Female Breast, Ovary and Genital

Pathology

Normal Breast Development

Not fully formed at birth, the terminal ducts will
start developing lobules at menarche and the
interlobular stroma increases, all under hormonal
control
With each menstrual cycle, the breast tissue will
change: quiescent in the follicular phase with
vacuolization and edema being prominent in the
secretory phase
There is a complete morphological and functional
change during pregnancy with incomplete
regression post partum

Congenital Anomalies
Polythelia/Supernumerary Nipples: along the milk
line, accessory nipples
Polymastia: accessory true mammary glands and can
undergo the same pathology the main breasts can
Amastia: congenital absence of breast
Congenital inversion of the nipple: can be mistaken for
carcinoma (because some cause retraction)
Macromastia: very large breast which can be treated
by reduction mammoplasty
Micromastia: very small breast which can be treated
by augmentation, implants, TRAM (transverse rectus
abdominis myocutaneous flap)

Galactocele
Cystic Dilation of obstructed duct during
lactation
Is a very painful lump
May get infected with persistent induration

Fibrocystic Change (FCC)

Synonyms: chronic cystic mastitis, mammary dysplasia, fibrocystic disease
Age: during reproductive life usually after 35-40 but can persist after
menopause
Clinically:
Lumps, pain, tenderness, continuous or cylindrical with the menstrual cycle
Over 50% of female are affected but most are incidental findings (at autopsy)
Can give cobblestone texture

Risk Factors:
Oral contraceptive use decreases the risk

Pathogenesis:
Exaggerated, distorted cyclical changes associated with hormonal changes of
menstrual cycle
Even with the normal breast, there may be some irregularity of texture within
the menstrual cycle
Change is in the stroma where fibrosis occurs along with ductal epithelium
proliferation which can be mild simple to severe atypical
There may or may not be cysts (micro or macro) termed BLUEDOMED cysts
Can be CALCIFIED (shown on mammography) in concretions of secretions or
necrosed epithelial cell heaps (which can often be mistaken for carcinoma)

FCC-Categories

Nonproliferative/Simple FCC:

No hyperplasia of epithelium, just cysts and fibrosis of the stroma

Mutlifocal and usually bilateral
1-5 cm Blue Domed cysts filled with serous, turbid fluid
Apocrine metaplasia: cysts are lined by large polygonal cells with abundant granular, eosinophilic
cytoplasm with small round, deeply chromatic nuclei
Lymphomononuclear infiltrate (not always)
In smaller cysts, the epithelium is more cuboidal to columnar and is sometimes multilayered in focal
areas where larger cysts have have flattened or even totally atrophic epithelium
Occasionally mild epithelial proliferation leads to pile-up masses or small papillary excrescences

Proliferative FCC:

Epithelial hyperplasia of the ducts and lobules

Ranges from mild to typical or even atypical in structure
Contains cribiform pattern
Ductal papillomatosis (mild, moderate, severe)
Risk of Ca correlates with the degree of atypical hyperplasia
Simple FCC + Nipple Discharge and MICROCALCIFICATION on mammography

Sclerosing Adenosis

**Clinically and Histologically most mimics carcinoma**

Hard rubbery mass with dense fibrous stroma and may be positive for CALCIFICATION on mammography
Back to Back arrangement of masses of proliferated ducts and ductules (like prostate cancer)
Double layer of myoepithelial cells
Very low risk of carcinoma transformation

Simple
Non-proliferative

FCC
Unruptured
Blue-Dommed
Cyst

Proliferative
Sclerosing Adenosis

Apocrine
Metaplasia
with
eosinophilia

Higher degree
of atypia
(ductal prolif)
with increased
risk of
malignancy

Mild Atypia

Unlike Carcinomas,
here the acini are
arranged in a swirling
pattern and the outer
border is usually well
circumscribed.
The overgrowth of
fibrosis compresses
the lumina of the
acini and ducts ->
solid cords of cells

 Types:

Inflammations of the Breast

Acute mastitis (abscess): usually in the lactating state with inspissated

(thickening by dehydration) secretions; fissures in the nipples will attract
bacteria like:
Staph: small, localized under the nipple and may leave residual indurated scar
Strep: whole breast with marked swelling and tenderness but heals without a scar

Mammary duct ectasia (dilation of the lactiferous ducts)

AKA plasma cell mastitis or granulomatous mastitis
Inflammation, granular debris and leucocytes with foamy histiocytes,
lymphomononuclear cells, plasma cells and granulomas
Produces induration (hardening) and nipple retraction
Clinically mimics carcinoma

Traumatic Fat Necrosis

Uncommon but will present with history of trauma

Grossly: large pendulous (hanging down loosely) breasts
Cholesterol clefts, neutrophils and lipid laden macrophages
More chronically, lymphocytes, fibrosis, cysts with out without CALCIFICATIONS
Clinically mimics carcinoma

Reaction to implants
Paraffin or Silicone can lead to abscess formation or foreign body granulomas
Can eventually lead to fistulae

Clinically very similar: Pain and Tenderness

Fibroadenoma
Commonest benign tumor of the breast in females
Usually appear in young women with the peak in the third decade of life

Associated with FCC and Fibroadenosis

Clinically:
Single, discrete, mobile, encapsulated nodule ranging 1-10 cm
Can get larger during menstrual cycle and pregnancy and can regress after menopause
NEVER BECOMES MALIGNANT

Pathogenesis:
Absolute or relative increase in estrogen activity is thought to be the contributing factor to its
development
The stromal cells are monoclonal and so represent the neoplastic element of these tumors

Gross Morphology:
All are firm, with a tan-white color on cut section, punctuated with softer yellowish-pink specks
representing the glandular areas

Histology Morphology:
Tumor of stromal cells
Loose and edematous myxoid fibroplastic stroma and ductlike epithelial lined spaces
Pericanalicular pattern: oval ducts surrounded by stroma (ductal spaces are open, round to oval and fairly
regular)
Intracanalicular: compressed by extensive proliferation of the stroma so that on cross-section they appear
as slits or irregular, star shaped structure
Mixed Pattern
Clinically it does not have any different for the type of pattern
Can calcify during after menopause: POPCORN-LIKE CALCIFICATION

Treatment: most are scooped out via excision

Fibroadenoma
~ 7cm

Intracanalicular: compression of the

glands to where they look like slits

Pericanalicular pattern: ductal

spaces are open, round to oval and
fairly regular

Phylloides Tumor
AKA: Cystosarcoma Phylloides
Thought to arise from the periductal stroma and not from preexisting fibroadenomas
Usually start off as small (3-4 cm) masses but usually grow to
massive (10-15 cm) lobulated and cystic masses (sometimes) and
often distend the breast
On gross cross section, they exhibit leaf-like clefts and slits
On histology: increased stromal cellularity with anaplasia and high
mitotic activity accompanied by rapid increase in size, usually with
invasion of adjacent breast tissue my malignant stroma
Most will remain localized and can be cured by excision but
malignant lesions may recur (again these tend to remain localized)
Only 15% metastasize to distant sites through hematogenous
routes therefore no LN involvement

Phylloides Tumor
Because of the slits, grossly,
can appear lobulated
Leaf Like Clefts/Slits

Stromal Proliferation

Intraductal Papilloma
Neoplastic papillary growth within a duct, most often solitary and unilateral
Found within the principle lactiferous ducts or sinuses
Clinically present:
As a result of the appearance of serous or bloody nipple discharge
As a result of the presence of a small subareolar tumor a few mm in diameter
As a result of nipple retraction (rarely)

Morphology:
Solitary and less than 1 cm in diameter
Delicate, branching growths within a dilated duct or cyst
Histology: multiple papillae, each having a connective tissue axis and fibrovascular
core covered by cuboidal or cylindrical epithelial cells that are frequently double
layered, with the outer epithelial layer overlying a myoepithelial layer
There is no atypia or mitosis

If there are multiple, there is recurrence and risk of Papillary Carcinoma

Treatment:
Excise the whole duct system that is involved

Intraductal Papilloma
Fibrovascular Core
Double Layer
Of Epithelium
(Cuboidal Cells
Over Myoepithelial
Cell)

Breast Carcinoma
Second most common malignancy in women behind lung cancer and accounts for
20% of cancer death in females
Age: over 40 years old and 25% are post-menopausal (rare in males but possible)
Clinically:
Mass, induration, fixation to pectoralis, skin retraction
Lymphedema with skin thickening around the hair follicles (looks like peau de orange)

Site:
Upper outer quadrant 50% of the time, more often on the Left Breast when unilateral
Bilateral 4-10% of the time
LN involvement at time of diagnosis is usually axillary, internal mammary and in later
stages the supraclavicular

