Primary and Metastatic Lung Tumors in the
Pediatric Population
A Review and 25-Year Experience at a Large Children’s Hospital
Megan K. Dishop, MD; Supriya Kuruvilla, MD
● Context.—Primary lung neoplasms are rare in children,
but they comprise a broad and interesting spectrum of le-
sions, some of which are familiar from other tissue sites,
and some of which are unique to the pediatric lung.
Objective.—To determine the relative incidence of pri-
mary and metastatic lung tumors in children and adoles-
cents through a single-institution case series, to compare
these data to reports in the medical literature, to discuss
the clinical and pathologic features of primary tumors of
the tracheobronchial tree and lung parenchyma in chil-
dren, and to provide recommendations for handling pedi-
atric lung cysts and tumors.
Data Sources.—A 25-year single institutional experience
with pediatric lung tumors, based on surgical biopsies and
resections at Texas Children’s Hospital from June 1982 to
May 2007, an additional 40 lung tumors referred in con-
sultation, and a review of the medical literature.
Conclusions.—A total of 204 pediatric lung tumors were
P rimary lung neoplasms are rare in children. Lung mas-
ses in children are approximately 10 times more likely
to represent a benign developmental or reactive lesion
than a neoplasm, with a ratio of primary tumors to met-
astatic tumors to nonneoplastic lesions of 1:5:60.1 Common
malformations forming solid and cystic masses of the pe-
diatric lung include bronchogenic cyst, segmental bron-
chial atresia, intralobar and extralobar pulmonary seques-
tration, congenital pulmonary airway malformation (con-
genital cystic adenomatoid malformation), and congenital
lobar overinflation. The vast majority of solid parenchymal
lung masses in children represent inflammatory, infec-
tious, or reactive processes, with a differential diagnosis,
including granulomatous inflammation (fungal, mycobac-
terial, parasitic, sarcoidosis, vasculitis); abscess; pneumo-
nia (bacterial, viral); septic embolus; infarction; or hema-
toma.2 Of the lung neoplasms in children, metastatic tu-
mors far exceed the number of primary lesions. Of the
Accepted for publication January 12, 2008.
From the Department of Pathology, Texas Children’s Hospital, Baylor
College of Medicine, Houston.
The authors have no relevant financial interest in the products or
companies described in this article.
Reprints: Megan K. Dishop, MD, Department of Pathology, MC
1-2261, Texas Children’s Hospital, Baylor College of Medicine, 6621 Fan-
nin St, Houston, TX 77030 (e-mail: mkdishop@texaschildrenshospital.
org).
Arch Pathol Lab Med—Vol 132, July 2008
diagnosed at our institution, including 20 primary benign
lesions (9.8%), 14 primary malignant lesions (6.9%), and
170 secondary lung lesions (83.3%). The ratio of primary
benign to primary malignant to secondary malignant neo-
plasms is 1.4:1:11.6. The common types of lung cancer in
adults are exceptional occurrences in the pediatric popu-
lation. The most common primary lung malignancies in
children are pleuropulmonary blastoma and carcinoid tu-
mor. Other primary pediatric lung tumors include congen-
ital peribronchial myofibroblastic tumor and other myofi-
broblastic lesions, sarcomas, carcinoma, and mesothelio-
ma. Children with primary or acquired immunodeficiency
are at risk for Epstein-Barr virus–related smooth muscle
tumors, lymphoma, and lymphoproliferative disorders.
Metastatic lung tumors are relatively common in children
and also comprise a spectrum of neoplasia distinct from
the adult population.
(Arch Pathol Lab Med. 2008;132:1079–1103)
primary lung tumors in children reported in the literature,
malignancies exceed the number of benign neoplasms,
with a ratio of approximately 3:1.3 The most common be-
nign tumor of the pediatric lung is inflammatory myofi-
broblastic tumor (52%), and the most common primary
malignancies are carcinoid tumor and pleuropulmonary
blastoma.3 Based on German registry data, malignant tu-
mors of the trachea, bronchus, and lungs represent 0.2%
of all malignancies in children.4 The mortality rate for pri-
mary benign lung neoplasms in children is low (8.7%),
and the mortality rate for primary malignant tumors is
approximately 30% overall. Excluding the ‘‘bronchial ad-
enomas,’’ which are associated with a favorable prognosis,
the mortality rate of the malignant tumors rises to ap-
proximately 50%.3
Given the rarity of primary lung neoplasms in children,
clinical detection remains a challenge. Some cases are
asymptomatic and detected only incidentally on imaging
studies. Other nonspecific respiratory symptoms may be
attributed initially to asthma or other inflammatory pro-
cesses, resulting in a delay of diagnosis until only after
symptoms persist or are unresponsive to conventional
therapy. Even if a mass is recognized, endobronchial le-
sions and cystic parenchymal lesions may be radiograph-
ically indistinguishable from reactive processes or lung
malformations. The possibility of a lung neoplasm should
be considered clinically in any child presenting with
Pediatric Lung Tumors—Dishop & Kuruvilla 1079
 Table 1. Classification of Primary Pediatric Lung Tumors Based on Histogenesis*
Benign
Embryonic Hamartoma
Mature teratoma
Mesenchymal Myofibroblastic tumors
IMT
CPMT
Myofibromatosis
Hemangioma
Lymphangioma
Neurofibroma
Leiomyoma/smooth muscle tumor (with or without EBV)
Chondroma
Granular cell tumor
Lymphohistiocytic Lymphoid neoplasms
Lymphoproliferative disorders (with or without EBV),
polyclonal
Histiocytoses
Langerhans cell histiocytosis
Non-LCH histiocytosis
Epithelial Papilloma/papillomatosis
Mucous gland adenoma
Mesothelial
* IMT indicates inflammatory myofibroblastic tumor; CPMT, congenital peribronchial myofibroblastic tumor; EBV, Epstein-Barr virus; LCH, Lan-
gerhans cell histiocytosis; and BAC, bronchioloalveolar carcinoma.
wheezing, persistent cough, hemoptysis, or recurrent
pneumonia. Regardless of the clinical working diagnoses,
the pathologist should remain vigilant to the possibility
of a primary lung neoplasm in a child, particularly in as-
sessing cystic lung lesions.
Several clinical reviews of pediatric lung neoplasms are
available.1,3–12 Pathologic features of pediatric lung neo-
plasms have also been reviewed previously by Dehner al-
most 20 years ago.13 The objectives of this review are (1)
to provide additional relative incidence data for both pri-
mary and metastatic lung neoplasms from a single large
institutional experience, (2) to provide an update on our
current understanding of pathologic features and diag-
nostic terminology for these rare tumors, and (3) to pro-
vide recommendations for the practicing surgical pathol-
ogist on handling cystic and/or solid masses of the pe-
diatric lung.
TEXAS CHILDREN’S HOSPITAL EXPERIENCE: 25 YEARS
OF PRIMARY AND METASTATIC LUNG TUMORS
Incidence data on primary lung tumors in children are
limited in the medical literature due to the predominance
of individual case reports and diagnosis-specific case se-
ries. As a result, cumulative historical data from literature
reviews are difficult to interpret due to an uneven repre-
sentation of these rare lesions and significant differences
in diagnostic criteria and terminology, which have evolved
during the decades typically encompassed by such re-
views. For example, bronchogenic carcinoma has been re-
ported to occur with some frequency in other reviews of
pediatric lung tumors, but it appears to be overrepresent-
ed in the literature relative to current experience. Other
1080 Arch Pathol Lab Med—Vol 132, July 2008
Malignant
Pleuropulmonary blastoma
Type I (cystic)
Type II (solid and cystic)
Type III (solid)
Immature teratoma
Malignant germ cell tumor
Synovial sarcoma
Rhabdomyosarcoma
Ewing sarcoma family of tumors
Malignant peripheral nerve sheath tumor
Leiomyosarcoma (with or without EBV)
Bronchopulmonary fibrosarcoma
Angiosarcoma
Kaposi sarcoma
Lymphoid neoplasms
Lymphoproliferative disorders (with or without
EBV), monoclonal
Lymphoma
Hodgkin
Non-Hodgkin
Carcinoid tumor
Mucoepidermoid carcinoma
Adenoid cystic carcinoma
Squamous cell carcinoma
Adenocarcinoma
BAC
Mesothelioma
than the low-grade neuroendocrine carcinomas (carcinoid
tumors), primary lung carcinoma is vanishingly rare and
a reportable occurrence in children. Table 1 presents a
classification of pediatric lung neoplasms according to his-
togenesis, adapted from Tischer et al.4 A previous review
of 465 pediatric lung specimens from a single institution
(a 250-bed children’s hospital in Cape Town, South Africa)
during a 31-year period revealed a total of 8 primary lung
tumors (6 originating at this institution and 2 reviewed in
consultation) and 35 metastatic tumors.1 Primary lung tu-
mors in this series included 50% malignant and 50% be-
nign lesions: plasma cell granuloma (3), pleuropulmonary
blastoma (2), mucoepidermoid carcinoma (1), endobron-
chial fibrosarcoma (1), and capillary hemangioma (1).
Metastatic tumors included Wilms tumor (16), osteosar-
coma (9), rhabdomyosarcoma (5), neuroblastoma (4), and
hepatoblastoma (1).1
In an attempt to provide additional relative incidence
data, a similar review of the experience at Texas Children’s
Hospital (Houston) was performed for a 25-year period
(June 1982–May 2007). Texas Children’s Hospital is a large
tertiary care center with 639 licensed hospital beds, in-
cluding a 36-bed inpatient hematology-oncology unit and
a 15-bed bone marrow transplant unit. The Texas Chil-
dren’s Cancer Center receives approximately 25 000 out-
patient visits annually. Based on registry data from 2000
to 2004, an average of 289 children were diagnosed with
malignancies annually at our institution, including 91 new
solid tumor diagnoses per year. Primary and metastatic
lung lesions were identified by performing a natural lan-
guage search of the anatomic pathology information sys-
Pediatric Lung Tumors—Dishop & Kuruvilla
tem for the dates specified, using terms for site (lung, tra-
chea, bronchus, bronchial, pleura); general descriptors
(cancer, tumor, neoplasm, benign, malignant, malignancy,
mass, nodule, metastatic, juvenile, infantile); and specific
tumor types (carcinoma, blastoma, sarcoma, lymphoma,
hamartoma, adenoma, pleuropulmonary, lymphoprolifer-
ative, Hodgkin/Hodgkin’s, leukemia, Wilms, neuroblas-
toma, hepatoblastoma, osteosarcoma, rhabdomyosarcoma,
fibrosarcoma, chondrosarcoma, leiomyoma, leiomyosar-
coma, liposarcoma, lipoblastoma, glioblastoma, clear cell,
neuroendocrine, carcinoid, melanoma, myofibroblastic,
adenocarcinoma, histiocytosis, mesothelioma, Kaposi/Ka-
posi’s, granular cell tumor/myoblastoma, and papilloma/
papillomatosis). Patients with juvenile respiratory papil-
lomatosis were included if the excised squamous papillo-
mas were specifically designated from tracheal, bronchial,
or pulmonary sites. Other patients with papillomas ex-
cised only from the larynx/vocal cords, oropharynx, na-
sopharynx, esophagus, and/or other sites not specified
were excluded from tabulation.
During this 25-year period, the total number of surgical
pathology specimens was 227 655, with annual specimen
numbers ranging from 5309 in 1982 to 14 055 in 2006. We
received a total of 3980 surgical specimens designated
from the trachea, bronchus, or lung (1.7%), including both
biopsies and resections. Of these, 507 specimens were
from lung transplant recipients (12.7%), and 3473 were
from other patients (87.3%). There were 273 biopsy and
resection specimens for primary or metastatic neoplasms
of the lung, representing 6.9% of all tracheobronchial and
lung specimens. Pathologic slides were examined for the
primary benign and malignant tumors to ensure accuracy
of diagnosis. Among these, 1 ‘‘mesenchymoma’’ was re-
classified as lipoblastoma, and 2 cases of ‘‘spindle cell sar-
coma’’ included one with myofibroblastic differentiation
and another subclassified as a fibrosarcoma.
