheochromocytomas. However,
bilateral pheochromocytomas occur and pheochromocytomas
may arise in a background of adrenal medullary hyperplasia.
Pheochromocytomas are paragangliomas arising from adre-
nal medulla chromaffin cells [1]. Pheochromocytomas is the
term used for intra-adrenal paragangliomas and may be used
for extra-adrenal paragangliomas of the sympathetic neuro-
endocrine system. They may be distinguished as sympathetic
paragangliomas when they arise in sympathetic chains, in the
pelvis, or in the retroperitoneum, whereas parasympathetic
paraganglia arise in association with vagus and glossopharyn-
geal nerve branches, such as the paragangliomas of the head
and neck. The molecular basis of pheochromocytomas and
paragangliomas continues to be elucidated.
147
148
Normal Adrenal Histology
Fig. 20.1 Normal adrenal histology. Right and left adrenal glands are
shown in this gross photograph. When evaluating adrenal gland weight,
one must dissect the gland carefully from the associated adipose tissue.
Grossly normal adrenal glands in adults each weigh 6 g or less [2]. The
size and weight of adrenal glands in infants and children vary by stage
of development and age. The right adrenal gland appears triangular or
pyramidal, whereas the left is crescent shaped [1]
Fig. 20.2 Normal adrenal histology. This is a cross-section of a nor-
mal adrenal gland that has been fixed in formalin. The adrenal cortical
tissue is approximately 2 mm thick and surrounds the adrenal medulla
[1]
20 Adrenal Gland Histology
Fig. 20.3 Normal adrenal histology. This histologic cross-section
shows the zonation of the adrenal cortex. The peripheral subcapsular
thin zona glomerulosa contains small nests of cells with compact cyto-
plasm. The subjacent zona fasciculata comprises approximately 70 %
of the adrenal cortex [1]. The cells of the zona fasciculata have promi-
nent lipid-rich cytoplasm, which merges with the zona reticularis
Fig. 20.4 Normal adrenal histology. The thin zona glomerulosa is dis-
continuous and is involved in the synthesis of mineralocorticoids such
as aldosterone. The subjacent zona fasciculata comprises most of the
cortex and has cells with prominently lipidized cytoplasm showing
clearing. The zona fasciculata is associated mainly with cortisol
production
Normal Adrenal Histology
Fig. 20.5 Normal adrenal histology. The zona fasciculata lipidized
cells with clear cytoplasm comprise most of the normal adrenal cortex.
The cells of the adrenal cortex show immunopositivity for keratin
(Cam5.2), Mart1/MelanA, and synaptophysin and are negative for
chromogranin. Adrenal medullary tissues and tumors (pheochromocy-
tomas) are positive for synaptophysin and chromogranin and negative
for keratin and Mart1/MelanA
Fig. 20.6 Normal adrenal histology. The clear cells of the zona fas-
ciculata merge with the subjacent zona reticularis, which has more
eosinophilic, less lipidized cytoplasm and may contain lipochrome pig-
ment. The zona reticularis is the innermost zone of the adrenal cortex
and is associated with the synthesis of sex steroids, such as dehydroepi-
androsterone sulfate
149
Fig. 20.7 Normal adrenal histology. This cross-section shows the
zonation of the adrenal cortex: the subcapsular thin, discontinuous zona
glomerulosa containing small balls of cells; the prominent subjacent
zona fasciculata comprising most of the cortical cells; and the inner-
most zona reticularis. The zona reticularis merges with the chromaffin
cells of the adrenal medulla, as seen at the bottom of the photograph
Fig. 20.8 Normal adrenal histology. The cells of the zona reticularis
have less lipidized, more compact eosinophilic cytoplasm than the zona
fasciculata and may have lipochrome pigment [1]. In this photograph,
the cells of the zona reticularis are merging with the subjacent chromaf-
fin cells of the adrenal medulla
150
Fig. 20.9 Normal adrenal histology. Chromaffin cells of the adrenal
medulla are in small nests and cords. The cells have amphophilic to
basophilic cytoplasm and indistinct cytoplasmic membranes. Mitotic
figures generally are absent in normal adrenal medullary tissue [1]
Fig. 20.10 Normal adrenal histology. Adrenal cortical tissue is present
in the most central aspect of the photograph around the central adrenal
vein in the center of the adrenal gland. The adrenal cortical tissue often
encircles the adrenal vein, even within the medulla. The arterial supply
is via three arteries that divide into numerous branches and invest the
capsule
20 Adrenal Gland Histology
Fig. 20.11 Normal adrenal histology. Adrenal medullary chromaffin
cells have granular cytoplasm that is amphophilic to basophilic and
indistinct cell membranes. The nuclei are hyperchromatic or vesicular
and may be quite variable in some cases. Mitotic figures generally are
not seen in normal adrenal medullary tissue
Fig. 20.12 Normal adrenal histology. Scattered adipocytes are noted
in an area of this normal adrenal gland. Foci of lipomatous change
occasionally may be seen in the adrenal cortex
Normal Adrenal Histology 151

Fig. 20.15 Normal adrenal histology. This cortical extrusion is no lon-

Fig. 20.13 Normal adrenal histology. A focus of adipocytes and lym- ger connected to the adrenal gland in this section. Accessory cortical
phocytes is seen in this normal adrenal gland. In addition to lipomatous nodules may be identified in the periadrenal fat with or without
change, foci of myelolipomatous change, as well as a few lymphocytes, encapsulation
may be seen with the adipocytes in otherwise normal adrenal glands

Fig. 20.14 Normal adrenal histology. Partially encapsulated cortical

extrusions, such as seen in this excrescence, and accessory cortical nod-
ules may be identified in the periadrenal fat in clinically and function-
ally normal adrenal glands
152
Heterotopia of Adrenal Tissue
Fig. 20.16 Heterotopia of adrenal tissue. This accessory cortical nod-
ule is unencapsulated in the periadrenal fat
Fig. 20.17 Heterotopia of adrenal tissue. Heterotopic and accessory
adrenal tissues are identified in the abdomen and along the embryologic
path of the gonads [1]. This focus of adrenal heterotopia is encapsulated
and composed of adrenal cortical tissue with intermixed adipocytes
20 Adrenal Gland Histology
Fig. 20.18 Heterotopia of adrenal tissue. The adrenal cortical tissue in
this field is intermixed with adipocytes and foci of lymphocytes in this
adrenal heterotopia. Occasionally, medullary tissue also may be
present
Fig. 20.19 Heterotopia of adrenal tissue. Heterotopic adrenal cortical
tissue is present in this kidney. Heterotopic tissue is seen in the upper
pole of the kidney, usually in a subcapsular space, as well as in the area
of the celiac axis, which may be the most common site; the broad liga-
ment; adnexa of testes; and spermatic cord [1]
References 153

Adrenal Infection References

1. Lack EE. Tumors of the adrenal glands and extraadrenal garagan-
glia. In: Silverberg SG, Sobin LH, editors. AFIP atlas of tumor
pathology, vol. 8. Washington: American Registry of Pathology;
2007. p. 500.
2. Studzinski GP, Hay DC, Symington T. Observations on the weight
of the human adrenal gland and the effect of preparations of cortico-
tropin of different purity on the weight and morphology of the
human adrenal gland. J Clin Endocrinol Metab. 1963;23:24854.
3. Agarwal J, et al. Isolated Pneumocystis carinii infection of adrenal
glands causing Addisons disease in a non-immunocompromised
adult. Endocr Pathol. 2001;12(1):8791.
4. Dinleyici EC, et al. Adrenal insufficiency associated with cytomeg-
alovirus infection in two infants. Int J Infect Dis. 2009;13(4):1814.

Fig. 20.20 Adrenal infection. Necrotizing inflammation in an adrenal

gland affected by histoplasmosis. Disseminated fungal infections
involve the adrenal gland in up to 80 % of cases at autopsy [1]. These
include histoplasmosis and paracoccidioidomycosis, and less com-
monly blastomycosis, cryptococcosis, and coccidioidomycosis [1].
Patients may present with bilateral or unilateral adrenal enlargement.
Adrenal insufficiency may occur as the result of destruction of the adre-
nal glands in infections

Fig. 20.21 Adrenal infection. Necrotizing inflammation in an adrenal

gland affected by disseminated histoplasmosis. Adrenal infections may
be unilateral or bilateral and associated with adrenal insufficiency.
Fungi and bacteria both are known to be associated with adrenal infec-
tions. Isolated Pneumocystis carinii infection of adrenal glands causing
Addison disease has been described [3]. Viral infections, such as cyto-
megalovirus, also may be associated with adrenal insufficiency, includ-
ing in newborns and infants [4]
 Adrenal Cysts
21

Cystic lesions of the adrenal gland are uncommon and may
be associated with a variety of histologic features. Adrenal
cysts may be endothelial, epithelial, or parasitic, or pseudo-
cysts [1, 2]. Adrenal cysts usually are unilateral; most occur
in adults, with a female predominance [1, 2]. Pseudocysts
and endothelial cysts are the most common, followed by epi-
thelial cysts and parasitic cysts. Adrenal cysts may be associ-
ated with general or vague symptoms and may increase in
size if there is intracystic hemorrhage; however, many are
asymptomatic and discovered at autopsy. In a series of 41
macroscopically cystic adrenal lesions from patients who
underwent surgery at the Mayo Clinic over a 25-year period,
32 were pseudocysts, 8 were endothelial cysts, and 1 was an
epithelial cyst. Six of the 32 pseudocysts were associated
with adrenal neoplasms, including 2 adrenal carcinomas, 2
adrenal adenomas, and 2 pheochromocytomas (1 of which
was associated with an endothelial cyst) [3]. In another insti-
tutional series, of 31 adrenal lesions with a predominant cys-
tic component, 12 (39 %) were pseudocysts, 2 (6 %) were
endothelial cysts, and 17 (55 %) were epithelial cysts [4].

L.A. Erickson, Atlas of Endocrine Pathology, Atlas of Anatomic Pathology, 155

DOI 10.1007/978-1-4939-0443-3_21, Springer Science+Business Media New York 2014
156 21 Adrenal Cysts

Fig. 21.3 Adrenal cyst. Endothelial-lined adrenal cysts are uncom-

mon. The endothelium may be quite attenuated in both endothelial- and
Fig. 21.1 Adrenal cyst. This is a fibrous-walled adrenal pseudocyst. epithelial-lined cysts
Pseudocysts are the most common adrenal cysts, followed by endothe-
lial, epithelial, and parasitic cysts

Fig. 21.4 Adrenal cyst. This CD31-immunostained sample shows

Fig. 21.2 Adrenal cyst. This adrenal pseudocyst is fibrous walled, positivity in the endothelial cells lining an adrenal cyst, confirming the
with residual normal adrenal parenchyma in the lower portion of the diagnosis of an endothelial cyst
photograph
References 157

References
1. Lack EE. Tumors of the adrenal glands and extraadrenal paragan-
glia. In: Silverberg SG, Sobin LH, editors. AFIP atlas of tumor
pathology, vol. 8. Washington: American Registry of Pathology;
2007. p. 500.
2. Abeshouse GA, Goldstein RB, Abeshouse BS. Adrenal cysts;
review of the literature and report of three cases. J Urol. 1959;
81(6):7119.
3. Erickson LA, et al. Cystic adrenal neoplasms. Cancer. 2004;
101(7):153744.
4. Sebastiano C, et al. Cystic lesions of the adrenal gland: our experi-
ence over the last 20 years. Hum Pathol. 2013;44(9):1797803.

Fig. 21.5 Adrenal cyst. This is an epithelial-lined adrenal cyst. This

type of cyst is quite uncommon. Keratin and CD31 immunostain may
be used to differentiate epithelial from endothelial adrenal cysts
 Adrenal Cortical Hyperplasia
Adrenal cortical hyperplasia is characterized by an increase
in cortical cells, which usually occurs bilaterally [1]. Adrenal
cortical hyperplasia generally affects both adrenal glands
and may be diffuse or nodular or show features of both pat-
terns [1]. Adrenal glands may show hyperplasia primarily
and secondarily. Primary adrenocorticotropic hormone
(ACTH)-independent cortical hyperplasia is seen sporadi-
cally or in Carney complex. ACTH-dependent cortical
hyperplasia occurs in congenital adrenal hyperplasia (adre-
nogenital syndrome), an autosomal recessive defect in an
enzymatic step of steroid synthesis (most commonly
21-hydroxylase). The adrenal glands are enlarged as the
result of continuous stimulation of the adrenal cortex by
ACTH. Congenital adrenal hyperplasia is the most common
cause of primary adrenal insufficiency in children. Secondary
adrenal cortical hyperplasia is caused by pituitary ACTH
adenoma, often a microadenoma, or ectopic ACTH produc-
tion. The adrenal glands show a diffuse and/or micronodular
pattern. These specimens, however, rarely are removed and
evaluated by pathologists, because removal of the pituitary
tumor is the mainstay of treatment. Other ectopic sites of
ACTH production may occur and may be associated with
L.A. Erickson, Atlas of Endocrine Pathology, Atlas of Anatomic Pathology,
DOI 10.1007/978-1-4939-0443-3_22, Springer Science+Business Media New York 2014
22
hypercortisolism. Primary adrenal cortical hyperplasia, such
as macronodular hyperplasia with marked adrenal enlarge-
ment, which is a primary (autonomous) adrenal cause of
Cushing syndrome, may occur but is rare [1]. The adrenal
glands are enlarged bilaterally, and cortical nodules are pres-
ent grossly. The underlying etiology for this is unclear.
Bilateral nodular adrenal cortical disease also may show pig-
mentation and may be associated with Carney complex. This
complex is characterized by primary pigmented nodular
adrenocortical disease (PPNAD); lentigines; atrial, mucocu-
taneous, and uterine myxomas; large cell calcifying Sertoli
cell tumors; mammary myxoid fibroadenomas; pituitary
adenomas; and psammomatous melanotic schwannomas
[24]. This autosomal dominant disorder has been identified
with an area on chromosome 2p16 (Carney locus) and the
PRKAR1A gene on chromosome 17q22-24 [2, 57]. Primary
hyperaldosteronism also may be associated with adrenal
hyperplasia, but the adrenals may be enlarged only slightly
with micro- or macronodules or may not show any particular
abnormality grossly [1]. Histologically, hyperplasia of the
zona glomerulosa may be seen in some cases of primary
idiopathic hyperaldosteronism.
159
160 22 Adrenal Cortical Hyperplasia