Metastasis:
Lungs, bone, liver, adrenals or anywhere else in the body
Can remain dormant after treatment of primary lesion and reappear 15 years later

Diagnosis:
Self inspection and palpation should be done as screening
In high risk individuals, mammography should be done every 1-2 years after age of 40
If lump found, FNAC or lumpectomy should be performed
In recent trials, nipple aspiration, ductal lavage, or random periareolar FNA
Core needle biopsy with vacuum assistance
Advanced breast biopsy instrument (ABBI)

Breast Carcinoma Risk Factors

Geographic: US > Japan, Taiwan

Genetic:

About 5-10% of breast cancers are related to specific inherited mutations and women
are likely to carry a breast cancer susceptibility gene is they develop breast cancer
before menopause
Typically will have bilateral cancer, and have other associated cancers like ovarian
Will have a significant family history with multiple relatives affected before menopause
Certain ethnic groups
Higher incidence in Ashkenazi Jews (usually develop disease 15-20% before sporadic
cases)

Early Menarche or Late Menopause (higher exposure to estrogen)

Nulliparous (never given birth) or if the first child is after 30 years of age
Obesity, high fat diet due to excess estrogen
Estrogen therapy in postmenopausal women
Virus: not to be proven in man but in mice so far (Bittner Milk Factor)
Ionizing radiation
Oral contraceptive use: Reduces the risk of Ovarian Cancer but Increases Breast
Gene mutations:

p53 (tumor suppressor gene): Li Fraumeni Syndrome

BRCA-1 (Chrom 17): 1:800 women: MORE COMMON
BRCA-2 (Chrom 13): less common with earlier onset
FCC with atypical epithelial hyperplasia, complex proliferative and sclerosing adenosis

Carcinoma of The Breast

Breast Carcinoma Types

Ductal Carcinoma In Situ (DCIS): Comedo Subtype (Usually only 5% of all types)
Cells with high-grade nuclei distending spaces with extensive central necrosis
Necrotic tissue can be extruded from transected ducts with gentle pressure
CALCIFICATIONS are frequently associated with DCIS as a result of either calcified
necrotic debris or secretory material
Cells in better differentiated masses express estrogen and less often progesterone
receptors
Excellent prognosis after simple mastectomy
Some can develop distant metastasis without local recurrence: extensive high-nuclear
grade DCIS and at least 1/3 of women with these small areas will eventually develop
invasive carcinoma and will usually develop in the same breast and quadrant as the
previous DCIS

Infiltrating duct Ca NOS (not otherwise stated)

Commonest tumor (75%)

Scirrhous: hard, dense, desmoplastic
Cords and nests of cells
Usually 3-4 cm masses with infiltrative edges and irregular margins
Contains necrosis and CALCIFICATION
Microscopic appearance: heterogeneous, ranging from tumors with well-developed
tubule formation and low-grade nuclei to tumors consisting of sheets of anaplastic cells
Advanced cancers may cause dimpling of the skin, retraction of the nipple, or fixation to
the chest wall
2/3 express estrogen or progesterone receptors and about 1/3 overexpress HER2/NEU

DCIS Non-Invasive

Ductal proliferation
With No Invasion of
The Stroma

Invasive Ductal Carcinoma

Anaplastic Cells Invading the Stroma

Ductal Proliferation

Breast Carcinoma Types-Ductal Subtypes

Colloid Carcinoma (mucinous)

Rare subtype of Infiltrative Ductal Carcinoma

Tumor cells produce abundant quantities of extracellular mucin
that dissects into the surrounding stroma
Often present as well-circumscribed masses and can be mistaken
for fibroadenomas
Grossly: usually soft an gellatinous and most express hormone
receptors but rarely overexpress HER2/NEU (both good things)

Medullary Carcinoma (dysgerminoma and seminoma testis)

Fewer than 1% of cases
Sheets of large anaplastic cells with pushing, well-circumscribed
borders
Can be mistaken for fibroadenomas
Pronounced lymphoplasmacytic infiltrate
DCIS is usually minimal or absent
Better prognosis than most
Structure is similar to dysgerminoma ovary and seminoma testis
Fried Egg Neoplastic Cells and Lymphocytes

Breast Carcinoma Types

Lobular Carcinoma in Situ (LCIS)

Uniform appearance with monomorphic, bland, round nuclei and occur in loosely
cohesive clusters in ducts and lobules
Intracellular mucin vacuoles (signet rink cells) are common
Usually always an incidental finding and does not form masses and is only rarely
associated with calcifications
1/3 of women will develop and invasive carcinoma and can arise in either breast at a
significant frequency (DCIS goes to same breast, unilaterally)
1/3 will become lobular carcinoma but most are of no special type

Invasive Lobular Carcinoma

Arise from the terminal ductules (acini)

Consists of cells morphologically identical to cells of LCIS
2/3 of the cases are associated with adjacent LCIS
Cells invade individually into the stroma and are often aligned in chains or strands
(Indian file) and occasionally they surround cancerous or normal-appearing ducts or
acini creating a BULLs EYE PATTERN
Cells are oval with no pleomorphism and no mitosis
A significant group may have a diffusely invasive pattern without a desmoplastic
response and may be clinically occult
More commonly to metastasize to the CSF, serosal surfaces, GI tract, Ovary and Uterus,
and Bone Marrow
Most often multicentric and bilateral
If alongside duct carcinoma (mixed pattern)

LCIS Non-Invasive

Hyperproliferation of
Acinar Cells with no
Stromal Invasion

Rarely forms masses

Rarely Calcifies

Invasive Lobular Carcinoma

Indian File

No pleomorphism; No Mitoses; Can wrap around normal or cancerous ducts/acini -> Bulls Eye Pattern

Breast Carcinoma Types

Inflammatory Carcinoma

Occasionally a carcinoma in pregnancy

Aggressive behavior and clinically mimics an abscess in that it is hot and tender
Enlarged, swollen, erythematous breast, usually without a palpable mass
Cancer is generally poorly differentiated and diffusely invades the breast
parenchyma
Most have distant metastasis and therefore have a Poor prognosis

Pagets Disease of the Breast

Extension of DCIS up to the lactiferous ducts and into the contiguous skin of the
nipple
Malignancy cells disrupt the normal epidermal barrier, which allows extracellular
fluid to be extruded onto the surface
Clinical appearance is usually of a unilateral crusting exudate over the nipple and
areaolar skin
of cases have an underlying invasive carcinoma and the prognosis is based on
the underlying carcinoma and is not worsened by the presence of Padget disease
Biopsy: large hyperchromatic nucleus with a halo (Padget Cell) PAS+ve
Sign/Symptoms: Hyperemia, edema, fissuring, ulcer and oozing, eczema even
without a palpable mass
When trying to determine malignancy:
Bilateral, no history of weight loss, Pain, associated with menstrual cycle = low chance of malignancy
Unilateral, No tenderness, Weight Loss, no association with menstrual cycle = high chance of
malignancy

Padgets Disease of the Breast

Padget Cells filled with
Mucin

H&E

Epidermis

Dermis

Crusted Over
Erythema

PAS Stain

Grading and Staging

Grade I, II, III
I: well differentiated
III: poorly differentiated

Staging:
0: DCIS, LCIS, Padgets with a 92% 5 yr survival
I: Invasive Ca 2 cm or less in diameter without nodal involvement (this includes carcinoma in situ with
microinvasions) (80% 5 yr survival)
II: Invasive Ca 5 cm or less in diameter with up to 3 involved axillary LN or an invasive Ca greater than 5 cm
with no LN (65% 5 year survival)
III: Invasive carcinoma 5 cm or less in diameter with 4 or more axillary LN involved or Invasive carcinoma
greater than 5 cm with nodal involvement; can involve ipsilateral internal mammary lymph nodes or skin
carcinoma (40% 5 yr survival rate)
IV: Any breast cancer with distant metastases (10% 5 yr survival rate)

Upon resection of any mass

Estrogen Receptor/Progesterone Receptor (ER/PR) status

Size, Type, Grade

Distance to Margin
Lymphatic Space Invasion
LN status: if positive then less than 0.2mm, 0.2-2.0 mm, greater than 2.0 mm
Hormone receptor status
60% express ERs
Treatment: ER+/PR+ tumors respond to Tamoxifen in 60-70% of cases
ER+/PR-: 40% response rate
ER-/PR-: <10% response rate

HER2/NEU Status: Determined via immunohistochemistry and FISH

Predicts the response to Herceptin
20% of Her2+ patients will response

Male Breast
Gynecomastia
Male analog of FCC
Relative or absolute increase in Estrogen
Liver Cirrhosis, Klinefelters XXY, Estrogen Therapy
Button like nodule beneath the areola
Microscopy: intraductular hyperplasia