The spectrum of tracheobronchial or lung parenchymal
tumor diagnoses is summarized in Table 2, including the
number of individual patients and age distribution for
each lesion. Of these lung tumors, 34 (16.7%) were pri-
mary lung tumors, and 170 (83.3%) reflected metastatic
disease or secondary involvement by a hematolymphoid
or histiocytic process. Of the primary tumors, 20 (59%)
were benign, and 14 (41%) were malignant. During this
25-year period, the average annual incidence of new pri-
mary lung malignancies (n ⫽ 14) in our pediatric popu-
lation was 0.56 per year. Based on this average annual in-
cidence of lung malignancies and the recent average an-
nual incidence of all new malignancies (289 per year) at
our institution, we estimate that primary pediatric lung
malignancies account for 0.19% of all new pediatric ma-
lignancies diagnosed annually.
The ratio of primary benign to primary malignant to
secondary (metastatic) malignant tumors was 20:14:162 (or
1.4:1:11.6), indicating that excisions for metastatic tumors
were almost 12 times more common than primary malig-
nant tumors. The most common benign lesions were squa-
mous papillomas associated with human papilloma virus
infection ( juvenile respiratory papillomatosis), inflamma-
tory myofibroblastic tumor, and Epstein-Barr virus (EBV)–
associated smooth muscle tumors. The 8 patients with re-
spiratory papillomas often had multiple surgical proce-
dures, ranging from 1 to 5 excisions and averaging 2.9 per
patient. The most common primary malignancies of the
lung were pleuropulmonary blastoma (57.1%) and carci-
Arch Pathol Lab Med—Vol 132, July 2008
noid tumor (14.3%). Pleuropulmonary blastoma accounted
for 72% (8/11) of parenchymal malignancies, and carci-
noid tumor accounted for 67% (2/3) of tracheobronchial
malignancies. One mucoepidermoid carcinoma and one
type I pleuropulmonary blastoma have been reported pre-
viously in the medical literature.14,15 In our patient popu-
lation, Wilms tumor and osteosarcoma were the 2 most
common solid tumor diagnoses leading to surgical exci-
sion of metastatic lung disease, accounting for 31.2% and
20.3% of these patients, respectively. Due to the role of
surgical oncologic management for metastatic osteosar-
coma, it should be noted that the 28 patients with osteo-
sarcoma had a total of 57 thoracic surgeries for excision
of metastases, ranging from 1 to 6 surgeries per patient.
Consultation cases referred from other institutions were
also reviewed during a similar time period and were tab-
ulated separately from institutional cases (Table 3). These
tumors included the following additional diagnoses not
represented in our institutional data set: congenital peri-
bronchial myofibroblastic tumor, synovial sarcoma, soli-
tary fibrous tumor, bronchioloalveolar carcinoma, and
pleuropulmonary blastoma type II, as well as Burkitt lym-
phoma and metastatic juvenile secretory breast carcinoma.
A summary of the data is also provided in comparison to
prior literature review (Table 4).
Clinical and pathologic features of these and other pe-
diatric lung tumors reported in the medical literature are
reviewed below, beginning with tracheobronchial lesions
and followed by specific benign and malignant parenchy-
mal lesions.
TRACHEOBRONCHIAL MASSES IN CHILDREN
Juvenile Respiratory Papillomatosis
Respiratory papillomatosis is caused by human papil-
lomavirus infection, typically acquired during delivery,
and results in multiple recurrent squamous papillomas
(Figure 1, A and B), most often of the larynx and trachea
but also involving the distal bronchial tree and esophagus
in some cases, especially after longstanding duration of
disease. Their clinicopathologic features are distinctive,
and there is little difficulty in the differential diagnosis
with other types of neoplasms. Spread into the lung pa-
renchyma occurs rarely (Figure 1, C and D), and may pro-
duce solid nodules or cystic air-filled cavities.2 Malignant
transformation to squamous cell carcinoma has been re-
ported, in some cases related to prior radiation therapy,
and is distinguished by marked cellular pleomorphism
and atypia, loss of maturation, dyskeratosis, and invasion
into the bronchial wall or lymphatic channels. Treatment
for squamous papillomas may include surgical excision,
CO2 laser vaporization, and/or adjuvant antiviral or in-
terferon therapy.10
Hamartoma
Hamartomas contain disorganized tissues intrinsic to
the lung and show peak incidence in the fourth to sixth
decades.7 They are typically lobulated and encapsulated
masses, which may be endobronchial or intraparenchy-
mal. They are rare in children, but they may present as
large parenchymal masses with respiratory distress. Chest
computed tomography classically shows fat and ‘‘pop-
corn’’ calcifications, which suggest the diagnosis. Micro-
scopically, cartilage, fat, and fibrous tissue are typically the
most prominent components, although smooth muscle,
Pediatric Lung Tumors—Dishop & Kuruvilla 1081
 Table 2. Pediatric Lung Tumors: 204 Patients With Surgical Pathology Specimens During a 25-Year Period at
Texas Children’s Hospital (Houston), June 1982–May 2007*
Benign Malignant
Age Age
No.† Range No. Range
Primary
Tracheobronchial Squamous papilloma 7 1–18 y Carcinoid tumor 2 11–15 y
Hemangioma 1 5 mo Mucoepidermoid CA 1 10 y
JXG 1 7 mo
IMT 1 4y
Chondroma 1 13 y
Parenchymal EBV-SMT 3 5–11 y PPB type I 6 3 mo–2 y
IMT 1 7y PPB type III 2 4–11 y
Myofibromatosis 1 10 y Spindle cell sarcomas 2 3–8 y
Lipoblastoma 1 1y Fibrosarcoma
Lymphangioma 1 11 y Myofibroblastic
Congenital immature mesenchymal 1 0d Squamous cell CA 1 6y
tumor
Squamous papillomas 1 3y
Total 20 Total 14
Secondary
Lymphohistiocytic/ LPD, polymorphous 4 11 mo–6 y LPD, monomorphous 3 2–15 y
hematopoietic LCH 3 6 mo–2 y NHL (LBCL, other) 3 4–17 y
Histiocytic, non-LCH 1 1 mo HL 15 9–19 y
ALL 1 4y
AML 1 6y
CML 1 7y
Total 8 Total 24
Metastatic solid Wilms tumor 43 1–11 y
tumors Osteosarcoma 28 6–26 y
EWS/PNET 13 7–18 y
RMS 10 3–14 y
Germ cell tumor 6 16–19 y
NB 6 7 mo–13 y
HB 4 10 mo–1 y
HCC 1 9y
Rhabdoid/ATRT 3 9 mo–11 y
CCSK 1 2y
Cellular MN 1 9 mo
DSRCT 1 20 y
Other sarcomas 14
UDS 3 11–15 y
Synovial sarcoma 2 10–12 y
CCST 1 10 y
Angiosarcoma 1 10 y
Liposarcoma 1 4y
Fibrosarcoma 2 14 y, 20 y
Myofibrosarcoma 1 10 y
MFH 1 9y
ASPS 1 3y
Sarcoma, NOS 1 17 y
Other carcinomas 5
NPC 1 17 y
ACC 1 12 y
AdenoCA, colon 1 9y
Clear cell CA, SC 1 4y
Squamous cell CA 1 6y
Other malignant, NOS 3 3–16 y
Total 138
* CA indicates carcinoma; JXG, juvenile xanthogranuloma; IMT, inflammatory myofibroblastic tumor; EBV-SMT, Epstein-Barr virus–associated
smooth muscle tumor; PPB, pleuropulmonary blastoma; LPD, lymphoproliferative disorder; LCH, Langerhans cell histiocytosis; NHL, non-Hodgkin
lymphoma; LBCL, large B-cell lymphoma; HL, Hodgkin lymphoma; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CML,
chronic myeloid leukemia; EWS/PNET, Ewing sarcoma/primitive neuroectodermal tumor; RMS, rhabdomyosarcoma; NB, neuroblastic tumor; HB,
hepatoblastoma; HCC, hepatocellular carcinoma; ATRT, atypical teratoid rhabdoid tumor; CCSK, clear cell sarcoma of the kidney; MN, mesoblastic
nephroma; DSRCT, desmoplastic small round cell tumor; UDS, undifferentiated sarcoma; CCST, clear cell sarcoma of soft tissue; MFH, malignant
fibrous histiocytoma; ASPS, alveolar soft part sarcoma; NOS, not otherwise specified; NPC, nasopharyngeal carcinoma; ACC, adrenocortical
carcinoma; and SC, sacrococcygeal.
† No. indicates the number of individual patients with tumor diagnosis on surgical pathology specimens; multiple specimens per patient are not
included in numerical data.

1082 Arch Pathol Lab Med—Vol 132, July 2008 Pediatric Lung Tumors—Dishop & Kuruvilla
 Table 3. Pediatric Lung Tumors: 40 Additional Consultation Cases Referred to Texas Children’s Hospital (Houston)
During a 25-Year Period*
Benign Malignant
Age Age
No. Range No. Range
Primary
Tracheobronchial Neuroendocrine CA 1 13 y
Mucoepidermoid CA 1 8y
Parenchymal CPMFT 3 0–2 wk PPB type I 4 8 wk–4 y
Congenital immature mesenchymal 2 2 wk–5 mo PPB type II 2 3y
tumor Bronchopulmonary fibrosarcoma 1 5y
Solitary fibrous tumor 1 Synovial sarcoma 1
BAC 1
Total 6 Total 11
Secondary
Systemic LPD, polymorphous 4 3 mo–12 y LPD, monomorphous 1 14 y
LCH 2 ND, 13 y Burkitt lymphoma 1 2y
Metastatic Osteosarcoma 5 8–21 y
Wilms tumor 3 5–13 y
GNB 1 6y
Hepatoblastoma 2 1–7 y
Hepatocellular CA 1 8y
Synovial sarcoma 1 15 y
DSRCT 1 ND
Breast CA, juvenile secretory 1 8y
Total 6 Total 17
* CA indicates carcinoma; CPMFT, congenital peribronchial myofibroblastic tumor; PPB, pleuropulmonary blastoma; BAC, bronchioloalveolar
carcinoma; LPD, lymphoproliferative disorder; LCH, Langerhans cell histiocytosis; GNB, ganglioneuroblastoma; DSRCT, desmoplastic small round
cell tumor; and ND, no data.

bone, and entrapped respiratory epithelium also may be
seen. Tumors with a single dominant component may be
diagnosed as a chondroma, fibroma, or lipoma, although
careful search may demonstrate foci of other mesenchymal
elements.
Chondroma
Chondromas are benign cartilaginous tumors that occur
as single or multiple encapsulated lesions that arise in con-
tinuity with bronchial cartilage and do not have other
mesenchymal elements, as in the hamartomas described
above (Figure 1, E). Pulmonary chondromas have been de-
scribed in the Carney triad, a syndrome almost exclusively
seen in young females comprising functioning paragan-
glioma, epithelioid gastrointestinal stromal tumor, and
pulmonary chondroma.16,17 Due to potential complications
of the associated lesions, children with pulmonary chon-
droma may benefit from periodic screening for meta-
chronous development of paragangliomas or gastrointes-
tinal stromal tumors.
Other Benign Tracheobronchial Lesions
Other benign tracheobronchial tumors reported in chil-
dren include leiomyoma, granular cell tumor, and mucous
gland adenoma. Primary solitary leiomyomas are benign
smooth muscle tumors, histologically similar to leiomyomas
in other locations, which may be asymptomatic or present
as endobronchial masses with obstruction. Leiomyomas as-
sociated with EBV infection are discussed below. Multiple
fibroleiomyomatous hamartomas (benign metastasizing leio-
myomas) have been described in a child with a history of
rhabdomyosarcoma.18 Bronchial granular cell tumors are re-
ported rarely and have histologic features similar to those
described in the oral cavity, comprising sheets of round cells
Arch Pathol Lab Med—Vol 132, July 2008
with small nuclei and abundant granular eosinophilic cyto-
plasm.7,9,19–21 The term bronchial adenoma is a misnomer pre-
viously used to refer collectively to 4 distinct lesions (carci-
noid tumor, mucoepidermoid carcinoma, adenoid cystic car-
cinoma, and mucous gland adenoma). Bronchial mucous
gland adenoma is the only benign lesion among these, and
only 2 cases were described in a literature review up to
1983.7 Histologically, mucous gland adenomas are composed
of a well-circumscribed mass of distended mucus-filled cysts
and tubules lined by a single layer of columnar goblet cells.