Adrenal Cortical Hyperplasia, Diffuse

Fig. 22.3 Adrenal cortical hyperplasia, diffuse. This cut section of the
right adrenal gland shows secondary diffuse cortical hyperplasia caused
by ectopic ACTH production by a neuroendocrine tumor metastatic to
the liver. The ectopic ACTH is causing hyperplasia of the adrenal corti-
cal cells
Fig. 22.1 Adrenal cortical hyperplasia, diffuse. This (left) adrenal
gland, weighing 21.4 g, is affected by secondary diffuse adrenal cortical
hyperplasia. In this case, the secondary hyperplasia is from a pancreatic
neuroendocrine tumor metastatic to the liver producing multiple hor-
mones, including ACTH. Secondary hyperplasia often is caused by a
pituitary adenomaoften a microadenomaproducing ACTH, but
ACTH production by other tumors also may result in diffuse or
micronodular cortical hyperplasia, as occurred in this case

Fig. 22.4 Adrenal cortical hyperplasia, diffuse. The adrenal cortex is

diffusely enlarged in this adrenal gland affected by cortical hyperplasia.
The zona fasciculata is enlarged in cases associated with hypercorti-
solism, and the zona reticularis is enlarged in some cases of primary
idiopathic primary adrenal cortical hyperplasia associated with aldoste-
Fig. 22.2 Adrenal cortical hyperplasia, diffuse. The right adrenal rone production
gland (17.4 g) also is affected by secondary diffuse adrenal cortical
hyperplasia due to a pancreatic neuroendocrine tumor metastatic to the
liver producing multiple hormones, including ACTH. Secondary hyper-
plasia usually affects both adrenal glands
Adrenal Cortical Hyperplasia, Nodular 161

Adrenal Cortical Hyperplasia, Nodular

Fig. 22.5 Adrenal cortical hyperplasia, diffuse. Diffuse enlargement

of the adrenal cortex, with increased numbers of adrenal cortical cells,
is seen in this adrenal gland affected by diffuse hyperplasia

Fig. 22.7 Adrenal cortical hyperplasia, nodular. This adrenal gland is

affected by adrenal cortical hyperplasia with a nodular pattern. The dis-
tinction between macro- and micronodules is somewhat arbitrary. A
rare primary adrenal cause of Cushing syndrome is macronodular
hyperplasia with marked adrenal enlargement, although the enlarge-
ment may not be as marked as the name suggests [1]

Fig. 22.6 Adrenal cortical hyperplasia, diffuse. This photograph

shows increased numbers of adrenal cortical cells in diffuse hyperplasia
of the adrenal cortex

Fig. 22.8 Adrenal cortical hyperplasia, nodular. Adrenal gland

affected by macronodular adrenal cortical hyperplasia. Multiple nod-
ules of adrenal cortical cells appear quite distinct on low-power view.
However on higher power, these nodules may be less defined
162
Fig. 22.9 Adrenal cortical hyperplasia, nodular. Nodular adrenal corti-
cal hyperplasia showing multiple nodules, which seem to merge into
one another histologically. Both macro- and micronodules may be seen
in nodular adrenal cortical hyperplasia
Fig. 22.10 Adrenal cortical hyperplasia, nodular. This adrenal gland is
affected by nodular adrenal cortical hyperplasia showing an area of
endocrine atypia with enlarged hyperchromatic cells, a feature that
may be seen in many benign endocrine conditions
22 Adrenal Cortical Hyperplasia
Primary Pigmented Nodular Adrenocortical
Disease
Fig. 22.11 Primary pigmented nodular adrenocortical disease. These adre-
nal glands are affected by PPNAD, a bilateral micronodular hyperplasia
with variable pigmentation due to lipofuscin. Carney complex is character-
ized by PPNAD; lentigines; atrial, mucocutaneous, and uterine myxomas;
large cell calcifying Sertoli cell tumors; mammary myxoid fibroadenomas;
pituitary adenomas; and psammomatous melanotic schwannomas [24]
Fig. 22.12 Primary pigmented nodular adrenocortical disease. These cut
sections show adrenal glands affected by PPNAD with slight enlarge-
ment. The cortex contains prominent brown-black nodules ranging from
0.1 to 0.5 cm. This is a prominent feature of Carney complex. In a review
of more than 150 cases of Carney complex, other features included car-
diac myxomas (61 %), skin myxomas (37 %), breast myxomas (20 %),
and lentigines and nevi in the conjunctiva (67 %) and face and lips.
Endocrine tumors affected the adrenal in 33 %, testis in 30 %, and pitu-
itary adenomas in 11 % of cases. Schwannomas of the upper gastrointes-
tinal tract and sympathetic chain (11 %) also were identified [5]
Primary Pigmented Nodular Adrenocortical Disease 163

Fig. 22.13 Primary pigmented nodular adrenocortical disease. This Fig. 22.15 Primary pigmented nodular adrenocortical disease. The
adrenal gland affected by PPNAD has nodules at the corticomedullary nodules in PPNAD are composed of zona reticularistype large globu-
junction. Nodules also may be in the periadrenal adipose. Foci of lar cells with abundant lipofuscin pigment
myelolipomatous change also may be seen. Affected patients may have
Cushing syndrome, and cyclic or intermittent glucocorticoid hyperse-
cretion may be absent. Patients usually are treated with bilateral adre-
nalectomy. The glands in PPNAD are very distinct, and few entities are
in the differential diagnosis. Limited biopsy material may be more diag-
nostically challenging

Fig. 22.14 Primary pigmented nodular adrenocortical disease. This

adrenal gland affected by PPNAD shows nodules of cells containing
lipofuscin. The differential diagnosis includes melanoma, adrenal or
kidney oncocytoma, and black adenoma. Patients with metastatic mela-
noma usually have a history of melanoma. Both adrenal cortical tissue
and melanoma cells are positive for MelanA/Mart1, but melanoma also
is positive for S100 and HMB45, which are negative in adrenal cortical
tissue. PPNAD has multiple nodules, whereas black adenoma and
oncocytoma are single nodules, and oncocytomas usually are not
pigmented
164 22 Adrenal Cortical Hyperplasia

References 4. Carney JA, Stratakis CA. Epithelioid blue nevus and psammoma-
tous melanotic schwannoma: the unusual pigmented skin tumors of
the Carney complex. Semin Diagn Pathol. 1998;15(3):21624.
1. Lack EE. Tumors of the adrenal glands and extraadrenal paragan-
5. Boikos SA, Stratakis CA. Carney complex: pathology and molecu-
glia. In: Silverberg SG, Sobin LH, editors. AFIP atlas of tumor
lar genetics. Neuroendocrinology. 2006;83(34):18999.
pathology. 8th ed. Washington: American Registry of Pathology;
6. Kirschner LS, et al. Mutations of the gene encoding the protein
2007. p. 500.
kinase A type I-alpha regulatory subunit in patients with the Carney
2. Stratakis CA, Horvath A. Carney complex. In: Pagon RA, Adam
complex. Nat Genet. 2000;26(1):8992.
MP, Bird TD, et al. editors. GeneReviews [Internet]. Seattle:
7. Stratakis CA. Adrenocortical tumors, primary pigmented adrenocor-
University of Washington; 2003. Available from: http://www.ncbi.
tical disease (PPNAD)/Carney complex, and other bilateral hyper-
nlm.nih.gov/books/NBK1286/.
plasias: the NIH studies. Horm Metab Res. 2007;39(6):46773.
3. Carney JA. Carney complex: the complex of myxomas, spotty pig-
mentation, endocrine overactivity, and schwannomas. Semin
Dermatol. 1995;14(2):908.
 Adrenal Cortical Adenoma
Adrenal cortical adenomas are benign neoplasms of adrenal
cortical cells that may or may not have functional activity [1,
2]. Adrenal cortical adenomas usually are single unilateral
tumors that are more common in females. The incidence is
unclear, particularly because many are identified as inciden-
talomas. Nonfunctional tumors often are identified as inciden-
talomas or in autopsies. A nonfunctional adrenal cortical
adenoma may be associated with clinical symptoms if it is
associated with hemorrhage or reaches a large size, although
this is uncommon. Functional tumors may be associated with
cortisol production (Cushing syndrome), aldosterone produc-
tion (Conn syndrome), or sex steroidproducing tumors (viril-
ization or feminization). Feminizing or virilizing tumors are
quite uncommon, and the presence of these features is con-
cerning for malignancy. Adrenal cortical adenomas may show
degenerative features, hemorrhage, and cystic change. They
have the same immunophenotype as normal adrenal cortical
tissues, hyperplasia, and carcinoma. Adrenal adenomas are
positive for synaptophysin, Melan-A/Mart-1, and -inhibin,
and usually show staining for keratin. Adrenal cortical tissues
and tumors are negative for chromogranin and S100. Adrenal
cortical adenomas must be distinguished from adrenal cortical
carcinomas. Adrenal cortical carcinomas usually are larger
than adenomas, but they may overlap in size. Tumors larger
than 100 g are particularly worrisome for malignancy;
L.A. Erickson, Atlas of Endocrine Pathology, Atlas of Anatomic Pathology,
DOI 10.1007/978-1-4939-0443-3_23, Springer Science+Business Media New York 2014
23
however, tumors less than 100 g have metastasized, and ade-
nomas may weigh more than 100 g. Adrenal adenomas lack
histologic features of malignancy, such as vascular invasion,
necrosis, fibrous bands, capsular invasion, increased mitotic
rate, atypical mitoses, and nuclear atypia. However, this dis-
tinction may be difficult in some cases. Dr. Weiss [3] found the
combination of nine criteria (nuclear grade III or IV, mitotic
rate >5 per 50 high-power fields [hpf], atypical mitoses, clear
cells comprising 25 % or less, diffuse architecture, micro-
scopic necrosis, and invasion of venous, sinusoidal, and capsu-
lar structures) useful in differentiating benign from malignant
adrenal cortical tumors. Eighteen of 19 tumors with four or
more criteria and none of the 24 tumors with two or fewer
criteria recurred or metastasized [3]. A subsequent study
found that the presence of three or more criteria was associ-
ated with malignancy, with a specificity of 96 % and sensitiv-
ity of 100 % [4]. Evaluating adrenal cortical tumors in children
is extremely difficult. Malignant features in pediatric adrenal
cortical tumors are weight greater than 400 g, size greater than
10.5 cm, vena cava invasion, capsular and/or vascular inva-
sion, extension into periadrenal soft tissue, confluent necrosis,
severe nuclear atypia, more than 15 mitoses per 20 hpf, and
atypical mitoses [5]. By multivariate analysis, vena cava inva-
sion, necrosis, and increased mitoses (>15 mitoses per 20 hpf)
independently suggest malignancy [5].
165
166 23 Adrenal Cortical Adenoma

Fig. 23.2 Adrenal cortical adenoma. This adrenal cortical adenoma

Fig. 23.1 Adrenal cortical adenoma. This adrenal cortical adenoma was associated with Cushing syndrome. Adrenal adenomas generally
(7.2 cm, 91.5 g) was associated with subclinical Cushing syndrome. weigh less than 50 g and are unilateral, although rare bilateral adeno-
The cross-section of this adenoma is yellow, with a central area of irreg- mas have been reported [1, 2, 10]. Bilateral adrenal lesions associated
ular red discoloration due to myelolipomatous change. Hemorrhage and with Cushing syndrome likely are macronodular hyperplasia rather
cystic change are not uncommon and should be differentiated from than bilateral adenomas. This adenoma is composed of broad sheets of
necrosis, which is a worrisome gross finding. Grossly, adrenal adeno- adrenal cortical cells with lightly eosinophilic cytoplasm and an area in
mas are well-circumscribed and may appear encapsulated. The gross the upper portion showing pale, lipid-rich cells. Cells may have vari-
and histologic features may correlate with tumor functionality, but able cytoplasmic clearing and may intermingle or appear more distinct.
function may be impossible to determine based on these features alone This photograph highlights the various cytologic appearances that may
and requires correlation with clinical and laboratory information. be seen in adrenal adenomas
Adenomas usually are smaller than carcinomas. Of 66 adrenal cortical
tumors larger than 100 g, 93 % were carcinomas and 7 % were adeno-
mas [6]. In a study of 67 cases, no tumor smaller than 8 cm had metas-
tases; however, some large tumors (21 cm) also did not [7]. Another
study found only tumors greater than 150 g metastasized [8], although
tumors as small as 40 g have metastasized [9]. Thus, weight cannot be
used alone to determine malignancy. However, adrenal tumors greater
than 100 g should be studied very carefully for other features of
malignancy