Carcinoma
Rare with M:F being 1:125
Rapid Infiltration because less amount of breast
substance in males

Ovarian Disease
The ovaries are affected by physiological changes involving the menstrual
cycle, changes associated with aging and a variety of tumors from its
component tissues
Because pathologies affecting the ovaries are clinically silent for so long (a
log of space to grow within), there is a high lethality associated with them.
They become clinically evident when there is increased pressure or
swelling, pelvic discomfort, heaviness or frequent micturition
There can be hormonal affects, although rare, which include menstrual
irregularities affecting the endometrium, hirsutism, breast enlargement,
etc.
Any of these pathologies can affect the ability for ovulation and can lead to
infertility
Tumors specifically:
Less common that those of the uterus and breasts but produce a higher level of
lethality because of the late detection
4th most common cancer after lung, breast and colon
Pregnancy and Oral Contraceptives REDUCE the risk of ovarian cancer but
INCREASES the risk of Breast Cancer, decreases risk of FCC

Ovarian Cysts
Follicular vs Luteal Cysts
Follicular cysts are lined by layers of cuboidal granulosa cells (UNRUPTURED)
Luteal cysts are hemorrhagic cysts lined with lutinized cells (RUPTURED AND SEALED)
Are often multiple and develop immediately subjacent to the serosal covering of the
ovary
Clinically:
Usually small (1-1.5cm, can reach 4-5 cm) and are filled with clear, serous fluid: larger cysts can be
palpable and usually produce pelvic pain
As fluid accumulates, pressure causes atrophy of these cells and can sometimes rupture producing
intraperitoneal bleeding and acute abdominal symptoms (Secondary to Torsion)
Can also cause endometrial hyperplasia

Diagnosis:
Ultrasound

**Most Common Complication is Torsion Cysts where it turns and causes infarction
(pain)**

Chocolate Cysts:
This is a result of ENDOMETRIOSIS causing repeated cyclical hemorrhage giving the
chocolate appearance
This induces mass amounts of fibrosis, adhesions and pain
Grossly, there are normal looking endometrial glands within stroma plus RBCs and lots
of hemosiderin (Need two of the three for diagnosis)
Cysts can extend along the pelvic ligaments
Usually associated with infertility, and therefore must be distinguished from luteal cysts
for proper and timely removal

Simple Cysts

Polycystic Ovarian Disease (PCOD)

AKA Stein Leventhal Syndrome

Young women, post menarche

Clinically:
Oligomenorrhea (infrequent menstruation), Hirsutism, Infertility, Obesity, secondary amenorrhea: OHIO

Gross Morphology:
Ovaries are twice the normal size with a thick, hypertrophied stroma
Ovaries are gray-white with a smooth outer cortex and are studded with subcortical cysts (0.5-1.5 cm)

Histo Morphology:
Thickened fibrotic outer tunica, overlying innumerable cysts lined by granulosa cells with a hypertrophic
and hyperplastic luteinized theca interna
Conspicuous absence of corpora lutea
Hormones: High LH, Low FSH (LH:FSH; 3:1), High Testosterone
Ovaries and adrenals produce excess androgens which are turned into estrogens in the fat which inhibit
FSH release by pituitary
Increased LH:FSH stimulates theca cells to produce more estrogens and the cycle continues
Hyperinsulinemia due to peripheral resistance to insulin

Clinical consequence of hormones:

Excess Estrogen: endometrial hyperplasia and stimulates adipocytes -> obesity; increased endometrial
and breast cancer
Excess Androgens: hirsutism, virilization, create more estrogen

Diagnosis:
Hormonal Assay or Transvaginal US

Treatment:
Hormonally break the cycle
Chlomiphene induces ovulation
In the Past, wedge resection of ovary to help ovulation and reduce the mass (not done anymore)

PCOD

Ovarian Tumors
Very diverse pathologically due to the 3 different cell types that make up
the normal ovary
Multipotential surface (coelomic) covering epithelium
Totipotential germ cells
Multipotential sex cord/stromal cells

Most are neoplasms of surface epithelial origin and their malignant forms
account for 90% of all ovarian cancers
80% of tumors are benign in 20-45 year old women
20% of tumors are malignant in 40-65 year old women
Most often are bilateral, occur more often in nulliparous women, there is
usually a family history, and oral contraceptives reduce the overall risk
Commonest tumor: Epithelial (Serous)
Commonest malignancy: Serous Cystadenocarcinoma
Commonest bilateral tumor: Serous Cystadenocarcinoma (66%),
Metastasis
Spread:
Into the peritoneum and cause ascites or omental pancakes
Into LN (iliac and paraaortic)
Through the blood to the lungs

Surface Epithelial Tumors

Origin:
Derived from the coelemic mesothelium that covers the surface of the ovary

Pathogenesis:
With repeated ovulation and scarring, the surface epithelium is pulled into the cortex of the ovary,
forming small epithelial cysts
With time these can undergo metaplasia and neoplastic transformation

Classification: (based on differentiation)

Towards the fallopian tube: columnar cells with cilia: SEROUS

Towards the endocervix: tall mucin secreting cell: MUCINOUS
Towards the endometrium: nonciliated columnar cell: ENDOMETROID
Towards the transitional epithelium: transitional cells: BRENNERS TUMOR

Behavior:
Benign: Cystadenoma (if they involve the stroma: cystadenofibroma)
Borderline: Intermediate carcinoma of low malignant potential
Malignant Cystadenocarcinoma

Gross Morphology:
Small to very large, filling the abdomen
Benign: Cystic, unilocular, little to no papillae, smooth
Malignant: Solid, multilocular, papillae, nodular

Clinically:

Abdominal pain (not typical unless late/large), swelling, dragging sensation, tumor mass/compression
GI symptoms, dysuria, increased frequency of urination, pelvic pressure
Resection of a benign tumor is the cure
Malignant: progressive weakness, weight loss, cachexia with seeding into the peritoneum causing massive
ascites
Tumor implants grow on the surface of other structures but do NOT invade
Regional LN can be involved and can metastasize to liver, lung, GIT and the time to the opposite ovary

Surface Epithelial: Serous

Lined by a single layer of tall columnar ciliated

Cysts are filled with serous fluid
30% of all ovarian tumors
60% BENIGN (20-50 yrs) with 20% being bilateral
Psammoma bodies (round collection of calcium)

15% BORDERLINE
Multi-layering with moderate mitosis and nuclear atypia
No stromal invasion
75% 5 year survival

25% MALIGNANT (over 50 years) with 66% being bilateral

More numerous Papillae and Polyps

Psammoma bodies (round collection of CALCIUM at the tips of papillae)
Solid nodules indicate serosal penetration (malignancy)
Multi-layering, nuclear atypia and stromal invasion
10-20% 5 year survival

10-15 cm in diameter filling the abdomen

Lining is smooth and glistening when benign and nodular when malignant
**Cystadenofibroma variant: abundant fibrous tissue under epithelium and
usually benign
MOST ARE BENIGN AND UNILATERAL, IF MALIGNANT -> BILATERAL

Serous Cystadenoma
No Stromal Invasion
In Either Benign or
Borderline

Psammoma
Bodies
Benign

Columnar Cells with Cilia

Borderline

Serous Cystadenocarcinoma
Cystic Component

More numerous Papillae

More Cellular Atypia

Nodular Component

Surface Epithelial: Mucinous

Multiloculated cysts, sticky gelatinous material rich in glycoproteins

Tall columnar cells with apical mucous vacuole and NO cilia
25% of all Ovarian Tumors
80% BENIGN
Most are unilateral
Few Locules

10-15% BORDERLINE
70% 10 year survival

5-10% MALIGNANT
Most are unilateral unlike serous
Mutliloculated and solid nodules with increased papillae than benign lesions
35% 10 year survival *better than serous*

Papillary Formations and Polyps are Less Frequent, NO psammoma bodies

Occasionally mixed with Dermoid Cyst or Brenners Tumor
**Pseudomyxoma Peritonei
2-5% of mucinous tumors (only borderline and malignant)
Peritoneal cavity is filled with mucoid material, with matted tumor implants all over the
abdomen on serosal surfaces
Can be a complication of mucocele of the appendix due to carcinoma of the appendix
Mucocele can be caused by fecolith blocking the lumen of the appendix but cannot
cause pseudomyxoma peritonei (need monoclonal cells)

Mucinous Cystadenoma

Mucinous Secreting Columnar Cells

Mucinous Cystadenocarcinoma

PAS +ve Mucin

Surface Epithelial: Endometroid

20% of all ovarian tumors
15-30% are associated with concomitant endometrial carcinoma (not
metastasis)
Gross:
Small, Solid or Cystic
Papillae with velvety surface
Can develop a mass projecting from the wall of an endometriotic cyst filled
with chocolate-colored fluid (tumor on top of a cyst on the ovary)

