Far Eastern University – Nicanor Reyes Medical Foundation
Pathology B – Female Genital Tract
Francis Dematera M.D.
Development of the Female Genital Tract:
 Germ cells
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 Arise in the wall of the yolk sac by the 4 week of gestation
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 5 – 6 week they migrate to the urogenital ridge and induce
proliferation of mesodermal epithelium giving rise to
epithelium and stroma of the ovary.
 Mullerian ducts
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 Form at about 6 week through invagination and fusion of
the coelomic lining epithelium.
 Progressively grow caudally and medially to fuse with the
urogenital sinus at the mullerian tubercle.
 Unfused upper portions mature into the fallopian tubes.
 Fused lower portions give rise to uterus, cervix, upper vagina
 Urogenital Sinus
 Develops when the cloaca is divided by the urorectal septum
 Forms the lower part of the vagina and vestibule
 Mesonephric ducts
 Normally regresses in female.
 Remnants may persist as epithelial inclusions adjacent to the
ovaries, fallopian tube, and uterus.
 In the cervix and vagina, may be cystic - Gartner duct cyst
 Epithelial lining of the tract and the ovarian surface share a
common origin from coelomic epithelium (mesothelium), which
may explain morphologically similar lesions.
Infections
 Some infections such as Candida, Trichomonas, and Gardnerella
are very common and may cause significant discomfort but
without any serious sequelae.
 Others such as N. gonorrhoeae, Chlamydia may cause infertility.
 U. urealyticum and M. hominis are implicated in preterm delivery
 HSV can cause painful genital ulcerations.
 HPV is involved of cervical, vaginal, and vulvar cancer.
 Many of these infections are sexually transmitted.
INFECTIONS OF LOWER GENITALACT TRACT
Herpes Simplex Virus
 Involves, in order of frequency, the cervix, vagina, and vulva.
 HSVs are DNA viruses that include 2 serotypes (HSV-1, -2).
 HSV-1 typically results in oropharyngeal infection
 HSV-2 usually involves genital mucosa and skin
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 HSV-1 may be detected in the genitalia same as HSV-2 may be
detected in the oral mucosa.
 1/3 are symptomatic, lesions develop 3-7 days after transmission
associated with systemic symptoms.
 Progress to vesicles and then to painful coalescent ulcers.
 Easily visible on vulvar skin and mucosa, while cervical & vaginal
lesions present with severe purulent discharge and pelvic pain.
 Lesions around the urethra may result to painful urination.
 Mucosal skin lesions heal spontaneously in 1-3 weeks.
 Virus migrates to regional lumbosacral nerve ganglia and
establishes a latent infection may be triggered and reactivates.
 Transmission occurs on the active phase but may occur during
the latent phase due to subclinical viral shedding.
 Women are more susceptible then men.
 Highest risk of infection is active during delivery of a neonate.
 Diagnosis is based on typical clinical findings and HSV detection:
 Purulent exudate is aspirated & inoculated on tissue culture
 After 48-72 hours, viral cytopathic is seen & can be serotyped
 Some offer more sensitive PCR, ELISA, Direct IF Ab tests.
Morphology
 On biopsy, it is typically in the phase of an ulcer.
 Desquamated epithelium, acute inflammation in the ulcer bed.
 Cytopathic change consists of multinucleated squamous cell with
eosinophilic to basophilic viral inclusions with ground-glass
appearance
Molluscum contagiosum
 Caused by poxvirus, four viruses (MCVs 1-4).
 MCV-1 being the most prevalent
 MCV-2 being the most often sexually transmitted
 Common in young children between 2-12 years of age,
transmitted to direct contact or shared articles.
 Most common on the trunk, arms, and legs.
 In adults, it is typically sexually transmitted.
 Average incubation period is 6 weeks.
 Diagnosis is based on the appearance of pearly, dome-shaped
papules with a dimpled center measuring 1-5 mm and the
central waxy core contains cells with cytoplasmic viral inclusions.
Fungal Infections
 Especially those caused by yeasts (Candida) are common.