Fig. 23.3 Adrenal cortical adenoma. This adrenal cortical adenoma

shows intermingling of larger pale lipid-rich cells, which are variable in
size, with smaller cells with eosinophilic cytoplasm. Variation in cell
size often is seen in benign lesions. In many endocrine lesions, includ-
ing adrenal tumors, it would be more concerning to see sheets of
monotonous cells with high nuclear-to-cytoplasmic ratios, as often is
seen in adrenal cortical carcinoma
Adrenal Cortical Adenoma
Fig. 23.4 Adrenal cortical adenoma. Adrenal adenoma with small
nests of pale-staining cells associated with Cushing syndrome. The
cells in this adenoma have pale cytoplasm due to the cytoplasmic lipid
and fairly well-defined cytoplasmic membranes. The cells are some-
what variable in size and usually larger than normal cortical cells. The
cytologic features in an adenoma may vary throughout the tumor. These
varying cell morphologies are similar to those seen in the normal adre-
nal cortex
Fig. 23.5 Adrenal cortical adenoma: pleomorphism. An area of
marked cellular and nuclear pleomorphism is seen in this adrenal corti-
cal adenoma. Foci of endocrine atypia are not uncommon in benign
endocrine lesions. Monotonous sheets of cells with high nuclear-to-
cytoplasmic ratios are more worrisome for malignancy, whereas foci of
endocrine atypia often are seen in benign endocrine lesions
167
Fig. 23.6 Adrenal cortical adenoma. Adrenal cortical adenoma with
eosinophilic cells with less lipidized cytoplasm. The nuclei are slightly
variable in size. The cells in adenomas may be pale, with some nearly
clear; have more eosinophilic less-lipidized cytoplasm than transitional-
type cells; or have abundant eosinophilic cytoplasm. The histologic
features often vary within a tumor
Fig. 23.7 Adrenal cortical adenoma. Areas of lipomatous or myeloli-
pomatous change are not uncommon in adrenal cortical adenomas. This
tumor has a prominent area of myelolipomatous change with a mixture
of adipocytes, myelolipomatous elements and cells, and nests of cells of
adrenal cortical adenoma
168
Fig. 23.8 Adrenal cortical adenoma. On medium power, the different
cellular components of this area of myelolipomatous change are more
clearly identifiable in this adrenal cortical adenoma. The nests of pale
lipid-rich adrenal cortical adenoma cells are identified interspersed with
myelolipomatous elements
Fig. 23.9 Adrenal cortical adenoma: gross aldosterinoma. This adre-
nal cortical adenoma was associated with primary hyperaldosteronism
(Conn syndrome). The tumor has a bright yellow appearance grossly,
which is quite characteristic of aldosterone-secreting adenomas.
Aldosterone-producing adrenal adenomas account for most cases of
primary hyperaldosteronism
23 Adrenal Cortical Adenoma
Fig. 23.10 Adrenal cortical adenoma. Adrenal cortical adenoma with
primary hyperaldosteronism, with large lipid-rich cells throughout the
tumor. These large lipid-rich cells predominate in aldosterone-secreting
adenomas. A nested pattern commonly is seen in aldosterone-secreting
adenomas. These large lipid-rich cells give the tumor a characteristic
bright yellow appearance grossly
Fig. 23.11 Adrenal cortical adenoma. Smaller, compact eosinophilic
cells such as these may be seen in aldosterone-secreting adenomas.
They often are admixed with the more characteristic large lipid-rich
pale cells of aldosterone-secreting adenomas
Adrenal Cortical Adenoma
Fig. 23.12 Adrenal cortical adenoma. Spironolactone bodies are iden-
tified in this aldosterone-secreting adrenal adenoma, indicating that the
patient was treated preoperatively with spironolactone
Fig. 23.13 Adrenal cortical adenoma. This alveolar pattern of growth
is an unusual finding in an adrenal cortical adenoma, but it is known to
occur. Recognizing the variability of growth patterns in adrenal cortical
tumors is important to avoid mistaking them for another tumor or a
metastasis to the adrenal gland
169
Fig. 23.14 Adrenal cortical adenoma. This aldosterone-producing
adrenal cortical adenoma has a pseudoglandular growth pattern
Fig. 23.15 Adrenal cortical adenoma. Low-power view of extensive
trabecular growth in an adrenal cortical adenoma that produced aldoste-
rone. Understanding that many different growth patterns may be seen in
adrenal cortical adenomas is important in recognizing the tumor as
adrenal cortical
170
Fig. 23.16 Adrenal cortical adenoma. This is a virilizing adrenal corti-
cal adenoma. The functional status is not diagnostic of tumor behavior,
as adrenal cortical adenomas and carcinomas both may be functional or
nonfunctional. However, virilizing or feminizing tumors are particu-
larly concerning for malignancy
Fig. 23.17 Adrenal cortical adenoma. This virilizing adrenal cortical
adenoma is composed of epithelioid cells with lightly eosinophilic
cytoplasm. The tumor cells lack mitotic activity and necrosis. Histologic
features diagnostic of malignancy were not identified, but the virilizing
functional status is concerning
23 Adrenal Cortical Adenoma
Fig. 23.18 Adrenal cortical adenoma. This adrenal cortical adenoma
has prominent myxoid change with spindle cells. Myxoid change is
seen in benign and malignant adrenal cortical neoplasms [11]. In a
study from the Mayo Clinic, 14 myxoid adrenal cortical neoplasms (6
adenomas and 8 carcinomas) showed staining of the myxoid areas with
Alcian blue and generally were negative on periodic acid-Schiff and
mucicarmine staining [11]. The tumors had an immunophenotype simi-
lar to that of other adrenal cortical neoplasms and were positive for
synaptophysin, -inhibin, vimentin, and keratin (focal) [11]
Fig. 23.19 Adrenal cortical adenoma. This adrenal cortical adenoma
shows prominent myxoid change and epithelioid cells. The same histo-
logic criteria used to differentiate benign from malignant adrenal corti-
cal tumors should be used with adrenal cortical tumors with myxoid
change. Myxoid adrenal tumors are in the differential diagnosis of myx-
oid retroperitoneal tumors and metastases to the adrenal gland
Adrenal Cortical Adenoma
Fig. 23.20 Adrenal cortical adenoma. Oncocytic adrenal cortical neo-
plasms are rare and usually discovered incidentally, as only 17 % are
functional [12]. Oncocytic adrenal adenomas lack the major criteria
(high mitotic rate, atypical mitoses, venous invasion) and minor criteria
(large size and huge weight, necrosis, capsular invasion, sinusoidal
invasion) for malignancy that are used to identify oncocytic adrenal car-
cinomas [13]. Oncocytic adenomas are composed of cells with eosino-
philic cytoplasm reflecting abundant mitochondria. These tumors have
an immunophenotype similar to that of other adrenal cortical tumors
Fig. 23.21 Adrenal cortical adenoma. This adrenal cortical adenoma
has marked cystic degeneration, a feature not uncommon in adrenal
adenomas. Radiographically, areas of hemorrhage or cystic degenera-
tion with hemorrhagic organization may be difficult to differentiate
from necrosis, which is an ominous finding in an adrenal cortical tumor
171
Fig. 23.22 Adrenal cortical adenoma. This is a black adrenal cortical
adenoma. The terminology reflects the gross appearance. Black adrenal
cortical adenomas may vary in color from brown to black. Black adeno-
mas measure 23 cm and weigh less than 35 g [1, 2]. Grossly, black
adenomas might be mistaken for melanoma or hemorrhage [1]. Black
or diffusely pigmented adenomas are rare. Black adenomas often are
associated with Cushing syndrome and occasionally with primary
hyperaldosteronism [1, 2]. Patients with black adenomas and Cushing
syndrome may have lower urinary 17-ketosteroid and serum aldoste-
rone concentrations than those with yellow adenomas [14]
Fig. 23.23 Adrenal cortical adenoma. This black adrenal cortical ade-
noma is composed of cells with eosinophilic cytoplasm and abundant
lipofuscin. The number of compact cells is greater in black adenomas
than in yellow adenomas or hyperplastic adrenal tissue [14]. Clusters of
lipid-rich cells and foci of myelolipomatous metaplasia may occur. A
few small clusters of lipid-rich pale-staining cells are seen at the bottom
right. On the left is adrenal medullary tissue and on the far left, residual
adrenal atrophic cortical tissue
172 23 Adrenal Cortical Adenoma

References
1. Lack EE. Tumors of the adrenal glands and extraadrenal para-
ganglia. In: Silverberg SG, Sobin LH, editors. AFIP atlas of
tumor pathology, vol. 8. Washington, DC: American Registry of
Pathology; 2007. p. 500.
2. Lack EE. Tumors of the adrenal gland and extra-adrenal paragan-
glia. In: Rosai J, editor. Atlas of tumor pathology, vol. 19.
Washington, DC: Armed Forces Institute of Pathology; 2007. p.
468.
3. Weiss LM. Comparative histologic study of 43 metastasizing and
nonmetastasizing adrenocortical tumors. Am J Surg Pathol.
1984;8(3):1639.
4. Aubert S, et al. Weiss system revisited: a clinicopathologic and
immunohistochemical study of 49 adrenocortical tumors. Am
J Surg Pathol. 2002;26(12):16129.
5. Wieneke JA, Thompson LD, Heffess CS. Adrenal cortical neo-
plasms in the pediatric population: a clinicopathologic and immu-
nophenotypic analysis of 83 patients. Am J Surg Pathol.
Fig. 23.24 Adrenal cortical adenoma. The cells of this black adrenal 2003;27(7):86781.
cortical adenoma have compact eosinophilic cytoplasm containing 6. Sasano H, Suzuki T, Moriya T. Adrenal cortex. In: Lloyd RV, editor.
brown pigment. The nuclei have small eccentric nucleoli Endocrine pathology: differential diagnosis and molecular
advances. Totowa: Humana Press; 2004. p. 21126.
7. Erickson LA, et al. Pathologic features and expression of insulin-
like growth factor-2 in adrenocortical neoplasms. Endocr Pathol.
2001;12(4):42935.
8. van Slooten H, et al. Morphologic characteristics of benign and
malignant adrenocortical tumors. Cancer. 1985;55(4):76673.
9. Gandour MJ, Grizzle WE. A small adrenocortical carcinoma with
aggressive behavior. An evaluation of criteria for malignancy. Arch
Pathol Lab Med. 1986;110(11):10769.
10. Tung SC, et al. Bilateral adrenocortical adenomas causing ACTH-
independent Cushings syndrome at different periods: a case report
and discussion of corticosteroid replacement therapy following
bilateral adrenalectomy. J Endocrinol Invest. 2004;27(4):3759.
11. Brown FM, et al. Myxoid neoplasms of the adrenal cortex: a rare
histologic variant. Am J Surg Pathol. 2000;24(3):396401.
12. Mearini L, et al. Adrenal oncocytic neoplasm: a systematic review.
Urol Int. 2013;91(2):12533.
13. Bisceglia M, et al. Adrenocortical oncocytic tumors: report of 10
cases and review of the literature. Int J Surg Pathol.
2004;12(3):23143.
14. Komiya I, et al. Black (or brown) adrenal cortical adenoma: its
characteristic features on computed tomography and endocrine
data. J Clin Endocrinol Metab. 1985;61(4):7117.
 Adrenal Cortical Carcinoma
Adrenal cortical carcinomas (ACCs) are rare; account for
3 % of endocrine tumors; affect people of all ages, includ-
ing children; are more common in females; and have an
incidence of one per one million patient-years. Up to 49 %
of ACCs are functional, with androgen secretion (viriliza-
tion) and glucocorticoid secretion (Cushing syndrome)
common [13]; functional tumors are more frequent in
females [3, 4]. ACCs may vary in size (130 cm), but usu-
ally are large (1013 cm) and may show necrosis [1, 4].
Rarely, ACCs may be cystic [5]. Differentiating ACC from
adenoma may be very difficult; ACCs usually are larger
than adenomas. Tumors 100 g are particularly worrisome
for malignancy; however, tumors less than 100 g have
metastasized, and adenomas may weigh more than 100 g.
ACCs recapitulate normal cortex but show more diffuse
growth and eosinophilic cytoplasm and lack the zonation
of normal adrenal cortex. Histologic features of malig-
nancy are vascular invasion, necrosis, fibrous bands, cap-
sular invasion, increased mitotic rate, atypical mitoses, and
nuclear pleomorphism. In a study by Dr. Weiss [6] of 43
adrenal cortical tumors, nine criteria were found to be use-
ful in differentiating benign from malignant adrenal corti-
cal tumors. These include nuclear grade III or IV, mitotic
rate greater than 5 per 50 high-power fields (hpf), atypical
mitoses, clear cells comprising 25 % of the tumor, diffuse
architecture, microscopic necrosis, venous (smooth muscle
in wall) invasion, sinusoidal (no smooth muscle in wall)
invasion, and capsular invasion. Eighteen of 19 tumors with
four or more criteria and none of the 24 tumors with two
or fewer criteria recurred or metastasized [6]. A subsequent
L.A. Erickson, Atlas of Endocrine Pathology, Atlas of Anatomic Pathology,
DOI 10.1007/978-1-4939-0443-3_24, Springer Science+Business Media New York 2014
24
study showed that the presence of three or more criteria
was associated with malignancy, with a specificity of 96 %
and sensitivity of 100 % [7]. Diagnosing ACC in children
is extremely difficult, and the criteria differ from those in
adults. Malignant features in pediatric tumors are weight
greater than 400 g, size greater than 10.5 cm, vena cava
invasion, capsular and/or vascular invasion, extension into
periadrenal soft tissue, confluent necrosis, severe nuclear
atypia, more than 15 mitoses per 20 hpf, and atypical mito-
ses [8]. By multivariate analysis, vena cava invasion, necro-
sis, and increased mitotic activity (>15 mitoses per 20 hpf)
independently suggest malignancy [8]. Recent transcrip-
tome studies revealed differences between adenomas and
carcinomas and identified subgroups of carcinomas corre-
lating with survival and tumor grade based on mitotic rate
[9, 10]. Insulin-like growth factor 2 overexpression occurs
in 90 % of adrenal carcinomas and rarely in adenomas, and
transcriptome studies have shown separation of carcinomas
from adenomas [9, 11]. Poor-prognosis tumors show over-
expression of cell cyclerelated genes, p53 alteration, or
Wnt/-catenin activation [9]. ACCs are aggressive tumors,
with up to 52 % presenting with distant metastases [4].
Lung, lymph node, liver, and bone are common metastatic
sites [4]. Survival is greater with localized disease that is
completely removed surgically [3]. Other factors associated
with prolonged survival are a disease-free interval longer
than 12 months, size, and functional tumors [4]. Surgery is
the main treatment [3]. Cytotoxic chemotherapy, op-DDD,
and radiation are not particularly beneficial [2, 3]. The 3-
and 5-year survival rates are 37 and 25 %, respectively [2].
173
174 24 Adrenal Cortical Carcinoma