The differential diagnosis of endobronchial masses in chil-
dren also includes reactive vascular lesions, including gran-
ulation tissue and pyogenic granuloma, chronic foreign body
reaction, and granulomatous inflammation, for example, due
to histoplasmosis or mycobacteria.10
Carcinoid Tumor
Carcinoid tumors are considered low-grade neuroen-
docrine carcinomas due to their potential for locally ag-
gressive growth and low potential for metastasis. These
lesions are typically obstructive endobronchial masses of
older children and adolescents (Figure 1, F), presenting
with symptoms of wheezing, cough, hemoptysis, or pneu-
monia.6,7,9,22–24 The carcinoid syndrome caused by produc-
tion of neurosecretory peptides is very rare in the absence
of metastatic disease. Carcinoid tumors have been report-
ed to account for up to 80% to 85% of primary malignant
lung tumors in children, although this is likely an over-
estimate. They may arise from the lobar bronchi (75%),
mainstem bronchi (10%), or within the lung parenchyma
(15%).6 Microscopic features include sheets, nests, and
cords of monotonous small cells with stippled nuclear
chromatin and a delicate vascular network in the back-
ground (Figure 1, G). Treatment is primarily surgical, and
Pediatric Lung Tumors—Dishop & Kuruvilla 1083
 Table 4. Primary Lung Tumors in Children: Summary of Data From Literature Review and Single-Institution Data
(Texas Children’s Hospital [TCH], Houston)*
TCH Total Cases, No.
Literature Review TCH Surgical TCH Consult (% of Total,
(Hancock et al3), No. (%) Cases, No. (%) Cases, No. n ⴝ 51)
Benign
IMT 48 (52.2) 2 (10) 2 (3.9)
CPMFT 3 3 (5.9)
Myofibromatosis 1 (5) 1 (2.0)
Hamartoma 22 (23.9)
Neurogenic tumor 9 (9.8)
Leiomyoma/EBV-SMT 6 (6.5) 3 (15) 3 (5.9)
Mucous gland adenoma 3 (3.3)
Granular cell tumor 3 (3.3)
Benign teratoma 1 (1.1)
Squamous papillomatosis 8 (40) 8 (15.7)
Hemangioma 1 (5) 1 (2.0)
Lymphangioma 1 (5) 1 (2.0)
Chondroma 1 (5) 1 (2.0)
Juvenile xanthogranuloma 1 (5) 1 (2.0)
Lipoblastoma 1 (5) 1 (2.0)
Immature mesenchymal tumor 1 (5) 2 3 (5.9)
Solitary fibrous tumor 1 1 (2.0)
Total 92 20 6 26
Malignant
Carcinoid tumor 48 (16.5) 2 (14.3) 1 3 (5.9)
Mucoepidermoid CA 39 (13.4) 1 (7.1) 1 2 (3.9)
Adenoid cystic carcinoma 4 (1.4)
‘‘Bronchial adenoma,’’ NOS 27 (9.3)
Pleuropulmonary blastoma† 57 (19.6) 8 (57.1) 6 14 (27.5)
Bronchogenic carcinoma 49 (16.8) 1 (7.1) 1 2 (3.9)
Bronchopulmonary fibrosarcoma 28 (9.6) 1 (7.1) 1 (2.0)
Rhabdomyosarcoma 11 (3.8) 1 1 (2.0)
Leiomyosarcoma 11 (3.8)
Other sarcoma 3 (0.9) 1 (7.1) 1 2 (3.9)
Hemangiopericytoma 4 (1.4)
Plasmacytoma 4 (1.4)
Lymphoma 3 (1.0)
Immature teratoma/GCT 3 (1.0)
Total 291 14 11 25
* IMT indicates inflammatory myofibroblastic tumor; CPMFT, congenital peribronchial myofibroblastic tumor; EBV-SMT, Epstein-Barr virus–
associated smooth muscle tumor; CA, carcinoma; NOS, not otherwise specified; and GCT, germ cell tumor.
† Pleuropulmonary blastoma includes historic cases in children reported as pulmonary blastoma, mesenchymoma, as well as sarcomas and
rhabdomyosarcoma arising in cystic malformations.

endoscopic resection is not recommended due to risk of
hemorrhage and incomplete resection. Depending on lo-
cation and size, complete excision and removal of involved
lymphatics may be achieved with bronchial sleeve resec-
tion, lobectomy, or even pneumonectomy. Local invasion
or distant metastasis has been reported in a significant
percentage of children (27%), and overall survival in chil-
dren is approximately 90%.6,9
Mucoepidermoid Carcinoma
Mucoepidermoid carcinoma (MEC) is reported to rep-
resent approximately 10% of malignant lung neoplasms in
children. This tumor is rare in children, with just more
than 30 cases of tracheobronchial MEC reported in the
medical literature. Similar to carcinoid tumors, presenting
symptoms may include recurrent pneumonia, respiratory
distress, persistent cough, wheezing, or hemoptysis. Mu-
coepidermoid carcinoma arises in the tracheobronchial
tree from the salivary-type mucous cells of the submucosa,
most commonly occurring in the mainstem bronchus or a
proximal lobar bronchus. These tumors are typically exo-
phytic polypoid masses that cause bronchial obstruction
(80% of cases).14,23,24 Grading of MEC in the tracheobron-
1084 Arch Pathol Lab Med—Vol 132, July 2008
chial tree is similar to that in other salivary gland sites
and is divided into low-, intermediate-, and high-grade
tumors. Low-grade MEC is composed of predominantly
mucous cells arranged in large cystic spaces, and it is the
most common type described in the tracheobronchial tree
in children.9 Intermediate-grade MEC is composed of pre-
dominantly intermediate cells and occasional mucous
cells, forming a solid pattern with infrequent cysts and
glands (Figure 1, H and I). High-grade MEC contains pre-
dominantly epidermoid cells and infrequent intermediate
cells arranged in solid sheets, and it is characterized by
increased pleomorphism and high mitotic activity. The
low-grade tumors tend to have local tissue invasion but
only rare metastasis.14 Treatment is primarily surgical,
with chemotherapy and radiotherapy reserved for those
tumors with incomplete resection.25 The 5-year survival
rate of adults with MEC is 88%.25 The prognosis in chil-
dren appears to be more favorable, with no deaths re-
ported in the literature after surgical resection alone.
Adenoid Cystic Carcinoma
Adenoid cystic carcinoma is a slowly growing infiltra-
tive salivary gland–type neoplasm that is rare in the tra-
Pediatric Lung Tumors—Dishop & Kuruvilla
Figure 1. Bronchial tumors. A and B, Respiratory papillomatosis. Often multiple and recurrent, respiratory papillomas are caused by perinatally
acquired human papillomavirus infection and are characterized by a squamous epithelial proliferation with papillomatous architecture, fibrovas-
cular stroma, and often subtle viral cytopathic effect, including binucleation and perinuclear halos. C and D, Intrapulmonary squamous papillo-
matosis. This 2-year-old girl with longstanding respiratory papillomatosis developed multiple small nodules on chest x-ray. The nodules were
formed by squamous epithelial proliferations with high-grade atypia extending from the terminal bronchioles into the surrounding alveolar spaces.
Direct tissue invasion or overt malignant features were not identified. E, Chondroma. Distinct from chondromatous hamartoma, chondromas are
proliferations of benign hyaline cartilage, typically associated with central airways. This example was removed from the right upper lobe of a 13-
year-old girl with Carney triad and concurrent diagnosis of an epithelioid gastrointestinal tumor of the stomach. F and G, Carcinoid tumor. An 11-
year-old boy presented with hemoptysis and was found to have a 2.7-cm mass occluding the right mainstem bronchus. Histologic features include
cords of cells with characteristic uniform round nuclei and stippled chromatin. H and I, Mucoepidermoid carcinoma. Mucoepidermoid carcinoma
is graded based on varying degrees of 3 major cell types: glandular, squamoid, and intermediate cells. This intermediate-grade mucoepidermoid
carcinoma shows cystic spaces with well-formed mucin-producing cells, admixed with smaller solid areas with squamoid and intermediate cells
(gross tumor, bronchial resection [F] and hematoxylin-eosin [A through E, G through I]; original magnifications ⫻20 [A], ⫻200 [B and D], and
⫻100 [C, E, and G]).

cheobronchial tree. Histologic features are similar to those
seen in the salivary glands, consisting of cribriform, glan-
dular, and solid patterns of small hyperchromatic cells.
There is a tendency for submucosal spread, circumferen-
tial bronchial involvement, and late local recurrence. At
the time of literature review in 1983, only 4 cases were
reported in children.7 Treatment is complete surgical ex-
cision with or without adjuvant radiation therapy.25 Due
to the infiltrative nature and tendency for local recurrence,
frozen section examination may be helpful in assuring
negative bronchial margins at the time of surgery. Ade-
noid cystic carcinoma has a higher likelihood of distant
Arch Pathol Lab Med—Vol 132, July 2008
metastasis compared with mucoepidermoid carcinoma
and has poorer survival (55% 5-year survival).25
MYOFIBROBLASTIC TUMORS
Inflammatory Myofibroblastic Tumor
Previously called inflammatory pseudotumor or plasma cell
granuloma, inflammatory myofibroblastic tumor is a slow-
growing tumor which shows characteristics of both reac-
tive and neoplastic lesions.26–28 Although theorized to re-
sult from a repair response, antecedent injury cannot be
documented in most cases. Although many tumors are
asymptomatic (30%), others present with symptoms of
Pediatric Lung Tumors—Dishop & Kuruvilla 1085
cough or fever. Excluding respiratory papillomatosis, it is
estimated that inflammatory myofibroblastic tumor ac-
counts for approximately 52% to 70% of benign primary
lung tumors reported in the literature in children.3,14 Most
children with pulmonary inflammatory myofibroblastic
tumor are older than 5 years (75%), but cases involving a
few infants and young children are reported, and there is
an equivalent sex distribution.7 Chest x-ray typically dem-
onstrates a solitary well-circumscribed nodule, ranging in
size from 1 to 12 cm. Grossly, these nodular lesions may
be either endobronchial (17%; Figure 2, A) or intraparen-
chymal (83%).3,7 Histologic features include a proliferation
of bland spindled and stellate cells with abundant eosin-
ophilic cytoplasm, admixed with scattered inflammatory
cells, including lymphocytes and, occasionally, prominent
plasma cells and eosinophils (Figure 2, B). Immunohisto-
chemistry for smooth muscle actin and/or muscle-specific
actin may be helpful in demonstrating the myofibroblastic
nature of these cells. Treatment is primarily surgical, and
complete but conservative surgical excision is recommend-
ed. Inflammatory myofibroblastic tumors have a tendency
for local recurrence if incompletely excised.
Myofibromatosis
Myofibromas are relatively common benign soft tissue
tumors in children, most often presenting as a firm nod-
ular mass in the subcutaneous or deep soft tissue. Al-
though most often solitary, they may be multifocal and
involve both soft tissue and visceral organs, so-called my-
ofibromatosis (Figure 2, C). Myofibromatosis is more often
diagnosed in infants and young children than in older
children. The cellularity of these lesions varies, often
showing some hypocellular hyalinized zones as well as
other zones of hypercellularity. Characteristic protrusion
of bland spindled cells into adjacent vasculature is occa-
sionally seen and should not be interpreted as an aggres-
sive feature. Hemangiopericytomatous vasculature may be
prominent. Pulmonary involvement by myofibromatosis
may be a manifestation of multifocal systemic disease or
regional involvement of the chest wall. Multifocality in the
lung should not be misinterpreted as aggressive or met-
astatic disease.