Micro:
Resemble endometrial carcinoma but not functional like endometriosis (not
normal endometrium like seen in endometriosis)

Most are malignant and behave like carcinomas due to a mutation in the
PTEN suppressor gene (same as endometrial cancer)
40% are bilateral
4-50% 5 year survival
**Clear Cell Carcinoma variant

Surface Epithelial: Brenners Tumor

Transitional Epithelial Cells (may come from urogenital
remnants) with the addition of dense fibrous tissue
Gross:
Small, solid multiple nodules (not cysts)
Usually smoothly encapsulated and gray-white on transection
with a range of sizes (can be 20 cm in diameter-palpable mass)

Micro:
Occasionally, the nests of cells are cystic and are lined by
columnar mucus-secreting cells

Clinically:
Silent most of the time
Most often benign but there is chance of malignancy
Mostly Unilateral

Brenners Tumor
Tumor

Transitional Epithelium

CA125
Screening Marker for Ovarian Malignancy
High levels seen in the blood of 75-95% of women with
epithelial ovarian cancers
Problems:
Problematic if the tumor is only limited to the ovary, giving
half of them a false negative
Can have increased values in benign lesions and in nonovarian cancers

Can be useful in screening of asymptomatic

postmenopausal women for ovarian malignancy
**Most useful in measuring effectiveness of
treatment (response to therapy)**

Germ Cell Tumor

15-20% of ovarian tumors
95% are benign cystic teratomas
5% are in children/young adults and are
malignant
Also includes, dysgerminoma, endodermal
sinus tumor, choriocarcinoma (nongestational)
in addition to teratoma

Mature Teratoma
Mature benign cyst (Dermatoid Cyst)
Seen in young women in active reproductive years
Origin:
Marked differentiation of totipotential germ cells into mature tissues representing all
three germ cell lays (ectoderm, mesoderm, endoderm)

Morphology:
Usually formation of a cyst lined by recognizable epidermis replete with adnexal
appendages: dermoid cyst
Often filled with sebaceous secretion and matted hair that when removed reveal a
hair-bearing epidermal lining
Sometimes there is a nodular projection from which teeth protrude
Occasionally, foci of bone and cartilage, nests of bronchial or GI epithelium and other
recognizable lines of development are also present

Clinically:
90% are unilateral and more often on the right; rarely exceed 10 cm in diameter
For unknown reasons, sometimes can produce infertility
1% have malignant transformation of one of the tissue elements usually taking the form
of squamous cell carcinoma
Prone to undergo torsion, like simple cysts producing an acute surgical emergency

Diagnosis:
Usually incidental on abdominal radiographs or scans because they contain foci of
CALCIFICATION produced by contained teeth

Dermatoid Cyst
Poor Prognostic Factor
Connective Tissue
Neuroepithelium

Epidermis
Hair Follicle

Immature/Malignant Teratoma
Mean age of 18 years old
Morphological:
Often bulky, are predominantly solid or near-solid on transection and are
punctuated here and there by areas of necrosis
One of the cystic foci, although rare, may contain sebaceous secretions, hair
and other features similar to those in the mature teratoma

Micro:
**Distinguishing Feature: variety of immature or barely recognizable areas of
differentiation toward cartilage, bone, muscle, nerve and other structures**
**Ominous are foci of neuroepithelial differentiation because most such
lesions are aggressive and metastasize widely**

Graded and stages in an effort to predict their future

Grade I, Stage I can be cured with appropriate therapy
Grade III: more grave outlook

Can be mixed with choriocarcinoma, endodermal sinus tumor and

embyronal carcinoma

Specialized Teratomas
Struma Ovarii is composed entirely of mature
thyroid tissue that may hyperfunction and
produce hyperthyroidism
Appear small, solid, unilateral brown ovarian masses

Can also have ovarian Carcinoid Tumor which in

rare instances has produced carcinoid syndrome
Strumal Carcinoid: Combinations, although
extremely rare, do exist in the same ovary
One of these components can become malignant

Struma Ovarii

Endodermal Sinus Tumor (Yolk Sac)

Occurs in children and young women

Expresses malignant behavior
Rich in AFP and Alpha 1 Antitrypsin
Morphology:
Cystic Spaces
Papillary Projections
**Schiller Duval Bodies: layers of epithelial cells
around blood vessels which resemble glomeruli**
Contains Cytoplasmic Pink Inclusions: inclusions of
AFP

Dysgerminoma
2% of all ovarian cancers (very rare)
Peak Incidence:
20s-30s and occurs with gonadal dysgenesis

Location:
Mostly Unilateral

Morphology:
Solid, Large to small gray masses
Sheets or cords of large cleared cells separated by scant fibrous
strands
Stroma contain lymphocytes and occasional granuloma

Behavior:
All are malignant but only 33% are aggressive

Treatment:
Cured by surgery and is radiosensitive

Similar to seminoma testis and medullary carcinoma of the breast

Dysgerminoma

Fried Egg
Lymphocytes

Choriocarcinoma (nongestational)

Peak Incidence:

First three decades of life

Location:
Unilateral

Morphology:
Identical to placental tumor
Small, hemorrhagic focus with two types of epithelium: cytotrophoblast and
syncytiotrophoblast
Pleomorphism, giant cells and multi-nucleation

Behavior:

Metastasize early and widely

Primary focus may disintegrate which only leaves secondary mets
Resistant to chemotherapy and are highly fatal
**No paternal component to battle the maternal component like in placental
choriocarcinoma**

Serum Levels:
Secrete Chorionic Gonadotrophin (CGT)/Human Chorionic Gonadotropin (HCG): to be
used as marker
Raised CGT/HCG in the urine and blood

Other rare tumors: Embryonal carcinoma, polyembryoma, mixed germ cell tumor

Choriocarcinoma

Complete Disaster Zone: High levels of atypia

Sex Cord Stromal Tumor

Granulosa-Thecal Cell
Peak Incidence:

Most are postmenopausal (66%) but any age

Location:
Unilateral

Morphology:
Tiny or large
Gray to yellow with cystic spaces
Mixture of cuboidal granulosa cells in cords, sheets or strands and spindle or plump lipid-laden
thecal cells
Granulosal elements may recapitulate ovarian follicle as Call-Exner Bodies

Behavior:
Large amounts of estrogen from the thecal elements and so may promote endometrial or breast
carcinoma, precocious puberty or endometrial hyperplasia
Granulosa element may be malignant, but not theca cells

Thecoma-Fibroma
Peak incidence:
Any age

Location:
Unilateral

Morphology:
Solid gray fibrous cells to yellow, lipid-laden plump thecal cells

Behavior:
Most are hormonally INACTIVE (few elaborate estrogen)
40% will produce ascites and hyrdothorax on right side Meigs Syndrome (Fibroma)
Rarely malignant but sometimes associated with basal cell nevus syndrome

Granulosa Cell Tumor

Call-Exner Bodies

FibroThecoma

Fibrosis

Can express Estrogen

Lipid Laden
Theca Cells

Sex Cord Tumor

Sertoli-Leydig cell tumor (androblastoma)
Peak Incidence:
20-30s

Location:
Unilateral

Morphology:
Usually small, gray to yellow-brown and solid
Recapitulates the cells of testis

Behavior:
Many masculinizing or defeminizing
Defeminizing: Atrophy of breasts, amenorrhea, sterility, loss of hair
Masculinizing: Hirsutism, male distribution of hair, hypertrophy of clitoris,
voice changes

Rarely malignant

Gonadoblastoma: Germ Cell Tumor + Sex Cord Tumor

Metastasis to Ovary
Peak Incidence:
Older ages

Location:
Mostly bilateral

Morphology:
Solid, gray-white masses as large as 20 cm in diameter
Anaplastic tumor cells, cords, glands, dispersed through fibrous
background
Cells can be signet ring, mucin-secreting (Diffuse Gastric AdenoCa)

From:
GIT tumors, Breast tumors
Krukenberg (bilateral ovarian and Gastric Adenocarcinoma)
Signet Ring Cells

Krukenberg Tumor
Signet Rings

Normally equal size bilateral

But in this case one is enlarged
More than the other, but both
Are affected

Normal Phases of the Endometrium

Day 1-13: proliferation phase mediated by the
presence of estrogen
Straight Glands
Cuboidal to tall epithelium; Single to Double layer
Dense stroma with compact cells

Day 14: ovulation

Day 15-28: secretory phase mediated by the
presence of progesterone
Coiled glands
Tall cells with vacuoles; Single Layer
Edematous stroma with plump cells and conspicuous
arterioles