Fig. 24.3 Adrenal cortical carcinoma. This ACC shows diffuse growth
Fig. 24.1 Adrenal cortical carcinoma. This ACC is a large tumor with of tumor cells with high nuclear-to-cytoplasmic ratios and cellular
necrosis. ACCs usually are large tumors, but may range in size from 1 monotony. The tumor cells have nucleoli and mitotic activity
to 30 cm [1, 4]. Tumor size and weight are not diagnostic of malig-
nancy, but tumors larger than 50 or 100 g are particularly worrisome
and require very careful evaluation. Of 66 adrenal cortical tumors
greater than 100 g, 93 % were carcinomas and 7 % were adenomas [12].
In a study of 67 adrenal cortical tumors, no tumor smaller than 8 cm
metastasized; however, some large tumors (21 cm) were not associated
with metastases [1]. Tumors as small as 40 g have metastasized [13].
Thus, weight or size cannot be used alone to diagnose malignancy

Fig. 24.4 Adrenal cortical carcinoma. An area of invasive growth is

Fig. 24.2 Adrenal cortical carcinoma. The ACC on the right has a dif- seen in this ACC. Invasive growth, particularly into adjacent structures,
fuse growth pattern and cells with high nuclear-to-cytoplasmic ratios. is helpful in identifying malignancy
Compressed residual normal adrenal cortex is present on the left
Adrenal Cortical Carcinoma
Fig. 24.5 Adrenal cortical carcinoma. Necrosis, as seen in this ACC,
is a very helpful diagnostic feature of malignancy. Necrosis must be
differentiated from hemorrhage and infarction, which are not uncom-
mon in adrenal cortical adenomas
Fig. 24.6 Adrenal cortical carcinoma. Extensive necrosis in an ACC
with viable tumor cells around vascular spaces
175
Fig. 24.7 Adrenal cortical carcinoma. Punctate microscopic foci of
necrosis are helpful in diagnosing malignancy in adrenal cortical
tumors. Often, these foci of necrosis are easier to identify as true tumor
necrosis than larger areas that may be difficult to differentiate from
infarction or organizing hemorrhage. This ACC has cells with high
nuclearcytoplasmic ratios and mitotic activity, and shows necrosis
Fig. 24.8 Adrenal cortical carcinoma. Numerous mitotic figures are
seen in this ACC. Mitotic figures may not be this obvious in ACC. In
evaluating adrenal cortical tumors, mitotic activity is measured per
50 hpf. A mitotic rate greater than 5 per 50 hpf is one of nine criteria for
malignancy (nuclear grade III or IV; atypical mitoses; clear cells com-
prising 25 %; a diffuse architecture; microscopic necrosis; invasion of
venous, sinusoidal, and capsular structures; and a mitotic rate >5 per
50 hpf) [6]. Tumors with four or more of these criteria are malignant,
and those with two or fewer usually are benign
176
Fig. 24.9 Adrenal cortical carcinoma. Mitoses in ACC are helpful
diagnostically and may be prognostic. In a study evaluating the prog-
nostic significance of histologic features, tumors with more than 20
mitoses per 50 hpf had a median survival of 14 months, whereas those
with 20 had a median survival of 58 months [14]. A series of 67 ACCs
from the Mayo Clinic were histologically graded 14 based on mitotic
activity and necrosis, and the higher-grade carcinomas had decreased
survival [1]
Fig. 24.10 Adrenal cortical carcinoma. This ACC has more polymor-
phous cells with vesicular nuclei and intranuclear holes. The tumor
cells in this carcinoma have distinctive cytoplasmic membranes and are
organized into small nests
24 Adrenal Cortical Carcinoma
Fig. 24.11 Adrenal cortical carcinoma. Although many ACCs have
monotonous cells with high nuclear-to-cytoplasmic ratios, pleomor-
phism may be seen in ACC, as demonstrated in this tumor. Although
the pleomorphism may be striking, it must be differentiated from the
endocrine atypia seen in benign endocrine tumors. Monotonous cells
with high nuclear-to-cytoplasmic ratios are suspicious for malignancy
Fig. 24.12 Adrenal cortical carcinoma. The trabecular growth pattern
seen in this ACC is very characteristic of ACCs
Adrenal Cortical Carcinoma
Fig. 24.13 Adrenal cortical carcinoma. The cells in this ACC have
high nuclear-to-cytoplasmic ratios and a monotonous appearance
within the trabeculae. Numerous mitotic figures also are present
Fig. 24.14 Adrenal cortical carcinoma. This ACC has a pseudoglan-
dular growth pattern. This pattern may be focal or present throughout
the tumor
177
Fig. 24.15 Adrenal cortical carcinoma. The pseudoglandular pattern
in this ACC may be mistaken for a metastasis to the adrenal gland. In
difficult cases, immunoperoxidase studies may be helpful, as adrenal
carcinomas generally are positive for MelanA/Mart1, keratin (Cam5.2),
-inhibin (particularly in functioning tumors), and synaptophysin
Fig. 24.16 Adrenal cortical carcinoma. This small cell variant of ACC
must be differentiated from lymphoma; small round blue cell tumors,
including neuroblastoma, which may occur in the adrenal; and metasta-
sis to the adrenal gland
178
Fig. 24.17 Adrenal cortical carcinoma. Small cell cytomorphology in
ACC may be challenging to diagnose if one is unaware of this appear-
ance. An understanding of the various features that may be seen ACC is
important in recognizing the unusual variants of this tumor
Fig. 24.18 Adrenal cortical carcinoma. This ACC has extensive myx-
oid change. Although some have suggested myxoid change is concern-
ing for malignancy, it may be seen in benign and malignant adrenal
cortical tumors and is not indicative of behavior [15]. Myxoid adrenal
cortical tumors are positive for Alcian blue and usually negative with
periodic acid-Schiff and mucicarmine [15]. The immunophenotype oth-
erwise is typical of adrenal cortical tumors [15]
24 Adrenal Cortical Carcinoma
Fig. 24.19 Adrenal cortical carcinoma. This myxoid ACC has nests
and cords of cells with high nuclear-to-cytoplasmic ratios floating in
mucin. Differentiating benign from malignant myxoid adrenal cortical
tumors is achieved using the same criteria as those for conventional
adrenal cortical tumors. Myxoid adrenal cortical tumors also must be
differentiated from retroperitoneal myxoid tumors and metastases to
the adrenal gland
Fig. 24.20 Adrenal cortical carcinoma. This unusual ACC has small
epithelial cells with high nuclear-to-cytoplasmic ratios and mitotic
activity, as well as pools of mucin
Adrenal Cortical Carcinoma
Fig. 24.21 Adrenal cortical carcinoma. A variety of growth patterns
and cytologic features may be seen in ACCs. This ACC shows promi-
nent spindle cell change. A tumor such as this must be differentiated
from a mesenchymal neoplasm and sarcomatoid carcinoma metastasis
to the adrenal gland
Fig. 24.22 Adrenal cortical carcinoma. ACCs may show cellular spin-
dling and sarcomatoid features. Although sarcomatoid adrenal cortical
carcinomas are not common, they are well-described in the literature
[16, 17]
179
Fig. 24.23 Adrenal cortical carcinoma. This is a cystic ACC. In a series
of 41 macroscopically cystic adrenal lesions from the Mayo Clinic, 2
were ACCs [5]. Both patients with cystic ACCs died of disease [5].
Although this is an uncommon presentation, it is important to sample
cystic adrenal masses extensively to rule out malignancy [5]. Adrenal
cortical adenomas and pheochromocytomas also may be cystic [5]
Fig. 24.24 Adrenal cortical carcinoma. This oncocytic ACC has
sheets of cells with eosinophilic cytoplasm. In a series of 67 adrenal
cortical carcinomas, 6 (11.2 %) were oncocytic [1]. The tumors ranged
from 8 to 20 cm [1]. Three of the six patients died of disease [1]. Only
one of the six oncocytic ACCs, a feminizing tumor measuring 20 cm,
was clinically functional [1]. A recent literature review noted that adre-
nal oncocytic neoplasms are rare and usually detected incidentally, as
only 17 % are functional [18]
180 24 Adrenal Cortical Carcinoma

Fig. 24.25 Adrenal cortical carcinoma. This oncocytic ACC has Fig. 24.26 Adrenal cortical carcinoma. The cells in this oncocytic
necrosis, a criterion for malignancy. Criteria for malignancy in onco- ACC have abundant eosinophilic cytoplasm and mitotic activity.
cytic adrenal cortical neoplasms include major criteria (high mitotic Ultrastructural studies confirm the abundant mitochondria in the cyto-
rate, atypical mitoses, and venous invasion) and minor criteria (large plasm of these cells [20]
size and weight, necrosis, capsular invasion, and sinusoidal invasion)
[19]. The presence of one major criterion indicates malignancy, the
presence of one to four minor criteria indicates uncertain malignant
potential (borderline), and the absence of all major and minor criteria
usually indicates the tumor is benign [19]
Adrenal Cortical Carcinoma 181

a b

c d

Fig. 24.27 Adrenal cortical carcinoma. ACCs usually are positive for
keratin (Cam5.2). Vimentin (a) also is positive in ACC. MelanA/Mart-1
(b) is helpful in identifying adrenal cortical tissues and tumors and dif-
ferentiating them from medullary tissue and pheochromocytoma, which
are negative. Because melanomas also are positive for MelanA/Mart-1,
S100 and HMB45 are useful because they are negative in adrenal corti-
cal tumors and positive in melanoma. Pheochromocytomas may show
staining for S100, but it is limited to the sustentacular cells. ACCs are
positive for synaptophysin (c) and negative for chromogranin.
Pheochromocytomas are positive for synaptophysin and chromogranin.
Ki67 (MIB1) reveals a markedly elevated proliferation index in this
ACC (d). Ki67 may be helpful in evaluating adrenal cortical tumors, but
there may be overlap in the Ki67 proliferative activity in benign and
malignant adrenal cortical tumors
182 24 Adrenal Cortical Carcinoma

References 10. Giordano TJ. Adrenocortical tumors: an integrated clinical, patho-

logic, and molecular approach at the University of Michigan. Arch
Pathol Lab Med. 2010;134(10):14403.
1. Erickson LA et al. Pathologic features and expression of insulin-
11. Gicquel C et al. Rearrangements at the 11p15 locus and overexpres-
like growth factor-2 in adrenocortical neoplasms. Endocr Pathol.
sion of insulin-like growth factor-II gene in sporadic adrenocortical
2001;12(4):42935.
tumors. J Clin Endocrinol Metab. 1994;78(6):144453.
2. Bodie B et al. The Cleveland Clinic experience with adrenal corti-
12. Sasano H, Suzuki T, Moriya T. Adrenal cortex. In: Lloyd RV, editor.
cal carcinoma. J Urol. 1989;141(2):25760.
Endocrine pathology: differential diagnosis and molecular
3. Crucitti F et al. The Italian Registry for Adrenal Cortical Carcinoma:
advances. Totowa: Humana Press; 2004. p. 21126.
analysis of a multiinstitutional series of 129 patients. The ACC
13. Gandour MJ, Grizzle WE. A small adrenocortical carcinoma with
Italian Registry Study Group. Surgery. 1996;119(2):16170.
aggressive behavior. An evaluation of criteria for malignancy. Arch
4. Didolkar MS et al. Natural history of adrenal cortical carcinoma:
Pathol Lab Med. 1986;110(11):10769.
a clinicopathologic study of 42 patients. Cancer. 1981;47(9):
14. Weiss LM, Medeiros LJ, Vickery Jr AL. Pathologic features of
215361.
prognostic significance in adrenocortical carcinoma. Am J Surg
5. Erickson LA et al. Cystic adrenal neoplasms. Cancer. 2004;101(7):
Pathol. 1989;13(3):2026.
153744.
15. Brown FM et al. Myxoid neoplasms of the adrenal cortex: a rare
6. Weiss LM. Comparative histologic study of 43 metastasizing and
histologic variant. Am J Surg Pathol. 2000;24(3):396401.
nonmetastasizing adrenocortical tumors. Am J Surg Pathol.
16. Coli A et al. Sarcomatoid carcinoma of the adrenal gland: a case
1984;8(3):1639.
report and review of literature. Pathol Res Pract. 2010;206(1):5965.
7. Aubert S et al. Weiss system revisited: a clinicopathologic and
17. Collina G et al. Primary sarcomatoid carcinoma of the adrenal
immunohistochemical study of 49 adrenocortical tumors. Am J
gland. First case report. Virchows Arch A Pathol Anat Histopathol.
Surg Pathol. 2002;26(12):16129.
1989;415(2):1617.
8. Wieneke JA, Thompson LD, Heffess CS. Adrenal cortical neo-
18. Mearini L et al. Adrenal oncocytic neoplasm: a systematic review.
plasms in the pediatric population: a clinicopathologic and immu-
Urol Int. 2013;91(2):12533.
nophenotypic analysis of 83 patients. Am J Surg Pathol. 2003;27(7):
19. Bisceglia M et al. Adrenocortical oncocytic tumors: report of 10 cases
86781.
and review of the literature. Int J Surg Pathol. 2004;12(3):23143.
9. Assie G, Giordano TJ, Bertherat J. Gene expression profiling
20. el-Naggar AK, Evans DB, Mackay B. Oncocytic adrenal cortical
in adrenocortical neoplasia. Mol Cell Endocrinol. 2012;351(1):
carcinoma. Ultrastruct Pathol. 1991;15(45):54956.
1117.
 Adrenal Myelolipoma
25