 Yeasts are part of normal vaginal flora.
 Development of symptomatic candidiasis is a result of a
disturbance in the patient’s vaginal microbial ecosystem.
 Compromising neutrophil or TH17 T-cell functions are permissive
to such infections (DM, Antibiotics, and Pregnancy).
 Vulvovaginal pruritus, erythema, swelling & curd-like discharge.
 Diagnosis is based on finding pseudospores or filamentous
hyphae in wet KOH mounts of the discharge or on a Pap smear.
Trichomonas vaginalis
 T. vaginalis is a large, flagellated ovoid protozoan transmitted via
sexual contact and develops within 4 days to 4 weeks.
 Asymptomatic with yellow, frothy vaginal discharge, vulvovaginal
discomfort, dysuria, and dyspareunia (painful intercourse).
 Mucosa typically has fiery-red appearance with marked dilation
of mucosal vessels resulting in a strawberry cervix appearance.
Gardnerella vaginalis
 Gram-negative bacilli cause of bacterial vaginosis (vaginitis).
 Present with thin, green-gray malodorous (fishy) discharge.
 Pap smears reveal superficial and intermediate squamous cells
covered with shaggy coating coccobacilli and clue cells.
 Cultures reveal G. vaginalis and other bacteria (anaerobic
peptostreptococci and aerobic α-hemolytic streptococci).
 Implicated in premature labor in pregnant patients.
INFECTIONS OF THE LOWER AND UPPER GENITAL TRACT
Pelvic Inflammatory Disease (PID)
 Infection that begins in the vulva/vagina and spreads upward to
involve most of the structures, results in pelvic pain, adnexal
tenderness, fever, and vaginal discharge.
 Neisseria gonorrhea is a common cause of PID.
 Chlamydia is another cause.
 Infections after spontaneous or induced abortions and normal or
abnormal deliveries (puerperal infections) are also causes of PID.
 Infections are typically polymicrobial caused by staphylococci,
streptococci, coliforms, and Clostridium perfringens.
 Gonococcal infections appear 2-7 days after inoculation.
 Most commonly involves the endocervical mucosa, may also
begin in the Bartholin gland or other vestibular glands
 Non-gonococcal infections spread upwards via lymphatics or
venous channels rather than mucosal surfaces producing more
inflammation with deeper layers of the organs than gonococcal.
Morphology
 Gonococcal infection is marked by acute inflammation.
 Show phagocytosed gram-negative diplococci within neutrophils
 Definitive diagnosis requires culture or detection of gonococcal
RNA or DNA.
 Endometrium is usually spared in spread, but within the fallopian
tubes causes acute suppurative salpingitis.
 Tubal mucosa becomes congested resulting in epithelial injury
and sloughing of the plicae, tubal lumen fills with purulent
exudate that may leak out of the fimbriated ends.
 Infection may spread to the ovary to create salpingo-oophoritis.
 Collection of pus may accumulate in the ovary and tube (tubo-
ovarian abscess) or tubal lumen (pyosalpinx).
 Infecting organisms may disappear but the plica may adhere and
slowly fuse in a reparative, scarring process forming gland-like
spaces and blind pouches, referred as chronic salpingitis.
 Hydrosalpinx may develop due to consequence of fusion of the
fimbria and subsequent accumulation of secretions.
 Non-gonococcal PID show more inflammation within the deeper
tissue layers, often spread throughout the wall to involve the
serosa, broad ligaments, peritoneum.
 Bacteremia more common complication of non-gonococcal PID.
 Acute complications of PID:
 Peritonitis  Bacteremia
 Endocarditis  Meningitis
 Suppurative Arthritis
 Chronic Sequelae
 Infertility  Tubal Obstruction
 Ectopic Pregnancy  Pelvic Pain
 Intestinal obstruction
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Vulva
 Because it is constantly exposed to secretions and moisture, it is
more prone to superficial infections than skin elsewhere.
 Non-specific vulvitis occurs in setting of immunosuppression.
 Most skin cysts and tumors can also occur in the vulva.
