Prostate Lung

Penis Larynx
Testis Gall bl. +ducts
Ovary Pancreas
Endo Myometrium Liver
Cervix Pituitary
Breast malignant Andrenal
Oral Thyroid
Salivary MEN
Esophagous Bone
Stomach CNS
GI PNS
Kidney Heart
Urinary Melanocytes

adenocarcinoma of the prostate

men older than age 50 years, peak incidence around 75 years of age
Pathogenesis:
1. Hormonal, Genetic, Environmental factors
2. Diet – high in animal fat (red meat) and low in antioxidants (selenium, vitamin E)
3. express androgen receptors: anti-testosterone treatment
Differentiation:
1. HMWCK positive = PIN LM: dysplastic glands;
2. HMWCK negative = well differentiate PCC low grade PIN
HMWCK – high molecular weight cytokeratin ↓
Gross: ↓
high grade PIN
1. multifocally peripheral posterior zone of the prostate microinvasive carcinoma
2. firm, grayish-yellow masses
LM:
1. adenocarcinomas
a. HMWCK negative (no basal layer)
b. PSA positive
Spread:
1. Continuous spread: seminal vesicles
2. Lymphatic spread: below the bifurcation of the common iliac arteries
3. Hematogenous spread (retrograde): spine, pelvis and ribs; and to the lungs
Grading:
Gleason score system of grading – combination of:
1. very well differentiated
2. well differentiated
3. moderately differentiated
4. poorly differentiated
5. very poorly differentiated
Staging: Anatomic extent (stages) of PCC
1. T1 – incidental finding
2. T2 – confined to the prostate
3. T3 – invades the seminal vesicles
4. T4 – invasion of the bladder neck, external sphincter, rectum, levator muscles and/or pelvic wall
Clinical features:
1. 75% of patients at the time of diagnosis have T3 cancer
2. UTO, Back pain from vertebral metastases ± pathologic bone fracture, Anemia, Increased level of
serum PSA
Prognosis
1. (T1-T2): surgery or radiotherapy - 15-y survival rate is 90%
2. (T3-T4): anti-testosterone therapy ± radiotherapy: response may be achieved
 Tumors of the Penis
1. Condyloma acuminatum – benign
a. Venereal wart
b. HPV 6 and 11
c. raised reddish, cauliflower-like lesion (papillomas)
d. LM – acanthosis, papillomatosis, koilocytes
2. Erythroplasia of Queyrat – premalignant tumor
a. Plaques on the glans, prepuce and orifice
b. squamous cell carcinoma in situ
3. Invasive squamous cell carcinoma – malignant tumor
a. Rare, 65 years
b. Risk factors
1. HPV 16 and 18
2. 30 or more sexual partners
3. Chronic irritation
4. No circumcision
5. Smoking
His squamous cell
c. Gross – ulcerative or fungating
d. LM – well or moderately differentiated squamous cell carcinoma
e. Slow course, Lymphatic metastases in the inguinal lymph nodes
f. 5 year– 70%

Testicular tumors
1. 95% germ cell tumors (malignant)
2. Precursor lesion – intratubular germ cell tumor
3. painless enlargement of the testis
4. Lymphatic –along the internal iliac arteries and aorta.
5. Hematogenous – lungs
6. Differentiation of primitive germ cells – classification of germ cell tumors
a. Spermatogonium – seminoma
b. Embryonal epithelium - embryonal carcinoma
c. Chorionic villi – chorio cc (HCG – human choriogonadotropin is the serologic marker)
d. Yolk sac – yolk sac cc (AFP – alpha fetal protein in the serum)
e. Somatic cells - teratoma
Seminoma
Features:
1. Most frequent germ cell tumors, 40 years, Spread is via lymphatics (no hematogenous metastases)
2. Radiosensitive, Good prognosis
3. Well demarcated homogenous mass, gray-white, no hemorrhage or necrosis, intact tunica albuginea
4. seminoma cells have clear, glycogen containing cytoplasm; nucleus has a prominent nucleolus;
Non-seminomatous GCTs (germ cell tumor) embryonal carcinoma, chorio cc, yolk sac cc, teratoma
Features:
1. Highly malignant tumors , 30 years of age; Infiltrative tumors with necrosis and hemorrhage
2. At diagnosis – lymph node and lung metastases
Staging of testicular tumors
1. pT1 - testis/testis+epididymis/tunica albuginea - without vascular or lymphatic invasion
2. pT2 – invade tunica vaginalis – with vascular or lymphatic invasion
3. pT3 – into spermatic cord ± vascular/lymphatic invasion
4. pT4 – into scrotum ± vascular/lymphatic invasion
Topic 159 – Tumors of the ovary

Origin, Main groups:

1. Surface epithelium (celomic) and stromal tumors  multipotential cells.
2. Germ cells tumors  totipotential cell.
3. Sex cord stromal tumors  multipotential sex cord-stromal cells.
• malignant forms of surface epithelial origin account for almost 90% of all ovarian cancers

A. Surface epithelium-Stromal tumors

General features:
Strictly epithelial or can have a distinct stromal component. Types:
1. benign (cystadenomas)
2. intermediate, borderline: currently referred to as tumors of low malignant potential
3. malignant (cystadenocarcinomas)
Tumor types: 1. Serous tumors. 2. Mucinous tumors 3. Endometrioid tumors
4. Cyst Adenofibroma 5. Brenner Tumor

1. Serous tumors
Features:
1. Commonest ovarian tumor.
2. Women between 30 and 40 years of age.
3. commonly cystadenomas and cystadenocarcinomas
4. 60% of cases are benign  serous cystadenomas.
5. 15% are borderline nature.
6. 25% are malignant serous cystadenocarcinomas.
7. borderline and malignant cases account for about 60% of all ovarian cancers
Morphology:
Macro:
1. variation in size 5-40 cm in diameter
2. 25% of the benign form and 66% of aggressive forms are bilateral
3. serosal covering
a. Benign cases are covered by smooth, glistening serosa.
b. malignant form penetrate the capsule  showing nodular irregularities on their surface
4. The small tumors may have a single cavity (unilocular).
5. The large tumors are multilocular.
6. the inner surfaces show papillary projections, which are more marked in malignant tumors, in the latter
solid areas may also be seen
LM:
1. Benign tumors, usually cystadenoma:
a. Lined by Single layered of tall columnar ciliated cells (may be ciliated).
b. papillary formations, psammoma bodies are common in the tips of papillae
2. Borderline cases: no significant stromal invasion
3. Carcinoma, serous cystadenocarcinoma:
a. cytologiacal atypia of the lining cells
b. complexed multilayered papillary structures
c. invasion of the stroma
d. contiguous spread within the pelvis and peritoneal dissemination
e. spread to regional lymph nodes is frequent but distant metastases are infrequent
Common feature of serous ovarian tumors:
Presence of psammoma bodies = small calcified bodies having a laminated concentric structure

Prognosis:
Prognosis is poor and depends on the stage at the time of the diagnosis
1. Malignant tumors confined to ovary:: 70% 5-- yr-survival
2. Borderline tumors confined to ovary: 100% survival
3. Malignant tumors penetrating the capsule: 13% 10-yr-survival
4. Borderline tumors penetrating the capsule: 80% 10-yr-survival, but there is extraovarial peritoneal
implantation in 40%,, thus these patients eventually die of their tumors

2. Mucinous Tumors
Features:
Compared to to serous tumors:
1. the epithelium consists of mucin-secreting cells
2. the age range is the same
3. mucinous lesions are considerably less malignant
4. benign 80%
5. low malignant potential, borderline 10%
6. malignant 10%
Morphology: only 5% of benign and 20% of malignant tumors is bilateral
Macro:
1. Cystic tumor contains mucinous material.
2. Often multilocular and larger.
3. papillary formations are uncommon
4. No psammoma bodies.
5. uneven inner surface, serosal penetration and solidified areas point to malignancy
LM:
1. Lining epithelium is similar to the epithelial cells of the endocervix = Single layer of mucin producing
columnar cells and no cilia.
2. Histochemistry – mucin producing cells are of two subtypes:
a. Endocervical-like (Müllerian) type;
b. Intestinal type.
3. Malignant lesions are identified by the presence of stromal invasion
4. Pseudomyxoma peritonei:
• Mucinous cystadenocarcinoma or that of borderline lesion ovarian lesions may rupture  spills
out into peritoneal cavity multiple tumor implant on all serosal surface.
• similar condition may result from the rupture of a carcinomatous mucocele of the appendix

3. Endometrioid tumors
Features:
1. Endometrioid tumors are usually malignant, although benign and borderline forms exist.
2. linings of the cysts are similar to those of the endometrium
3. they are bilateral in 30% of the cases
4. in 15-30% of these patients there is a concomitant endometrial carcinoma
5. well differentiated carcinomas: 62% 5-yr-survival
6. poorly differentiared carcinomas: 23% 5-yr-survival

4. Cystadenofibroma
Features:
 1. benign, small and multilocular
2. A variant of serous cyst adenoma with pronounced proliferation of the fibrous stroma.
3. malignant transformation is rare

5. Brenner Tumor
Features:
1. most are benign, but malignant and borderline cases were also described
2. rare, solid, usually unilateral ovarian tumor
3. abundant stroma + nests of transitional epithelium
4. encapsulated, d= a few cm -- 20 cm

B. germ cell Tumors

1. Teratomas
Features:
1. germ cell origin
2. 15-20% of ovarian tumors
3. arise in the first two decades of life
4. over 90% are benign cystic mature teratomas
5. the younger the patient the greater is the likelihood of malignancy

1. a. Benign (mature) cystic teratoma = Dermoid cyst

Features:
1. ectodermal differentiation of the totipotent germ cells
2. the cyst is lined by epidermis with large number of adnexal appendages, hence the common
designation: dermoid cyst
3. most are in young women, d << 10 cm
4. the cyst is often filled with sebaceous material and matted hair
5. nodular thickening in the wall from which teeth protrude,, bone, cartilage, nests of bronchial or
gastrointestinal epithelium may also occur
6. in 1% of the cases there is malignant transformation, squamouss cell carcinoma
7. specialized Teratomas
a. Struma ovarii is composed entirely of mature thyroid tissue, which may produce
hyperthyroidism. These are small, solid, unilateral brown ovarian masses.
b. Ovarian carcinoid rarely may produce carcinoid syndrome.
carcinoid syndrome = combination of symptoms usually produced by the release of serotonin from carcinoid tumors; consists of irregular
mottled blushing, flat angiomas of the skin, acquired tricuspid and pulmonary stenosis often with regurgitation, occasionally with some minor
involvement of valves on the left side of the heart, diarrhea, bronchial spasm, mental aberration, and excretion of large quantities of 5-
hydroxyindoleacetic acid.