Adrenal myelolipoma is a benign tumor composed of
mature adipose tissue and hematopoietic elements [1].
Myelolipomas usually occur in the adrenal gland, but have
been identified in the presacral area [2, 3], renal sinus and
hilum [4, 5], greater omentum [6], paravertebral area [7],
and pulmonary bronchus [8]. Rarely, simultaneous adrenal
and extra-adrenal myelolipomas occur [9]. Adrenal adeno-
mas usually are solitary, but bilateral adrenal myelolipomas
are reported [1012]. Adrenal myelolipomas affect males
and females similarly and most often affects middle-aged
adults, although it may occur over a wide age range [13].
Approximately half the cases are asymptomatic, often
incidental findings with characteristic imaging features.
Myelolipomas may be associated with pain, hypertension,
or hematuria [13]. They generally are not hormonally func-
tioning tumors. A few myelolipomas associated with adre-
nocortical hypersecretion have been reported; however,
upon resection and histologic evaluation of at least one
recent case, an adrenocortical adenoma with widespread
myelolipomatous metaplasia was identified [14]. Adrenal
myelolipomas, including bilateral myelolipomas, have been
identified in patients with congenital adrenal hyperplasia
[11, 12]. Adrenal myelolipomas vary in size and may be as
large as 34 cm [1].

L.A. Erickson, Atlas of Endocrine Pathology, Atlas of Anatomic Pathology, 183

DOI 10.1007/978-1-4939-0443-3_25, Springer Science+Business Media New York 2014
184
Fig. 25.1 Adrenal myelolipoma. This cut section of adrenal myeloli-
poma shows a circumscribed tumor. Adrenal myelolipomas may vary in
size, with tumors up to 34 cm reported [1]. Myelolipomas usually are
yellow as a result of the predominance of adipose. Mixtures of yellow
adipose tissue with areas of more prominent hematopoietic elements
also may be seen. Tumors may have dark red areas, indicating extensive
hematopoietic elements that may resemble a hematoma
Fig. 25.2 Adrenal myelolipoma. Adrenal myelolipoma is present on
the right, with adjacent adrenal cortical tissue to the left. The propor-
tions of mature adipose tissue and hematopoietic elements in a myelo-
lipoma may vary
25 Adrenal Myelolipoma
Fig. 25.3 Adrenal myelolipoma. The myelolipoma on the right
appears fairly well-demarcated from the adrenal cortical tissue on
the left, unlike areas of myelolipomatous change in adrenal or adrenal
cortical neoplasms, which often are less circumscribed
Fig. 25.4 Adrenal myelolipoma. This is an area of prominent hema-
topoietic elements with trilineage hematopoiesis and scattered mature
adipose cells in a myelolipoma. Myelolipomas must be distinguished
from myelolipomatous metaplasia, which is seen in the adrenal and
adrenal cortical adenomas and hyperplasia. Myelolipomas form a
solitary circumscribed mass composed of hematopoietic elements and
mature adipose tissue without admixed adrenal cortical cells, as would
be seen in an adenoma or hyperplasia with myelolipomatous metaplasia
References 185

References
1. Lack EE. Tumors of the adrenal glands and extraadrenal paragan-
glia. In: Silverberg SG, Sobin LH, editors. AFIP atlas of tumor
pathology, vol. 8. Washington: American Registry of Pathology;
2007. p. 500.
2. Fowler MR et al. Extra-adrenal myelolipomas compared with
extramedullary hematopoietic tumors: a case of presacral myeloli-
poma. Am J Surg Pathol. 1982;6(4):36374.
3. Grignon DJ, Shkrum MJ, Smout MS. Extra-adrenal myelolipoma.
Arch Pathol Lab Med. 1989;113(1):524.
4. Clark PE et al. A rare case of an extra-adrenal myelolipoma arising
in the renal sinus: a case report and review of the literature.
ScientificWorldJournal. 2005;5:10917.
5. Talwalkar SS, Shaheen 2nd SP. Extra-adrenal myelolipoma in the
renal hilum: a case report and review of the literature. Arch Pathol
Lab Med. 2006;130(7):104952.
6. Karam AR et al. Multifocal extra-adrenal myelolipoma arising in
the greater omentum. J Radiol Case Rep. 2009;3(11):203.
Fig. 25.5 Adrenal myelolipoma. This photograph shows the trilineage 7. Schittenhelm J, et al. Extra-adrenal paravertebral myelolipoma
hematopoietic cells with myeloid cells, erythroid cells, and a few mega- mimicking a thoracic schwannoma. BMJ Case Rep. 2009;2009.
karyocytes in adrenal myelolipoma. Extra-adrenal myelolipomas must 8. Huang WT, Zhao SJ, Lin DM. Pulmonary-bronchus myelolipoma
be distinguished from extramedullary hematopoiesis, which often is and review on extra-adrenal myelolipomas in Chinese literature.
associated with anemia and bone marrow hyperplasia [15] Chin Med J (Engl). 2012;125(17):318890.
9. Zieker D et al. Simultaneous adrenal and extra-adrenal myeloli-
pomaan uncommon incident: case report and review of the litera-
ture. World J Surg Oncol. 2008;6:72.
10. Wrightson WR et al. Bilateral giant adrenal myelolipomas: a case
report. Am Surg. 2002;68(6):5889.
11. Ioannidis O et al. Giant bilateral symptomatic adrenal myelolipo-
mas associated with congenital adrenal hyperplasia. Pathol Oncol
Res. 2011;17(3):7758.
12. McGeoch SC et al. Giant bilateral myelolipomas in a man with
congenital adrenal hyperplasia. J Clin Endocrinol Metab.
2012;97(2):3434.
13. Del Gaudio A, Solidoro G. Myelolipoma of the adrenal gland:
report of two cases with a review of the literature. Surgery.
1986;99(3):293301.
14. Lamas C et al. Myelolipomatous adrenal masses causing Cushings
syndrome. Exp Clin Endocrinol Diabetes. 2009;117(8):4405.
15. Brietta LK, Watkins D. Giant extra-adrenal myelolipoma. Arch
Pathol Lab Med. 1994;118(2):18890.
 Pheochromocytoma and Adrenal
Medullary Hyperplasia
The chromaffin cells of the adrenal medulla produce
catecholamines such as epinephrine. The adrenal medulla
appears gray-white grossly and comprises 10 % of the gland.
The medulla may be hyperplastic in adrenal medullary
hyperplasia, as may be seen in multiple endocrine neoplasia
(MEN) types 2A and 2B, cystic fibrosis, and Beckwith-
Wiedemann syndrome, as well as sporadically. Adrenal
medullary hyperplasia may have clinical and biochemical
findings similar to those of pheochromocytoma. Adrenal
medullary hyperplasia usually affects both adrenals, unlike
most sporadic pheochromocytomas. However, bilateral
pheochromocytomas occur and may arise in a background
of medullary hyperplasia. Pheochromocytoma is a tumor
of the neural crestderived medulla chromaffin cells.
Pheochromocytomas usually occur in adults, often with
hypertension, which may be intermittent, although 25 % are
asymptomatic [1]. These uncommon tumors may be identi-
fied incidentally and at autopsy. They usually occur as a
single lesion. Multiple tumors or tumors occurring in chil-
dren are concerning for a syndrome. Malignancy is defined
by the presence of metastatic disease. Similar to the organ of
Zuckerkandl, the adrenal medulla is part of the sympathetic
chain, and similar tumors of the organ of Zuckerkandl are
referred to as paragangliomas or extra-adrenal pheochromo-
cytomas. Extra-adrenal paragangliomas may be part of the
sympathetic or parasympathetic system. Pheochromocytoma
is the term used for intra-adrenal paragangliomas and may be
used for extra-adrenal paragangliomas of the sympathetic
L.A. Erickson, Atlas of Endocrine Pathology, Atlas of Anatomic Pathology,
DOI 10.1007/978-1-4939-0443-3_26, Springer Science+Business Media New York 2014
26
neuroendocrine system. Sympathetic paragangliomas arise
in sympathetic chains, the pelvis, and the retroperitoneum,
whereas parasympathetic paraganglia arise in association
with vagus and glossopharyngeal nerve branches, such those
of the carotid body and the head and neck. At least 30 % of
paragangliomas and pheochromocytomas are familial. A
mutation rate of 41 % has been reported, suggesting that all
patients should be offered genetic testing [2]. Mutations may
involve the RET proto-oncogene, as in MEN2A or MEN2B;
von HippelLindau gene (VHL) in VHL type 1 and type 2;
neurofibromatosis gene (NF1) in neurofibromatosis type 1;
transmembrane protein 127 gene (TMEM-127); MYC-
associated factor X gene (MAX), and succinate dehydroge-
nase gene (SDH). SDH mutations include SDHD
(paraganglioma type 1 [PGL1] syndrome, multifocal tumors,
<35 years), SDHB (PGL4 syndrome, often malignant),
SDHC (PGL1 syndrome), SDHAF2 (PGL2 syndrome), and
SDHA [1, 3]. The mutations correlate with clinical features,
behavior, and location. Recently described syndromes are
Carney-Stratakis syndrome with paraganglioma and gastro-
intestinal stromal tumor (SDH mutation) and a syndrome of
multiple paragangliomas, duodenal somatostatinomas, and
polycythemia (HIF2a gain-of-function mutation) [3, 4].
Mutations have been grouped with VHL and SDH in cluster
1 (pseudohypoxic) and RET, NF1, TMEM127, and MAX in
cluster 2 (kinase receptor signaling) based on pathogenesis
or the pathway disrupted [5]. RET and VHL mutations usu-
ally are associated with intra-adrenal tumors.
187
188 26 Pheochromocytoma and Adrenal Medullary Hyperplasia

Adrenal Medullary Hyperplasia

Fig. 26.1 Adrenal medullary hyperplasia. This adrenal gland shows
medullary hyperplasia. Adrenal medullary hyperplasia may be seen
sporadically and in association with MEN2A, MEN2B, cystic fibrosis,
and Beckwith-Wiedemann syndrome. Adrenal medullary hyperplasia
usually affects both adrenal glands
Fig. 26.3 Adrenal medullary hyperplasia. Adrenal medullary tissue
with an irregular, somewhat trabecular growth pattern in adrenal medul-
lary hyperplasia. The growth may be diffuse or nodular

Fig. 26.2 Adrenal medullary hyperplasia. Adrenal medullary hyper-

plasia showing expansion of the medullary tissue. This may be diffuse
or nodular, and separating adrenal medullary hyperplasia from pheo-
chromocytoma may be difficult and arbitrary [6]. Historically, a cutoff
of 1 cm was suggested to differentiate medullary hyperplasia from
pheochromocytoma, but this now is considered arbitrary and not used
Pheochromocytoma 189

Pheochromocytoma

Fig. 26.4 Pheochromocytoma. Gross image of a pheochromocytoma

forming a circumscribed, mottled, white-gray mass with yellow adrenal
cortical tissue present around the periphery at the lower right aspect of
the tumor. Pheochromocytomas usually measure 35 cm, but size may
vary greatly [7]

Fig. 26.5 Pheochromocytoma. Gross image showing bilateral pheochromocytomas in a patient with MEN. Bilateral pheochromocytomas or
multiple paragangliomas often are syndrome-associated tumors
190
Fig. 26.6 Pheochromocytoma. Pheochromocytoma with a characteris-
tic nested or zellballen growth pattern. Pheochromocytomas may have
various growth patterns, including a nested or zellballen, an alveolar and
trabecular, a trabecular, and, rarely, a spindle cell growth pattern [7]
Fig. 26.7 Pheochromocytoma. Nests of pheochromocytoma cells in a
highly vascular background with prominent red blood cells.
Pheochromocytomas, like most neuroendocrine tumors, are highly vas-
cular, as would be expected in a tumor producing hormones and other
substances
26 Pheochromocytoma and Adrenal Medullary Hyperplasia
Fig. 26.8 Pheochromocytoma. This pheochromocytoma is composed
of nests of epithelioid cells with variably eosinophilic, finely granular
cytoplasm to more basophilic cytoplasm. The cells are epithelioid with
indistinct cell membranes and vesicular nuclei with nucleoli. This
tumor shows nuclear clearing in some nuclei. The delicate spindled sus-
tentacular cells around the nests generally require S100 immunostain-
ing to identify
Fig. 26.9 Pheochromocytoma. Cells in this pheochromocytoma show
nuclear pleomorphism. This finding is relatively common and without
particular significance in pheochromocytoma. Histologic features are
not particularly useful in predicting the behavior of a pheochromocy-
toma. The most definitive criterion for malignancy is metastasis
Pheochromocytoma 191