Congenital Peribronchial Myofibroblastic Tumor
Congenital peribronchial myofibroblastic tumor is a
very rare and distinctive benign lung tumor of the fetus
and infant, with only approximately 25 cases reported
previously in the medical literature.29–33 It has been de-
scribed under various terminology, including massive con-
genital mesenchymal malformation of the lung, hamartoma of
the lung, bronchopulmonary leiomyosarcoma, and primary
bronchopulmonary fibrosarcoma.29 The tumor is thought to
arise from the pluripotent mesenchyme found around the
developing bronchi at approximately 12 weeks’ gestation,
with potential for both smooth muscle and cartilaginous
differentiation. Interestingly, congenital peribronchial my-
ofibroblastic tumor is morphologically similar to 2 other
types of myofibroblastic tumors presenting in the neonatal
period: congenital mesoblastic nephroma (classic type)
and congenital spindle cell tumor of the intestinal tract.
Congenital peribronchial myofibroblastic tumor typically
presents in utero or at birth as a large 5- to 7-cm unilateral
lung mass with mediastinal shift and resulting in intra-
uterine polyhydramnios, hydrops, or immediate respira-
tory failure at delivery. Grossly, nearly the entire lung or
1086 Arch Pathol Lab Med—Vol 132, July 2008
a large portion of the lung is typically enlarged and re-
placed by a firm rubbery mass with a yellow-tan to gray
whorled cut surface containing bands of fibrous-appear-
ing tissue (Figure 2, D). Microscopically, bland spindled
cells form large fascicles following the planes of the bron-
chovascular bundles, interlobular septa, and pleura, often
forming a distinctive lobular compartmentalization of the
lung parenchyma (Figure 2, E). The tumor fascicles are
extrinsic to the airways but surround, displace, and distort
the airway structures. Malformed and enlarged cartilage
plates adjacent to entrapped airways are a prominent
component of some tumors. Occasional foci of extramed-
ullary hematopoiesis may be seen. Mitotic figures may be
frequent, but there is no cytologic atypia or atypical mi-
toses. The lesion tends to be more uniform in cellularity,
in contrast to other myofibroblastic tumors. Immunohis-
tochemistry shows diffuse positivity for vimentin and fo-
cal desmin, muscle-specific actin, or smooth muscle actin
positivity.30,32 Flow cytometric DNA ploidy analysis has
shown a normal diploid population.32 Cytogenetic study
in 1 case has shown a complex rearrangement of chro-
mosomes 4, 8, and 10.30 Electron microscopy shows spin-
dled cells with dilated rough endoplasmic reticulum,
scarce mitochondria, occasional lipid droplets, and scant
cytoplasmic filaments, some with dense bodies and at-
tachment plaques, consistent with myofibroblastic differ-
entiation.29,30,32 Although the lesion is cytologically bland,
the large size often results in respiratory or hemodynamic
compromise and has resulted in a high mortality rate in
reported cases (55% in 1 series).32 If early resection is
achieved, typically by pneumonectomy or bilobectomy,
long-term survival is expected.30
NEUROGENIC TUMORS
Neurogenic tumors of the lung may include neurofibro-
ma, schwannoma, malignant peripheral nerve sheath tu-
mors, and mucosal neuromas. A series of intrapulmonary
neurogenic tumors has shown 26% (9/34) occurring in
children younger than 16 years.34 Of these 9 tumors in
children, all were benign, including 4 neurofibromas and
5 schwannomas. Although most pulmonary neurofibro-
mas are nonsyndromic, the possibility of neurofibroma-
tosis should always be considered in a child with a pul-
monary neurofibroma.
VASCULAR LESIONS
Hemangiomas
Infantile hemangioma is a lobular proliferation of small
capillaries that typically appears in the first weeks of life
and shows a period of involution during the ensuing
months (Figure 3, A). The early proliferating lesions may
be highly cellular and mitotically active, whereas involut-
ing lesions have less capillary density with more widely
spaced and dilated thick-walled capillaries. Both prolif-
erative and involuting lesions are characterized by endo-
thelial positivity for the glucose transporter Glut-1 (Figure
3, B), a marker that distinguishes the infantile hemangio-
ma from most other vascular anomalies, including rapidly
involuting and noninvoluting congenital hemangiomas,
vascular malformations, and pyogenic granulomas. While
infantile hemangiomas are most commonly found in the
skin and soft tissue, visceral involvement also occurs, both
as isolated lesions and as a component of multifocal sys-
temic distribution of disease (hemangiomatosis).35 Tra-
Pediatric Lung Tumors—Dishop & Kuruvilla
Figure 2. Myofibroblastic tumors. A and B, Inflammatory myofibroblastic tumor. Inflammatory myofibroblastic tumors may be intraparenchymal
or associated with the bronchial tree. This large bronchial lesion filled the lumen of the right upper lobe bronchus and caused compression of
adjacent airways. The lesion is composed of a bland spindle cell proliferation with variable cellularity, including some collagen-rich zones. The
spindled cells are admixed with scattered inflammatory cells, predominantly lymphocytes. C, Myofibromatosis. A 10-year-old girl presented with
a 3-cm soft tissue mass of the chest wall and was found to have multiple small nodules on the visceral pleura, raising suspicion for metastatic
disease. The lesions corresponded to multiple ill-defined proliferations of benign spindled cells and collagen, in some areas associated with slitlike
and branching hemangiopericytomatous vessels. D and E, Congenital myofibroblastic tumor. This rare tumor typically results in stillbirth or respi-
ratory distress at birth requiring lobectomy. The tumor has a whorled stromal appearance on cut surface, corresponding to broad fascicles of bland
myofibroblastic cells traversing the bronchovascular bundles and interlobular septa, producing compartmentalization of the alveolar parenchyma
(gross tumor, right upper lobectomy [A]; gross tumor, cut surface [D]; and hematoxylin-eosin [B, C, and E]; original magnifications ⫻200 [B], ⫻40
[C], and ⫻20 [E]).

Arch Pathol Lab Med—Vol 132, July 2008 Pediatric Lung Tumors—Dishop & Kuruvilla 1087
Figure 3. Vascular lesions. A and B, Infantile hemangioma. This infantile hemangioma of the trachea shows a proliferation of compact and slitlike
capillaries surrounding and entrapping the submucosal glands. Endothelial expression of the glucose transporter type I (Glut1) is characteristic of
infantile hemangioma and distinguishes this diagnosis from vascular malformations and reactive capillary proliferations. C, Lymphatic malformation.
Lymphatic malformations (lymphangiomas) occur rarely as mass lesions in the lung and consist of a proliferation of complex anastomosing
lymphatic channels, often with small lymphoid aggregates in the walls. Proteinaceous lymphatic fluid may be admixed with red blood cells due
to secondary hemorrhage. Lymphatic differentiation may be confirmed by endothelial expression of the lymphatic marker D2-40. D and E, Vascular
malformation. A 1-year-old girl presented with thrombocytopenia and anemia and was found to have multiple nodules on chest x-ray. Wedge
biopsy showed multifocal vascular lesions consisting of nodular regions of dilated thin-walled blood-filled vessels. The architecture of the lesion
is highlighted by endothelial expression of CD34 (shown), and Glut1 was negative. The distribution of disease and pathologic features suggested
a diagnosis of cutaneovisceral angiomatosis (hematoxylin-eosin [A, C, and D], Glut1 immunohistochemistry [B], and CD34 immunohistochemistry
[E]; original magnifications ⫻100 [A and E], ⫻200 [B], and ⫻40 [C and D]).

1088 Arch Pathol Lab Med—Vol 132, July 2008 Pediatric Lung Tumors—Dishop & Kuruvilla
cheobronchial and parenchymal hemangiomas are identi-
fied occasionally due to symptoms of obstruction or re-
current hemoptysis.1,10 Lesions of the subglottis and upper
trachea are more common than the distal tracheal or en-
dobronchial lesions.10 Intraparenchymal hemangiomas are
very rare, but may be a component of multifocal systemic
lesions in diffuse neonatal hemangiomatosis.
It should be noted that pulmonary capillary hemangi-
omatosis is a different entity than the multifocal infantile
hemangiomas of diffuse neonatal hemangiomatosis. Pul-
monary capillary hemangiomatosis is a rare, poorly de-
fined lesion associated with pulmonary hypertension and
composed of a diffuse proliferation of capillaries within
the alveolar walls without formation of a mass lesion.36,37
Primarily seen in adults, pulmonary capillary hemangio-
matosis has been associated with pulmonary veno-occlu-
sive disease in some cases, and it may represent a postob-
structive reactive proliferation of capillaries distal to
thrombosis.
Lymphatic Malformations and Lymphangiomatosis
Although lymphatic malformations are common lesions
in infants and young children, solitary lymphatic malfor-
mations (lymphangiomas) occur rarely in the lung, form-
ing localized multicystic masses (Figure 3, C). In contrast,
lymphangiomatosis is a proliferation of lymphatic chan-
nels involving the lung more diffusely, typically in a septal
and pleural pattern of distribution. Secondary hemorrhage
and muscularization of the lymphatic channels in lym-
phatic malformations may produce confusion with a ve-
nous malformation, and the lymphatic marker D2-40 is
helpful in confirming the lymphatic origin of the vessels.
Vascular Malformations
Like hemangiomas and lymphatic malformations, ve-
nous or mixed vascular malformations may produce mass
lesions in the lung parenchyma. Arteriovenous malfor-
mations may be multiple and produce right-to-left shunt-
ing, resulting in high-output cardiac failure and cyanosis.
They are more often diagnosed by imaging techniques
and are diagnosed uncommonly in surgical pathology
specimens (Figure 3, D and E). The presence of multiple
arteriovenous malformations should raise consideration of
hereditary hemorrhagic telangiectasia (Osler-Weber-Ren-
du syndrome).
OTHER BENIGN PARENCHYMAL TUMORS
Teratomas within the lung parenchyma are reported as
isolated cases, including only 2 case reports before
1983.7,39–41 Pericardial or anterior mediastinal teratomas are
more common, and they may show secondary involve-
ment of the adjacent lung parenchyma by direct extension.
Primary teratomas of the lung are typically large cystic
and solid masses confined to the lung parenchyma, and Figure 4. Other benign parenchymal lung lesions. A, Lipoblastoma.
most contain derivatives of all 3 germ cell layers. Primary Lipoblastomas may occur in any site of the body, including soft tissue
malignant germ cell tumors of the lung are exceedingly and viscera. This rare lesion replacing the left upper lobe of a 16-
rare, although choriocarcinoma has been reported. month-old boy shows areas of immature mesenchyme with predomi-
Lipoblastoma is a benign tumor of adipose tissue typ- nantly vascular myxoid tissue containing scattered fat vacuoles and
maturing lipoblasts. B and C, Rhabdomyomatous dysplasia, nodular
ically characterized by an admixture of immature lipoblast form. Rhabdomyomatous dysplasia refers to ectopic skeletal muscle
in a vascular myxoid matrix, juxtaposed with zones of differentiation within the lung and is most often recognized incidentally
mature adipose tissue. Lipoblastomas occur most often in within the interstitium of extralobar pulmonary sequestrations. Rarely,
the soft tissue of infants and young children, but they may rhabdomyomatous dysplasia may form nodular lesions, as in this in-
also involve the viscera, including the lung (Figure 4, A). cidental lung nodule in a 1-week-old, 28-week gestation neonate, who
Ectopic tissues occasionally form nodular lesions of the died of pulmonary hypoplasia and respiratory failure (hematoxylin-eo-
sin, original magnifications ⫻40 [A], ⫻20 [B], and ⫻200 [C]).
lung. Rhabdomyomatous dysplasia is a rare entity com-
Arch Pathol Lab Med—Vol 132, July 2008 Pediatric Lung Tumors—Dishop & Kuruvilla 1089
Figure 5. Pleuropulmonary blastoma. A through C, Type I (cystic). The cystic type of pleuropulmonary blastoma is typically characterized by a
unilocular or multilocular lung cyst distending the surface of the lung, grossly identical to the large-cyst type of congenital pulmonary airway
malformation. Microscopically, the lesion is composed of thick and thin septa with variable cellularity and often containing isolated small islands
of immature-appearing cartilage. The diagnosis is confirmed by identifying small primitive round and spindled cells, often with a prominent capillary
network. These cells are from a cambium-like layer beneath the alveolar-type epithelium lining the septa, resembling that seen in botryoid
rhabdomyosarcoma. Hemorrhage and necrosis may be seen focally. D, Type II (solid and cystic). The higher grade pleuropulmonary blastomas
contain sheets of hyperchromatic primitive cells, expanding the broad cyst septa in this type II pleuropulmonary blastoma. E through H, Type III
(solid). The solid variant of pleuropulmonary blastoma is easily identified as a malignancy, composed of solid sheets of primitive tumor cells.