Bartholin Cysts
 Infection of the Bartholin gland produces acute inflammation
(adenitis) and may result in an abscess.
 Duct cysts are common, occur at all ages, and result from
obstruction of the duct by an inflammatory process.
 Cysts are usually lined by transitional or squamous epithelium.
 Excised or opened permanently (marsupialization).
NON-NEOPLASTIC EPITHELIAL DISORDERS
Leukoplakia
 Opaque, white, plaque-like epithelial thickening that may
produce pruritus and scaling, may be caused by disorders:
 Inflammatory dermatoses
 Lichen sclerosus and squamous cell hyperplasia
 Neoplasia such as vulvar interaepithelial neoplasia, Paget
disease, and invasive carcinoma.
Lichen Sclerosus
 Smooth, white plaques, or macules that may enlarge & coalesce
producing a surface that resembles porcelain or parchment.
 When entire vulva is affected, labia becomes atrophic and
agglutinated, and the orifice constricts.
 Thinning of the epidermis, degeneration of basal cells,
hyperkeratosis, sclerotic changes of dermis, and band-like
lymphocytic infiltrates.
 Most common in postmenopausal women.
 Increased chance of developing squamous cell carcinoma.
Squamous cell Hyperplasia
 Hyperplastic dystrophy or lichen simplex chronicus.
 Non-specific condition resulting from rubbing or scratching the
skin to relieve pruritus.
 Presents as leukoplakia, with thickening of the epidermis
(acanthosis) and hyperkeratosis.
 Lymphocytic infiltration of the dermis is present.
 Mitotic activity without atypia, not considered premalignant.
BENIGN EXOPHYTIC LESIONS
 Benign raised or wart-like lesions may be caused by infections or
reactive conditions of unknown etiology.
 Vulvar fibroepithelial polyps or skin tags are similar to skin tags
occurring elsewhere on the skin.
 Vulvar squamous papillomas are covered by non-keratinized
squamous epithelium, develop on vulvar surfaces.
Condyloma acuminatum
 Benign genital warts caused by low oncogenic risk HPV (6, 11).
 More frequently multifocal, involving vulvar, perineal, and
perianal areas, similar lesions those found on penis of males.
 Consist of papillary, exophytic, tree-like cores of stroma covered
by thickened squamous epithelium.
 Surface shows viral cytopathic change called koilocytic atypia
manifests as nuclear enlargement, hyperchromasia, and
cytoplasmic perinuclear halo.
 Non-precancerous lesion.
SQUAMOUS NEOPLASTIC LESIONS
Vulvar Intraepithelial Neoplasia and Vulvar Carcinoma
 Carcinoma of the vulva is uncommon, represents 3% of all
genital cancers, occur in 2/3 of women older than 60 years old.
 Squamous cell carcinoma is the most common histologic type.
 Can be divided into two based on etiology:
 Basaloid and warty carcinoma related to infection with high-
risk HPVs (16) are less common and occur at younger ages.
 Keratinizing squamous cell carcinoma unrelated to HPV is
more common occurring in older women.
 Basaloid and warty carcinoma
 Develop from in situ lesion called classic vulvar
intraepithelial neoplasia (VIN), occurs mainly in reproductive
age women, includes lesions designated formerly as
carcinoma in situ or Bowen disease.
 Risks are same with cervical squamous intraepithelial lesion
(young age at first intercourse, multiple sex partners, and
male partner with multiple sex partners).
 Risk of progression to invasive carcinoma is higher in women
older than 4 years of age.
 Keratinizing Squamous Cell Carcinoma
 Occurs with long-standing lichen sclerosus or squamous cell
hyperplasia, and is not related to HPV.
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 Peak occurrence is in the 8 decade.
 Arises from precursor lesion called differentiated vulvar
intraepithelial neoplasia (differentiated VIN) or VIN simplex
 Chronic epithelial irritation or squamous cell hyperplasia may
contribute to evolution to malignant phenotype.
Morphology
Classic VIN
 Discrete white hyperkeratotic or slightly raised pigment lesion.