1. b. Immature malignant teratoma

Features:
1. the mean age of the patients is 18 years
2. bulky, solid tumors with areas of necrosis
3. rarely areas resembling to mature teratoma are also present
4. Micro:: there is a variety of mature or immature barely recognizable areas of differentiation toward
cartilage, bone, muscle nerve and other structures.
5. presence of neuroepithelial differentiation predicts an aggressive behavior

2. Dysgerminoma (the counterpart of testicular seminoma)

Features:
1. Rare tumor, malignant primordial germ cell origin
 2. ovarian counterpart of seminoma found in men
3. children, young adults
4. surgery, radio—and chemotherapy: 5 year survival rate: 65-90%

3. Choriocarcinoma
Features:
1. rare, mostly in mixed germ cell tumors
2. opposite to the tumor of placental origin
3. poor reaction to chemotherapy, prognosis is poor

4. Endodermal sinus (Yolc sac) Tumor

1. differentiation toward yolc sac structures, AFP+ (marker during pregnancy also for neural tube closure defect and hepatocellular
carcinoma in adults)
2. children, young adults
3. grow rapidly and aggressively

C. sex cord - stromal Tumors

They originate either from the sex cords of the embryonic gonad and/or from the stroma of the ovary.
The tumors are frequently functional and mostly have feminizing effects.

1. Granulosa and Theca cells tumor

• various combinations of granulosa and theca cells
• two thirds occur in postmenopausal women
• usually unilateral solid and white-yellow tumor
• the granulosa component consists of small cuboidal cells having coffee bean nuclei,
characteristic:: Call-Exner bodies
• the thecal cell components are composed of spindle cells closely resembling those of a fibroma,
thecal cells contain lipid droplets
• Pure thecomas are benign
Clinical features:
1. These tumors have the potential of producing large amounts of estrogen!
2. Consequence: precocious sexual development, endometrial hyperplasia and predispose to
endometrial carcinoma.
3. All granulose cell tumors are potentially malignant,, with clinical malignancy
occurring in 5-25%, however, they are slow growing, and the 10-yr-survival rate is almost 85%.

2. Sertoli – Leydig cell tumors (Androblastomas)

1. Recapitulate the cells of testes commonly cause  masculinization (defeminization).
2. Usually unilateral.
3. composed of Sertoli cells + Leydig cells with stroma.
Metastatic tumors
• Metastases of abdominal and breast tumors to the ovary are common.
• Krukenberg tumor: metastatic bilateral ovarian cancer
primary tumor: signet ring cell carcinoma of stomach

Clinical correlation for all ovarian tumors

• Malignant tumors produce no symptoms or signs until they are well advanced.
• At the time of diagnosis the progression is often beyond the point of cure.
• 30% of all ovarian tumors are discovered incidentally on routine gynecological examination.
• Larger tumors cause an abdominal mass whereas smaller ones, particularly dermoid cysts may
become twisted on their pedicles, causing an acute abdomen.
• Malignant serous tumors often cause ascites
• Malignant mucinous tumors may cause pseudomyxoma peritonei.

Topic 157 – Diseases of the myometrium

Generally all these tumors manifest with bleeding from the uterus → earliest & alarming symptom.

Leiomyoma
Features:
1. Benign tumor of smooth muscle cells
2. The most common benign tumors in females
3. Found in 30-50% of females in reproductive years
4. More frequent in Black people.
5. Estrogens stimulate their growth.
6. The tumor shrinks postmenopause.
Macro:
1. Sharply circumscribed, firm, gray-white masses with a whorled
cut surface. Most often they are multiple
2. location:
a. intramural (in the myometrium)
b. subserosal (directly beneath the serosa)
c. submucosal (directly beneath the mucosa)
3. common changes in larger neoplasms:
a. ischemic Necrosis
b. hemorrhage
c. cystic softening
4. postmenopausal they may become densely collagenous or even calcified.
LM:
1. whorling bundles of smooth muscle cells, Degenerative regressive changes are often present
2. variant: Bizarre leiomyoma show high atypical nuclei and no mitotic figures - entirely benign.
3. Malignant change never occurs
Clinical features:
1. May be entirely asymptomatic
2. The most frequent manifestation is metrorrhagia with or without menorrhagia
3. No malignant manifestation

Leiomyosarcoma
Features:
1. Malignant tumor of smooth muscle cells
Clinical features:
 1. Arise directly from mesenchymal cells of the myometrium, not from pre-existing leiomyoma.
2. Almost always solitary tumors
3. Recurrences after removal & metastases are common;
4. 5-year survival rate is 40%.
5. The more anaplastic the tumor the poorer the outlook is.
Macro: Distinct patterns:
1. Bulky mass infiltrating the uterine wall.
2. Polypoid lesion projecting into the uterine cavity.
3. Discrete tumor mimicking large leiomyoma.
LM:
1. There’s a wide range of differentiation; from leiomyoma-like lesions to highly anaplastic.
2. Tumors at the interface between benign and malignant are designated leiomyoblastoma.
Diagnosis determined by the number of mitotic figures and the presence/degree or absence of cellular atypia

Tumors of the cervix

Cervical Intraepithelial neoplasms (CIN) and squamous cell carcinoma
Features:
1. Cervical cancer was once the most frequent form of cancer in women around the world
2. The Papanicolau cytological screening has dramatically lowered the incidence of invasive tumors by
detecting the early lesions when curative treatment is possible.

Cervical Intraepithelial neoplasms (CIN)

1. Cytologic examination can detect CIN (SIL=squamous intraepithelial lesion) long before any abnormality can be
seen grossly.
2. Precancerous epithelial changes may precede an invasive cancer by many years, perhaps by 20 years.
3. Only a fraction of CIN cases progress to invasive carcinoma

Grading by histology– 3 Categories of CIN: I – III

1. CIN I – mild dysplasia – minimal cellular atypia confined to the lower 1/3 of the epithelium.
koilocytic changes in the upper 2/3.
2. CIN II – moderate dysplasia – affects the lower 2/3 of the epithelium. koilocytic changes in the upper
1/3.
3. CIN III – severe dysplasia and cc in situ – affect the whole layers of the epithelium. Koilocytotic
changes have usually disappeared. These changes constitute carcinoma in situ
• CIN may extend into the endocervical glands
• koilocytes : HPV infected squamous cells s
koilocytosis: superficial cells contain irregular, angulated, pleomorphic nuclei surrounded by a clear
halo.

Another classification by cytology: SIL – squamous intraepithelial lesion

1. low grade SIL = CIN I
2. high grade SIL= CIN II & III

Prognosis:
CIN-I:
1. Spontaneous regression - 50-60% of cases
2. Long persistence - 30%
3. Progression to CIN III - 20% (& takes a long time)
4. Becomes invasive 1-5%
CIN-II or III – There’s greater risk for progression but many cases still do not progress to cancer.
Epidemiology and Pathogenesis:
Peak age incidence
1. CIN is 30 years
2. invasive carcinoma 45 years

Risk factors of CIN and invasive cancer:

1. Early age at 1st intercourse.
2. Multiple sexual partners – ↑ the risk to get other HPV types.
3. Male partners in the group with high risk factors (multiple previous sexual partners)
4. HPV is detected in 85- 90% of precancerous lesions and invasive neoplasms.
• High-risk types of HPV in order of frequency: 16, 18, 31 & 33. [Benign Condylomas are
typically associated with other low risk types - HPV 6, 11, 42 & 44]
5. + other influences , such as other carcinogens, cocarcinogens , genetic factors, altered immunity and
cigarette smoking

progression
1. likelihood of the progression to higher grades is correlated
• 1.) with the severity of the changes when first discovered and
• 2.) to the presence of high risk types of HPV such as 16 and 18.
2. viral typing does not predict the course. Only careful follow up PAP smears and biopsies if
necessary will determine the nature and gravity of the changes.

Invasive carcinoma of the Cervix

Macro:
1. fungating tumor
2. ulcerative tumor
3. infiltrative tumor
Micro:
1. 85- 90% are squamous cell cc, developed from precursor CIN.
2. The remaining are adenocarcinomas

Local spread: advanced lesions may extend into the rectum, into the base
of the urinary bladder or obstruct the ureters

Metastasis: regional lymph node, lungs, bones and liver

Clinical features:
1. carcinoma in situ is usually asymptomatic. The cervix may appear normal to
the naked eye, however kolposcopy may disclose abnormalities.
2. Invasive carcinoma: irregular vaginal bleeding, leukorrhea, dysuria Biopsy
is necessary
3. Mortality is more often related to its local effects than to distant
metastases.
4. At least a decade elapses between the in situ and invasive stages
5. The 5 year survival is directly proportional to the stage when the lesion is first discovered: from
stage 0 to 4: 100, 85, 75, 35 and 10%.

Stages:
pTis: CIN III cc in situ
pT1: carcinoma confined to the cervix uterus
pT2: carcinoma extends beyond the cervix,uterus but not the pelvic wall
pT3: carcinoma has extended onto the pelvic wall
pT4: carcinoma has extended beyond the true pelvis or has involved the bladder or
rectum pelvis or has involved the bladder or rectum

Topic 153 – Malignant tumors of the breast

Benign:
A. Stromal tumors
a. Fibroadenoma
b. Phyllodes tumor
B. Epithelial tumors
a. Intraductal papilloma = large duct papilloma
C. Other benign
a. Silicon implant associated pathology
b. Diabetic mastopathy
c. Radial scar / complex sclerosing lesions
Malignant: breast carcinoma
A. In-situ non invasive cc
a. DCIS
i. Paget's disease
b. LCIS
B. Invasive carcinoma
a. Invasive ductal cc
b. Invasive lobular cc
c. Tubular cc
d. Mucinous (colloid) cc
e. Medullary cc

A. Stromal tumors
1. Fibroadenoma
Features:
1. Most common benign tumor of the female breast.
2. Affects women of reproductive age.
3. Biphasic (fibroepithelial) tumor with epithelial and stromal component
4. may be associated with proliferative changes and slightly increased (negligible) risk of cancer
Clinically:
1. well-circumscribed, palpable mass, may be multiple
2. they grow in pregnancy and sometimes undergo infarction
3. with age fibroadenomas may calcify
Macro: solitary (sometimes multiple), white, rubbery nodules, from 1 to 10 cm in diameter (microscopic
examples are chance findings, and have no typical macroscopic appearence)
Micro: biphasic: stromal (cellular or sclerotic) + epithelial (pericanalicular and / or intracanalicular patterns)
component

2. Phyllodes tumor (Greek: leaf-like)

Features:
1. Relatively rare
2. Often occurs in the elderly, uncommon in the young
Morphology: Another biphasic (fibroepithelial). Stroma overgrows epithelial component forming slit like
lumen and gives ability to fall apart into layers having a leaf-like shape.
LM DD Signs of malignancy:
1. pleomorphism
2. mitotic activity
 3. overgrowth of the stromal component
4. invasion into adjacent breast tissue
Outcome: Most behave in a benign fashion, cured by local excision, rarely recur. Metastasis to the lung.

B. Epithelial tumors
1. Intraductal papilloma = large duct papilloma
Features:
1. Usually solitary papillary growth within the lactiferous duct.
2. Usually not palpable.
3. Micro: Intraductal papilloma. fibrovascular cores covered by myoepithelial and epithelial cells
4. serous or bloody discharge in the nipple
5. multiple papillomas represent increased risk of cancer
6. Nipple discharge is important clinical feature and usually signs of benign tumor. However in 7% of
cases in younger patients and 30% of cases in older women it is associated with cancer.