Myxoid areas resembling cartilaginous differentiation and larger round rhabdomyoblastic cells may be seen in some cases. These tumors often
have foci with anaplastic features, including marked pleomorphism, cytologic atypia, multinucleation, and atypical mitotic figures (gross tumor,
left upper lobe [A] and hematoxylin-eosin [B through H]; original magnifications ⫻20 [B and D], ⫻100 [C, F, and H], ⫻40 [E], and ⫻200 [G]).

posed of benign skeletal muscle cells within the lung pa-
renchyma, most often seen incidentally within lung mal-
formations, such as extralobar sequestration. Rarely, rhab-
domyomatous dysplasia forms a nodular focus of skeletal
muscle cells in otherwise normal lung (Figure 4, B and C).
Ectopic adrenal gland tissue and ectopic glial tissue have
also been reported as nodular lesions in the lung.38
PLEUROPULMONARY BLASTOMA
Pleuropulmonary blastoma (PPB) is a rare malignant
embryonal mesenchymal neoplasm of the lung and pleura
occurring almost exclusively in children that was de-
scribed as a unique entity distinct from pulmonary blas-
toma in 1988.42 In contrast to the adult-type biphasic pul-
monary blastoma (PB), PPB is a polyphenotypic mesen-
1090 Arch Pathol Lab Med—Vol 132, July 2008
chymal malignancy without an epithelial component. It
has been reported previously in the medical literature un-
der a variety of descriptors, including pulmonary blasto-
ma, mesenchymal cystic hamartoma, malignant mesen-
chymoma, and sarcomas (myxosarcoma or rhabdomyo-
sarcoma) arising in congenital cystic malformations.43–47
Pleuropulmonary blastoma is diagnosed primarily in in-
fants and toddlers, and rarely beyond age 12 years. Oc-
currence in adults is reported but extremely rare.48 These
lesions may be detected incidentally in utero or postna-
tally.15 Symptomatic presentation may result from spon-
taneous pneumothorax in the cystic lesions.49
Pleuropulmonary blastoma is subclassifed based on the
spectrum of gross morphology: purely cystic lesions (type
I), solid and cystic lesions (type II), and purely solid le-
Pediatric Lung Tumors—Dishop & Kuruvilla
sions (type III).49 Age at presentation varies depending on
morphologic type, with the type I lesions most often di-
agnosed in infancy (average age, 10 months), and the type
II and type III lesions more often diagnosed in toddlers
(average ages, 34 and 44 months, respectively).50,51 Grossly,
the low-grade cystic lesions (type I) are typically periph-
eral and pleural-based lesions, sometimes protruding
from the pleural surface (Figure 5, A). They are entirely
cystic, with no solid components or nodules and are
grossly indistinguishable from the large-cyst (Stocker type
I) congenital pulmonary airway malformation (CPAM).
Microscopically, they are virtually identical to what has
been described as the peripheral cyst (Stocker type IV)
CPAM. Type I PPBs have thin cyst walls lined by predom-
inantly alveolar-type epithelium and containing focal ar-
eas of hypercellularity and hypervascularity (Figure 5, B
and C). The hypercellular foci are composed of hyper-
chromatic compact spindled cells and small round cells,
often forming a cambium-like layer beneath the epitheli-
um lining the cyst walls. Foci of immature-appearing car-
tilage are present in some cases. The higher grade lesions
(type II and type III) have solid components on gross ex-
amination. Although entirely solid, the type III PPB may
have areas of necrosis and cystic degeneration. The solid
components of both type II PPB (Figure 5, D) and type III
PPB (Figure 5, E through H) also show higher grade cy-
tologic features, with sheets of spindled and pleomorphic,
sometimes anaplastic cells, resembling rhabdomyosarco-
ma. Fibrosarcoma-like areas and chondroid nodules are
other recognized patterns. It should be noted that type I
lesions may progress to the higher grade type II or type
III lesions, particularly if incompletely excised.
Immunohistochemistry of PPB demonstrates vimentin
in the primitive cell component, as well as myogenic dif-
ferentiation in some cases, specifically with expression of
desmin, muscle specific actin, smooth muscle actin, my-
ogenin, and/or myoglobin. Electron microscopy may also
show evidence of rhabdomyoblast differentiation with
myofibrils and z-band formation, as well as loose granular
matrix and abundant rough endoplasmic reticulum, indi-
cating chondrocytic differentiation.49,50 Cytogenetic analy-
sis of PPB has been described in a small number of cases,
primarily of higher grade lesions. Although a tumor-spe-
cific translocation has not been identified, there may be a
variety of karyotypic abnormalities (trisomy 8, trisomy 2,
and 17p deletions), and mutations in p53 have been de-
scribed.52–54
Pleuropulmonary blastoma may be solitary or multiple,
and additional lesions may be discovered synchronously
or metachronously in the same patient. Interestingly, PPB
may have familial predisposition, and genetic studies are
ongoing through the International Pleuropulmonary Blas-
toma Registry.55 In approximately 25% of cases, PPB is
associated with other extrapulmonary lesions in the same
patient or family members.49 The most common associated
lesion is cystic nephroma, but other embryonal tumors
(sarcomas, medulloblastoma, malignant germ cell tu-
mors), thyroid neoplasms, leukemia, Hodgkin lymphoma,
and Langerhans cell histiocytosis (LCH) have been asso-
ciated with PPB.56
Clinically, the diagnosis of PPB is infrequently enter-
tained preoperatively.15 Pathologists must consider the di-
agnosis of PPB for any child with a spherical unilocular
or multiloculated cystic lesion, mixed solid and cystic le-
sion, or large solid mass in the lung, particularly if the
Arch Pathol Lab Med—Vol 132, July 2008
lesion distorts the contour of the lung, is positioned pe-
ripherally, or is found to protrude from the pleural sur-
face. The differential diagnosis includes the more common
benign cystic lung malformations, as well as other rare
primary sarcomas of the lung. The most common sub-
mitting diagnosis and the principal pathologic differential
diagnosis for cystic type I PPB is CPAM (also called con-
genital cystic adenomatoid malformation [CCAM]).57 The
large-cyst (Stocker type I) CPAM and the peripheral cyst
type (Stocker type IV) CPAM are grossly identical to cystic
PPB. The large-cyst CPAM is distinguished easily micro-
scopically by a cyst lining composed predominantly of
respiratory type epithelium, with or without focal muci-
genic epithelium, often resembling small foci of gastric
foveolar epithelium. The respiratory epithelial lining
shows interdigitation with surrounding airspaces, which
may be secondarily enlarged and maldeveloped. The pe-
ripheral cyst (Stocker type IV) CPAM is much more prob-
lematic to distinguish from cystic PPB and, in fact, it has
been suggested that many examples of type IV CPAM
may actually represent unrecognized or insufficiently
sampled cystic PPBs.58,59 Stocker describes CPAM type IV
as having thin cyst walls lined by alveolar-type epithelium
and with increased vascularity of the septa. Cystic PPB
has a similar architecture, but it is distinguished by the
identification of hypervascular and hypercellular foci of
primitive cells in the cyst walls, a focal and subtle finding
in many cases due to the low-grade cytology. Any lesion
mimicking type IV CPAM on initial microscopic sections
requires extensive sampling to exclude the presence of
these hypercellular foci. The differential diagnosis of the
solid and cystic or purely solid lesions includes other pri-
mary sarcomas of the lung, including rhabdomyosarcoma
and synovial sarcoma. Some cases initially reported as
rhabdomyosarcoma of the lung likely represent high-
grade PPB.49,60 The lesion described in the literature as
‘‘mesenchymal hamartoma of the lung’’ in children is also
more appropriately classified as PPB.61,62 Finally, as men-
tioned above, PPB should be distinguished from the rare
adult-type PB, a tumor most often presenting in the fourth
or fifth decade of life, which has an associated epithelial
component not present in the childhood lesion.63,64 Entrap-
ment of alveolar or bronchiolar epithelium by PPB may
also mimic PB. In the pediatric population, a sarcomatous
lesion with a glandular-appearing epithelial component
mimicking biphasic PB should prompt consideration of sy-
novial sarcoma.
Treatment for PPB is primarily surgical for the cystic
(type I) lesions, although adjuvant chemotherapy may be
advantageous in cases with incomplete resection. Certain-
ly, the higher grade (type II and type III) lesions require
adjuvant chemotherapy after resection, and radiation ther-
apy is recommended for residual disease. In either case,
close clinical follow-up is warranted due to potential for
recurrence, metastasis, multifocality, and associated extra-
pulmonary lesions. Low-grade cystic lesions may recur as
a higher grade lesion, and this potential justifies chemo-
therapy for some type I tumors. Metastasis occurs in ap-
proximately 30% of types II and III tumors, and may occur
late in the disease course. The most commonly reported
sites of metastasis include the central nervous system and
bone.50 Five-year survival rate is 83% for type I PPB and
42% for types II and III PPB.50
Pediatric Lung Tumors—Dishop & Kuruvilla 1091
Figure 6. Sarcomas. A and B, Synovial sarcoma. Although rare, synovial sarcoma is one of the most common primary sarcomas of the pediatric
lung. It may mimic adult-type pulmonary blastoma due to its biphasic morphology, including compact spindled cells and larger epithelioid cells.
CD99 and BCL2 expression are helpful diagnostic features, and the characteristic t(X;18) translocation may be identified by cytogenetic analysis
or molecular identification of the SSX-SYT fusion transcript (hematoxylin-eosin, original magnifications ⫻20 [A] and ⫻100 [B].
PRIMARY SARCOMAS
Synovial Sarcoma
Although rare, synovial sarcoma is one of the more
common primary sarcomas of the lung in children. Di-
agnostic features are similar to those seen in other sites,
and morphology may be monophasic or biphasic (Figure
6, A and B). Immunohistochemistry for cytokeratin, epi-
thelial membrane antigen, CD99, and BCL2 are typically
positive. Cytogenetic analysis and/or molecular diagnos-
tic testing is helpful in demonstrating the characteristic
t(X;18) translocation, producing an SSX-SYT fusion tran-
script.