Fig. 26.10 Pheochromocytoma. The cells in this pheochromocytoma Fig. 26.12 Pheochromocytoma. This pheochromocytoma shows a
are nested, a common pattern in pheochromocytoma. Pheochromocytomas vaguely nested growth pattern, areas of nuclear pleomorphism, and
often have a mixture of alveolar and trabecular growth patterns, and occa- prominent vascularity
sional cases may show spindling

Fig. 26.11 Pheochromocytoma. The growth pattern in this pheochro- Fig. 26.13 Pheochromocytoma. Nuclear pseudoinclusions may be
mocytoma is quite irregular, and the cells show nuclear pleomorphism seen in pheochromocytomas. These pseudoinclusions may be well-
defined or irregular and generally have staining features similar to those
of the cytoplasm
192 26 Pheochromocytoma and Adrenal Medullary Hyperplasia

Fig. 26.14 Pheochromocytoma. This is an extra-adrenal pheochromo- Fig. 26.16 Pheochromocytoma. This pheochromocytoma shows
cytoma (paraganglioma) with a mitotic figure seen on the left. It is degenerative features with hyalinization and fibrosis
nearly impossible to differentiate a pheochromocytoma from a paragan-
glioma (extra-adrenal pheochromocytoma) histologically. Clinical
information regarding the location of the tumor generally is required.
As with pheochromocytomas, malignancy is diagnosed in paraganglio-
mas in the presence of metastases. The biologic potential of these
tumors cannot be determined with certainty by the histologic features

Fig. 26.17 Pheochromocytoma. This is a cystic pheochromocytoma

with prominent residual pheochromocytoma in the cyst wall. Of 41
macroscopically cystic lesions from the Mayo Clinic, 6 were associated
with adrenal neoplasms, including pheochromocytomas. Most of the
cysts were pseudocysts, but an endothelial cyst also was identified in
association with a pheochromocytoma [8]
Fig. 26.15 Pheochromocytoma. This gross photograph shows a pheo-
chromocytoma with degenerative features. Degenerative features are
not uncommon in pheochromocytomas, particularly in large tumors.
Fibrosis, cystic change, hyalinization, and hemosiderin deposition may
be seen
Pheochromocytoma
Fig. 26.18 Pheochromocytoma. Nests of pheochromocytoma cells are
present in the wall of this pheochromocytoma with a pseudocyst.
Extensive sampling is recommended when faced with a cystic adrenal
neoplasm to rule out an associated neoplasm
Fig. 26.19 Pheochromocytoma. Adrenal cortical adenoma is present
on the left, abutting a pheochromocytoma on the right. Although not
common, different tumors may be identified in the same adrenal gland
Fig. 26.20 Pheochromocytoma. This is a metastasis to the skull from
a paraganglioma. Histologic evaluation of the metastasis cannot deter-
mine whether this is from a pheochromocytoma or a paraganglioma
193
Fig. 26.21 Pheochromocytoma. This is a metastatic pheochromocy-
toma involving bone marrow. Metastasis is diagnostic of malignancy.
The Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) has
been suggested to determine malignancy; however it has high interob-
server variability and is not reproducible by others. Thus, metastasis
remains the diagnostic feature of malignancy in these tumors
Fig. 26.22 Pheochromocytoma. This is a metastasis to the ovary of a
pheochromocytoma/paraganglioma. Histologically, it is not possible to
determine whether this is from an adrenal pheochromocytoma or an
extra-adrenal tumor (paraganglioma). Metastases may develop decades
after diagnosis of the primary tumor; therefore, patients receive long-
term follow-up
194
Composite Pheochromocytoma
Fig. 26.23 Composite pheochromocytoma. Composite pheochromo-
cytomas are composed of pheochromocytoma and another component
resembling ganglioneuroma, ganglioneuroblastoma, or neuroblastoma
[7]. The tumor shown here is composed of pheochromocytoma (lower
left) and ganglioneuroma (upper right)
Fig. 26.24 Composite pheochromocytoma. Composite pheochromo-
cytoma showing an intermixture of pheochromocytoma and ganglio-
neuroma. The spindling neural elements are in the lower portion of the
photomicrograph. Composite pheochromocytomas often are function-
ally active tumors and secrete catecholamine [7]
26 Pheochromocytoma and Adrenal Medullary Hyperplasia
Fig. 26.25 Composite pheochromocytoma. Extensive area of ganglio-
neuroma in a composite pheochromocytoma. The amount of each com-
ponent varies in these lesions. The different components may be
admixed or have an abrupt transition
Fig. 26.26 Composite pheochromocytoma. Prominent ganglion cells
are seen the ganglioneuromatous component of this composite pheo-
chromocytoma. Nests of pheochromocytoma cells on the left are inter-
mixed with ganglion cells and neural elements in this composite
pheochromocytoma
References 195

References 5. Galan SR, Kann PH. Genetics and molecular pathogenesis of pheo-
chromocytoma and paraganglioma. Clin Endocrinol. 2013;78(2):
16575.
1. Mazzaglia PJ. Hereditary pheochromocytoma and paraganglioma.
6. Bahrami A, et al. Synchronous renal and adrenal masses: an analy-
J Surg Oncol. 2012;106(5):5805.
sis of 80 cases. Ann Diagn Pathol. 2009;13(1):915.
2. Fishbein L, et al. Inherited mutations in pheochromocytoma and
7. Lack EE. Tumors of the adrenal glands and extraadrenal paragan-
paraganglioma: why all patients should be offered genetic testing.
glia. In: Silverberg SG, Sobin LH, editors. AFIP atlas of tumor
Ann Surg Oncol. 2013;20(5):144450.
pathology, vol. 8. Washington, DC: American Registry of Pathology;
3. Karasek D, et al. An update on the genetics of pheochromocytoma.
2007. p. 500.
J Hum Hypertens. 2013;27(3):1417.
8. Erickson LA, et al. Cystic adrenal neoplasms. Cancer. 2004;
4. Pacak K, et al. New syndrome of paraganglioma and somatostatinoma
101(7):153744.
associated with polycythemia. J Clin Oncol. 2013;31(13):16908.
 Ganglioneuroma and Neuroblastoma
27

Although ganglioneuromas are benign and easily
recognizable tumors, primitive neural tumors of the adre-
nal gland, such as neuroblastoma, are malignant and
present much more complex problems in diagnosis and
classification. Ganglioneuromas may occur in a variety of
sites, including the adrenal gland. They are benign neu-
ral tumors composed of ganglion cells and Schwann cells.
Neuroblastomas are malignant tumors derived from primor-
dial neural crest cells. These tumors may be identified in a
variety of sites, including the adrenal gland. Neuroblastomas
usually are sporadic. They are the fourth most com-
mon malignant tumor in children; most occur in children
younger than 5 years, and one fifth are congenital [1]. These
tumors are classified by the International Neuroblastoma
Pathology Committee as undifferentiated neuroblastoma,
poorly differentiated neuroblastoma, differentiating neuro-
blastoma, nodular ganglioneuroblastoma, and intermixed
ganglioneuroblastoma (Shimada classification) [27].

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198 27 Ganglioneuroma and Neuroblastoma

Fig. 27.1 Ganglioneuroma. Ganglioneuromas may occur at a variety

of sites, including the adrenal gland, as is shown in this photograph of a
ganglioneuroma of the adrenal gland. These tumors may or may not be
encapsulated. On cross-section, the tumors are white to tan in appear-
ance. Extensive sampling of these tumors is needed to rule out the pos-
sibility of a stroma-rich ganglioneuroblastoma

a b

c d

Fig. 27.2 Ganglioneuroma. (a) This ganglioneuroma was diagnosed lights the axons in this ganglioneuroma. (c) Cathepsin D shows strong
on needle core biopsy. The ganglion cells are large and round, with staining in the large ganglion cells. (d) S100 highlights the Schwann
Nissl substance at the periphery of the cytoplasm. The ganglion cells cells in this ganglioneuroma
are in a background of spindled Schwann cells. (b) Neurofilament high-
Ganglioneuroma and Neuroblastoma
Fig. 27.3 Ganglioneuroblastoma. Ganglion cells are present at the
upper left in a background of spindled Schwann cells in the ganglioneu-
romatous portion of this tumor. Neuroblasts are identified at the upper
right. This tumor shows only microscopic nests of neuroblastoma and
more than 50 % schwannian stroma, and is classified as an intermixed
ganglioneuroblastoma
Fig. 27.4 Neuroblastoma. Neuroblastomas are malignant tumors
of primordial neural crest cells. Their classification is complex
and requires extensive sampling. The International Neuroblastoma
Pathology Committee (Shimada) classification is used to classify these
tumors
199
Fig. 27.5 Neuroblastoma. This tumor was classified as a differentiat-
ing neuroblastoma as it contained more than 5 % ganglion cells and
neuropil and schwannian stroma (<50 %) compared with poorly dif-
ferentiated neuroblastoma, which has less than 5 % ganglion cells and
no or minimal schwannian stroma
Fig. 27.6 Neuroblastoma. This neuroblastoma shows prominent neu-
roblasts. This tumor must be differentiated from other small blue cell
tumors
200 27 Ganglioneuroma and Neuroblastoma

Fig. 27.7 Neuroblastoma. This high-power view of a neuroblastoma
shows nests of neuroblasts
References
1. Lack EE. Tumors of the adrenal glands and extraadrenal paraganglia.
In: Silverberg SG, Sobin LH, editors. AFIP atlas of tumor pathol-
ogy, vol. 8. Washington, DC: American Registry of Pathology;
2007. p. 500.
2. Sano H, et al. International neuroblastoma pathology classification
adds independent prognostic information beyond the prognostic
contribution of age. Eur J Cancer. 2006;42(8):11139.
3. Shimada H. The international neuroblastoma pathology classifica-
tion. Pathologica. 2003;95(5):2401.
4. Peuchmaur M, et al. Revision of the International Neuroblastoma
Pathology Classification: confirmation of favorable and unfavorable
prognostic subsets in ganglioneuroblastoma, nodular. Cancer.
2003;98(10):227481.
5. Shimada H, et al. International neuroblastoma pathology classifica-
tion for prognostic evaluation of patients with peripheral neuroblas-
tic tumors: a report from the Childrens Cancer Group. Cancer.
2001;92(9):245161.
6. Goto S, et al. Histopathology (International Neuroblastoma
Pathology Classification) and MYCN status in patients with periph-
eral neuroblastic tumors: a report from the Childrens Cancer
Group. Cancer. 2001;92(10):2699708.
7. Shimada H, et al. The International Neuroblastoma Pathology
Classification (the Shimada system). Cancer. 1999;86(2):36472.
 Unusual Adrenal Tumors
28

A variety of unusual mesenchymal tumors involve the
adrenal gland primarily, such as hemangiomas, Kaposi
sarcomas, angiosarcomas, and benign and malignant
smooth muscle and neural tumors. Malignant melanoma is
an extraordinarily rarely reported primary in the adrenal
gland [1]; most malignant melanomas involving the adre-
nal gland are metastatic. Rare cases of primary lymphoma
of the adrenal gland also have been reported [2]. Other
unusual tumors in the adrenal gland are teratomas and ade-
nomatoid tumors. Adenomatoid tumors usually are identi-
fied in the urogenital system but may occur at a variety of
sites, including the adrenal gland. Although a variety of
unusual tumors rarely may be primary to the adrenal gland,
the histologic and immunophenotypic features of these
tumors are characteristic of the tumor and enable their
identification.

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202 28 Unusual Adrenal Tumors

Angiosarcoma of the Adrenal Gland

Fig. 28.3 Angiosarcoma of the adrenal gland. CD31 immunostaining

shows strong immunopositivity in the tumor cells of this adrenal
Fig. 28.1 Angiosarcoma of the adrenal gland. This is a primary angio- angiosarcoma
sarcoma of the adrenal gland. Angiosarcomas of the adrenal gland are
uncommon tumors, occurring in both men and women 4585 years of
age [3]. Adrenal angiosarcomas may be symptomatic, with abdominal
mass, pain, weight loss, fever, and weakness, or may be asymptomatic
[3]. Although rare, both benign and malignant vascular tumors may
involve the adrenal gland. Hemangioma, Kaposi sarcoma, and angio-
sarcoma all reportedly have involved the adrenal gland [35]. Vascular
tumors may involve the adrenal gland primarily or spread to the adrenal
gland secondarily