C. Other benign entities…

1. Silicon implant associated pathology
a. Capsule formation (fibrous tissue; pseudosynovial metaplasia)
b. Implant rupture (foreign body type reaction; also in the regional lymph nodes)
2. Diabetic mastopathy
a. In some cases of long-standing diabetes patients form fibrous lumps with lobulocantric
inflammation
3. Radial scar / complex sclerosing lesions
a. A mammographic and sometimes histologic mimic (false diagnosis) of BC

Breast Carcinoma
Very common cause of death
Risk factors:
1. Elderly women (average age at diagnosis >60 y)
2. A subset of premenopausal (younger) women with strong family history of BC (and/or ovarian cancer)
[BRCA1, BRCA2] BC susceptibility genes
3. Western women as compared to Asian women
4. Obese postmenopausal women
5. Long reproductive life (early menarche & late menopause)
6. Nulliparous women as compared to multiparous (breast feeding)
7. Women having their first child after the age of 30
8. Therapeutic irradiation of the breast at a young age
9. Following some pathological findings: ADH (atypical ductal hyperplasia) ALH (Atypicla lobular hyperplasia); ipsilateral
or contralateral breast cancer.

Breast cancer etiology - cause is unknown, however the following influences appear important:
1. genetic factors (about 10% of BCs are familial)
2. hormone imbalances: exposure to endogenous (or unopposed exogenous) estrogens
+
1. environmental influences
2. dietary fat
3. oncogenic viruses – not in humans (Mouse Mammary Tumor Virus)
4. environmental polluants that may have estrogenic effects
Factors involved in breast cancer progression
1. Susceptibility (?)
2. Oncogens, tumor suppressor genes, genes involved in apoptosis (imbalance)
3. Increased expression of cell cycle proteins
4. Loss/decrease of/in cell-to-cell adhesion
5. Angiogenetic factors (angiogenesis)
6. Tissue proteases (invasion)
Not all of these mechanisms are involved to the same extent in all carcinomas

Progression of BC (IDC)
FEA = Flat Epithelial Atypia

ADH = atypical ductal hyperplasia

LG DCIS IG DCIS HG DCIS

IDC GI IDC GII IDC GIII

DCIS
Low-grade pathway High-grade pathway

ductal carcinoma in situ (DCIS)

intraductal carcinoma (IDC)

BC distribution
1. 50% of cases affect outer upper quadrant of breast.
2. 30% are in the remaining 3 quadrants. 10% each.
3. The remaining 20% are in the subareolar area of the breast
(under the nipple)

Screening for Breast cancer

• Before the advent of breast cancer screening programs breast cancer was mainly detected as a
symptomatic disease.
• In the era of BC screening many cases are detected in an asymptomatic (nonpalpable) stage; many in the
non-invasive or „in situ” phase

Major Types of Breast Cancer

1. 25-30% of cancers are of the in situ type - either ductal or lobular cc in situ (DCIS or LCIS).
a. Both are traditional names and do not reflect the origin of the lesions; both arise from the
terminal ductulolobular units
b. Paget’s disease of the nipple (in practice, always associated with in situ carcinoma of large
lactiferous ducts or invasive carcinoma)
2. The remaining 70-85% are invasive infiltrating cancers:
b. 80% are invasive ductal cc of the common type, Not-Otherwise Specified (NOS)
c. 10% of cases are invasive lobular cc.
d. The remaining 10% are rare variants with better prognosis (medullary, tubular, papillary)
In situ, non-invasive carcinomas
A. DCIS (Ductal CC In Situ)
Features:
1. Neoplastic proliferation of ductal epithelial cells confined by the ductal BM  not reaching the
interstitium.
microscopy
1. main patterns of DCIS are:
a. solid (the whole lumen is filled by proliferating cells).
b. Cribriform (lace-like) when there are small holes in the proliferating tissue
c. papillary, micropapillary
d. Comedo type – looks like a black head. Containing greasy discharge. Central portion
undergoes necrosis
2. They are further classified by nuclear grade: low (I) – intermediate (II) – high (III); the latter being
the worst.
 Myoepithalial cell marker immunostain
 E-cadherin immunohistochemistry
Prognosis:
2. When treated by breast conserving surgery alone, ~ 50% recur, half of the recurrences are invasive
3. The current treatment of DCIS is aimed at eradicating the lesion by surgery (mastectomy) or surgery
and radiation (breast conservation).
4. DCIS (nowadays) is most commonly detected as mammographic calcifications.

• Paget’s disease - DCIS can spread from lactiferous ducts into the continuous skin of the nipple without
invading through the basement membrane The nipple appears eczematous and ulcerated.

B. LCIS
Features:
1. characterized by a proliferation of small, uniform cells within ducts and lobules that fill at least
50% of the acinar units of a single lobule and are bordered by the myoepithelial layer and the
basement membrane.
2. LCIS is nearly always an incidental pathology finding because it never forms a mass and is rarely
associated with calcifications.
3. It may be bilateral and multifocal
4. Is not only a risk factor, but also a precursor lesion
Prognosis:
1. 10-(25%) lifetime risk of developping invasive carcinoma
2. Invasive carcinoma (lobular/ductal; ipsilaterpal/ contralateral) follows this lesion after 15-20 years
5. Bilateral mastectomy (advocated earlier) is considered an overtreatment now

The intraepithelial neoplasia concept

• ALH, LCIS are often referred to as lobular intraepithelial neoplasia (LN, LIN)
• ADH, DCIS are often referred to as ductal intraepithelial neoplasia (DIN)
Invasive Cancer - histological types
1. Invasive ductal carcinoma NST (No Special Type) / NOS (Not Otherwised Specified) -(about 80%
of the invasive cases)
2. Special type carcinomas
a. Invasive lobular carcinoma (~ 10%)
b. Tubular carcinoma and cribriform carcinoma (~6%)
c. Mucinous (colloid) carcinoma (~ 2%)
d. Medullary carcinoma (~ 2%)
e. Other less common types

1. Invasive ductal cc (NST / NOS)

a. The commonest form (80% of all invasive cc).
b. composed of malignant cells arranged in tubules, cribriform structures, solid cell nests or cords.
c. Dense stromal reaction may be present; this responsible for the hard consistency of the tumor
(scirrhous carcinoma)
2. Invasive lobular cc
a. <10% of invasive carcinomas.
b. More often multifocal and bilateral than other types of breast carcinoma.
c. The lack of E-cadherin is believed to be responsible of the distinct morphological pattern. E-
cadherin is a calcium dependent cell-to-cell adhesion molecule.
d. Discohesive cells arranged in „indian files”, or in „goose lines”, often in a targetoid pattern
around normal duct.
e. LM: Small uniform cells that have tendency to arrange in parallel lines = Indian Files Pattern.
f. Tumors can be scirrhous or can have a diffusely invasive pattern that is difficult to detect
clinically and mammographically.
g. Lobular carcinomas have a distant metastatic pattern that differs from the ductal cancers. They
more often metastasize to the meninges, serosal surfaces, ovary, uterus and bone marrow
3. Tubular (cribriform) cc
a. Often less than 1 cm in size
b. Detected as mammographic speculated masses
c. Well-formed tubules or cribriform nests with low-grade nuclei and a low mitotic index (by
definition a low grade / well differentiated carcinoma)
d. This histologic type has the best prognosis
4. Mucinous (colloid) cc
a. Slowly growing
b. Most commonly in older women
c. Often circumscribed, Soft, gelatinous tumor
d. The tumor has mucin producing cells  lakes of mucin appear extracellularly.
e. tumor contains gelatinous lakes with small islands of mucin producing cells→ good prognosis
5. Medullary cc
a. <5% of all breast carcinomas
b. Affecting younger women.
c. Is more common in women carrying BRCA1, BRCA2 mutations
d. relatively large (few cm), soft, well-circumscribed averaging 2-3cm in diameter
LM:
e. absence of desmoplasia
f. moderately dense lymphocytic infiltrate
g. large, pleomorphic tumor cells growing in sheets

Common Macroscopical features to all carcinomas:

1. fixation to adjacent structures= Matting
 2. Retraction (dimpling) of the nipple or covering skin (if it reaches the skin).
3. orange-peal appearance of the breast skin. Resulting from lymphedema, due to tumorous
involvement of lymphatic pathway
4. inflammatory carcinoma

Breast cancer Spread:

1. To regional lymph nodes (somewhat dependent on the primary tumor site).
sentinel” lymph node: first regional lymph node where metastasis may occur
a. Axillary lymph nodes (most common; outer quadrant tumors)
b. Internal mammary (parasternal) lymph nodes (less common; more common with inner
quadrant tumors)
a. (Intramammary lymph nodes)
2. To distant sites: Bones, lung, liver, skin, adrenals…etc (invasive lobular carcinomas have a different
pattern; predilection for visceral sites, meninges and serosal surfaces)

Breast cancer – prognostic factors

Prognostic factors: parameters which affect the outcome of the disease (without treatment)
1. Distant metastasis (Stage IV disease). The presence of distant metastases infers the worst prognosis
2. Lymph node metastases (The most important prognostic factor in those without evident distant
metastasis) With increasing numbers of involved lymph nodes the prognosis worsens:
a. Node-negative tumors have 70-80% 10-y-survival
b. Node-positive tumors >9 positive nodes have 10-15% 10-y-survival
3. Tumor size (the larger the tumor, the worse the prognosis)
4. Tumor stage (first 3 factors are combined in the TNM classification and the STAGEs of the disease)
5. Tumor histologic grade (breast cancers are graded in a 3-tiered system on the basis of their tubule
formation, nuclear pleomorphism and mitotic rate:
a. grade 1 – well differentiated
b. grade 2 – moderately differentiated
c. grade 3 –poorly differentiated
6. Lymphatic or vascular / (lympho)vascular invasion; its presence is an adverse sign
7. Histologic types: tubular, cribriform, mucinous carcinomas are favourable types
8. Estrogen and progesterone receptor (ER, PR) status: ER and PR positive tumors have somewhat
better prognosis and are likely to react to hormonal treatment (ER and PR status is also a predictive
marker – i.e. predicts the responsiveness to a given therapy) ER
9. HER-2 (c-erb-B2; NEU) status. HER-2 is an oncogen located on chromosome 17q21; it is amplified
in 15-30% of breast cancers; the gene amplification is paralleled by protein overexpression. HER-2
positive tumors have worse prognosis. The HER-2 status is predictive of the response to targeted
therapy against the HER-2 oncoprotein (HERCEPTIN – trastuzumab; humanized moAb – the 1st
targeted therapy agent for solid tumors)
10. resection margin status (involved margins are predictive of local recurrence)

Breast cancer (pathological) diagnosis

1. FNAC (Fine Needle Aspiration Cytology)
2. Core needle biopsy
3. Vacuum assisted core needle biopsy
4. Incision biopsy
5. Excision biopsy
6. Prognostic and predictive markers
Staging:
1. Stage 1 - < 2 cm Ø with no metastases.
2. Stage 2 - <5cm Ø with involved movable axillary nodes, or >5cm with no metastases. Usually
medullary cancers.
3. Stage 3 – any size with fixation to adjacent structures (skin) & fixed lymph node metastases.
4. Stage 4 - breast cc with distant metastases.