 Epidermal thickening, nuclear atypia, increased mitoses, and lack
of cellular maturation, analogous to that of cervical SILs.
 Invasive CA that arise in classic VIN may be exophytic or
indurated with central ulceration.
 Basaloid carcinoma consists of nests and cords of small, tightly
packed cells that lack maturation.
 Warty carcinoma is characterized by exophytic, papillary
architecture and prominent koilocytic atypia.
Differentiated VIN
 Marked atypia of the basal layer of the squamous epithelium
and normal-appearing differentiation of the more superficial.
 Invasive keratinizing SCCA contain nests and tongues of
malignant squamous epithelium with prominent central keratin
pearls.
 Risk of cancer development depends on duration and extent of
the disease and the immune status of the patient.
 Invasive CA - associated lichen sclerosus, squamous cell hyperplasia.
 Lympho-hematogenous dissemination to lungs, liver, other
organs may occur.
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GLANDULAR NEOPLASTIC LESIONS
 Vulva contains modified apocrine sweat glands.
Papillary Hidradenoma
 Presents as sharply circumscribed nodule.
 Most commonly on the labia majora and interlabial folds.
 Confused with carcinoma because of its tendency to ulcerate.
 Identical histology to intraductal carcinoma of the breast.
 Consist of papillary projections covered by 2 layers of cells,
an upper columnar secretory cell, and a deeper flattened
myoepithelial cells.
Extramammary Paget Disease
 Similar in its manifestations to Paget disease of the breast.
 Pruritic, red, crusted, map-like area, usually on the labia majora.
 In contrast to Paget disease of nipple, in which 100% of patients
have underlying ductal breast CA, vulvar Paget is not associated
with underlying cancer, and is confined to the epidermis.
Morphology
 Distinctive intraepithelial proliferation of malignant cells.
 Paget cells are larger than surrounding keratinocytes, seen singly
or in small clusters within the epidermis.
 Cells have pale cytoplasm containing mucopolysaccharide stains
with PAS, Alcian blue, or mucicarmine stains.
 Cells express cytokeratin 7.
 Displays apocrine, eccrine, and keratinocyte differentiation, and
arise from multipotent cells within mammary-like gland ducts of
the vulvar skin.
Malignant Melanoma (from old PPT)
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 Peak at 6 to 7 decade of life.
 5 year survival of less than 32%
 Depth of invasions if deeper than 1 mm is associated with more
than 60% of mortality rate.
 (+) S100, (-) cytokeratin, lacks mucopolysaccharide.
Vagina
 Free from primary disease, most serious primary lesions is
vaginal squamous cell carcinoma.
 Inflammation often affects the vulva and perivalvular areas and
spreads to the cervix without significant vaginal involvement
DEVELOPMENTAL ANOMALIES
Septate or Double Vagina
 Failure of mullerian duct fusion, accompanied by double uterus
or uterus didelphys.
Vaginal Adenosis
 During development, the vagina is initially covered by columnar,
endocervical type of epithelium, normally replaced by squamous
cell epithelium upwards from the urogenital sinus.
 Small patchy residual glandular may persist in adults recognized
as vaginal adenosis, presents as red, granular areas that stand
out from surrounding pale-pink mucosa.
 Consists of columnar mucinous epithelium.
 35-90% of women exposed to DES in utero.
 Clear cell carcinoma arising in DES-related adenosis.
Gartner Duct Cysts
 Common, found along the lateral walls of the vagina.
 Derived from Wolffian (mesonephric) duct rests.
 1-2cm fluid filled cysts occur in the submucosa.
 Other cysts may occur in the proximal vagina are derived from
mullerian epithelium.
PREMALIGNANT AND MALIGNANT NEOPLASMS OF THE VAGINA
 Most benign tumors occur in reproductive age women includes
stromal tumors, leiomyomas, and hemangiomas.
 Most common malignant tumor is carcinoma spreading from the
cervix, followed by squamous cell CA.