Fig. 28.2 Angiosarcoma of the adrenal gland. This epithelioid angio-

sarcoma of the adrenal gland has irregular spaces lined by atypical
epithelioid-appearing cells. Hemosiderin deposition also is noted. This
tumor was diagnosed on needle biopsy
Schwannoma of the Adrenal Gland
Leiomyosarcoma of the Adrenal Gland
Fig. 28.4 Leiomyosarcoma of the adrenal gland. This is a primary
adrenal leiomyosarcoma. Primary smooth muscle tumors, both benign
and malignant, of the adrenal gland are very rare but have been reported
[6]. Smooth muscle tumors of the adrenal gland are thought to arise
from the smooth muscle associated with the central adrenal vein [1]
Fig. 28.5 Leiomyosarcoma of the adrenal gland. This primary adrenal
leiomyosarcoma is histologically and immunophenotypically similar to
leiomyosarcoma of other sites. The tumor shows fascicles of spindle
cells with atypia and mitotic activity. The tumor cells are positive for
smooth muscle actin and desmin
203
Schwannoma of the Adrenal Gland
Fig. 28.6 Schwannoma of the adrenal gland. Primary adrenal schwan-
nomas are rare but have been reported [7]. Patients may be symptomatic
with abdominal pain [7]. Other mesenchymal neural tumors have been
reported in the adrenal gland, but they are exceptionally rare
Fig. 28.7 Schwannoma of the adrenal gland. Shown is a schwannoma
of an adrenal gland, with spindle cells and characteristic architectural
features. The tumor was immunoreactive for S100 and CD34
204
Teratoma of the Adrenal Gland
Fig. 28.8 Teratoma of the adrenal gland. Teratomas of the adrenal
gland are quite uncommon. This photomicrograph shows a portion a
teratoma and adrenal cortical tissue below
28 Unusual Adrenal Tumors
Adenomatoid Tumor of the Adrenal Gland
Fig. 28.9 Adenomatoid tumor of the adrenal gland. Adenomatoid
tumors are uncommon benign tumors of mesothelial origin that usually
are identified in the genital tract but may occur in the adrenal gland [8],
lymph node [9], pleura [10], and heart [11]. Grossly, adrenal adenoma-
toid tumors are smooth, white, and homogeneous [1]. These tumors
usually are asymptomatic and identified incidentally
Fig. 28.10 Adenomatoid tumor of the adrenal gland. An adrenal ade-
nomatoid tumor is seen on the left intermingling with adrenal cortical
cells on the right. Histologically, the tumor has cells with characteristic
features of an adenomatoid tumor, with a sieve-like appearance from
cytoplasmic vacuoles and glandular appearing spaces [1].
References
References
Fig. 28.11 Adenomatoid tumor of adrenal gland. Adenomatoid
tumors have many small glandular-appearing spaces. The associated
tumor cells appear vacuolated and have eosinophilic cytoplasm
10. Minato H, et al. Adenomatoid tumor of the pleura. Pathol Int.
11. Natarajan S, Luthringer DJ, Fishbein MC. Adenomatoid tumor of
Fig. 28.12 Adenomatoid tumor of the adrenal gland. A small group of
adrenal cortical cells and focal lipomatous metaplasia are surrounded
by adenomatoid tumor. Adenomatoid tumors are positive for calretinin,
keratin AE1/AE3, Cam5.2, keratin 7, vimentin, and keratin 5/6 (weak)
and negative for CD15, CD31, CD34, keratin 20, MOC31, and poly-
clonal antiserum to carcinoembryonic antigen [8]
205
1. Lack EE. Tumors of the adrenal glands and extraadrenal paragan-
glia. In: Silverberg SG, Sobin LH, editors. AFIP atlas of tumor
pathology, vol. 8. Washington, DC: American Registry of
Pathology; 2007. p. 500.
2. Frankel WL, Shapiro P, Weidner N. Primary anaplastic large cell
lymphoma of the adrenal gland. Ann Diagn Pathol. 2000;4(3):
15864.
3. Wenig BM, Abbondanzo SL, Heffess CS. Epithelioid angiosar-
coma of the adrenal glands. A clinicopathologic study of nine cases
with a discussion of the implications of finding epithelial-specific
markers. Am J Surg Pathol. 1994;18(1):6273.
4. Weiss JM, Schulte JW. Adrenal hemangioma: a case report. J Urol.
1966;95(5):6046.
5. Kern WH, Smart RD, Sherwin RP. Angiosarcoma of lungs and
adrenal gland: unusual clinical and pathologic manifestations.
Minn Med. 1967;50(9):133943.
6. Lin J, et al. Leiomyoma of the adrenal gland presenting as a non-
functioning adrenal incidentaloma: case report and review of the
literature. Endocr Pathol. 2007;18(4):23943.
7. Lau SK, Spagnolo DV, Weiss LM. Schwannoma of the adrenal
gland: report of two cases. Am J Surg Pathol. 2006;30(5):6304.
8. Isotalo PA, et al. Adenomatoid tumor of the adrenal gland: a clini-
copathologic study of five cases and review of the literature. Am J
Surg Pathol. 2003;27(7):96977.
9. Isotalo PA, et al. Extragenital adenomatoid tumor of a mediastinal
lymph node. Mayo Clin Proc. 2003;78(3):3504.
2009;59(8):56771.
the heart: report of a case. Am J Surg Pathol. 1997;21(11):
137880.
 Metastases to the Adrenal Gland
29

Tumors metastatic to the adrenal gland are more common
than primary adrenal tumors. Understanding the histologic
spectrum of primary adrenal tumors as well as the immuno-
phenotype enables differentiation of tumors metastatic to the
adrenal gland. Adrenal cortical tumors are positive for the
broad-spectrum neuroendocrine marker synaptophysin, but
negative for chromogranin. This enables differentiation of
adrenal cortical tumors from adrenal medullary tumors and
neuroendocrine tumors metastatic to the adrenal glands.
Mart-1/MelanA is very helpful in identifying adrenal corti-
cal tumors and differentiating them from metastases [1].
Adrenal cortical tumors show immunopositivity for Mart-1/
MelanA and are negative for S100, enabling distinction from
malignant melanoma. -Inhibin often is positive in adrenal
cortical tumors, particularly functioning tumors, but may
show immunopositivity in a steroidogenic tumor, so it is of
less utility. Adrenal cortical tumors usually are positive for
keratin, particularly Cam5.2, although keratin staining in
adrenal cortical tumors may be focal and weak. Metastatic
adenocarcinoma from the lung usually is positive for keratin
7 and thyroid transcription factor 1, enabling distinction
from adrenal tumors. Breast carcinomas usually are positive
for keratin 7 and negative for MelanA/Mart-1, differentiating
them from adrenal cortical tumors. Metastatic colon carci-
noma usually is positive for keratin 20 and CDX2. Renal cell
carcinoma is negative for MelanA/Mart-1, which helps dis-
tinguish it from an adrenal cortical tumor. In difficult cases,
additional immunostains characteristic of each tumor may be
helpful in distinguishing primary tumors of the adrenal from
tumors metastatic to the adrenal gland.

L.A. Erickson, Atlas of Endocrine Pathology, Atlas of Anatomic Pathology, 207

DOI 10.1007/978-1-4939-0443-3_29, Springer Science+Business Media New York 2014
208 29 Metastases to the Adrenal Gland

Fig. 29.1 Renal cell carcinoma metastatic to the adrenal gland. This is
a gross photograph of renal cell carcinoma metastatic to the adrenal
gland. In patients with an adrenal mass and a history of renal cell carci-
noma or synchronous renal tumor, metastatic renal cell carcinoma must
be ruled out. In a study of 80 cases of coexisting renal and adrenal
masses, 76 of the renal masses were renal cell carcinoma; 56 % of the
adrenal masses were benign, and 43 % were metastatic renal cell
carcinoma [2] Fig. 29.3 Melanoma metastatic to the adrenal gland. Metastatic mela-
noma is forming large tumefactive nodules in this metastasis to the
adrenal gland. Although exceptionally rare, cases of primary melanoma
of the adrenal have been reported; the vast majority of malignant mela-
nomas involving the adrenal gland are metastatic to the adrenal

Fig. 29.2 Renal cell carcinoma metastatic to the adrenal gland. This is
a renal cell carcinoma, classic clear cell type, metastatic to the adrenal
gland. Clear cell renal cell carcinoma has clear cytoplasm and may be
confused with lipid-rich cells of adrenal cortical neoplasms. In difficult
cases, immunoperoxidase studies may be helpful. Adrenal cortical tis-
sues and tumors are positive for MelanA and often for -inhibin, and
renal cell carcinomas usually are negative
Fig. 29.4 Melanoma metastatic to the adrenal gland. This is a meta-
static melanoma involving the adrenal gland. Melanin pigment is pres-
ent focally; however, in difficult cases immunoperoxidase studies may
be helpful. Both adrenal cortical tumors and melanomas show immu-
nopositivity for MelanA/Mart-1, but adrenal cortical tumors are nega-
tive for S100 and HMB45. S100 may be seen in sustentacular cells of
pheochromocytoma. Pheochromocytoma is negative for MelanA/
Mart-1
References 209

References
1. Loy TS, Phillips RW, Linder CL. A103 immunostaining in the diag-
nosis of adrenal cortical tumors: an immunohistochemical study of
316 cases. Arch Pathol Lab Med. 2002;126(2):1702.
2. Bahrami A, et al. Synchronous renal and adrenal masses: an analysis
of 80 cases. Ann Diagn Pathol. 2009;13(1):915.

Fig. 29.5 Breast cancer with prominent mucin. This breast cancer
shows mucinous features and might be confused with mucinous or
myxoid adrenal cortical tumors, as might other mucinous or myxoid
carcinomas or mucinous or myxoid mesenchymal tumors. In difficult
cases, immunostaining may be helpful, as breast carcinomas usually are
strongly and diffusely positive for keratin 7 and negative for MelanA/
Mart-1

Fig. 29.6 Breast cancer with prominent mucin. Mucinous features

may be seen in metastases to the adrenal gland, such as seen in this
breast cancer with mucinous change, and in primary adrenal cortical
tumors. It is important to keep in mind that both primary adrenal corti-
cal tumors and tumors metastatic to the adrenal gland may show myx-
oid or mucinous change
 Index

A tumor size and weight, 174

ACC. See Adrenal cortical carcinoma (ACC) unilateral tumors, 165
ACTH. See Adrenocorticotropic hormone (ACTH) Adrenal cortical hyperplasia
Acute thyroiditis, 14 autosomal dominant disorder, 159
Adenomatoid tumor description, 159
asymptomatic and identified, 204 diffuse
cortical cells and focal lipomatous ectopic ACTH production, 160
metaplasia, 205 enlargement, 161
spaces, small glandular, 205 pancreatic neuroendocrine tumor, 160
Adrenal cortical carcinoma (ACC) secondary hyperplasia, 160
aldosteronism, 168 zona fasciculata, 160
alveolar pattern, 169 nodular
cellular and nuclear pleomorphism, 167 definition, 161
cystic degeneration, 171 endocrine atypia, 162
cytotoxic chemotherapy, 173 macro- and micronodules, 161, 162
description, 173 PPNAD (see Primary pigmented nodular adrenocortical
eosinophilic cells, 167, 168 disease (PPNAD))
eosinophilic cytoplasm, 170, 172, 179, 180 PRKAR1A gene, 159
feminizing/virilizing tumors, 165 Adrenal cysts
histologic features, 173 CD31-immunostained sample, 156
insulin-like growth factor 2, 173 endothelial-lined adrenal cysts, 156
keratin, 181 fibrous-walled adrenal pseudocyst, 156
lipid-rich adrenal cortical adenoma cells, 168 pheochromocytomas, 155
lipofuscin, 171 pseudocysts, 155, 156
lipomatous/myelolipomatous, 167 vague symptoms, 155
lymphoma, 177 Adrenal gland
mitotic figures, 175 abnormalities and pathogenic processes, 147
multivariate analysis, 165 adipocytes and lymphocytes, 151
myxoid change central adrenal vein, 150
and epithelioid cells, 170 chromaffin cells, 150
and spindle cells, 170 encapsulated cortical extrusions, 151
necrosis, 175 formalin, 148
nuclear-to-cytoplasmic ratios heterotopia (see Heterotopia)
and cellular monotony, 174 medullary hyperplasia, 147
monotonous cells, 176 pheochromocytomas, 147
mucin, 178 right and left adrenal glands, 148
pleomorphism, 176 scattered adipocyte, 150
oncocytic adenomas, 171 zona
pale lipid-rich cell, 166 fasciculata, 149
pale-staining cells, 167 glomerulosa, 148
pediatric tumors, 173 reticularis, 149
polymorphous cells, 176 Adrenal gland tumors
primary hyperaldosteronism, 168 adenomatoid, 204205
pseudoglandular growth pattern, 169 angiosarcoma, 202
pseudoglandular pattern, 177 leiomyosarcoma, 203
punctate microscopic foci, 175 teratoma, 204
small cell cytomorphology, 178 Adrenal medullary hyperplasia
spindle cell change, 179 description, 187
spironolactone bodies, 169 MEN2A, MEN2B and cystic
subclinical Cushing syndrome, 166 fibrosis, 188
trabecular growth pattern, 176 pheochromocytoma, 188
tumor behavior, 170 trabecular growth pattern, 188