Breast cancer treatment

1. Surgical: mastectomy vs. breast conserving surgery ± axillary surgery (dissection vs. sampling vs.
SLN biopsy)
2. Radiotherapy: locoregional treatment which reduces recurrences and improves survival
3. Systemic:
a. Hormonal (ER+/PR+ are supposed to be the most responsive)
b. Chemotherapy
c. Targeted treatment (anti-HER2)
d. Novel agents (e.g. anti-angiogenetic therapy)

Special presentations of breast cancer

1. Inflammatory carcinoma
a. Cancer, clinically presenting as inflammation (peau d’orange sign – resulting from oedema;
or frank redness, inflammation)
b. This is generally associated with dermal lymphatic vessel invasion, although this latter
(without the clinical symptoms) is not sufficient for diagnosing inflammatory cancinoma
c. Poor associated prognosis; this is generally not a surgical disease in this stage – pT4d in the
TNM classification
2. Occult carcinoma
a. Cancer presenting as metastasis either to the lymph nodes or to distant sites with no evidence
of the primary tumor
b. Originally, it meant non-palpable tumors with metastases, and such tumors were not so rare.
c. Now this means non-palpable tumors without imaging (mammographic or ultrasound)
evidence. (MRI, PET can be further added to imaging modalities) They are rare; many are of
lobular type.
3. Male breast cancer
a. In men carcinomas tend to invade skin and chest wall earlier as there is much less amount of
surrounding breast tissue.
b. Matched by stage, prognosis is similar in men and women

Breast Sarcoma
Angiosarcoma
1. May occur spontaneously or
2. After radiation because of breast cancer.
3. It may also develop on the basis of chronic lymphedema of the upper arm following mastectomy =
Stewart-Treves syndrome

Tumors and premalignant conditions of oral mucosa

1) Leukoplakia
• white plaque on buccal mucosa, floor of the mouth, tongue, or hard palate
 • Cannot be removed by scraping
• tobacco use, alcohol, ill-fitting dentures, etc.
• 80%: epithelial proliferation without atypia
• 20%: dysplasia, cc-in-situ, or superficially invasive squamous cell cc
2) Erythroplakia
• Superficial erosions with dysplasia, cc-insitu, or superficially invasive squamous cell cc in 60% to
90% of the cases, Intense subepithelial inflammatory reaction with vascular dilatation accounts for
the red appearance of the lesion
3) Squamous papilloma
• benign epithelial tumour
• HPV 6 and 11
• Localization: on soft palate, tongue, and lips
• fingerlike projections of fibrovascular core and squamous epithelial proliferation
4) Invasive squamous cell cc
• 50- 60 years; men
• smoking, alcohol, sunlight (lower lip), chewing of betel nut in India
• floor of the mouth, tongue, hard palate, base of the tongue, lower lip
• Gross: ulcerated lip: may be fungated
• LM: a range from well-diff. keratinizing neoplasm (keratin pearls and intercellular bridges) to
anaplastic tumours
• Lymphatic metastases: submandibular and cervical nodes
• Haematogeneous metastases: lungs
• Best prognosis: lip cc
• Poorest: mouth floor and tongue base lesions (5-y survival rate: 30%)

Tumors of the Salivary gland

Adenomas -70%
1. Pleiomorphic adenoma (mixed tumour)
• Encapsulated, 2-6 cm, In 2% of cases: cc arises in pleiomorphic adenoma
• Removal: preservation of the facial nerve is difficult -> may recur locally
• LM: A mixture of epithelial and stromal elements; proliferation of myoepithelial and
ductal cells; the stroma is myxoid and may contain foci of cartilage
2. Papillary cystadenoma lymphomatosum (Warthin tumour)
• parotid gland, males, encapsulated, 2-5 cm
• tubular epithelial parenchyma, lymphoid stroma; tubules form papillary processes, which
localize in dilated cystic spaces
Adenocarcinomas - 30%
1) Mucoepidermoid carcinoma
• 40-60 ys of age, Grows slowly, up to 8 cm, parotid gland
• LM: variable mixture squamous cells, mucus-secreting cells and intermediate hybrids
• Low-grade variant: composed largely of mucus-secreting cells 5-y survival rate: 90 %
• High-grade variant: anaplastic squamous cells; 5-y survival rate: 40-60 %
2) Adenoid cystic carcinoma
• minor salivary glands, high tendency to infiltrate perineural spaces
• LM: uniform cells form cribriform structures. epithelial nests are separated by acellular spaces
which contain excess basement membrane material
• develop late, distant metastasis, 5-y survival rate: 60 %
3) Acinic cell carcinoma
• cells resembling the normal serous cells of salivary glands
 • Low-grade malignant tumour, 5-y survival rate is 90%
Tumors of the esophagus
a) Squamous cell cc -
• males over 50 ys of age.
• Etiology: Europe: smoking alcohol.China: deficiency of vitamins, fungal contamination of
foodstuffs, nitrites.
• Localization: 20% in the upper third, 50% in the middle third, 30% in the lower third.
• Gross: fungating , infiltrative, ulcerative.
• Lymph node metastasis:
a. upper third: cervical nodes,
b. middle third: mediastinal, paratracheal, and tracheobronchial nodes.
c. lower third: gastric and coeliac nodes. Fungating cc in the lower third of the oesophagus
• Hematogenous metastasis: lungs
• Stages: T1 - Lamina propria, submucosa.
a. T2 - muscularis propria.
b. T3 – adventitia.
c. T4 - adjacent structures.
• Clinical features:
a. Insidious onset, then progressive dysphagia.
b. Complications: esophagotracheal fistula, aspiration pneumonia, sepsis, invasion to
mediastinum, bleeding, extreme weight loss.
c. If lymph node metastasis is present at the time of surgical resection, 5-y survival rate is 5%.
b) Adenocarcinoma
• association with Barett’s oesophagus, May invade the adjacent cardia, LM: mucin producing
adenocc.
• Poor prognosis, comparable to squamous cc.

Epithelial tumors of the stomach

A) Benign – Polyps
1. 90% - hyperplastic (inflammatory) polyps
• frequently in chronic gastritis; non-neoplastic in nature.
• small, multiple, mostly in the antrum.
2. 10% - adenomatous polyps
• sessile or pedunculated, single, up to 4 cm, mostly in the antrum.
• LM: tubular/tubulovillous/villous adenoma
3. Gastric stromal cell tumours
• Rare. Leiomyomas, schwannomas, neurofibromas, lipomas.
Fungating tumorous mass

Gastric carcinoma
Risk factors of gastric cc, intestinal type
- Environmental factors: H. pylori-gastritis, Nitrites in food and water, Smoked
salted foods, pickled vegetables, chili peppers.
- Host factors: Chr. autoimmune gastritis with intestinal metaplasia, Gastric
adenomas, blood group A.
Risk factors for gastric cc, diffuse type are not well defined.
Favoured locations:50-60 % - lesser curvature.25 % - cardia.
Macroscopical types:
1. Expansive: fungating.
2. Infiltrative: flat.
3. ulcerated.
LM Ulcerated carcinoma
1. Expansive carcinomas derive from metaplastic intestinal cells resembling colonic
adenocc: adenocc of intestinal type  better prognosis.
2. Infiltrative carcinomas derive from gastric mucous cells:adenocc of diffuse type  bad prognosis.
• mucus secretion produces signet-ring conformation: signet-ring cc.
• Infiltrative cc-s often evoke a strong desmoplastic reaction →linitis plastica.
Pattern of spread
1. Directly to the serosa; local invasion to duodenum, pancreas, and retroperitoneum.
2. Peritoneal dissemination: carcinosis of peritoneum.
• Krukenberg tumor: signet-ring cc metastasis in both ovaries.
3. Lymphatic metastases: local lymph nodes.
• Virchow node: (left) supraclavicular lymph node metastasis for obscure reasons.
4. Haematogeneous metastases: liver → then lungs.
Postoperative tumor stage
• Early gastric cc: confined to mucosa or submucosa, ± lymph node metastasis
5-y survival rate: 80-90 %
• Advanced gastric cc: beyond the tunica muscularis, 5-y survival rate: 10 %.
Summary
Stomach
T1 Lamina propria , submucosa
T2 Muscularis propria , subserosa
T3 Penetrates serosa
T4 Adjacent structures
N1 Perigastric <3 cm from primary
N2 >3 cm from primary , along left gastric , common hepatic , splenic or celiac arteries.

Polyps of the small and large bowel, polyposis

Polyp = tumor-like protrusion of the intestinal mucosa.Types:

Hyperplastic polyps
• most common intestinal polyps, age 60, Discovered incidentally
• Gross: Small (<0.5 cm), rectum, single or multiple.
• LM: hyperplasia of colonic crypts.
• No malignant potential.

Hamartomatous (Hamartoma: tumor-like lesion, focal overgrowth of mature cells and tissues)
• Juvenile polyps:
o Rectum, young children (< 5 ys of age)
o Gross: Single, pedunculated, diameter: 1- 3 cm.
o LM: mucus-filled cystic glands and edematous, inflammed stroma.
o Cause rectal bleeding.

• Peutz-Jeghers polyps
o Autosomal-dominant. Multiple intestinal polyps, in the small intestine.
o Melanotic macules on the lips, buccal mucosa, palms.
o Risk of intussusceptions and cancer in the lungs, breast, uterus and pancreas.
o Morphology: PJ-polyp: Normal intestinal mucosal glands rich in goblet cells on an arborizing
network of connective tissue and smooth muscle.
Adenomas: sporadic
• age 60, incidence increase with age. asymptomatic or cause bleeding.
• Risk of malignant transformation.

1. Tubular (polypous) adenoma

• rectosigmoid .single or multiple, pedunculated <1 cm,.
• LM: tubular glands lined by dysplastic columnar epithelium
• >2.5 cm: usually with areas of intramucosal cc.
2. Villous adenoma:
• rectum. Solitary, sessile, up to 10 cm.
• Composed of villi =fingerlike protrusions lined with dysplastic columnar
epithelium.
• Adenocc arises VA>4 cm in diameter.
Villous adenoma with malignant
• May hypersecrete protein and K+ → hypoproteinemia and hypokalemia. transformation
3. Tubulovillous adenoma:
• Some tubular adenomas contain villous parts. If the villous components comprise > 40% of the total
→ tubulovillous adenoma. may be sessile or pedunculated.
Adenomas : Familial:
• Familial adenomatous polyposis (FAP)
• Variants of FAP: Gardner sy, Turcot sy
• Peutz-Jeghers sy.