Ewing Sarcoma Family of Tumors
The Ewing sarcoma family of tumors includes Ewing
sarcoma of bone and soft tissue, as well as peripheral
primitive neuroectodermal tumor. These tumors are uni-
fied by the rearrangement of the Ewing sarcoma gene
with one of a variety of fusion partner genes, most com-
monly Fli-1, produced by a characteristic t(11;22)(q24 ; q12)
translocation. By immunohistochemistry, the Ewing sar-
coma family of tumors characteristically demonstrates
membranous staining with CD99, an important diagnostic
feature in clinical practice. In addition, primitive neuro-
ectodermal tumors show evidence of neural differentia-
tion, either by immunohistochemistry or electron micros-
copy. On a practical level, distinguishing primitive neu-
roectodermal tumor from Ewing sarcoma is unnecessary,
as treatment is the same for both, and there is conflicting
evidence for any prognostic difference between primitive
neuroectodermal tumor and Ewing sarcoma. Although
the Ewing sarcoma family of tumors may occur anywhere
in the body, including soft tissue, bone, and viscera, the
chest wall is one site of predilection, so-called Askin tu-
mor of the thoracopulmonary region. Chest wall involve-
ment may result in a mass with intrathoracic growth, lytic
destruction, and fusiform expansion of ribs, cortical thick-
ening, little or no periosteal reaction, and pleural effu-
sion.8 Involvement of the pleural cavity with extension
into the lung parenchyma is not uncommon and may lead
1092 Arch Pathol Lab Med—Vol 132, July 2008
to partial resection of lung with chest wall resection. Rare-
ly, these tumors may arise primarily in the lung, but they
most often originate in the rib or chest wall.
Rhabdomyosarcoma
While several cases of pulmonary rhabdomyosarcoma
reported in the literature likely actually represent cases of
pleuropulmonary blastoma, true primary rhabdomyosar-
coma of the lung also occurs, often manifesting as an en-
dobronchial mass.7,65,66 Pulmonary rhabdomyosarcoma is
estimated to represent approximately 0.5% of all rhabdo-
myosarcomas in children.3 After Ewing sarcoma family of
tumors, rhabdomyosarcoma is the second most common
malignancy of the chest wall in children, and it may pro-
duce direct involvement of the thoracic cavity or pulmo-
nary metastasis in this setting.8
Leiomyosarcoma
A few cases of bronchopulmonary leiomyosarcoma have
been reported in children.67–71 Rare cases in newborns may,
in fact, represent congenital myofibroblastic tumor, rather
than true leiomyosarcoma.67 Potentially arising from ei-
ther bronchial or vascular smooth muscle, these lesions
may be located in the tracheobronchial tree or in the pa-
renchyma. Leiomyosarcoma in older children may show
aggressive local invasion, metastasis, and poor prognosis.
Nuclear atypia, necrosis, and hemorrhage distinguish leio-
myosarcoma from both leiomyomas and the myofibro-
blastic tumors. Epstein-Barr virus is associated with some
lesions in the immunocompromised population (see be-
low).
Bronchopulmonary Fibrosarcoma
Primary bronchial fibrosarcoma in children is consid-
ered to be the equivalent of congenital infantile fibrosar-
coma of soft tissues. It is quite rare, with 26 cases reported
in the literature to 1989.1 Grossly, bronchopulmonary fi-
brosarcoma may form an endobronchial polyp or intra-
parenchymal mass. Histologically, it is composed of cel-
lular sheets and interlacing bundles of spindle cells, often
Pediatric Lung Tumors—Dishop & Kuruvilla
with focal hemorrhage. The mortality associated with
bronchopulmonary fibrosarcoma is 21%, with metastatic
disease reported in 2 of 26 cases.72
Other Sarcomas
A number of other types of sarcomas have been re-
ported as primary lung neoplasms in children, including
angiosarcoma, Kaposi sarcoma, malignant peripheral
nerve sheath tumor, and liposarcoma.73 The spectrum of
pulmonary and thoracic sarcomas has been reviewed else-
where.74,75
BRONCHOGENIC CARCINOMA
Bronchogenic carcinoma is most common in adults 55
to 75 years of age, and it is rare in individuals younger
than 40 years, accounting for 1.2% of all patients with lung
cancer.76–88 Patients 18 to 30 years old diagnosed with lung
cancer have a higher incidence of female sex, no associa-
tion with smoking history, and more favorable prognosis.89
Survival in these young patients is associated primarily
with stage, but it is not dependent on sex, age younger or
older than 30 years, smoking history, histologic type, or
degree of differentiation.90 Lung cancer in children and
adolescents younger than 18 years is extremely rare, with
0.16% of all lung cancers occurring in the first decade of
life and 0.7% in the second decade.91 As of 1983, a review
of the medical literature included 47 children reported to
have ‘‘bronchogenic carcinoma,’’ representing approxi-
mately 17% of reported primary lung malignancies in chil-
dren.3,7 Almost certainly an overestimate of true incidence,
this percentage appears to be inflated by cases in the older
medical literature. The actual incidence of bronchogenic
carcinoma in children is difficult to determine and is lim-
ited to individual case reports and small case series in the
modern era.92 A 21-year review of pediatric primary epi-
thelial lung malignancies from Memorial Sloan-Kettering
Cancer Center yielded a total of 11 patients (age range,
12–21 years) with pathologic diagnoses of adenocarcino-
ma (4, including 1 well-differentiated fetal adenocarcino-
ma), basaloid carcinoma (2), carcinoid tumor (4), and
MEC (1).93 A 24-year review of the records from Boston
Children’s Hospital (1957–1981) revealed 6 primary bron-
chial tumors in children, with no cases of bronchogenic
carcinoma.9 In 1999, Mizushima et al89 reported a large
series of young lung cancer patients (26 patients younger
than 30 years), none of whom were younger than 18 years.
Our current 25-year cumulative experience, including both
institutional and consultation cases, includes 23 primary
lung malignancies, but only 1 case of bronchial squamous
cell carcinoma in a 6-year-old child, and no cases of ade-
nocarcinoma.
Reported cases of pediatric lung carcinoma in the med-
ical literature are most commonly undifferentiated carci-
noma, followed by adenocarcinoma and squamous cell
carcinoma. It is difficult to determine whether the histor-
ical cases of undifferentiated carcinoma truly represent
small cell carcinoma or perhaps atypical carcinoid tumors.
Adenocarcinoma may result in consolidation of a lobe or
‘‘white-out’’ of a lung, with or without pleural effusion.92
The 3 patients with conventional pulmonary adenocarci-
nomas in the Memorial Sloan-Kettering series all present-
ed with stage IV disease, and 2 had rapidly progressive
fatal disease within 2 months of diagnosis.93 Well-differ-
entiated fetal adenocarcinoma, also called pulmonary en-
dodermal tumor, is an extremely rare variant of adeno-
Arch Pathol Lab Med—Vol 132, July 2008
carcinoma for which there are only isolated reports in chil-
dren.93,94 Thought to be related to pulmonary blastoma,
this tumor is composed of complex branching tubules and
glands and has been compared with fetal lung in the
pseudoglandular stage of development. Unlike conven-
tional pulmonary adenocarcinoma, well-differentiated fe-
tal adenocarcinoma has a relatively good prognosis, with
only 15% mortality.93 Bronchioloalveolar carcinoma has
been reported rarely arising from CPAM (Figure 7, A
through C).94–104 The mucigenic epithelium of the type I
CPAM is the purported precursor cell for bronchioloal-
veolar carcinoma in this setting.105–107
Squamous cell carcinoma (Figure 7, D) seems to account
for a smaller proportion of lung carcinoma cases in chil-
dren (12%) relative to adults (35%–50%).7 Only 6 cases of
bronchogenic squamous cell carcinoma were reported in
children until 1995, with an age range of 1 to 15 years.108
A pathogenetic relationship with human papillomavirus
has been proposed, given the known potential for pro-
gression of respiratory papillomatosis to squamous cell
carcinoma.109 A minute squamous cell carcinoma has also
been reported in the wall of a congenital lung cyst.110 Bas-
aloid carcinoma, a rare variant of non–small cell lung car-
cinoma described in 1992, has been reported recently in
the pediatric population.93 It is an aggressive tumor
thought to arise from the basal bronchial epithelial stem
cells and is characterized microscopically by small cells
growing in a characteristic nesting pattern with peripheral
palisading.93
Primary lung carcinoma in children may be aggressive,
with frequent metastatic disease at diagnosis, high mor-
tality (90%), and average survival of 7 months after di-
agnosis.3,7 Symptoms may include cough, chest pain,
pneumonia, or hemoptysis due to local effects, but initial
presentation may also be heralded by bone pain, weight
loss, or anemia due to metastatic disease. Delay in diag-
nosis and metastasis at presentation has led to generally
poor survival in the few cases of bronchogenic carcinoma
in children reported.108
DIFFUSE MALIGNANT MESOTHELIOMA
Primary pleural neoplasms in the pediatric population
are quite rare, representing 2 of 1925 pleural lesions in 1
series.111 Diffuse malignant mesothelioma is extremely
rare in children, with only 4.5% of mesotheliomas in 1
series occurring in patients younger than 21 years.112 There
is no clear causal relationship with asbestos exposure in
children, although a history of possible asbestos exposure
has been reported in isolated pediatric cases.113 Diffuse
malignant mesothelioma may also occur as a second ma-
lignancy following radiation therapy, and there is one re-
port of pediatric mesothelioma associated with prenatal
isoniazid exposure.114 Three large series of diffuse malig-
nant mesothelioma in children have shown pleural in-
volvement in 72% of cases (18/25 total patients), with an
age range of 4 to 19 years.113,115,116 Reported mortality in
children ranges from 50% to 71%.113,115,116 Histologic pat-
terns are similar to those seen in adults, and they have
included epithelial, mixed, and fibrous types, as well as
papillary, tubuloglandular, solid, and sarcomatoid pat-
terns.4,113,115
PRIMARY LUNG TUMORS IN IMMUNOSUPPRESSED
AND IMMUNOCOMPROMISED CHILDREN
Lymphoma and Lymphoproliferative Disorders
All immunodeficiency states carry a higher risk of lym-
phoma relative to the immunocompetent population, in-
Pediatric Lung Tumors—Dishop & Kuruvilla 1093
Figure 7. Carcinoma. A, Congenital pulmonary airway malformation. A 9-year-old girl presented with spontaneous pneumothorax and was found
to have an inflamed complex cystic lesion with focal mucigenic epithelium, yielding a diagnosis of type I congenital pulmonary airway malfor-
mation. B and C, Bronchioloalveolar carcinoma, mucinous type, arising in a recurrent congenital pulmonary airway malformation. One year later,
she presented again with a recurrent cyst. The resection specimen showed multifocal glandular proliferations extending from the cyst wall and
consisting predominantly of mucin-rich columnar cells extending along alveolar septa. Some airspaces contained detached atypical cell groups
admixed with abundant mucin. D, Squamous cell carcinoma. A 6-year-old boy presented with a large lung tumor invading the chest wall.
Lobectomy showed a squamous cell carcinoma eroding a large bronchus and showing extensive parenchymal infiltration and intrapulmonary
lymphatic spread. The bronchial wall demonstrates islands and sheets of squamous cells in the submucosa entrapping benign glands but without
glandular differentiation. Extensive keratinization and necrosis were present in many islands of invasive tumor (hematoxylin-eosin, original mag-
nifications ⫻100 [A and C], ⫻20 [B], and ⫻40 [D].

cluding patients with human immunodeficiency virus
(HIV) infection, solid organ transplant, bone marrow
transplant, and congenital immunodeficiencies. These
lymphomas are most often high-grade or intermediate-
grade non-Hodgkin lymphomas, typically diffuse large B-
cell lymphomas, and often involve extranodal sites. Burk-
itt lymphoma, Burkitt-like lymphoma, Hodgkin lympho-
ma, and human herpesvirus 8–associated primary effu-
sion lymphoma also are reported with higher incidence in
the HIV-infected population.117
Epstein-Barr virus–driven lymphoproliferative disor-
ders occur most commonly in immunosuppressed recipi-
ents of solid organ or bone marrow transplants (posttrans-
plant lymphoproliferative disorder [PTLD]), as well as
children with primary immunodeficiency (Figure 8, A). In
general, PTLD is most common after heart, lung, or heart-
lung transplantation (5%–13% of patients) and less com-
1094 Arch Pathol Lab Med—Vol 132, July 2008
mon after liver, kidney, or bone marrow transplantation
(1%–3%).117 Lung involvement by PTLD manifests as peri-
airway and parenchymal nodular and interstitial lym-
phoid infiltrate, and primary involvement of the lung is
highest in lung transplant or heart-lung transplant recip-
ients. The pathogenesis of PTLD is related to EBV-stimu-
lated B-lymphocyte proliferation, which is unopposed due
to iatrogenic inhibition of regulatory T-lymphocyte func-
tion, and the biologic spectrum ranges from polymor-
phous to monomorphous and may be polyclonal, oligo-
clonal, or monoclonal. The monoclonal forms most often
resemble diffuse large B-cell lymphoma and may be as-
sociated with regions of necrosis. Epstein-Barr virus DNA
probes are positive in most PTLDs but may be negative,
particularly late (more than 5 years) after transplantation.