Vaginal Intraepithelial Neoplasia and Squamous Cell Carcinoma
 Virtually, all primary carcinomas are SCC associated with high
risk HPV infections.
 Greatest risk factor is a previous carcinoma of the cervix or vulva
 SCC arise from premalignant lesion, vaginal intraepithelial
neoplasia, analogous to cervical squamous intraepithelial lesion
 Most invasive tumors affects the upper vagina, particularly the
posterior wall at the junction of ectocervix.
 Lesions in the lower 2/3 metastasize to inguinal lymph nodes.
 Lesions in the upper vagina spread to regional iliac lymph nodes.
Embryonal Rhabdomyosarcoma (Sarcoma botryoides)
 Composed of malignant embryonal rhabdomyoblasts.
 Most frequently found in infants and in children younger than 5
years of age.
 Grow as polypoid, rounded, bulky masses, grape-like clusters.
 Cells are small, have oval nuclei, small protrusions of cytoplasm
from one end, resembling a tennis racket.
 Rarely, striations can be seen within the cytoplasm.
 Beneath the vaginal epithelium, tumor cells are crowded in a
cambium layer, but in the deep regions they lie within a loos
fibromyxomatous stroma.
 Tumors invade locally and cause death by penetration into the
peritoneal cavity or by obstruction of the urinary tract.
Cervix
 Composed of:
 Ectocervix – external, vaginal portion covered by squamous
epithelium continuous with the vaginal wall, the lining
converges centrally at a small opening called external os.
 Endocervix – lined by columnar, mucus-secreting epithelium.
 The squamocolumnar junction moves upward with time.
 There are areas where columnar epithelium abuts the squamous
epithelium termed the transformation zone.
INFLAMMATIONS
Acute and Chronic Cervicitis
 Intravacuolar glycogen in the squamous cells provides substrate
for various endogenous vaginal aerobes and anaerobes,
predominantly Lactobacilli.
 They produce lactic acid, maintains pH below 4.5, suppressing
growth of saprophytic and pathogenic organisms.
 If pH becomes alkali due to bleeding, sexual intercourse, or
douching, H2O2 production of lactobacilli decreases.
 Antibiotic therapy may suppress lactobacilli.
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 The alkali pH may promote overgrowth of other organisms.
 Infections by gonococci, chlamydiae, mycoplasmas, and HSV may
produce significant acute or chronic cervicitis.
ENDOCERVICAL POLYPS
 Common benign exophytic growths that arise within endocervix
 Vary from small, sessile bumps to large polypoid masses.
 Composed of loose fibromyxomatous stroma covered by mucus-
secreting endocervical glands, often accompanied by inflamm.
 Source of irregular vaginal spotting or bleeding.
 Curettage or excision is curative.
PREMALIGNANT AND MALIGNANT NEOPLASMS OF THE CERVIX
Pathogenesis
 High-risk HPVs are the most important factor.
 HPVs are DNA viruses grouped into high- or low-oncogenic risk
 15 high risk HPVs
 But HPV-16 alone accounts for almost 60% of cervical CA
 HPV-18 accounts for another 10% of cases.
 Other HPV types contribute to less than 5%
 Also implicated in SCC of many other sites (penis, vulva, vagina,
anus, tonsil, and other oropharyngeal locations).
 Low-risk HPVs cause warts (condyloma acuminatum).
 Genital infections are asymptomatic and do not cause tissue
damage hence undetected on pap smear.
 50% of infections are cleared via immune response within 8
months, and 90% are cleared within 2 years.
 High-risk HPV infection lasts longer than low-risk HPVs.
 HPVs infect immature basal cells of the squamous epithelium in
areas of epithelial breaks or immature metaplastic squamous cell
at the squamocolumnar junction.
 HPV cannot infect mature squamous cells.
 The ability of HPV to act as carcinogen depends on its viral
proteins E6 and E7, which interfere tumor suppressor proteins.
 E7 binds to active forms of TB and promotes its degradation.
 E6 up regulates expression of telomerase, and binds to p53
(a tumor suppressor) and promotes its degradation.