Endometrium
Double Layer of Cells

Some hemorrhage is normal when

Proliferation compresses spindle
Arteries causing some leakage of RBC
Single Layer of Cells
Proliferative Phase

Vacuolization

Secretory Phase

Possible Symptoms
Amenorrhea (primary or secondary): absence of
menstrual cycle from the beginning or after menarche
Menorrhagia: excessive amount of regular bleeding
(cyclical)
Metrorhagia (Epimenorrhea): irregular non-cyclical
bleeding
Dysmenorrhea:
Primary-onset at menarche; abnormal activity of nerves
and muscles of the cervix
Secondary-onset later in life: endometriosis, leiomyoma

Infertility: congenital anomalies, neoplasms,

endometrial diseases
Mass: felt only when large

Abnormal Endometrial Cycles

Unopposed Estrogen Effect
Anovulatory cycles with a persistent Graafian Folicle
Typically occurs at the extremes ends of reproductive life
Causes:
Failure of ovulation such as seen around menopause
Prolonged administration of estrogenic steroids without counterbalancing
with progesterone
Polycystic Ovaries (Stein Levinthal) producing estrogen
Cortical stromal hyperplasia
Granulosa-theca cell tumors of the ovary (fibrothecoma to lesser extent)
Obesity because adipose tissue processes steroid precursors into estrogens

Effects: persistent proliferation and irregular breakdown (DUBdysfunctional uterine bleeding), endometrial hyperplasia,
endometrial carcinoma, breast cancers

Exogenous Progesterone Effect

AKA Pill endometrium due to Contraceptive Pill with Progesterone
Causes abundant stroma with plump cells (pseudodecidual)
Glands are small and atrophic (lack of priming by estrogen)

Abnormal Endometrial Cycles

Inadequate Luteal Phase
Irregular ripening with an inadequate corpus luteal with
lowered progesterone
Poorly developed secretory endometrium/glands
Leads to DUB with irregular breakdown
Low progesterone, LH, FSH

Persistent Luteal Phase

Normal menstruation is induced by abrupt cessation of
progesterone secretion by the corpus luteum
If the corpus luteum continues to secrete low levels of
progesterone the endometrium will become protracted and
there will be irregular shedding
Periods are regular but bleeding is excessive and prolonged
(10-14 days)
Persistent secretory phase even after 5 days of menstruation

Endometriosis

Characterized by the presence of endometrial glands and stroma in a location outside the
endomyometrium
Incidence is high in women with infertility
Clinically:

Dysmenorrhea, menorrhagia, cyclical bleeding from UT, Rectum, Umbilicus, Surgical Scars
Pelvic pain
Pelvic mass filled with degenerating blood (chocolate cyst)
Infertility
Fibrosis -> intestinal obstruction, risk of tubal pregnancy, urinary obstruction
Can regress following pregnancy or after oral contraceptive use

Location:
Frequently multifocal and may involve tissue in the pelvis (ovaries, pouch of Douglas, uterine ligaments,
tubes and rectovaginal septum)
Less frequently in the peritoneal cavity and about the umbilicus
Uncommonly in LN, lungs, heart, skeletal muscle or bone
Laparotomy or Caesarian Scars

Pathogenesis:
Regurgitation theory:

Menstrual backflow through the fallopian tubes with subsequent implantation

Metaplastic Theory:

Endometrial differentiation of ceolomic epithelium which is the origin of the endometrium itself

Vascular or Lymphatic Dissemination Theory:

Invoked to explain extrapelvic or intranodal implants which cannot be explained in the previous two theories

Endometriosis
Morphology:
Most commonly contains functioning endometrium which undergoes cyclical
bleeding
Because blood collects in these aberrant foci, they usually appear as red-blue
to yellow-brown nodules or implants
Can be anywhere from 1-2 cm in diameter and lie on or just under the affected
serosal surface
Individual lesions can and often coalesce to form large masses
On the ovaries they form large masses called Chocolate Cysts as the blood ages

Consequences:
Seepage and organization occurs leading to fibrosis
Adherence of pelvic structures and sealing of the tubal fimbriated ends ->
Infertility
Distortion of the oviducts and ovaries

Histological Diagnosis:
Required two of the following three:
Endometrial glands, stroma or hemosiderin pigment

**Different than Adenomyosis (endometriosis interna): diffuse; if focal

(adenomyoma); non-functional endometrial tissue

Endometritis

Inflammation of the endometrium seen in:

Causes:

Can be part of pelvic inflammatory disease (PID) which has consequences for
the integrity of the fallopian tubes and fertility
May be associated with retained products of conception subsequent to
miscarriage or delivery or a foreign body such as an IUD
Retained products act as a nidus for infection, usually by flora ascending from
the vagina or intestinal tract

Classification:
Acute: Neutrophilic Response
N. gonorrhea and C. trachomatis are likely culprits
Histologically: neutrophilic infiltrate in the superficial endometrium and glands co-exist
with stromal lymphoplasmacytic infiltrate
Postpartum: puerpural sepsis leading to offensive lochia (foul smelling discharge)
Pyometrum obstruction leading to neoplasm or fibrosis

Chronic: Lymphoplasmacytic Response (mainly plasma cells)

IUD, retained products
Tuberculosis may present with granulomatous endometritis frequently with tuberculous
salpingitis and peritonitis

Clinically:
All forms may present with fever, abdominal pain, menstrual abnormalities,
infertility and ectopic pregnancy due to damage to the fallopian tubes

Endometrial Hyperplasia

Caused by an excess of estrogen relative to progesterone (unopposed estrogen)

If this remains for a long period of time, it will induce exaggerated endometrial
hyperplasia/proliferation which can be pre-neoplastic
Causes of the estrogen excess:

Failure of ovulation such as seen around menopause

Prolonged administration of estrogenic steroids without counterbalancing with progesterone
Polycystic Ovaries producing estrogen
Cortical stromal hyperplasia
Granulosa-theca cell tumors of the ovary
Obesity because adipose tissue processes steroid precursors into estrogens

Ranges from:
Simple Cystic Hyperplasia

Negligible risk of carcinoma transformation

Complex Hyperplasia
Complex Atypical Hyperplasia

20% risk carcinoma transformation (endometrial carcinoma)

Continuum based on the level and duration of the excess

With enough time, the hyperplasia may become autonomously proliferating and no longer
needs the strong estrogen influence (not good because high malignant potential)
Risk of developing carcinoma is based on the level of atypia and the severity of the
hyperplastic change
Diagnosis/Treatment:
Look for source of estrogen
Biopsy tissue to see for transformation
Balance with progesterone or correct underlying condition

Endometrial Hyperplasia

Simple Cystic

Complex

Endometrial Polyp
Occurs around menopause (perimenopausal)
Morphology:
Ranges from 0.5-3 cm in diameter, usually sessile and hemispheric
Large enough lesions can protrude into the uterine cavity

Histologically:
Composed of endometrium resembling the basalis, frequently with small
muscular arteries
Some have normal endometrial architecture but more often they have
cystically dilated glands
Stromal cells are monoclonal and have a cytogenic rearrangement making it
clear it is neoplastic

This is a result/reaction to extreme hyperplasia of the endometrium

Usually asymptomatic but can cause metrorrhagia (uterine bleeding at
irregular intervals)
Malignant transformation is very rare

Endometrial Carcinoma

Epidemiology:
55-65 years old
Perimenopausal women with estrogen excess: endometroid histology
Older women with endometrial atrophy: serous carcinoma histology

Risk Factors:

Obesity due to increased synthesis of estrogen

Diabetes
Hypertension
Infertility: women tend to be nulliparous, often with nonovulatory cycles
Estrogen-secreting ovarian tumors (PCOD)
Background of endometrial hyperplasia and are termed endometroid because of their similarity to
normal endometrial glands
**Breast cancer occurs more frequently with endometrial cancer than by chance alone because both have
same risk factors**

Pathogenesis:
Second most common cancer associated with HNPCC (mismatch repair)
Sporadic cases have a high frequency of inactivation of these genes by methylation of the promoter and as
a consequence have a relatively unstable genome (MSI)
Mutations in PTEN tumor suppressor gene (rare in Serous Type but p53 is evident)

Clinically:
Marked Leukorrhea (thick, whitish-yellowish vaginal discharge) and irregular bleeding and in
postmenopausal women this signifies erosion and ulceration of the endometrial surfaces
With time, palpable enlargement and it will become fixed to surrounding structures by extension of the
cancer beyond the uterus

Endometrial Carcinoma Types

Endometroid Carcinoma:

Closely resembles normal endometrial tissue

Exophytic or infiltrative
Patterns: mucinous, tubal (ciliated) and squamous (usually adenosquamous) differentiation
Tumors originate in the mucosa and may infiltrate the myometrium and enter vascular spaces
Metastases to regional LN
Staging

Stage I: confined to the corpus

Stage II: involvement of the cervix
Stage III: beyond the uterus but within the true pelvis
Stage IV: distant metastases or involvement of other viscera

**Synchronous endometroid tumor: two separate primary neoplasms is not stage III, are both Stage I and
has favorable prognosis

Serous Carcinoma:

Forms small tufts and papillae rather than glands

Much greater cytologic atypia
Poorly differentiated cancers and are not graded
Aggressive cancers

Metastases:

Local: myometrium, cervix, vagina, rectum

Peritoneum
LN: iliac and paraaortic
Blood: lung and liver

Endometrial Carcinoma
Exophytic

Serous Carcinoma
Severe Atypia

Malignant mixed Mullerian Tumor

Mixed Mesodermal Tumor
Over 55 years old
Origin:
From residual Mullerian mesodermal cells in the
endometrium
Carcinosarcoma

Morphology:
Large, fleshy mass with hemorrhage and necrosis

Composition:
Epithelial and mesenchymal cells (leio, rhabdo,
chondro, osteo)

Similar Risk Factors for Endometrial Carcinoma

Poor Prognosis

Leiomyoma

Common, benign smooth muscle tumor

Age group is 20-40 years old; BLACKS
Estrogen DEPENDENT tumor (regresses after menopause), but estrogen is NOT cause
Morphology:
Because very fibrous, often termed FIBROIDS
Monoclonal and non-random chromosomal abnormalities
Sharply circumscribed, firm gray-white masses with a characteristic WHORLED cut surface (whorling
bundles of smooth muscle)
Occur singly but most often multiple tumors are scattered within the uterus
Size can range from small seedlings to massive neoplasms

Large neoplasms may develop foci of ischemic necrosis with areas of hemorrhage and cystic softening and after
menopause they may become densely collagenous and even CALCIFIED

Subserous: directly underneath the serosa

May develop attenuated stacks an even become attached to the surrounded organs from which they develop a
blood supply and then free themselves from the uterus to become a parasitic leiomyoma

Submucosal: directly underneath the endometrium

Intramural: within the endometrium

Clinically:

Asymptomatic
Menorrhagia, with or without metrorrhagia
Large masses: dragging sensation
Acutely, pain, red degeneration (necrosis) especially in pregnancy

No malignant potential
Treatment:
Laparoscopic resection or hysterectomy, myomectomy

Uterine Fibroid Smooth Muscle Whorls

Leiomyosarcoma
Typically arise de novo from the mesenchymal cells of the myometrium, NOT a preexisting leiomyoma
Morphology:
Almost always single in contradiction to frequently multiple leiomyoma
Grossly:

Bulky masses infiltrating the uterine wall

Polypoid lesions projecting into the uterine cavity
Deceptively discrete tumors that masquerade as large, benign leiomyomas
Soft, hemorrhagic and necrotic

Histology:
Closely resembling leiomyomas
Wildly anaplastic tumor
Because it is difficult to differentiate some, they are termed smooth muscle tumors of uncertain
malignant potential

Diagnosis:
Tumor Necrosis, cytologic atypia, mitotic activity (need all three)

Poor Prognosis because recurrence after removal is common and high level of
metastases typically to the lungs
40% 5 yr survival rate
Anaplastic lesions have a poorer prognosis than the better differentiated tumors

Cervix
Ectocervix: lined by hormonally responsive
stratified squamous epithelium (nonkeratinized);
post puberty, mature cells store glycogen which
supports the growth of normal flora
Endocervix: lined by simple columnar epithelium;
endocervical glands are crypt-like spaced lined by
the same epithelium
Squamo-Columnar Junction: initially at the
external cerival os

Cervicitis
Acute
Typically in the endocervix (not erosion)
Organisms: Gonococcal, Chalmydia, Candida, Trichomonas, Herpes, one or
more types of HPV
Can be post-partum or post dilation and curettage (procedure in which
material inside the uterus is removed)
Causes purulent vaginal discharge

Chronic
Non-specific, usually incidental
Inflammatory infiltrate consists of lymphocytes and plasma cells normally
present in the wall of the cervix
Granularity and thickening occurs as a result of fibrosis
As the overgrowth of the regenerating squamous epithelium blocks the orifices
of endocervical glands in the transformation zone, it produced retention
(nabothian) cysts that are lined by columnar mucus secreting epithelium

**Squamous Cell Metaplasia**

Non-specific response to irritation with NO malignant potential

Squamous Metaplasia of Cervix

Normal Ectocervix

Transformation
Zone Metaplasia

Normal
Endocervix

Endocervical Polyp
Etiology:
Pre-menopausal women

Morphology:
Can be as large as a few cm, are soft and yielding to palpation
Smooth glistening surface with underlying, cystically dilated spaces
filled with mucinous secretion

Histology:
Surface epithelium and lining of the underlying cysts are composed of
the same mucus-secreting columnar calls

Complications:
Superimposed chronic inflammation may lead to squamous
metaplasia of the covering epithelium and ulcerations
May bleed and thus cause some concern but NO malignant potential

Condyloma Acuminatum
Condylomas: Anogenital Warts and In the moist environment of the Vulva
they tend to be large
2 forms exist: Condyloma lata (secondary syphilis) and acuminatum

Condyloma acuminatum may be papillary and distinctly elevated or

somewhat flat and rugose and can occur anywhere on the anogential
surface
Often are singly found but can be in multiple sites
Histological:
Perinuclear cystoplasmic vauolization with nuclear angular pleomorphism and
koilocytosis which are hallmarks of HPV infections

Strong association with HPV 6 and 11 and can be transmitted venereally

and identical lesions can be found on men on the penis and around the
anus
Vulvular condylomas are not precancerous but may coexist with foci of
intraepithelial neoplasia in the vulva (VIN I) and cervix
Flat lesions are associated with HPV 16,18,31,32 and there is a risk of
carcinoma by inactivating tumor suppressors p53 and Rb and activation of
cyclinE leading to uncontrolled proliferation

Condyloma acuminatum

Maturation of the Cervix

Normal squamous epithelium:
Basal cells are small and cuboidal or columnar with
relatively high N:C ratio
Mitoses are rare and limited the basal layer
As cells rise in the epithelium, the nuclei shrink and the
cytoplasm increases and becomes flat
Cells begin to store glycogen

Loss of Maturation:
Sequence from bottom to top is lost beginning at the basal
layer and progressing until the entire thickness of the
epithelium is involved
Nuclei remain large and the cells remain cuboidal
Mitoses appear above the basement membrane
Glycogen is not stored

Carcinoma In Situ of the Cervix

Peak incidence is 30 years old where invasive carcinoma is about 45 years

Almost all invasive cervical squamous cell carcinomas arise from precursor epithelial changes
referred to as CIN; however, not all CIN changed progress to cancer and can persist without
change or even regress
Considered Dysplasia and can be rated mild, moderate or severe corresponding to the rating
CIN I, II, and III, respectively
Can progress from CIN I to III or can spontaneously begin as CIN III
Can also regress to a lower stage or normal from any point as long as it is still CIN (cannot regress from
cancer)

Squamous intraepithelial lesion (SIL): can be split into two categories, low grade (CIN I) or
high grade (CIN II, III)
Risk Factors for the development of CIN and this Invasive Ca:

Frequent coitus, Early at at first intercourse

A male partner with multiple previous sexual partners, Prostitutes
Multiparity
Rare in nuns, jews, muslims

Diagnosis:
HPV can be diagnosed by molecular methods like FISH
Most important is to do routine PAP smears

PAP smears:

Yearly, if found to be negative twice, then less frequent

Colposcopy: use illumination to see for the vascular pattern and thickening (appear white)
Schiller Test: Paint the cervix with iodine and look for unstained pale patches
If a smear is abnormal, then follow up with biopsy

CIN

Normal

CIN II

CIN I

CIN III

PAP Smear

Increased Nuclear to Cytoplasmic Ration With Increased Grade

Carcinoma of the Cervix

Most are squamous cell carcinoma with keratin pearls but rarely can be
adenocarcinoma (adenocarcinoma types have been increasing because glandular
lesions have not been detected as well by PAP smears)
Overall they have been on the decline because of the use of PAP smears, but this
has meant the levels of CIN have risen (occurs from 30-50 yrs old)
Usually occurs 10-15 years after the precursor has been detected