L.A. Erickson, Atlas of Endocrine Pathology, Atlas of Anatomic Pathology, 211

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212 Index

Adrenal myelolipoma colloid, 34

adjacent adrenal cortical tissue, 184 cystic-appearing lymph node metastasis, 36
bilateral, 183 growth patterns, 34
cortical tissue, 184 intranuclear holes, 34
description, 183 invasive, 32
hematopoietic elements, 184 low-power photomicrograph, 35
hypersecretion, 183 multiple ill-defined firm masses, 32
trilineage hematopoietic cells, 185 Orphan Annie nuclei, 32
yellow adipose tissue, 184 papillae with fibrovascular cores and cystic change, 32, 33
Adrenal tumors, metastatic prominent papillae with fibrovascular cores, 32, 33
breast cancer, 209 psammoma bodies, 33
cortical, 207 Columnar variant of PTC, 47
medullary, 207 Composite pheochromocytoma
melanoma, 208 composition, 194
neuroendocrine, 207 ganglioneuroma, 194
primary, 207 Cowden syndrome, 25
renal cell carcinoma, 208 Cribriform-morular variant of PTC
Adrenocorticotropic hormone (ACTH) aberrant nuclear and cytoplasmic staining, -catenin, 41
in congenital adrenal hyperplasia, 159 arches and anastomosing bars, 40
cortical hyperplasia, 159 autosomal dominant syndrome, 40
neuroendocrine tumor, 160 morules, 41
Amiodarone thyroid, 56 nuclear staining, TTF1, 41
Amyloid goiter, 25, 2829 spindle/oval tumor cells, 41
Anaplastic thyroid carcinoma
adjacent structures, invasion, 72
atypical spindle cells, 73 D
composition, 71, 73 de Quervain thyroiditis. See Granulomatous
distant metastases, 71 (de Quervain) thyroiditis
hemorrhage and necrosis areas, 72 Diffuse hyperplasia. See Graves disease
Hurthle cell carcinoma, dedifferentiation, 74 Diffuse sclerosing variant of PTC, 43
papillary thyroid carcinoma (PTC), 7475 Dyshormonogenetic goiter, 2728
Rhabdoid features, 74
Riedel (fibrous) thyroiditis, 71, 73
TTF1, 71 F
vascular invasion, 72 Familial isolated hyperparathyroidism (FIH), 131
Angiosarcoma, 92, 202 Fibrous (Riedel) thyroiditis, 13, 16, 71, 73
Atypical parathyroid adenoma FIH. See Familial isolated hyperparathyroidism (FIH)
composition, 128 Focal lymphocytic thyroiditis, 13, 18
hypercellular and fibrosis, 128 Follicular adenoma
indolent behavior, 128 adipocytes, 57
irregular growth and fibrous bands, 129 clear cell change, 56, 57
Ki67 labeling index, 129 degenerative feature and hyalinization, 59
monotonous growth, 129 description, 55
parathyroid carcinoma, 128 extensive signet ring cell change, 58
immunoperoxidase markers, 56
medium-power view, 59
B metaplastic bone/ossification, 59
Breast cancer, 209 microfollicular and macrofollicular architectural
Brown tumor of bone, 113 pattern, 56
mucin, 57
prominent spindle cell change, 58
C signet ring cell change, 58
Calcifications, 81 thyroid, 56
Carcinoembryonic antigen (CEA), 84 Follicular carcinoma
Carcinoma showing thymus-like differentiation (CASTLE), 9495 capsular invasion, 60
CASTLE. See Carcinoma showing thymus-like clear cell change, 61, 62
differentiation (CASTLE) description, 60
C cells, tumors mushroom-like area, 60
hyperplasia, 78 signet ring cell change, 62
medullary thyroid microcarcinoma, 7879 spindle cell change, 62
MTC (see Medullary thyroid carcinoma (MTC)) thrombus, 61
CEA. See Carcinoembryonic antigen (CEA) vascular invasion, 60, 61
Chief cells, parathyroid histology, 103104 Follicular thyroid neoplasms
Classic PTC adenomas (see Follicular adenoma)
cervical and ipsilateral lymph nodes, 35 carcinomas (see Follicular carcinoma)
characteristic cytologic features, 33 cytologic specimens, 55
Index 213

histologic patterns, 55 extracellular eosinophilic hyaline fibrosis, 52

malignancy, 55 prominent eosinophilic intranuclear
tumors with extensive vascular invasion, 55 inclusions, 52
Follicular variant of papillary thyroid RET/PTC rearrangements, 51
carcinoma (FVPTC) tumor cells, 52
characteristic features, 38 Hyperparathyroidismjaw tumor syndrome
classic PTC, 37, 39 (HP-JT), 131
cumulative diagnosis, 37
elongated follicles, 38
encapsulated tumors, 37 L
HBME-1 immunostain, 40 Langerhans cell histiocytosis, 91
low-power photomicrograph, 39 Leiomyosarcoma, 203
numerous patterns, 38 Lipoadenomatous hyperplasia, 114
photomicrograph shows, 38 Lipohyperplasia, 109
thyroid parenchyma, 39 Low-grade fibromyxoid sarcoma, 93
Lymphoma, 90

G
Ganglioneuroma M
adrenal gland, 198 Medullary thyroid carcinoma (MTC)
needle core biopsy, 198 acinar growth pattern, 82
recognizable tumor, 197 amyloid, 79
spindled Schwann cells, 199 calcifications, 81
stroma-rich, 198 calcitonin, 83
Granulomatous (de Quervain) thyroiditis CEA, 84
multinucleated giant cells, 15 composition, 81
noncaseating granulomas, 15 epithelioid cells, 80
patchy areas, neutrophils and microabscesses, 14 growth patterns, 80
patients, 13, 14 intranuclear pink holes, 80
Graves disease neuroendocrine markers, 83
complications, 21 oxyphilic, 82
cut section, 22 papillary architectural pattern, 83
diffuse hyperplasia, 23 recognization, 82
diffusely enlarged thyroid, 22 solid growth, necrosis, 81
follicular epithelium, 24 spindle cells, 80
hyperthyroidism, 21 syndromic, 79
low-power photomicrograph, 22 TTF1, 83, 84
papillae, 22, 23 Metastases to parathyroid
patients treatment with iodine, 24 carcinoma, 144
thyroid carcinomas, 21 medullary thyroid carcinoma, 144
thyroid parenchyma, 22 primary thyroid tumors, 143
thyroid tumors, 144
Metastases to thyroid
H breast cancer metastatic, 100
Hashimoto thyroiditis melanoma metastatic, 101
fibrous variant, 18 primary tumors, 99
prominent lymphoid follicles, 17 renal cell carcinoma metastatic, 100
solid cell nests, 18 resection, 99
thyroid, 13 Minocycline thyroid, 56
H&E. See Hematoxylin and eosin (H&E) MTC. See Medullary thyroid
Hematoxylin and eosin (H&E), 1, 4 carcinoma (MTC)
Heterotopia Multinodular goiter, 2627
adipocytes and foci, lymphocytes, 152 Multiple endocrine neoplasia (MEN) types
cortical nodule, 152 1 and 2A, 109
embryologic path, 152
subcapsular space, 152
Hobnail variant of PTC, 48 N
HP-JT. See Hyperparathyroidismjaw tumor Nephrolithiasis, 121
syndrome (HP-JT) Neuroblastoma
Hurthle cell adenoma, 63, 64 children, 197
Hurthle cell carcinoma, 65 classification, 197, 199
Hurthle cell thyroid neoplasms, 6365 ganglion and Schwann cells, 197
Hyalinizing trabecular tumor malignant, 197
Carneys group, 51 nests, 200
description, 51 primordial neural crest cells, 199
encapsulation and separation, 52 sporadic, 197
214 Index

Normal thyroid glandular growth pattern, 135

central lumen containing colloid, 3 hemosiderin deposition, 134
chromogranin immunostain, 4 HRPT2 tumor suppressor gene, 131
cut section, 2 hyperplasia and, 133
fat cells, 4 intrathyroidal, 133
follicles, 3 invasive growth, 132
gross image, 2 monotonous growth pattern, 134
immunopositivity, TTF1, 3 multiple mitotic figures, 134
thyroglobulin, immunopositivity, 3 nuclear atypia and mitotic activity, 137
oxyphilic, 135136
palisading, 136137
O perithyroidal soft tissue, 132
Oncocytic/Hurthle cell, 44 postoperative radiation, 131
Oxyphilic cells, 104 prognostic factors, 131
PTH, 131
skeletal muscle, neck, 132133
P trabecular growth pattern, 136
Palpation thyroiditis, 7 vascular thrombus, 133
Papillary thyroid carcinoma (PTC) Parathyroid histology
BRAF mutations, 31 chief cells, 103104
classic (see Classic PTC) clear cytoplasm and pyknotic nuclei, 105
columnar variant, 47 cysts and inflammation, 103, 105106
cribriform-morular variant (see Cribriform-morular normal, 104
variant of PTC) in older patients, 105
diffuse sclerosing variant, 43 oxyphilic cells, 104
and FVPTC (see Follicular variant of papillary thyroid parathyroiditis, 106107
carcinoma (FVPTC)) Parathyroid hormone (PTH), 109, 131
histologic variants, 31 Parathyroid hyperplasia
hobnail variant, 48 asymmetric enlargement, 109
microcarcinoma, 36, 37 brown tumor of bone, 113
oxyphilic variant, 44 lipoadenomatous hyperplasia, 114
patients, 31 lipohyperplasia, 109
radioactive iodine, 31 multiple endocrine neoplasia (MEN) types 1 and 2A, 109
solid variant, 45 primary
tall cell variant, 46 adipocytes, 110
warthin-like variant, 42 chief and clear cells, 111
Papillary thyroid microcarcinoma glandular growth pattern, 112
benign thyroid disease, 37 nodular enlargement, 110
gross photograph, 36 nodular grow, 111
Paraganglioma, 96 nuclear palisading, 112
Parathyroid adenoma oxyphilic cells, 111
atypical parathyroid adenoma, 128129 parenchymal mass, 110
chief cell primary clear cell hyperplasia, 113114
composition, 123 PTH, 109
cystic change, 124 secondary
degenerative edema, 123 chief cells, 116
diffuse cellularity, 122 diffuse hyperplasia, 117
edematous change, 123 fibrosis and fibrous bands, 117
features, 122 foci of amyloid, 118
fibrous connective tissue capsule, 122 hemosiderin deposition, 117
glandular growth, 124 nodular growth, 115
hyalinization and metaplastic bone, 123 nodular hyperplasia, 115
large dilated follicular-like spaces, 125 oxyphilic cells, 116
parenchyma cells and adipocytes, 122 parathyroid tissue, implant, 118
signet ring cell change, 124 parenchymal mass, 115
spindle cell change, 125 tertiary parathyroid hyperplasia, 118
stromal fat, 123 Parathyroiditis, 106107
clear cell, 126 Parathyroid lipoadenoma, 127
molecular basis, 121 Parathyromatosis
nephrolithiasis, 121 calcimimetic agents, 139
oxyphil cell, 125126 features, 140
parathyroid lipoadenoma, 127 hypercellular parathyroid tissue, nodules, 140
screening calcium, 121 serum calcium level, 140
Parathyroid carcinoma Pendred syndrome, 25
clear cell, 137 Pheochromocytoma
dilated follicular structures, 135 adrenal cortical adenoma, 193
features, 132 alveolar and trabecular growth patterns, 191
FIH, 131 composite, 194
Index uploaded by [stormrg] 215

degenerative features, hyalinization Thyroid goiter

and fibrosis, 192 amyloid, 25, 2829
description, 187 Cowden syndrome, 25
epithelioid cells, 190 dyshormonogenetic goiter, 2728
histologic features, 190 endemic, 25
macroscopically cystic lesions, 192 malignancy, 25
metastasis, skull, 193 medications, 25
mitotic figure, 192 meta-analysis, 25
neuroendocrine tumors, 190 multinodular goiter, 2627
nuclear nontoxic, 25
pleomorphism, 191 Pendred syndrome, 25
pseudoinclusions, 191 toxic multinodular, 25
paraganglioma, 193 Thyroid histology
pseudocyst, 193 calcitonin mRNA, 1
syndrome-associated tumors, 189 C cells, 1
yellow adrenal cortical tissue, 189 colloid, 1
zellballen growth pattern, 190 ectopic thyroid tissue, 8
Poorly differentiated thyroid carcinoma immunohistochemical stains, 1
external-beam radiotherapy, 67 minocycline and amiodarone, 56
insular growth pattern, 68 normal thyroid (see Normal thyroid)
necrosis, 68 palpation thyroiditis, 7
operational pathologic definition, 67 radiation changes, 5
relapse-free and cause-specific survival solid cell nests (see Solid cell nests)
rates, 67 struma ovarii, 910
TP53 mutations, 68 thyroglossal duct cyst, 9
Turin criteria, 67 thyroid needle-biopsy site, 7
uniform tumor cells, 68 TTF1, 1
PPNAD. See Primary pigmented nodular adrenocortical Thyroiditis
disease (PPNAD) acute inflammation, 13, 14
Primary pigmented nodular adrenocortical de Quervain granulomatous, 13, 1415
disease (PPNAD) fibrous (Riedel), 13, 16
affected adrenal glands, 162 focal lymphocytic, 18
bilateral micronodular hyperplasia, 162 Hashimoto, 13, 1718
corticomedullary junction, 163 Thyroid needle-biopsy site, 7
description, 159 Thyroid-stimulating hormone (TSH), 3
lipofuscin, 163 Thyroid transcription factor 1 (TTF1), 1, 3, 83, 84
zona reticularistype, 163 Thyroid tumors
angiosarcoma, 92
CASTLE, 9495
R langerhans cell histiocytosis, 91
Renal cell carcinoma, 208 low-grade fibromyxoid sarcoma, 93
Rhabdomyosarcoma, 94 lymphoma, 90
Riedel thyroiditis. See Fibrous (Riedel) thyroiditis paraganglioma, 96
rhabdomyosarcoma, 94
sclerosing mucoepidermoid carcinoma,
S 8788
Schwannoma, 203 solitary fibrous tumor, 91
Sclerosing mucoepidermoid carcinoma squamous cell carcinoma, 89
in adult women, 87 synovial sarcoma, 93
invasive growth recognization, 88 teratoma, 95
mucous cells, 88 TSH. See Thyroid-stimulating hormone (TSH)
Solid cell nests TTF1. See Thyroid transcription factor 1 (TTF1)
oval cells with fine chromatin, 4
PTCs, 4
Solid variant of PTC, 45 U
Solitary fibrous tumor, 91 Unusual adrenal tumors
Squamous cell carcinoma adenomatoid, 201, 204205
adolescent, Hashimoto thyroiditis, 89 angiosarcoma (see Angiosarcoma)
keratinization, 89 leiomyosarcoma, 203
pure squamous differentiation, 89 malignant melanoma, 201
Struma ovarii, 910 primary lymphoma, 201
Synovial sarcoma, 93 schwannoma, 203
teratoma, 204

T
Tall cell variant of PTC, 46 W
Teratoma, 95, 204 Warthin-like variant of PTC, 42
Thyroglossal duct cyst, 9