Flow cytometric analysis is an essential component of the
diagnostic evaluation of suspected PTLD and allows de-
Pediatric Lung Tumors—Dishop & Kuruvilla
Figure 8. Lung tumors in immunocompromised children. A, Lymphoproliferative disorder, Epstein-Barr virus associated. Epstein-Barr virus–driven
lymphoproliferative disorders in immunosuppressed patients may be monomorphous or polymorphous, and they typically produce nodular and
interstitial infiltrates of lymphocytes. This monotonous lymphoid infiltrate in a 4-year-old girl with a congenital T-cell immunodeficiency showed
a clonal population of B lymphocytes by flow cytometric analysis. In situ hybridization for Epstein-Barr virus (Epstein-Barr virus–encoded RNA
[EBER]) demonstrates numerous cells with strong nuclear positivity. B through D, Smooth muscle tumor, Epstein-Barr virus associated. An 11-year-
old boy with human immunodeficiency virus/AIDS was found to have 2 nodules of the right upper lobe. The nodules consisted of bland prolif-
erations of whorled smooth muscle cells similar to conventional leiomyomas (shown). In situ hybridization for Epstein-Barr virus (EBER) shows
strong nuclear expression in the majority of cells (hematoxylin-eosin [A and C]; gross tumor, right upper lobe [B]; and EBER DNA probe in situ
hybridization [D]; original magnifications ⫻40 [A], ⫻200 [C], and ⫻100 [D]).

termination of clonality. Reduction of immunosuppression
is the first-line management of these disorders, with or
without anti-CD20 antibody therapy (rituximab), al-
though cytotoxic chemotherapy may also be necessary for
treatment of persistent lesions and the more aggressive
monoclonal forms of PTLD.
Smooth Muscle Tumors
(Leiomyoma and Leiomyosarcoma)
Epstein-Barr virus–associated smooth muscle tumors
have been described in children with HIV/AIDS (Figure
8, B and C), as well as solid organ transplant recipients
and children with primary immunodeficiency.118–122 These
tumors may be solitary or multifocal, and site of predilec-
tion include the gastrointestinal and respiratory tracts.
Similar to the EBV-driven lymphoproliferative tumors,
there is a spectrum from benign to malignant morpholo-
gy, that is, leiomyoma and leiomyosarcoma, and there is
potential for regression of tumors with modulation of im-
Arch Pathol Lab Med—Vol 132, July 2008
munosuppression. Epstein-Barr virus DNA probes are
typically strongly positive in these tumors (Figure 8, D).
Kaposi Sarcoma
Kaposi sarcoma associated with human herpesvirus 8
infection may occur in HIV-infected patients and follow-
ing solid organ transplantation. Although cutaneous Ka-
posi sarcoma typically predominates clinically, visceral in-
volvement may occur, most often affecting lymph nodes,
the gastrointestinal tract, or the lungs. Pulmonary involve-
ment may produce endobronchial or parenchymal viola-
ceous lesions, and it is a cause of pulmonary hemorrhage,
cough, and dyspnea in this population.
SECONDARY INVOLVEMENT OF THE LUNG IN
SYSTEMIC DISEASE
Langerhans Cell Histiocytosis
In adults, LCH in the lung typically occurs as a solitary
nodule in smokers, previously called eosinophilic granulo-
Pediatric Lung Tumors—Dishop & Kuruvilla 1095
Figure 9. Histiocytic lesions. A and B, Langerhans cell histiocytosis. The histiocytic disorders tend to produce patchy regions of interstitial
infiltration. Langerhans cell histiocytosis is characterized by cells with ovoid, folded, and coffee-bean–shaped nuclei, sometimes accompanied by
eosinophil infiltrates. Langerhans cell phenotype is confirmed by immunohistochemical expression of CD1a or CD207 (Langerin). C and D, Juvenile
xanthogranuloma. This example of juvenile xanthogranuloma produced an intraluminal obstructive mass in the trachea of a 7-month-old boy. It
is characterized by sheets of histiocytic cells, some with foamy xanthomatous cytoplasm and including scattered multinucleate giant cells (he-
matoxylin-eosin [A, C, and D] and CD1a immunohistochemistry [B]; original magnifications ⫻400 [A], ⫻100 [B], ⫻ 40 [C], and ⫻200 [D]).

ma.123 In children, LCH in the lung typically reflects in-
volvement by systemic disease rather than isolated lung
involvement.124 Langerhans cell histiocytosis occurs most
often in infants and young children, and presenting signs
may include a rash, bone lesions, or pituitary involvement.
Skeletal survey may show punched-out lytic bone lesions
of the skull or other long bones. If there is lung involve-
ment, chest computed tomography may show a reticulo-
nodular pattern with nodules ranging from 1 to 10 mm
in diameter, larger cavitary nodules, pneumatoceles, bi-
lateral cystic disease, and/or pneumothorax.8 Histologi-
cally, LCH typically demonstrates patchy infiltrates in-
volving the interstitium, pleura, and bronchovascular bun-
dles (Figure 9, A). Extension of LCH cells into the alveolar
spaces is often associated with the infiltrates expanding
the alveolar walls. The histiocytes have typical indented
and grooved nuclei and may be admixed with occasional
eosinophils. If necessary, confirmation of Langerhans cell
phenotype is achieved using immunohistochemistry for
CD1a (Figure 9, B) or Langerin (CD207). S100 is also pos-
itive but less specific than CD1a or CD207. Electron mi-
1096 Arch Pathol Lab Med—Vol 132, July 2008
croscopy demonstrates characteristic pentalaminar rods
with bulbous ends (Birbeck granules) formed by internal-
ized invaginations of the cell membrane. The differential
diagnosis of interstitial infiltrates and histiocytic nodules
includes leukemia, granulomatous processes, and non-
LCH, such as juvenile xanthogranuloma (Figure 9, C and
D).
Leukemia and Lymphoma
Although pulmonary infiltrates in leukemia patients
prompt primary consideration of infection, leukemic infil-
tration of the lung may cause a similar pattern radiograph-
ically. Lung involvement by leukemia usually manifests as
patchy interstitial, septal, or pleural infiltrates (Figure 10,
A and B), in contrast to non-Hodgkin and Hodgkin lym-
phoma, which tend to form larger, well-circumscribed
nodules obscuring the background lung parenchyma (Fig-
ure 10, C and D). An associated mediastinal mass or hilar
adenopathy are variable features. The differential diag-
nosis for lymphoma involving the lung in children in-
cludes primarily Hodgkin lymphoma, non-Hodgkin lym-
Pediatric Lung Tumors—Dishop & Kuruvilla
Figure 10. Lymphoid and hematopoietic lesions. A and B, Acute myeloid leukemia. Leukemic infiltrates in the lung tend to produce ill-defined
interstitial infiltrates, in contrast to the nodular masses produced by metastatic solid tumors. This example of acute blast crisis of juvenile myelo-
monocytic leukemia shows sheets of blasts producing a pleural plaque with subpleural parenchymal and peribronchial infiltrates. C and D, Hodgkin
lymphoma. This Hodgkin lymphoma metastatic to the lung demonstrated destruction of a bronchial wall and large zones of necrosis. Characteristic
Reed-Sternberg cells and Hodgkin variant cells are distributed within the background infiltrate of small mature lymphocytes and eosinophils. E,
Burkitt lymphoma. Burkitt lymphoma forms both nodular infiltrates and more diffuse interstitial infiltrates of lymphoma cells. The ‘‘starry sky’’
pattern produced by apoptotic cells in the infiltrate is apparent even in this metastatic lesion and reflects the high proliferative rate of this tumor
(hematoxylin-eosin, original magnifications ⫻40 [A], ⫻200 [B through D], and ⫻20 [E]).

Arch Pathol Lab Med—Vol 132, July 2008 Pediatric Lung Tumors—Dishop & Kuruvilla 1097
phoma (acute lymphoblastic lymphoma, Burkitt lympho-
ma [Figure 10, E], diffuse large B-cell lymphoma), and
PTLD. Other types of pulmonary lymphoid proliferations
have been reviewed by Colby and Yousem.125
METASTATIC SOLID TUMORS OF CHILDHOOD
Metastatic tumors account for approximately 80% of all
lung tumors in children and more than 95% of malignant
tumors of the lung in this population.14 Although a wide
variety of sarcomas and embryonal tumors of childhood
produce lung metastases in children, Wilms tumor and
osteosarcoma are the most frequent.2 Metastases appear
as single or multiple circumscribed nodules, often periph-
eral and preferentially involving the lower lobes in those
with hematogenous spread.2 A reticular or military pat-
tern may occur with those demonstrating lymphangitic
spread. Cavitation and pneumothorax are rare but are fea-
tures most often associated with Wilms tumor, Hodgkin
lymphoma, and osteosarcoma.6
Metastasectomy
While some metastatic lung nodules are excised for di-
agnosis and staging, others are removed as a part of on-
cologic management to achieve long-term survival and ef-
fect cure. Kayton126 has recently provided an excellent re-
view of clinical indications and surgical techniques used
for pulmonary metastasectomy in pediatric patients. This
approach began in the 1950s but achieved greater popu-
larity after 1971, when survival advantage was reported
in osteosarcoma patients with excision of metastatic le-
sions (3-year survival of 45% vs 5%, with and without
metastasectomy).126 Long-term survival (more than 20
years from diagnosis) can also be achieved in some pa-
tients with aggressive and repeated excision of lung nod-
ules. It is also now recognized that the effectiveness of
surgical management for metastatic tumor is dependent
on histologic type. Currently, pulmonary metastasectomy
remains most common for osteosarcoma due to the dem-
onstrated survival advantage of repeated wedge excisions
for metastatic disease. Metastasectomy also plays a central
role in management for other tumor types that are resis-
tant to chemotherapy and radiation therapy, such as ad-
renocortical carcinoma and chondrosarcoma. Conversely,
surgical management of metastatic disease is uncommon
for chemosensitive and radiosensitive malignancies, such
as Wilms tumor, Ewing sarcoma, neuroblastoma, rhab-
domyosarcoma, thyroid carcinoma, and germ cell tumors.
Clinical features and management principles are dis-
cussed briefly below for pulmonary metastasis in selected
pediatric solid tumors.
Osteosarcoma
In addition to the sporadic cases, osteosarcoma occurs
with increased frequency in children with p53 mutations
in the Li-Fraumeni syndrome, in children with Rothmund-
Thomson syndrome, in retinoblastoma patients, and as a
second malignancy in children treated with alkylating
agents. Approximately 10% to 15% of children with os-
teosarcoma will have pulmonary metastasis at presenta-
tion (Figure 11, A and B).127 Pulmonary metastases are
typically asymptomatic and detected by imaging studies.
Large studies have demonstrated a strong correlation be-
tween complete resection of primary and metastatic le-
sions at presentation and overall survival.126 Repeated ex-
cision of additional lung metastases is often necessary and
1098 Arch Pathol Lab Med—Vol 132, July 2008
provides additional survival benefit. Excision of metastatic
lesions should be complete due to the proven survival
benefit, and is indicated even after demonstrated chemo-
therapy response.