Colorectal carcinoma
• The 3rd most common carcinoma in industrialized countries.
Pathogenesis:
Dietary factors:
• Low-fiber food, High calories, High fat and refined sugar, decreased stool bulk, Prolonged fecal
transit time, Altered bacterial flora produce carcinogens. All stagnate in the colon.
Genetic changes:
a. 85%: APC/β-catenin pathway adenoma →cc.
b. 15%: Nonpolyposis colorectal cancer (NPCC) pathway.
a. APC/β-catenin pathway: normal colon→ adenoma → cc.
Normal colon:
• Loss of Adenomatous Polyposis Coli (APC) gene + β-catenin mutation: ↓cell adhesion and ↑
proliferation. Adenoma: Mutation of k-ras, Loss of SMAD4, Loss of p53, Activation of telomerase 
Invasive cc: Additional mutations, Gross chromosomal alterations→ Invasive carcinoma.
b. NPCC pathway:
• Microsatellites are fragments of repeat sequences which misalign during DNA replication, corrected
by the DNA mismatch repair genes. Mutations in these genes →alteration of microsatellites →
→invasive colorectal cc.
Morphology:
Localization:
• Left side, 65%
• Transverse colon, 10%
• Right side, 25%
Gross:
• Left side: Annular napkin-ring lesions, ulcerated → obstruction.
• Right side: fungating, obstruction is uncommon.
Spread:
 • The tumors eventually penetrate the wall; infiltrate the subserosa, and then the serosal.
• Metastases
o Lymphatic: subserosal lymph nodes
o Hematogeneous: liver
o Transcelomic: carcinosis of peritoneum.
LM:
• 95%: mucinous adenocarcinoma.Tumors arising close to the anus: adenosquamous cc, Rare
variant: small cell undifferentiated cc.
Adenocc-s due to microsatellite instability:
• right colon. mucinous adenocc-s, Are infiltrated by ly-s

Clinical features: 60 to 70 ys. asymptomatic or produce occult bleeding, changes in bowel habit, intestinal
obstruction, weakness of obscure origin, or unexplained iron deficiency anemia.

TNM Prognosis:
T1 - Tu invades submucosa.
T2 - Tu infiltrates the muscularis propria.
T3 - Tu infiltrates the subserosa.
T4 - Tu directly invades other organs or structures.

5-y survival rate:

T2: 70%, T3: 20%, Distant metastases: <10%

Carcinoid tumors, lymphomas + stromal tumors of the GI tract

Carcinoid tumors
• Location:
o appendix, 40%
o colon, 30%
o ileum, 25%
o stomach, 5%
• Arises from mucosal neuroendocrine APUD cells, cells are cuboidal contain neuroendocrine granules.
Form intramucosal or submucosal nodules (95% are < 2 cm).
• Carcinoid of appendix or rectum: semimalignant.

Clinical features
• asymptomatic or obstruction or bleeding.
• May produce serotonin→ Carcinoid sy if hepatic metastases are present:
o Intestinal hypermotility with diarrhea and cramps.
o Facial flushing.
o Bronchospasm.
o Stenosis of the valves of pulmonary artery.
o 5-HIAA in the urine (5-hydroxyindoleacetic acid).

5) Gastrointestinal lymphoma
• No evidence of liver, spleen, mediastinal lymph node, or bone marrow involvement at time of the dg.
• Conditions predisposing to primary GI lymphoma: H. pylori-gastritis, celiac disease, AIDS.
• 3 Types:
1. MALToma: low grade malignant B cell lymphoma originating from the mucosa-associated
lymphoid tissue.
 2. Diffuse large B cell lymphoma.
3. T cell lymphoma.

6) Mesenchymal tumors
• Lipomas; in the submucosa of small intestine or colon.
• Gastrointestinal stromal tumors: LM: spindle or epitheloid cells, c-KIT positive.
• Leiomyoma and leiomyosarcoma.

Clinical features: asymptomatic or may cause mucosal ulceration with bleeding, or intussusception.

Tumors of the kidney

Adults: Malignant (87%): Renal Cell cc., Urothelial Cell cc.
Benign (13%): Oncocytoma, Angiomyolipoma.
Children: Malignant: Nephroblastoma.

Renal cell carcinoma (RCC)

1. Derives from renal tubular cells. The most common renal tumor.
2. Risk factors: smoking. Male : Female ratio - 1.5:1. 60 years.
3. Types: clear cell - most frequent, papillary, chromophobe.
4. Morphology: Spherical mass, 3-15 cm in diameter
Types:
1) Clear cell: Bright yellow to gray-white tissue. empty cytoplasm
2) Papillary. Papillary structure. LM: Small cells with basophilic nuclei, foaming ma-s and psammoma
bodies in the stroma.
3) Chromophobe RCC: LM: pale eosinophilic cytoplasm, perinuclear halo.

Tumor stage: T1< 7cm – limited to kidney.

T2 >7 cm – limited to kidney.
T3 - perinephric and/or renal vein invasion.
T4 – beyond Gerota fascia. (renal fascia)
Metastases: Lymphatic  paraaortic nodes.
Hematogenous  lung bones, liver etc.

Clinical features: symptoms:

Microhematuria - 90%.
Costovertebral pain, palpable mass, fever, malaise, weakness, weight loss.
tendency to metastasize widely before giving rise to any local symptoms. On average 45% survive 5 years.

Paraneoplastic sy:
erythropoietin  polycythemia.
parathyroid hormone  hypercalcemia.
renin  hypertension.

Familial RCC:
2% of RCCs. Autosomal dominant. Multiple bilateral RCCs in younger adults.
2 variants: Clear cell, Papillary.

Urothelial Cell Carcinoma (UCC) of the renal pelvis and ureter

• Earlier manifestation due to hematuria, renal colics, UTO.
• Prognosis: low grade UCCs (5 years survival rate: 70%).
high grade UCCs (5 years survival rate: 10%).
• UCC of ureter  hydronephrosis.

Oncocytoma (benign):
Derives from intercalated cells of collecting ducts, encapsulated. brown + central stellate scar. Diameter up
to 12 cm. LM: eosinophilic granular cytoplasm.
May be difficult to differentiate from chromophobe RCC.

Angiomyolipoma (benign):
Composed of fat cells, vessels and SMCs. May be large up to 20cm.

Nephroblastoma (Wilm's tumor)

Composed of cells found in the fetal metanephros mainly sporadic. Deletion of tumor suppressor genes
WT1 and WT2. usually one sided.
Morphology: Gross: Soft, large, well - circumscribed mass.
LM: blastema cells: resembling to fetal mesenchyme.
stromal cells: spindle cell resembling fetal renal CT
epithelial cells: from Tubules, resembling those in metanephros.
Clinical features:
• diagnosed between 2-5 years of age, Large abdominal mass, Hematuria, pain in the abdomen,
obstruction of bowels, appearance of hypertension.
• Chemo + nephrectomy  95% cure. Therapy-resistant patients have already anaplastic wilms (5%).

Tumors of the urinary collecting system and the urinary bladder.

Features:
1. 50-80 ys of age
2. Risk factors: cigarette smoking, industrial carcinogens: naphtylamine, benzidine, etc, Schistosoma
haematobium infection (bilharzia) in Egypt
3. May be multifocal
Classification
a. 90%: urothelial cell cc (UCC)
b. 10%: squamous cell cc or adenocc
Precursor lesions
a. Non-invasive papillary UCC (pTa): exophytic, well-differentiated, low grade cytologic atypia
b. Non-invasive flat UCC (pTis): in situ cc, high grade atypia; multifocal
Invasive lesions
a. 70% - cauliflower-like: papillary UCC, well-differentiated, low grade cytologic atypia;
b. 30% - ulcerated: non-papillary UCC, poorly differentiated, high grade atypia, deeply invasive
Other types:
Squamous cell cc: on the basis of Schistosoma-induced chronic cystitis
Adenocc (CK20 positive): resembles to colonic cc, may derive from urachal remnants

Tumour stage
pTa, pTis: intraepithelial tumour
pT1: invasion of the submucosa
pT2: invasion of the detrusor muscles
pT3: invasion of the perivesical fat
pT4: invasion of adjacent structures: prostate, uterus, vagina

Clinical features
a. Painless haematuria, sometimes with frequency and urgency
 b. Superficial UCCs: usually low grade tumours; treated with transurethral resection; recurrences are
frequent and may exhibit a higher grade; good prognosis
c. Muscle invasive UCCs: high-grade, treated with radical cystectomy; the overall prognosis is poor

Tumors of the lung

Pathogenesis: tobacco smoking, asbestos, air pollution, Radiation, occupational inhaled substances (nickel)
General features
• 95% of primary lung tumors arise from the bronchial epithelium. (bronchogenic carcinoma)
• starts as small mucosal lesions, firm, grey white
Types of lung cc.:
1. small cell lung carcinoma (20%-25%)
2. non-small cell carcinomas (70%-75%)
a. squamous cell carcinoma (25%-40%)!
b. adenocarcinoma (25%-40%) !
i. not otherwise specified (NOS)
ii. bronchioloalveolar carcinoma (BAC)
c. large cell carcinoma (10%-)
3. combined patterns (5%-10%)
a. squamous cell cc + adenocarcinoma
b. squamous cell cc + small cell carcinoma

1. small cell lung carcinoma (20%-25%) (neuroendocrine cells)

 best treated with chemotherapy ± irradiation, men, smoking, centrally located ,give metastis
early, worse prognosis,
 specific feature: neurosecretory granules in the cytoplasm. chromogranine +

2. non-small cell carcinomas (70%-75%) - less metastatic, no chemotherapy, best treated with surgery
subtypes:
a. squamous cell carcinoma (25%-40%)!
b. adenocarcinoma (25%-40%) !
i. not otherwise specified (NOS)
ii. bronchioloalveolar carcinoma (BAC)
c. large cell carcinoma (10%-)

2.1.Squamous cell carcinoma(bronchial epithelium)

respond poorly to chemotherapy. Best treated with surgery, men, smoking, late symptoms, arise in the
central bronchi, dissemination outside the thorax occurs late. histology: CK17+

atypical adenomatous hyperplasia (AAH) – precursor lesion of adenocarcinoma. proliferation of type 2

pneumocytes with atypia
CK17+
2.2.a Adenocarcinoma not otherwise specified NOS
Man and women, no relation to smoking, peripherally located, grow slowly
Histological type: acinar, papillary, solid, mixed subtypes

2.2.b bronchioloalveolar carcinoma (BAC)

Man and women, no relation to smoking, arising in the terminal bronchioloalveolar regions
Tumor cells grow along preexisting structures such as bronchioli and alveoli, structure is preserved
prognosis good after resection imunohistochemistry CK7+, thyroid transcription factor TTF1+

2.3 large cell carcinoma:

Lack of cytological differentiation, poor prognosis, spread distant early.