High association with HPV 16 and 18 and possible HSV-2

Morphology:
Usually occur at the transformation zone and range from microscopic foci of early
stromal invasion to grossly conspicuous tumors encircling the os
Tumors may be exophytic necrotic fungating masses, ulcerating lesions or invisible
(rarely are infiltrative)
Tumors that encircle the cervix and penetrate into the underlying stroma -> barrel
cervix which can be determined on direct palpation

Course:
If the cancer extends into the parametrial soft tissue, it can fix the uterus to the pelvic
structures
Size of the lesions will determine the likelihood of spread to LN (bigger = more spread)
Distant metastases will occur much later and can involve: para-aortic nodes, remote
organ involvement, invasion of adjacent structures like bladder or rectum

Symptoms:
Leukorrhea, unexpected vaginal bleeding, painful coitus (dyspareunia), dysuria
Pyometron: obstruction of the cervix

Carcinoma of the Cervix

Micro-invasive Carcinoma Stage IA
Depth is less than 5 mm from the basement membrane
No lymphatic spread or hematogenous spread
Surgical excision is curative

Rare Adenocarcinoma type:

Only 10-15%, occurs in the endovervical canal with stages of carcinoma in situ
Also causes obstruction (pyometron)

Prognosis is based on stage: (5 yr survival rates)

Stage 0: 100%
Stage 1: 90%
Stage 2: 82%
Stage 3: 35%
Stage 4: 10%

Treatment mostly for CIN:

Cryo-surgery
Electrocoagulation
Laser
Cone biopsy: including total squamocolumnar junction
Chemotherapy can increase survival in cancer patients

Carcinoma

Exophytic Growth: Barrel Cervix

Growth into the Vaginal Canal

Keratin Pearls

Genital Herpes

Syncytial
Cells

Intranuclear Inclusion Bodies

Cowdry Type A Bodies

Lesions on the Vagina

Congenital Lesions of the vagina:
Total absence of the vagina
Septate or double vagina (usually associated with
a septate cervix and sometimes uterus)
Congenital small lateral Gartner duct cysts arising
from persistent embryonic remnants
(mesonephric duct)
Usually on the anterolateral wall of the vagina

Vaginal Adenosis
Occurs in girls (around 10 years) whose mother received
DES during pregnancy to prevent morning sickness
Characterized by endocervical type glands in the vaginal
wall
Pathogenesis:
Thought to be the inhibition of transformation of Mullerian
epithelium into squamous epithelium

Consequences:
Some girls can develop clear cell adenocarcinoma from age 1035

Morphology:
Appear as red granular foci and are lined by mucus-secreting or
ciliated columnar cells

Carcinomas of the Vagina

Squamous Cell Carcinoma
Women older than 60 with risk factors similar to carcinoma of the
cervix
Preexisting or concurrent cervical intraepithelial neoplasia or
carcinoma of the cervix is frequently present
Vaginal intraepithelial neoplasia is a precursor lesion associated with
HPV infection in nearly all cases and in half of the cases, HPV DNA is
found
Can be exophytic, polyoidal or fungating mass
Can involve the pelvic or inguinal nodes depending on the location
Poor prognosis

Clear Cell Carcinoma

Girls in their late teens to early 20s associated with their mothers use
of DES during pregnancy

Sarcoma Botryoides
Embryonal Rhabdomyosarcoma
Etiology:
Encountered in infants and children younger than age
5

Morphology:
Produces soft, polypoid masses
Appears like a bunch of grapes hanging in the vagina

May appear in other sites such as urinary bladder

or bile ducts
Highly Malignant

Vulva
Normal:
Consists of the majora, minora, vestibule and clitoris
Bartholin glands open into the vaginal introitus for
lubrication
Skenes glands around the uruthral opening
(homologous to the prostate glands in the male)

Pathology:
Bartholinitis:
Acute inflammation of the inferior part of the labium major
Can cause abscess formation
Associated with strep, staph, gonococci, and E. coli

Vulvitis
Moist hair-bearing skin and delicate membrane of the vulva
are vulnerable to many non-specific microbe-induced
inflammations and dermatologic disorders
Intense itching and subsequent scratching often only
exacerbates the primary condition
Five most important infectious agents in NA:
HPV -> condyloma acuminata and vulvar intraepithelial
neoplasia
Condyloma Latum -> plaque like papule of secondary syphilis

Herpes genitalis: HSV 1,2 -> vesicular eruption

Gonococcal suppurative infection of the vulvovaginal glands
Syphilis -> primary chancre at site of inoculation
Candida vulvitis

Leukoplakia (Non-neoplastic Epithelial

Disorders NNED)

Very important to look for neoplastic potential

Lichen Sclerosus (Kraurosis vulvae)

In postmenopausal women
Thinning of the epidermis and disappearance of the rete pegs, hydropic degeneration of
the basal cells, superficial hyperketosis, dermal fibrosis with a scant perivascular,
mononuclear infiltrate
Smooth, white plaques papules that with time can coalesce (parchment like) with dense
collagen
Very Low to NO malignant potential
High Levels of T cells and high association with other autoimmune diseases suggests
that it is Autoimmune in nature

Lichen Simplex Chronicus (Hyperplastic dystrophy)

End stage of many inflammatory dermatoses and is marked by epithelial thickening,
expansion of the stratum granulosum and significant hyperkeratosis
Appears clinically as leukoplakia
Epithelium may show increased mitotic activity in both the stratum basalis and
spinosum
High leukocyte infiltration in the dermis
No Atypia in the hyperplastic cells
Generally no predisposition to cancer but oddly it is found at the margins of established
cancer of the vulva

Bowens Disease (Carcinoma in situ)

Appears as leukoplakia
Pre-neoplastic lesion
Can appear as a reddish brown plaque
Needs surgical excision so that it doesnt
progress to carcinoma

Vulva intra epithelial Neoplasia (VIN)

Occurs in women over 60 years old
Two biological forms of vulvular carcinoma
1. Seen in younger women particular in cigarette smokers
and HPV 16 is often seen
Often found is a coexisting vaginal or cervical carcinoma,
carcinoma in situ or condyloma acuminata suggesting a common
cause, HPV.

2. Seen in older women not associated with HPV but is

often preceded by years of non-neoplastic epithelial
changes (usually lichen sclerosus)
Cells display dyskeratotic cells, angular budding and basal
keratinization

VIN is graded and can be found in multiple, apparently

separate foci or may coexist with an invasive lesion

Carcinoma Vulva
Usually occurs in women over 60 years old
Appears as a plaque, nodule or ulcerous lesion
Typically occurs on the anterior 2/3 of the labia
majora
Usually of the squamous cell variety
Spreads to the inguinal and pelvic nodes
Invasive Squamous cell carcinoma is ulcerated
with raised edges or can be a fungating tumor
mass

Extramammary Padget Disease

Essentially a form of intraepithelial carcinoma
Unlike the breast where it is associated with an underlying carcinoma, the
majority of cases of vulvar Padget Disease have no demonstrable
underlying carcinoma
Occasionally there is an accompanying subepithelial or submucosal
tumor arising in an adnexal structure, typically the sweat gland
Morphology:
Presents as a red, scaly, crusted plaque and may appear as an inflammatory
dermatosis

Histology:
Large epitheloid cells infiltrate the epithelium, singly and in groups, with
abundant granular cytoplasm and occasional cytoplasmic vacuoles containing
mucin that stain positive with PAS

When the cells are confined to the epithelium, they may persist for years
or even decades without evidence of invasion
When associated with an appendageal tumor, the cells extend into the
skin appendages and invade locally with ultimate metastases to more
distant sites (usually within the first 2-5 years)

Normal Placenta
Placental villi surrounded by maternal blood
Embryonic vessel contains nucleated red cells
Surrounded by loose mesenchyme
Covered by cytotrophoblasts and
syncitiotrophoblasts

Loose Mesenchyme
Nucleated
Fetal Blood

Ectopic Pregnancy
Implantation of the fertilized ovum in any site other than the
normal uterine location (about 1% of pregnancies)
90% of ectopic pregnancies are in the oviducts (tubal
pregnancy)
Other sites are the ovaries, abdominal cavity, intrauterine portion
of the oviducts (interstitial pregnancy)

Pathogenesis:
Any factor that retards passage of the ovum along its course
through the oviducts to the uterus predisposes to an ectopic
pregnancy
In half of the cases, the obstruction is base on chronic
inflammatory changes in the oviduct, although tumors and
endometriosis can also cause an obstruction

Morphology:
All are characterized by fairly normal early development of the
embryo with the formation of placental tissue, the amniotic sac
and decidual changes
Abdominal pregnancies are often carried to term