Cervical Intraepithelial Neoplasia
 Also called Squamous Intraepithelial Lesions.
 Cervical precursor lesion.
 LSIL is associated with productive HIV infection, there is high
level of viral replication and only mild alterations in host cells.
 LSIL does not progress directly to invasive carcinoma.
 Most of LSIL spontaneously regresses.
 Derangement of cell cycle in HSIL may become irreversible and
lead to a fully transformed malignant phenotype, thus all HSILs
are considered to be high risk for progression to carcinoma.
 LSILs are 10x more common than HSILs.
Morphology
 Diagnosis of SIL is based on identification of nuclear atypia
characterized by nuclear enlargement, hyperchromasia, coarse
chromatin granules, and variation in sizes.
 Accompanied by cytoplasmic halos consist of perinuclear
vacuoles termed koilocytic atypia.
 Grading is based on expansion of immature cell layer from its
normal, basal location.
 If the immature squamous cell is confined to the lower 1/3 of
the epithelium, lesion is graded as LSIL.
 If they expand to upper 2/3 of the thickness, it is HSIL.
 Highest viral loads are found in maturing keratinocytes in the
upper half of the epithelium.
 HPV E6 and E7 express markers in the upper portion of the
epithelium such as Ki-67 normally confined to the basal layer,
also overexpresses p16 due to disturbed growth.
 80% of LSILs and 100% HSIL are associated with HPV-16.
Cervical Carcinoma
 Average age is 45 years old.
 Squamous cell carcinoma is the most common type.
 Second most common is adenocarcinoma, develops from a
precursor lesion called adenocarcinoma in situ.
 Adenosquamous and neuroendocrine account for 5% of cases.
 All are caused by high-risk HPVs.
 In situ to invasive adenosquamous and neuroendocrine is
shorter than squamous cell carcinoma.
Morphology
 Either exophytic (fungating) or infiltrative masses.
 Squamous cell carcinoma
 Composed of nests and tongues of malignant squamous
epithelium, either keratinizing or not which invade the
underlying cervical stroma
 Adenocarcinoma
 Characterized by proliferation of glandular epithelium.
 Composed of malignant endocervical cells with large,
hypechromatic nulceri and mucin-depleted cytoplasm.
 Results in dark appearance of the glands.
 Adenosquamous carcinoma
 Composed of intermixed malignant glandular and squamous
epithelium.
 Neuroendocrine cervical carcinoma
 Has an appearance similar to small cell carcinoma of the
lungs, differs in being + for HPVs.
 Advanced cervical carcinoma spreads by direct extension to
contiguous tissue, includes bladder, ureters, rectum, and vagina
 Lymphvascular invasion results in local and distal LN metastasis.
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 Stage 0 – Carcinoma in situ (CIN III, HSIL).
 Stage I – Carcinoma confined to the cervix
 Ia – preclinical carcinoma, diagnosed only on microscopy
 Ia1 – Stroma invasion no deeper than 3mm, no wider than 7mm
 Ia2 – Maximum depth of invasion of stroma is deeper than
3mm and no deeper than 5mm, horizontal invasion not more
than 7 mm.
 Ib – Histologically invasive carcinoma confined to cervix.
 Stage II – Extends beyond the cervix but not the pelvic wall,
involves the vagina but not the lower third.
 Stage III – Extends to the pelvic wall, on DRE there is no cancer-
free space, tumor involves the lower third of the vagina.
 Stage IV – Extended beyond the true pelvis, involved the mucosa
of bladder or rectum, cancer with metastatic dissemination.
Clinical Features
 Early invasive cancers may be treated by cervical cone excision
alone, most invasive cancers are managed by hysterectomy with
lymph node dissection.
 Radiation therapy and chemotherapy for advanced lesion.
 Prognosis depends on the stage at time of diagnosis.
 Small-cell neuroendocrine tumors have very poor prognosis.
 Most die due to local invasion.