3. combined patterns: squamous cell carcinoma and adenocarcinoma or small cell carcinoma
Bronchogenic carcinoma TNM, factors determining stage:
1. size of tumor, involvement of main bronchus, location to distal carina, involvement of pleura, spreading
to chest wall, diaphragm, mediastinum, heart, large vessels.
Spread of bronchogenic carcinoma
2. lymph node metastasis: regional peribronchial, hilar mediastinal, Virchow node: supraclavicular node.
Lymphangitis carcinomatosa
3. distant metastasis bone, brain, suprarenal glands, liver

consequence of local spread

1. vena caval syndrome: the tumor may compress or infiltrate the superior vena cava
2. Pancoast tumors apical tumors apical tumors

Pancoast syndrome: may invade the brachial or cervical sym. plexus to cause severe pain in the
distribution of the ulnar nerve
Horner triad: ipsilateral enophthalmos, ptosis, miosis and anhidrosis

Clinical: silent, insidious lesions

a. cough, weight loss, chest pain, dyspnoe hemoptoe
b. death: respiratory insufficiency, infection, metastasis

prognosis:
a. combined overall 5 year survival rate is 14%
b. small surgically resectable tumors 45% 5 years survival
c. small cell cc almost always metastasize by the time of diagnosis
Paraneoplastic syndromes:
1. hypercalcemia (PTH ) most often associated with squamous cell carcinoma
2. hematologic symptoms: migratory thrombophlebitis, DIC most often associated with adenocarinoma
Mostly with small cell cc
3. Cushing syndrome (ACTH)
4. diabetes insipidus, (inappropriate secretion of ADH)
5. clubbing of fingers due to hypertrophic osteoarthropathy
6. hypocalcemia calcitonin

Other primary lesions

1. bronchial carcinoid
a. rare, characterized by neuroendocrine differentiation, surgical resection is curable in >90%
of cases.
b. atypical carcinoid: minority. more agressive , local invasion distant metastasis
c. typical carcinoid:
i. gross intrabrochial polypoid masses < 4 cm=d
ii. histology: composed of uniform small, round cells with neurosecretory granules
iii. immunohistochemistry: chromogranin+
iv. rarely induce carcinoid syndrome
2. Hamartoma: benign nodular tumor-like lesion composed of matured tissue

Metastatic tumours in the lung. primary sites:

Tumors drained by caval system: liver, kidneys etc
Laryngeal tumors
Vocal cord nodules (polyp)
• singers nodules, inflammatory in origin
• often on true vocal cords, fibrous tissue covered by stratified squamous epithelium

Laryngeal papilloma
• benign tumor, appear on the true vocal cords, HPV 6 and 11
• soft raspberry-like tumor less than 1 cm
• fingerlike projections of fibrovascular core covered by stratified squamous epithelium
• trauma may cause hemoptysis
• single in adults, multiple: juvenile laryngeal papillomatosis, spontanously regress

Carcinoma of Larynx
• > 40 ys. male: female, 7:1
• smoking, alcohol, asbestos exposure
• clinical :persistent hoarseness, pain, dysphagia, hemoptsis
• localization:
a. vocal cord carcinoma (75%)
b. supraglottic carcinoma (25-40%) 40%)
c. subglottic carcinoma (5%).
• types:
a. intrinsic confined to the larynx
b. extrinsic: arise or extends outside larynx
• Gross: pearly gray, wrinkled plaque. ulceration and fungation follows
• histology: 95% sqamous cell cc
• prognosis depends on location
a. vocal cord: better
- immobility, symptoms early
- sparse lymphatic supply
- spread beyond the larynx is rare
b. suppraglottic
- rich in lymphatics
- 1/3 already regional cervical lymph node metastasis at the time of diagnosis
c. subglottic worse, silent for longer period of time, presents as advanced disease presents as
• cause of death in one third of cases: infection, metastasis cachexia

Tumours of the gallbladder and the extrahepatic bile ducts.

Carcinoma of the gallbladder

• 7th decade, Predisposing factor: chronic calculous cholecystitis
• 2 patterns of growth: Infiltrating and Exophytic. adenocarcinoma; may be desmoplastic (rich in stroma)
• By the time of the dg: Most have spread locally and invaded the liver, cystic duct, adjacent bile
ducts, and the peritoneum
• Metastases in portal lymph nodes and liver
Outcome
• Symptoms are those of chronic cholecystitis (Recurrent attacks of steady or colicky pain, Often intolerance of fatty foods)
• Dg is usually late
• 5-yr-survival rate is a mere 1%
Carcinoma of the extrahepatic bile ducts
• elderly people, No significant association between previous history choledocholithiasis and cancer
Predisposing factors
• Primary sclerosing cholangitis
• Idiopathic inflammatory bowel disease
• Clonorchis sinensis (fluke) infection in Asia
Localization
• At the bifurcation of the right and left hepatic duct (Klatskin-tumour)
• In the common bile duct
• In the ampulla of Vater
Morphology
• Gross - Small; diffusely infiltrative or exophytic polypoid lesion
• LM - Desmoplastic adenocarcinoma, mucin secretion may be present
Clinical features
• Insidiously developing, painless jaundice
• Metastases in the portal lymph nodes
• Haematogeneous metastases in the liver
• Poor prognosis: mean survival 6-18 mo

Carcinoma of the pancreas. Islet cell tumors of the pancreas.

Carcinoma of the pancreas

• invasive ductal adenocc, Precursor lesion: Pancreatic Intraepithelial Neoplasm (PanIN)
• Smokers, 60-70 y
• Localization: 60% in the head,15% in the body, 5% in the tail, 20% diffuse
• Gross: hard, poor-defined mass. LM: Desmoplastic adenocarcinoma
• Spread - Highly invasive
• Continuous: peritoneum, stomach, lesser omentum
• Lymphatic: peripancreatic lymph nodes
• Haematogeneous: liver, bones, lungs
• (perineural spread is common – pain
• Clinical features: silent until impinge upon adjacent organs.Cc of the head: painless jaundice, Cc of
the tail ± migratory superficial thrombophlebitis (Trousseau’s sign)
• Poor prognosis: 5-y survival rate 1-3%

Cystic tumours
• Rare, women > 65, Painless, slow-growing masses
• Serous/ mucinous cystadenomas/carcinomas

Islet cell tumours

• Rare, arising from the pancreas or from the peripancreatic tissue
• Most produce pancreatic hormones, some are nonfunctional
Insulinoma
• Solitary, < 20 mm, encapsulated, 90% adenoma; 10% adenocarcinoma
• Hypoglycaemic attacks precipitated by fasting or exercise
Gastrinoma (Zollinger-Ellison sy)
• Locations: pancreas, peripancreatic region, wall of duodenum
• > half of the tumours are locally invasive or have already metastasized
• Hypergastrinaemia ⇒ extreme gastric acid secretion ⇒ multiple peptic ulcers in the stomach and
duodenum
 • May be part of MEN I

Tumors of the liver.

Benign tumor
1.1. Focal nodular hyperplasia
1. oral contraceptives, non-capsulated with central stellate scar

1.2. Adenoma
1. oral contraceptives, Benign tumor of hepatocytes, up to 30 cm portal tracts and bile ducts are absent
2. May rupture with massive hemorrhage

1.3. Cavernous hemangioma – no biopsy due to high risk of intraabdominal bleeding.

Malignant tumor
2.1. Hepatocellular carcinoma
1. 90% of primary liver cc. Middle to late decades of life

Risk factors: Cirrhosis, Hepatitis (HBV, HCV), Fungal aflatoxin, Alcohol, α1AT deficiency,
hemochromatosis
Morphology: unifocal / multifocal / diffuse LM: Trabecular , Acinar, Poorly differentiated
Proving hepatocellular origin: Bile formation, α fetoprotein +, PAS +
Clinically:
1. Survival is poor, death within 6 months
2. Intrahepatic spread and vascular invasion are common
3. Metastasis to portal lymph nodes, and lung

Fibrolamellar variant of hepatocellular cc

1. In the absence of risk factors, Age: 20-40 ys, better prognosis

2.2. Cholangiocellular carcinoma

Arises from the intrahepatic biliary tree mostly without risk factors.
Morphology: unifocal / multifocal / diffuse, Pale, do not secrete bile; firm. LM: adenocarcinoma
Clinically: Prognosis is poor
Metastasis to portal lymph nodes, and lung

Other malignant tuomors:

2.3. Hepatoblastoma – rare progressive childhood tumor
2.4 Angiosarcoma – arsen and Thorotrast are risk factors

Secondary
Most liver carcinomas are metastatic, They are usually multiple
Primary sites: colon, stomach, Pancreas, Lung, etc
 Tumours of the pituitary.
Pituitary adenomas
Types:
Nonfunctional - cause hypopituitarism, by destroying the native parenchyma
Functional –
1. Hormones commonly produced : Prolactin (PRL) – mainly, somatotroph, (GH), adrenocorticotropic
hormone (ACTH)
2. Hormones rarely produced: thyroid-stimulating hormone (TSH), follicle-stimulating-hormone (FSH),
luteinizing hormone (LH).
3. Most adenomas arise from a single somatic cell and usually produce a single hormone..
Morphology: Microadenomas <10mm in diameter. Macroadenomas >10mm in diameter.
Usually solitary, Larger adenomas may compress their surroundings and infiltrate adjacent structures LM:
monomorphous cells. granules in the cytoplasm

Prolactinoma – the most common type, representing 30% of all anterior lobe adenomas.
1. physiologic - occurs in pregnancy
2. pathologic hyperprolactinemia
a. lactotroph hyperplasia
b. damage to the dopaminergic neurons of the hypothalamus
c. pituitary stalk section (e.g.head trauma)
d. drugs that block dopamine receptors on lactotroph cells
3. Stalk Effect - mass that disturbss the normal inhibitory influence of the hypothalamus on PRL secretion,
4. macroadenoma.
5. The serum prolactin concentration is directly proportional to the size of the adenoma.
6. Clinical features in women: amenorrhea, galactorrhea, loss of libido & infertility
7. in older women and male the tumor may reach a considerable size before discovery

Somatotroph-cell adenoma – GH producing tumor; the 2nd most common adenoma.

1. excess GH with associated acromegaly and gigantism
2. clinical features:
a. Gigantism - before the closure of the epiphyses  generalized increase in body size with long
arms and legs
b. Acromegaly - after the closures of the epiphyses  enlargement of head, hands, feet, jaw,
tongue and soft tissues
3. macro: macroadenoma. micro: acidophilic or chromophobic granulated
4. Consequence: local mass effect
a. Local mass effect – enlargement of sella turcica, visual field abnormalities, increased intracranial
pressure (headache, nausea, vomiting), suppression of hormone production by non-tumorous
hypophysis.
5. Possible therapy: trans-sphenoidal surgical removal, radiation therapy, GH reducing drugs.

Corticotroph tumors –
1. macro: microadenomas, micro: basophilic or chromophobic.
2. chromophobic tumors are often larger and cause local mass effect
3. clinical features - Excess ACTH hypercortisolism, Cushing syndrome

Other tumors:
1. Thyrotroph (TSH producing) adenoma - 1% of all pituitary adenomas rare cause of hyperthyroidism
2. gonadotroph (LH & FSH) adenoma –
a. Clinical features:
 i. Typically neurological symptoms, impaired vision, headache, pituitary apoplexy.
ii. Hormone deficiencies can also be found e.g. decresed LH secretion
iii. in men the serum testosterone is low resulting in decreased energy and libido
iv. in premenopausal women there is amenorrhea
3. Other functioning adenomas - Pituitary adenomas may elaborate more than one hormone
a. mixed adenomas:: more than one cell population is present
b. other cases:: a single cell type is capable of synthetizing more than one hormone
4. non secretory pituitary adenomas = null cell adenomas - 20% of cases. typical presentation is local
mass effect.