Wilms Tumor
The lung is the most common site of metastasis in
Wilms tumor (Figure 11, C), the second most common
malignant solid tumor of childhood. Pulmonary metasta-
ses are typically detected by imaging rather than by clin-
ical symptomatology. Patients with favorable histology
Wilms tumor and pulmonary metastasis have a good
prognosis, with approximately 75% 4-year survival.128 Pul-
monary nodules in patients with Wilms tumor may be
excised for staging at initial diagnosis, but there is a lim-
ited role for metastasectomy for oncologic management in
the United States. Metastasectomy for Wilms tumor is
more commonly used in European centers to spare effects
of radiation therapy, but North American centers have not
adopted this approach as standard therapy. Based on Na-
tional Wilms Tumor Study group data, patients with fa-
vorable histology Wilms tumor have excellent survival af-
ter chemotherapy and/or radiation therapy only, with ac-
ceptably low rates of radiation pneumonitis. Nevertheless,
excision of metastases has been used selectively in indi-
vidual Wilms tumor patients with lesions refractory to
chemotherapy or radiation therapy, or in patients prior to
bone marrow transplant.126
Neuroblastoma
Children with neuroblastoma rarely present with lung
metastases, with an incidence at diagnosis of only 0.4% to
3.2%.126 When involving the lung, metastatic neuroblasto-
ma also typically involves other organs, in which case sys-
temic chemotherapy is more appropriate than pulmonary
metastasectomy. In the case of isolated pulmonary nod-
ules, however, excisional biopsy may be indicated to con-
firm diagnosis and staging prior to chemotherapy.
Rhabdomyosarcoma
Prognosis for rhabdomyosarcoma patients with pul-
monary metastasis is generally poor, and concurrent ex-
trapulmonary disease is common. Relative to children
with extrapulmonary metastases, children with isolated
pulmonary disease more commonly have nonalveolar his-
tology, parameningeal primary site, and lack of lymph
node involvement. Overall survival is better for patients
younger than 10 years in this group and for those who
received radiation therapy. There is currently no standard
role for surgical resection of metastases other than for bi-
opsy confirmation of diagnosis and perhaps resection of
isolated lesions.126
Ewing Sarcoma Family of Tumors
Ewing sarcoma (Figure 11, D and E) is generally sen-
sitive to both chemotherapy and radiation therapy, and
these are the mainstays of management for metastatic dis-
ease, as survival advantage after pulmonary metastasec-
tomy has not been clearly demonstrated. Surgical excision
of metastatic lesions at this time is typically performed for
confirmation of diagnosis and remains controversial for
resection of limited pulmonary disease.
Other Soft Tissue Sarcomas
Metastasectomy is a component of therapy for other
types of sarcomas, including alveolar soft part sarcoma,
Pediatric Lung Tumors—Dishop & Kuruvilla
Figure 11. Metastatic solid tumors of childhood. A and B, Osteosarcoma. Metastatic osteosarcoma may be excised for staging and also for surgical
oncologic management, and is therefore a common diagnosis in lung wedge excisions in adolescents. This example of osteoblastic osteosarcoma
shows atypical polygonal cells with focal necrosis and delicate osteoid production. C, Wilms tumor. Wilms tumor (nephroblastoma) produces
nodular masses composed of variable blastemal, stromal, and epithelial elements. This example shows predominantly blastemal cells with focal
epithelial tubule formation (upper right). D and E, Ewing sarcoma. The Ewing sarcoma family of tumors most often involves the lung by direct
extension from the chest wall, or distant metastasis from a soft tissue or bone primary, as in this case. Sheets of monomorphous small, round cells
show focal cytoplasmic clearing. Strong membranous expression of CD99 is typical of this tumor. F, Adrenocortical carcinoma. Adrenocortical
carcinoma is very rare in children, but it is one of the tumor types for which metastasectomy has a role in oncologic management. This example
from a 15-year-old boy with Li-Fraumeni syndrome shows mild pleomorphism with focal nuclear enlargement and atypia, features also seen in
many adrenocortical adenomas (hematoxylin-eosin [A through D and F] and CD99 immunohistochemistry [E]; original magnifications ⫻40 [A
and C], ⫻200 [B and E], and ⫻100 [D and F]).

Arch Pathol Lab Med—Vol 132, July 2008 Pediatric Lung Tumors—Dishop & Kuruvilla 1099
synovial sarcoma, chondrosarcoma, fibrosarcoma, and
malignant fibrous histiocytoma, and the approach is gen-
erally similar to that used for osteosarcoma.126 In partic-
ular, alveolar soft part sarcoma has a high incidence of
lung metastasis (60% of pediatric patients), and because it
shows incomplete response to chemotherapy, surgical re-
section is a necessary component of oncologic manage-
ment.126
Hepatoblastoma
Pulmonary metastases of hepatoblastoma may com-
pletely respond to chemotherapy, allowing long-term sur-
vival. For unresponsive or partially responsive tumors,
however, extended survival may be achieved by pulmo-
nary metastasectomy following chemotherapy, leading to
a combined approach in such patients.
Thyroid Carcinoma
Mortality is very low for pediatric thyroid cancer. De-
spite frequent lymph node metastasis, prognosis is gen-
erally favorable, and very few patients develop distant me-
tastasis. When present, pulmonary metastases tend to pro-
duce a miliary pattern of disease which would not allow
resection by metastasectomy. Instead, the primary thera-
peutic modality for pulmonary metastases of thyroid car-
cinoma is radioactive iodine (131I) treatment, and it allows
complete radiographic resolution of disease and long-term
survival in many cases. Metastasectomy is reported for
diagnostic purposes, but otherwise it is not a routine com-
ponent of oncologic management.
Adrenocortical Carcinoma
Pulmonary metastases are relatively frequent in patients
with stage IV adrenocortical carcinoma (Figure 11, F) and,
based on experience with adults, excision of these lesions
results in dramatically increased 5-year survival (71% vs
0%, with and without metastasectomy).126 Metastasectomy
is recommended early after detection and should be com-
plete, preventing recurrence and/or tumor spillage into
the thoracic cavity.
Chemotherapy Effect
If a metastatic nodule is removed after chemotherapy,
evidence of treatment effect may include necrosis, fibrosis,
or hemosiderin deposition. Cytodifferentiation after che-
motherapy occurs in some embryonal neoplasms, for ex-
ample, mature skeletal muscle fibers in rhabdomyosarco-
ma. A mixed germ cell tumor may show only residual
mature teratomatous components after therapy.
RECOMMENDATIONS FOR GROSS EXAMINATION OF
PEDIATRIC LUNG CYSTS AND TUMORS
The possibility of unsuspected malignancy should be
considered for both solid masses and cystic lesions of the
lung in children. These specimens should be received
fresh from the operating room, without prior formalin fix-
ation or prior incision into the lesion. Examination of the
gross specimen should include photography and routine
gross description, as well as consideration of sampling of
fresh lesional tissue for special studies. Solid masses or
mixed solid and cystic lesions warrant tissue collection for
electron microscopy (glutaraldehyde), cytogenetic analysis
(RPMI or other cell culture medium), and molecular di-
agnosis (frozen tissue). Additional tissue may be retained
frozen for research studies, with the consideration that the
1100 Arch Pathol Lab Med—Vol 132, July 2008
child may later be enrolled in a biology or treatment pro-
tocol (eg, Children’s Oncology Group, International Pleu-
ropulmonary Blastoma Registry). Recommended histolog-
ic sections include sampling of at least one section of tu-
mor per centimeter greatest tumor dimension, with pref-
erential sampling of heterogeneous areas and junction to
normal parenchyma. Sampling of resection margins
should include the bronchial margin(s), as well as paren-
chymal margins in the case of wedge excisions, partial
lobectomies, and lobectomies from lungs with an incom-
plete fissure, in which case there may be a stapled paren-
chymal margin at the point of division from the adjoining
lobe. Evaluation of surgical margins is not necessary for
most metastasectomy specimens obtained for diagnosis
and staging, but it should be reported for lesions removed
for surgical oncologic management (for example, osteo-
sarcoma).
The purely cystic lesions of the pediatric lung have a
broader differential diagnosis and require greater delib-
eration in the process of initial tissue handling. Although
cystic developmental anomalies are much more frequent
than the rare cystic type I PPB, the surgical pathologist
should be alert to the possibility of malignancy and con-
sider collecting tissue as described above in cases where
diagnosis is not clear from gross features. Knowledge of
the clinical and diagnostic imaging characteristics is ex-
tremely helpful in guiding the proper approach to the
specimen. For example, a new cystic lesion identified only
after medical illness, such as pneumonia or respiratory
distress, would suggest an acquired cyst, such as a pneu-
matocele or persistent pulmonary interstitial emphysema.
Chest computed tomography provides information on an-
atomic characteristics that might suggest a developmental
anomaly, such as systemic arterial supply (extralobar and
intralobar pulmonary sequestration), anomalous bronchial
anatomy (bronchial atresia, intralobar sequestration), or
lobar or segmental distribution (congenital lobar overin-
flation, bronchial atresia, intralobar sequestration). A clin-
ical or diagnostic imaging impression of a large-cyst
(Stocker type I) CPAM typically indicates the presence of
a large unilocular or multilocular purely cystic lesion,
with or without surrounding hyperinflation. Because as-
sociated bronchial or vascular anatomy is not always fully
characterized by computed tomography imaging, the ab-
sence of specific features does not exclude bronchial atre-
sia or intralobar sequestration from the differential diag-
nosis. At this point, the surgical pathologist should ex-
amine the lung externally for the same anatomic clues,
which would suggest a developmental anomaly: segmen-
tal or lobar parenchymal hyperinflation, aberrant systemic
arterial supply, a mucocele, or aberrant bronchial anatomy.
The hilar bronchi are probed in all directions to determine
their anatomic distribution and to identify any regions
that do not appear to be connected to the central airways.
If specific diagnosis is not established after review of the
diagnostic imaging and gross pathologic features, and if
large-cyst CPAM still remains a diagnostic consideration,
then the specimen should be treated as if it may be a PPB
type I, and fresh tissue collection is recommended prior
to transbronchial and transpleural injection inflation with
formalin. These large cystic lesions require extensive his-
tologic sampling to exclude foci of primitive cells, partic-
ularly for cysts lined by alveolar-type epithelium, mim-
icking the lesion described as peripheral cyst (Stocker type
IV) CPAM.
Pediatric Lung Tumors—Dishop & Kuruvilla
 The rarity of PPB and other primary malignancies of
the pediatric lung underscores the need for thoughtful dis-
section and, if indicated, fresh tissue collection for biologic
studies. Such studies will allow further definition of the
cytogenetic and molecular characteristics of these rare tu-
mors, and it will likely enhance not only our diagnostic
capabilities in the future, but also help to determine prog-
nosis and optimal therapy for these children.
SUMMARY
In this institutional review of pediatric lung biopsies
and resections, the ratio of primary benign to primary ma-
lignant to metastatic lung tumors in children is 1.4:1:11.6.
Metastases to the lung are approximately 12 times more
common than primary lung malignancies in children, and
they may be excised for diagnosis, staging, or therapeutic
purposes. The most common metastatic tumors excised in
the pediatric population are Wilms tumor and osteosar-
coma. Primary lung malignancies represent only approx-
imately 0.19% of all pediatric malignancies, and are often
not clinically suspected due to lack of symptoms or non-
specific nature of presenting symptoms. The spectrum of
primary tumors of the lung in children shows little over-
lap with the types of lung tumors seen in adults. The most
common primary lung malignancies in children are pleu-
ropulmonary blastoma and carcinoid tumor, and broncho-
genic carcinomas are exceptionally rare. The relationship
of neoplasia to CPAM remains unclear, as some malig-
nancies reported to arise in this setting are, in fact, cystic
forms of PPB. Bronchioloalveolar carcinoma arising from
congenital cysts has been observed rarely, primarily in
older children and adults. Immunosuppressed children
are susceptible to EBV-associated tumors, including lym-
phoproliferative disorders and smooth muscle tumors.
Given the rarity of primary lung neoplasms in children
and the high incidence of sarcomas and embryonal tu-
mors, consideration should be given for sampling of fresh
tissue for cytogenetic analysis, electron microscopy, mo-
lecular diagnostics, and tumor banking for research pro-
tocols.
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