 Cervical CA screening and prevention:
 Pap smear
 Histologic diagnosis and removal of precancerous lesion
 Surgical removal of invasive CA with adjunct chemo/radio
 HPV vaccination – quadrivalent for HPV 6, 11, 16, and 18
Body of Uterus and Endometrium
 2 major component: myometrium and endometrium.
 Myometrium is composed of interwoven bundles of smooth
muscles that form the wall of the uterus.
 Endometrium lines the inner cavity.
ENDOMETRIAL HISTOLOGY IN THE MENSTRUAL CYCLE
 Endometrium undergoes dynamic physiologic and morphologic
changes during the menstrual cycle in response to sex steroid
hormones produced in the ovary.
 “Dating” the endometrium may be used to assess hormonal
status, document ovulation, and determine causes of the
bleeding and infertility.
 Proliferative Phase Early Secretory Phase
Late Secretory Phase Menstrual Phase
 Cycle commences with menses during which the superficial
portion referred to as functionalis is shed.
 The Proliferative Phase
 Marked by rapid growth of the glands and stroma.
 The glands are straight, tubular structures lined by regular,
tall, pseudostratified cells, NO mucus secretion/vacuolization
 The stroma is composed of spindle cells with scant
cytoplasm.
 At ovulation, proliferation ceases and differentiation happens.
 Postovulation
 Initially marked by appearance of secretory vacuoles beneath
the nuclei of glandular epithelium.
 The basal vacuoles migrate to the apical surface, when
secretion is maximal (18-24 days), glands are dilated.
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 By 4 week, the glands are tortuous, producing a serrated
or saw-toothed appearance, accentuated by secretory
exhaustion and shrinkage
 Late Secretory Phase
 Stromal changes due to predominant progesterone.
 Spiral arterioles appear by days 21-22 with an increase in
ground substance and edema between stromal cells.
 By days 23-24, stromal cell hypertrophy, increased
cytoplasmic eosinophilia (predecidual change), resurgence of
stromal mitoses appear.
 Days 24-28 are accompanied by sparse infiltrate of
neutrophils and lymphocytes.
 With dissolution of corpus luteum and drop of progesterone
levels, functionalis degenerates and bleeding into the stroma
occurs, followed by breakdown and onset of next cycle.
Functional Endometrial Disorders
 Dysfunctional Uterine Bleeding
 Most commonly stems from hormonal disturbances.
 A clnical term for uterine bleeding that lacks an underlying
organic / structural abnormality.
 Any disturbances of the finely tuned system (hypothalamic
pituitary axis) results to dysfunctional uterine bleeding.
Page 6 of 16
Anovulatory Cycle
 Most frequent cause of dysfunctional bleeding is anovulation.
 Results from subtle hormonal imbalances and are most common
at menarche and in the perimenopausal period.
 Less commonly results from:
 Endocrine disorders
 Ovarian lesions
 Generalized metabolic disturbances
 Failure to ovulate results in excessive endometrial stimulation by
estrogens unopposed by progesterone.
 The endometrial glands undergo mild architectural changes
including cystic dilation, usually resolves due to next cycle.
 Repeated anovulation result in bleeding.
 Biopsies reveal stromal condensation and eosinophilic epithelial
metaplasia similar seen in menstrual endometrium.
 Lacks progesterone dependent features (glandular secretory
changes and stromal pre-decidualization).
 Most commonly, the endometrium is comprised of
pseudostratified glands and contains scattered mitotic figures.
Inadequate Luteal Phase
 Manifests clinically as infertility associated with either increased
bleeding or amenorrhea.
 Cause is believed to be inadequate progesterone production.
 Biopsy at an post ovulatory date show secretory endometrium
with features that lag behind those expected for the date.
Endometrial changes with OCP (from old PPT)
 Discordant appearance between the glands and stroma.
Menopausal and Postmenopausal change (from old PPT)
 Uninterrupted estrogen production can induce mild hyperplasia
and cystic dilation of the glands.
Inflammatory Disorders
 Uterus is relatively resistant to infection because endocervix
forms a barrier to ascending infection.
Acute Endometritis
 Uncommon, limited to bacterial infection after delivery or
miscarriage, retained products predispose to infection.