5. Pituitary carcinoma – are quite rare, most are nonfunctional, diagnosis requires the demonstration of
metastases.

Pathology of the adrenal medulla.

Pheochromocytoma - uncommon neoplasm.

• 85% arise within adrenal medulla, rest within extra-adrenal paraganglion system (paragangliomas)
• malignant in 2%-10% of adrenal lesions, 20-40% of extraadrenal lesions
• May occur: sporadically (90%) in adulthood, bilateral lesions: in 10-% of cases
• in association with familial syndromes like MEN II, III in childhood. bilateral : in 70% of the cases
Macro: size vary 1gr-4kg, pale gray or brown, hemorrhage, necrosis and cystic change, highly vascular
Micro: chromaffin cells forms small nests "Zellballen"granules contain catacholamines, chromogranin and
synaptophysin positivity
diagnosis: based exclusively on the presence of metastases. metastasis to lymph nodes, liver, lungs, bone
Clinical Dg: increased urinary excretion of free catecholamines and their metabolites
Symptoms: hypertension. tachycadia, palpitation, headache, sweating and tremor.

Neuroblastoma
Neuroblastoma is the most common extracranial solid tumor of childhood. originates in the adrenal medulla
or anywhere in the sympathetic nervous system. Most neuroblastomas are sporadic, although familial cases
occur. Metastases, appear early and widely. In addition to local infiltration and lymph node spread, there is a
pronounced tendency to spread through the bloodstream to involve the liver, lungs, and bones.

Tumors of the thyroid gland.

Benign tumors
Solitary thyroid nodules – common,. Higher incidence in endemic goiterous regions. more common in
women .the incidence ↑ with age.
Clues to the nature of thyroid nodules: neoplastic when:
• solitary nodules, below age 40, in men, history of head and neck irradiation
• hot nodules are likely to be benign

Thyroid adenomas
1. Solitary lesions. , malignant transformation is rare
Morphology:well demarcated, tumor compresses the surrounding gland, varied histology patterns
Clinical features: painless mass . usually cold nodules., 10% of cold nodules are malignant

Thyroid carcinoma
female preponderance, 90-95% are well differentiated, relatively not aggressive
Risk factors: Childhood head & neck ionizing radiation, Nodular goiter, Hashimoto thyroiditis.
1. Papillary carcinoma
1. 75-85% of all thyroid cancers.
2. radiation related thyroid cancers are almost always papillary
Morphology: solitary or multifocal infiltrative lesions
Micro: hypochromatic empty nuclei (Orphan Annie eyes) and nuclear grooves, psammoma bodies
Clinically:
1. in 50% of the cases there are cervical lymph node metastases at the time of the diagnosis
2. distant metastases are rare at presentation (5%)
3. 20-yr-survival is 90%

2. Folliclar Carcinoma
Represents 10-20% of thyroid malignancies, More common in areas of iodine deficiency.
Morphology: single nodule well circumscribed or infiltrative
Demonstration of vascular invasion is the diagnostic feature!
Spread: Metastases are mostly hematogeneos bones, lung and liver.

3. Medullary Carcinoma
1. 80% of cases are sporadic, 20% of cases are related to MEN IIa or IIb, neuroendocrine neoplasm
2. Develops from the calcitonin producing parafollicular cells (C cells).
3. Tumor cells produce calcitonin. Stroma contains amyloid

4. Anaplastic carcinoma
aggressive, undifferentiated tumors, Higher incidence in endemic goiter areas.
Prognosis: Dissemination occurs early wide local spread. cause of death is usually related to the local
aggressive growth in the neck region (trachea compression).

Multiple endocrine neoplasia (MEN).

Familial, autosomal dominant disorders

1. MEN-I (Werner’s syndrome) –pancreas, pituitary & parathyroid glands (“3Ps”).
a. Parathyroid hyperplasia or adenoma (95%) → hypercalcemia & kidney stones.
b. Pancreatic islet cell lesions: adenoma, carcinoma, hyperplasia.
• Zollinger-Ellison syndrome)→ recurrent peptic ulcers in gastrinoma.
• insulinoma → recurrent hypoglycemia.
c. Pituitary adenomas (66%) – usually non-functional.

2. MEN-IIa (Sipple’s syndrome) – medullary thyroid carcinoma-pheochromocytoma syndrome:

a. Medullary thyroid cc (100%) C-cell hyperplasia → producing calcitonin.
b. Pheochromocytoma (50%) – usually bilateral and extra-adrenal. Most lesions are benign.
c. Parathyroid hyperplasia or adenoma (25%).

3. MEN-IIb or III (William syndrome) –

a. similar to IIa, with additional features of neuromas or ganglioneuromas.
b. May be accompanied by marfanoid body habitus, and parathyroid hyperplasia.
c. mean survival shorter than MEN IIa (three to four decades).

Tumors of the bone.

1. Bone forming tumors

Osteoma - small benign sessile tumor, attached to the bone surface. made of dense sclerotic well-formed
bone. localized in the skull & facial bones as a small protruding lesion → cosmetic disturbances.

Osteoid osteoma - benign painful tumor. less than 2cm. near the proximal ends of tibia and femur.

Osteosarcoma.
malignant tumor cells form osteoid. Excluding multiple myeloma, Osteosarcoma is the most common
primary bone tumor. common in males.
Forms
1. Primary Osteosarcoma –age <20, no previous bone disease. localizes in long bones, Common around
the knee. Better prognosis.
2. Secondary Osteosarcoma –older people. Arises from pre-existing bone pathology as Paget disease or
radiation exposure. involves flat bones as jaws & pelvis and long bones. Highly aggressive neoplasm
Worse prognosis.

Pathogenesis –
Genetic influence Rb-gene mutation p53 mutation.
Constitutional influence – since it develops during active bone growth.
Environmental influence – mainly irradiation.

Clinical features - Focal pain, Tenderness, Swelling.

Gross appearance - grayish-white, invasive & destructive, with necrosis & hemorrhages.
X ray - penetrates the cortical area elevates the periosteum leading to formation of Codman’ s triangle.
Metastasis - to the lung.
Treatment - radiotherapy, chemotherapy & surgery → 5-year survival of 60%.

2. Cartilage forming tumors

Osteochrondroma (exostosis) -
a. common benign lesion, mushroom shaped lateral protrusion capped by hylaline cartilage
b. Localization - long bones, femur.

Chrondroma (enchondroma)
a. Benign tumor composed of matured hyaline cartilage.
b. single or multiple, in small bones of hands and feet.
c. X-ray: well circumscribed translucent and radiolucent lesion with sclerotic rim

Chondrosarcoma
a. malignant tumor, neoplastic mesenchymal cells produce cartilaginous matrix.
b. Primary: 75% of cases. Secondary: due to enchondromas or osteochondromas.
c. Localization - central skeleton, around the knee.
d. Metastases - lung.
e. morphology – translucent tumor, erodes the cortex. necrosis spotty calcifications
f. grades:I-III
g. Clinical features – pain.
h. Prognosis – 5 year survival. Grade I – 90%, Grade III – 43%

3. Other special tumors

Ewing sarcoma
1.rare, aggressive, malignant tumor composed of immature mesenchymal cells of the bone marrow, that
starts in the medullary cavity. Age 10-15 years.
 2.chromosomal translocation of Ewing sarcoma gene.
3.Localization: long bones. LM: reactive bone is formed in an onionskin pattern.
4.Immunohistochemistry - CD99+ (MIC2) – enables to differentiate from other round cells tumors
(lymphoma and neuroblastoma).
5.Clinically – initiates inflammation.
6.Metastasis - to lung & brain
7.radiation therapy, chemotherapy, surgery. 5 year survival rate = 75%.

Giant cells tumor of the bone (osteoclastoma).

1. benign locally aggressive tumor, affect long bones.
2. Localization - 50% in knees.
3. Gross appearance - Dark brown tumor with hemorrhage and necrosis. Histologically - neoplastic spindle
stromal cells, multinucleated giant cells, hemorrhage, hemosiderin.
4. Metastasis – rarely metastasize to the lung. Prognosis - 40-60% recur.

Fibrous dysplasia
1. tumor like lesion. The normal trabecular bone is replaced by proliferating fibrous tissue.
2.Clinically – pathologic fractures, bone deformity. Rarely, malignant transformation occur
3.Histologically – dense fibrous tissue form Chinese characters.

Metastases to bone
The most common originating sites for bone metastasis in descending order of frequency: prostate, breast,
lung, kidney, adrenal & thyroid.

Tumors of central nervous system.

Tumors of the brain, dura and intracranial nerves (classification according to cell origin)

Glia cell: Primitive Lymphoid cell Nerve

Arachnoidal
Astrocytoma neuroectodermal sheath cell
cell
Glioblastoma cell
Oligodendroglioma
Ependymoma

Gliomas Medulloblastoma Lymphoma Meningioma Schwannoma

Malignant Benign

• Gliomas
o Are graded Grade I–IV (very well, well, moderately and poorly differentiated)
o All positive for GFAP (glial fibrillary acid protein)

Clinical signs and symptoms of brain tumors:

Space-occupying lesions that act on adjacent brain causing
1. compression and/or destruction, depending on location:
a. Loss of motor functions – paralysis
b. Loss of sensory functions
 c. Stimulation of certain parts of brain – epileptic fits
2. peritumoral brain edema
3. Obstruction of CSF flow → Hydrocephalus
4. Brain tumors DO NOT metastasize – exception, medulloblastoma

Astrocytoma
Features: Develop in children and adults. Subtypes:

In children: Pilocytic astrocytoma (Gr I)

1. Slowly growing tumor
2. Most often located in the cerebellum
3. Gross – cystic and well circumscribed
4. LM – composed of very well differentiated fibrillary astrocytes (Grade I), often showing Rosenthal
fibers
5. Most tumors can be resected completely → good prognosis

Astrocytomas in adults
1. Poorly defined, gray-white tumors
2. Mostly in the cerebral hemispheres
3. Molecular genetics: inactivation of the p53 gene and over-expression of the PDGF-A and its receptor

Well-differentiated astrocytomas (Gr II)

1. Peak age: 35-40 ys
2. Composed of well-differentiated neoplastic astrocytes
3. Subtypes:
a. Fibrillary A :mild nuclear pleiomorphism, a meshwork of GFAP+ fibrillary processes
b. Gemistocytic A: excentrically placed nuclei, the cytoplasm is glassy pink
4. Intrinsic tendency to transfrom into anaplastic astrocytoma glioblastoma (inactivation of several
tumour suppr. genes: RB, p16/CDKNZA, etc.)
5. Mean survival with surgery and chemoth: 6-8 ys

Anaplastic astrocytoma (Grade III): dense cellularity, increase in nuclear pleiomorphism, mitoses

Glioblastoma (Grade IV)

Features:
1. Most common glioma
2. Peak incidence is 45-60 years
3. Arises de novo, or from progression from astrocytoma
4. Highly invasive;