Ectopic Pregnancy
Tubal Pregnancy and Rupture:
Increased risk with PID and tubal adhesions or endometriosis with fibrosis (50% are
idiopathic)
There is lack of space, poor vasculature and limited placental size and will usually
rupture 2-6 weeks after fertilization
The invading placenta eventually burrows through the wall of the oviduct causing
intratubal hematoma (hematosalpinx), intraperitoneal hemorrhage, or both
The tube distends by the contained mass of freshly clotted blood in which may be seen
bits of gray placental tissue and fetal parts
Curettings will show NO Chorionic Villi; will have secretory glands
**Rule out Spontaneous Abortion if Chorionic Villi**

Clinically:
Until rupture, an ectopic pregnancy will appear normal with cessation of menstruation
and elevation of serum and urinary placental hormones
Under the influence of these hormones, the endometrium undergoes the characteristic
hypersecretory and decidual changes
Upon rupture, there may be a sudden onset of intense abdominal pain and signs of an
acute abdomen followed by shock where prompt surgical intervention is necessary
If right sided, will mimic acute appendicitis
Lab values of HCG will be elevated as they would be in normal pregnancy, but upon
rupture, the values will quickly decline which will eventually lead to the degeneration
of the corpus luteum which leads to a decrease in estrogen and progesterone
The lack of hormones will lead to the breakdown of the endometrium -> bleeding

Ectopic Pregnancy

Abortion
Defined as delivery of the embryo from week 8 or the
fetus up to 20 weeks (anything from 20-40 weeks is
termed pre-mature delivery)
Usually caused by defective chromosomes
Symptoms:
Vaginal bleeding which is rapid and severe which can lead
to shock
Lower abdominal pain due to uterine contraction

Diagnosis:
Demonstrate chorionic villi or embryo
*In ruptured ectopic pregnancy -> no demonstrable
chorionic villi*

Placental Abnormalities
Placenta Previa:
The placenta implants over the internal os which leads to ante
partum hemorrhage
Diagnosed via ultrasound and requires caesarian section

Abruptio placenta:
Premature separation of the placenta which leads to ante
partum hemorrhage, shock, DIC, premature labor or fetal death

Placenta accreta:
Absence of plane of separation between the villi and
myometrium which leads to severe POST partum hemorrhage
Deep implantation of the placenta into the myometrium
Requires hysterectomy or can lead to maternal death

Pre-eclampsia/Eclampsia
Gestational Edema with proteinuria and hypertension GEPH with GE, P, H
occurring in the 3rd trimester (distinct from a hypertensive woman becoming
pregnant)
Occurs in 5% of pregnancies and 10% of PE patients develop seizures (eclampsia)
Solutions are to induce labor or a caesarian section
Problems disappear after birth of the baby
Risk Factors:

Primigravida (first pregnancy) over the age of 35 yrs

Multiple pregnancies
Hydramnios (excess amniotic fluid)
Pre-existing Hypertension (doesnt always cause pre-eclampsia)
Hydatidiform Mole

Pathology:
The basic feature underlying all cases is inadequate maternal blood flow to the
placenta, secondary to inadequate development of the spiral arteries of the placental
bed
In the 3rd trimester, the musculoelastic walls of the spiral arteries are replaced by a
fibrinous material, permitting them to dilate into wide vascular sinusoids but in preeclampsia and eclampsia, the walls are retained and the channels remain narrow
Can cause placental ischemia through the possible mechanism of an autoimmune
reaction to the placenta

Pre-eclampsia/Eclampsia
Consequences:
Placental hypoperfusion with an increased predisposition to the development of
infarcts
Reduced elaboration by the trophoblast of the vasodilators prostacyclin, prostaglandin
E2 and NO which normally oppose the effects of rennin and angiotensin, which leads
to the hypertension
Production of the ischemic placenta of thromboplastic substances such as tissue factor
and thromboxane which are the cause for the DIC
Acute atherosis of the spiral arteries: foamy macrophages in necrotic vessel walls which
is characteristic and later on macrophages and lymphocytes

Multiorgan changes
Kidneys:
Depends on the severity of the DIC
Changes consist of fibrin thrombi within the glomerular capillaries, accompanied by endothelial
swelling and possibly mesangial hyperplasia
Focal glomerulitis may ensue and when enough are affected, the blood flow to the cortex is reduced,
possible resulting in renal cortical necrosis that may be bilateral and fatal

Other organs:
Microvascular thrombi can occur in brain, pituitary, heart and elsewhere which have the potential for
producing focal ischemic lesions accompanied by microhemorrhages

Liver:
Periportal hypertension

Gestational Trophoblastic Disease

Broken up into three classifications: Hydatidiform
Mole (most benign), Invasive Mole and
Choriocarcinoma (most invasive)
All elaborate hCG which can be detected in the
circulating blood and urine at titers considerably
higher than those found during pregnancy
The levels considerably rise from partial hydatidiform
moles to choriocarcinoma to help in differentiating
the three
These levels apart from aiding in diagnosis also help
track the response to therapy

Hydatidiform Mole

Common before age 20 years and after age 40 years

Voluminous mass of swollen, sometimes cystically dilated, chorionic villi appearing grossly as
grapelike structures
Swollen villi are covered by varying amounts of normal to highly atypical chorionic
epithelium
Once one occurs, the risk is increased in other pregnancies
Complete:
Does not permit embryogenesis and therefore never contains any fetal parts
All of the chorionic villi are abnormal and the chorionic epithelial cells are diploid (46, XX or uncommonly
46, XY)
An empty egg is fertilized by two spermatozoa/diploid sperm yielding a diploid karyotype composed of
entirely paternal genes
May produce bilateral theca lutein cysts

Partial:
1:2000 pregnancies in the US and West (higher in Asian countries)
Compatible with early embryo formation and therefore contains fetal parts, has some normal chorionic
villi and is almost always triploid (69, XXY = 23X sperm and 23Y sperm plus 23X egg)
Normal egg is fertilized by two spermatozoa/diploid sperm resulting in a triploid karyotype with a
preponderance of paternal genes

Both result from abnormal fertilization

Clinically:

Amenorrhea, vomiting, +ve pregnancy test

Uterus will be larger compared to amenorrhea (large for date)
At 3-4 months, vaginal bleeding, grape like structures
On ultrasound, enlarged cystic placenta with absent fetus
Curettage to remove the lesion

Hydatidiform Mole
Complete

Partial

Karyotype

46, XX,XY: Diploidy

69,XXY: Triploidy

Villous Edema

All Villi

Some Villi

Trophoblast Prolif

Diffuse/Circum.

Focal/Slight

Atypia

Often

Absent

Serum hCG

Elevated

Less Elevated

hCG in tissue

++++

Behavior

2% Chorio Ca

Rare Chorio Ca

Invasive Mole (Chorioadenoma destruens)

Complete moles that are more invasive locally but do not have
aggressive metastatic potential of the choriocarcinoma
Retains the hydropic villi, which penetrates the uterine wall deeply,
possibly causing rupture and sometimes life-threatening
hemorrhage and necrosis
Local spread to the broad ligament and vagina may also occur
Microscopically:
Epithelium of the villi is marked by hyperplastic and atypical changes
with proliferation of both cuboidal and syncytial components

Hydropic villi may embolize to distant organs such as the lungs or

brain but they do not constitute true metastases and may actually
spontaneously regress
An invasive mole is harder to remove completely by curattage
because of its increased invasiveness and therefore the serum hCG
might remain elevated
Cure is possible through chemotherapy

Gestational Choriocarcinoma

Very aggressive malignant tumor either from gestational chorionic epithelium or

less frequently from totipotential cells within the gonads
Etiology:
High incidence in Asia and Africa but only 1:40k in the US and Western World
Risk is greater before the age of 20 and significantly increased after the age of 40
50% follow a mole, 25% follow an abortion, 23% follow a normal pregnancy and 2% follow an
ectopic pregnancy

Pathology:
Friable, hemorrhagic mass with extensive infiltration and metastases in the lung, brain and
liver
Cells are malignant cytotrophoblasts and syncitiotrophoblasts
Causes hemorrhage and necrosis (bloody discharge per vagina)
NO CHORIONIC VILLI
hCG is elevated but in order to confirm diagnosis, must biopsy

Chemotherapy yields good results and a possible cure

Follow up hCG levels are monitored
**Gestational Choriocarcinoma has a better prognosis and responds better to
therapy than ovarian choriocarcinoma because there is both a maternal and
paternal component. When the maternal component transforms, the paternal
component can product Ab towards the maternal component aiding in its
destruction.**

Gestational Choriocarcinoma

Placental Site Trophoblastic Tumor

Rare
Proliferation of the cytotrophoblasts in uterus
Follows an abortion or normal pregnancy
No villi, no fetal parts, no
syncitiotrophoblasts
Cells have placental lactogen but very little
hCG
Cured by curattage