Morphology:
Gross:
1. Heterogeneous cut surface due to areas of necrosis, hemorrhage, cystic Glioblastoma. Distortion of the
temporal WM and thalamus, note foci of
change necrosis and haemorrhage
2. May extend to other side of the brain
3. Surrounded by peritumoral edema
4. Midline structures are shifted contralaterally
5. Butterfly pattern – continuous spread through the corpus callosum
LM:
1. Hypercellularity
 2. Frank anaplasia (Anaplastic astrocytes)
3. Numerous mitoses
4. Necrotic foci Surrounded by pallisading tumor cells
5. Vascular proliferation frequently forming glomeruloid structures
Prognosis Extremely bad – mean survival is 1 year
Glioblastoma. Butterfly pattern of
spread through the corpus callosum
Oligodendroglioma (Grade II)
Features:
1. Uncommon cerebral tumor of adults (peak incidence at 40-60 years)
2. Molecular genetics: loss of heterozygosity for chromosomes 1p and 19q
Morphology:
Gross:
1. Arise in the cerebral hemispheres; relatively well-circumscribed
2. Calcification is common
LM: composed of neoplastic oligodendrocytes, the small, round nuclei are surrounded by a clear halo of
cytoplasm; low mitotic rate; Grade II
Prognosis 5 year survival rate following surgery, chemotherapy and radiotherapy = 75%

Ependymoma (Gr II)

Features:
1. Uncommon tumor, more often in children than in adults
2. Derived from ependymal cells lining the ventricles and spinal canal
3. In the brain, tumors usually occur near the fourth ventricle → secondary hydrocephalus
4. In the spinal cord, the tumor originates from the cauda equina
5. Prognosis depends on the respectability; recurrence is likely

Medulloblastoma (Gr IV)

Features:
1. Childhood tumor – peak at 7 years of age
2. Usually in the vermis of cerebellum
3. Metastases via the CSF to the spinal cord
4. Prognosis depends on the resectability
5. Responsive to postoperative chemotherapy and radiotherapy
6. 5 year survival = 70%
LM:
1. densely packed small “blue” cells (scant cytoplasm → see only nucleus) arranged into solid sheets
2. Frequent mitosis and necrosis
3. Grade IV

Metastases
1. metastatic carcinomas account for approximately 50% of intracranial tumors
2. 5 most common primary sites:
a. lungs cc
b. breast cc
c. malignant melanoma
d. renal cell cc of kidney
e. GI tract cc

Benign tumors
Meningioma
Features:
 1. Solitary tumor
2. Peak age – 50-70 years
3. More common in women (don’t know why)
4. attached to the dura, most often in the parasagittal region along the falx cerebri → compression of
the brain from outside
5. LM – meningothelial cells form whorls often with central calcification (psammoma bodies)
• Sheets of fusiform cells
6. Prognosis is excellent

Schwannoma
Features:
1. Benign tumor at the cerebellopontine angle, attached to the vestibular branch of the 8th cranial
nerve (acoustic neurinoma)
2. LM – mixture of two growth patterns:
• Cellular areas of elongated cells (Antoni A)
• Alternate with loose, myxoid regions (Antoni B)
3. Symptoms – from compression of the nerve → tinnitus, hearing loss

Tumors of the peripheral nervous system and leptomeninx

General:
1. Tumors may arise from schwann cells or fibroblasts ( neurofibroma – containing both schwann
cells and fibroblasts).
2. Immunohistochemistry shows S100 positivity.
3. Affect young patients with neurofibromatosis type I (Von-Recklinghausen disease) and adults.

1. Schwannoma – benign tumor of Schwann cells.

Main types:
a. Acoustic neurinoma – occurs in the vestibular branch of VIII at the pontocerebellar angle.
b.Spinal tumor – mainly in dorsal roots. It may extend through the vertebral foramen and acquire a
dumbbell configuration.
The tumor is well circumscribed & encapsulated, attached to the nerve but can be separated from it since
it contains no axons.
Histologically we differentiate: Antoni-A (highly cellular densely packed spindle cell areas) & Antoni-B
(less cellular, with fibroblasts & myxoid change).
2 growth patterns are present:
(1) In parallel rows → regimentation/palisading nuclei.
(2) Verocay bodies – nuclei lined in parallel around a center of cell processes.
Usually there’s no malignant change and they may be associated with neurofibromatosis.
2 special variants:
o Plexiform schwannoma – with microscopic multinodal growth.
o Degenerative schwannoma – with nuclear atypia among the degenerated cells.

2. Cutaneous/solitary neurofibroma
a. A benign tumor of nerves, involving the skin, appearing as a fusiform mass composed of Schwann
cells, fibroblasts & collagen. Occurs sporadically or in association with neurofibromatosis type-1.
b. The risk for malignant transformation is very small.

3. Plexiform neurofibroma
a. Extensively involves large trunks of nerves, converting them into a convoluted mass.
b. LM:
 1. Made of neurofibroma cells, low cellularity and mixed background.
2. Axons can be detected inside it and thus in contrast of schwannomas it can’t be separated
from the nerve. This tumor is the pathognomonic feature of Von-Recklinghausen disease,
having a potential for malignant transformation.
4. Granular cell tumor – benign peripheral nerve tumor derived from Schwann cells, occurs mainly in
the tongue and shows S100 positivity.

5. Ganglioneuroma – a neurofibroma of mature ganglionic granular cells and Schwann cells, mostly
in the post. mediastinum & retroperitoneum. Favorable prognosis.

6. Malignant Peripheral Nerve Sheath Tumor (MPN-STs)

a. Highly malignant, locally invasive tumor, with S100 positivity.
b. May arise de novo or from transformation of plexiform neurofibroma.
c. The tumor is poorly defined, invades nerves and neighboring soft tissue; aggressive local growth
with distant metastases (lung). .
d. It shows cytological atypia, the cells resembling FB cells w/ elongated nuclei
e. Foci of necrosis and hemorrhage, frequent mitotic figures
f. Triton tumors=MPN-STs with areas of rhabdomyosarcoma
7. Neuroblastoma
Features:
1. Most common solid tumor of childhood (other that CNSC neoplasms)
2. In <5 years, many in the first year of life.
3. Unique features: spontaneous regression + spontaneous- or therapy-induced maturation.
4. Of neural crest origin, arise anywhere in the sympathetic nervous system.
5. 75% in the abdomen(adrenal gland, paravertebral autonomous ganglia)

Morphology:
Gross:
1. Range from microscopic nodules  masses filling the abdomen.
2. Circumscribes or encapsulated.
3. Grows next to organs (kidney, liver, pancreas)
4. Gray-white tumor, soft, can undergo calcification and cystic degeneration.
LM:
1. Densely packed small “blue” cells (scant cytoplasm → see only nucleus) arranged into solid sheets
2. Homer-Wright pseudorosettes – tumor cells arrange around periphery of central space filled with
fibrillar expensions of cells
3. Neuron specific enolase – immunochemical detection.
4. Small, membrane-bound, cytoplasmic catecholamine secreting granules
5. Ganglioneuroblastoma + ganglioneuromas arise from spontaneous or therapy induced maturation

Staging:
I – tumor confined to organ of origin
II – tumor extends beyond organ of origin but doesn’t cross midline +/- ipsilateral lymph nodes
III – tumor extends beyond lymph nodes
IV – Metastases to viscera, distant lymph node metastases, soft tissue + skeleton
IV-S – Tumor of stage I or II with distant metastases of liver, skin, bone marrow but without involvement of
skeleton.

Heart tumour
• Rare
Primary tumours
 • arises most frequently in the left atrium
In adults: myxoma; arises atrium near the
the fossa ovalis;
• histologically benign
• In infants: rhabdomyoma
rhabdomyoma; grows from and obstructs a valvular orifice;
from the ventricular wall and orifice;
• hamartoma
hamartoma? true
true tumor?
• Lipoma: may
may occur anywhere in the heart

Secondary tumours
• Infrequent
• Usually involve the pericardium
pericardium, where they cause pericarditis and
and serosanguineous effusion
• Carcinomas of the
the lung and
and breast, malignant melanomas and lymphomas are the most common
primary
primary tumours that metastasize
metastasize to the
the heart

Tumors of melanocytes

Can be classified into 2:

1. Benign: pigmented naevus (moles)
a. Acquired
b. Congenital
2. Malignant melanoma

Melanoma - A malignant neoplasm, derived from cells that are capable of forming melanin

Benign: pigmented naevus (moles)

1. Aquired pigmented naevus – brownish tumor, < 6 mm, and well-defined borders. 3 subtypes:
a. Junctional naevus: do not usually undergo malignant transformation
i. Develops in children at puberty usually.
ii. Flat
iii. small ( 3-4 mm across)
iv. LM: intraepidermal nests of naevus cells.
b. Compound naevus: may undergo atypical changes
i. In young adults
ii. Raised and dome shaped
iii. intraepidermal and dermal nests of naevus cells
c. Intradermal naevus:
i. In adults (>30 year old)
ii. Raised and dome shaped
iii. Nests of naevus cells only in the dermis
iv. Spontaneous involution at old age (so in other words disappear)

2. congenital pigmented naevus

a. Present at birth.
b. Nests of naevus cells accumulate dermally around adnexa, nerves and blood vessel walls.
c. large variants may transform into malignant melanoma (10% of cases)

3. Atypical naevus (atypical naevus and not dysplastic)

a. in young adults
b. multiple, larger (> 6mm) than most acquired naevi
c. Variability of pigmentation, irregular borders. These tumors should be excised.
d. LM: compound naevus with atypical features, such as:
 Fusion of the nests of naevus cells within the epidermis
  Cytologic atypia in naevus cells

Clinical significance:
Atypical naevus must be removed and examined histologically because we need
to identify if it is:
Benign naevus
In situ melanoma
Invasive melanoma.

2. Malignant melanoma

Malignant melanoma features:

a. In skin, oral and anogential mucosa (less frequent), eye (uvea), meninges.
b. Highly malignant tumor – frequently kills the patient.
c. In the skin it arises de novo (40%) or in atypical naevus (50%) or in congenital naevus (10%)
d. peak of incidence: 50 years of age.
e. Melanin content: variable.

Warning signs (ABCD) of malignant melanoma:

A: Asymmetrical lesion with irregular borders.
B: Border and Bleeding (spontaneous or upon minor trauma).
C: Color: uneven pigmentation or change in color.
D: Diameter: >6 mm.

Pathogenesis of malignant melanoma:

1. UV-light exposure
2. Defect in repairing mutated DNA.
3. Lightly pigmented people (white race) have higher risk than darkly pigmented individuals.

Patterns of growth:
1. Horizontal (radial) growth within the epidermal and superficial dermis for years
Examples:
a. Superficial spreading MM - on back.
b. Lentigo maligna MM – on face.
c. Acral/mucosal lentiginous MM – on palms, soles mucosa.
No metastases occur until vertical growth is present.
2. Vertical growth: nodular melanoma.
a. Deep brown nodule.
b. LM: anaplastic tumor nests.
c. Highly malignant: haematogenous metastases develop very early.
d. May be melanotic or amelanotic.

Prognostic factors

Depth of invasion 5-y survival

Thin < 0.76 mm 95%
Intermediate 0.76-1.5 mm
Thick >1.5 mm 40-60%
Number of mitosis/mm2
vascular invasion
histological type (nodular MM)