 Causative agents include group A hemolytic streptococci,
staphylococci, and other bacteria.
 Inflammation is limited to the stroma, entirely non-specific.
 Curettage with antibiotic therapy clears infection.
Chronic Endometritis
 Occur in association with the following disorders:
 Chronic PID
 Retained gestational tissue, postpartum or post-abortion.
 Intrauterine contraceptive device
 Tuberculosis from miliary spread, or more often from
drainage of tuberculous salpingitis.
 Diagnosis rests on identification of plasma cells in the stroma.
 In about 15% of cases, no cause is apparent.
Endometriosis and Adenomyosis
 Endometriosis is defined by presence of ectopic endometrial
tissue at a site outside of the uterus.
 Most commonly involves glands and stroma, occurs in the sites
in decreasing order of frequency:
1. Ovaries 2. Uterine Ligaments
3. Rectovaginal Septum 4. Cul de sac
5. Pelvic Peritoneum 6. Intestines, appendix
7. Mucosa of cervix, 8. Laparotomy scars
vagina, fallopian tube
 Often causes infertility, dysmenorrhea, pelvic pain, etc.
 Disease of women in active reproductive life (30-40y/o).
 Uncommonly, may invade and spread.
Pathogenesis
 Proposed origins fall into 2 categories:
 Origin from the uterine endometrium
 Origin from cells outside the uterus has capacity to give rise
to endometrial tissue.
 Regurgitation Theory – endometrial tissue implants at ectopic
sites via retrograde flow of menstrual endometrium.
 Benign Metastasis Theory – tissue from uterus can spread to
distant site via blood vessels and lymphatic channels.
 Metaplastic Theory – Arises directly from coelomic epithelium,
from which the mullerian ducts originate.
 Extrauterine stem or Progenitor cell Theory – Stem/progenitor
cells from the bone marrow differentiate into endometrium.
Page 7 of 16
 Endometriotic implants show certain differences:
 Release of proinflammatory and other factors (PGE2, IL-1B,
TNFa, IL-6, IL-8, NGF, VEGF, MCP-1, MMPs, TIMPs).
 Increased estrogen production by endometriotic stromal
cells, high levels of aromatase, absent in normal stroma.
Estrogen enhances the survival and persistence. A link
between inflammation and estrogen is due to the ability of
PGE2 to stimulate local synthesis of estrogen.
 Shared mutations in specific genes PTEN and ARID1A with
ovarian cancer.
Morphology
 Endometriotic lesions bleed periodically in response to extrinsic
cyclic (ovarian) and intrinsic hormonal situation.
 The bleeding produces nodules with a red-blue to yellow-brown
appearance, on or just beneath the mucosa or serosal surface.
 Organizing hemorrhage may cause extensive fibrous adhesions.
 Ovaries may become distorted by large cystic masses filled with
brown fluid, resulting to hemorrhage; this is clinically called as
chocolate cysts or endometriomas.
 Diagnosis is made when both glands and stroma are present,
with or without hemosiderin.
 Atypical endometriosis, the likely precursor of endometriosis-
related ovarian carcinoma has 2 morphologic appearance:
 One consists of atypia lining the cyst without major changes.
 Second is marked by glandular crowding due to excessive
epithelial proliferation, often associated with atypia.
Clinical Features
 Severe dysmenorrhea, dyspareunia, pelvic pain due to bleeding.
 Pain on defecation in rectal wall involvement.
 Dysuria in involvement of the bladder serosa.
 Menstrual irregularities are common.
 Adenomyosis is defined as the presence of endometrial tissue
within the uterine wall (Myometrium), remains in continuity with
the endometrium signifying downgrowth.
 Irregular nests of endometrial stroma with or without glands are
arranged and separated from the basalis by at least 2-3mm.
 Clinical symptoms include menometrorhagia, colicky
dysmenorrhea, dyspareunia, and pelvic pain.
 May coexist with endometriosis.
Endometrial Polyps
 Exophytic masses of variable size that project into the cavity.
 Single or multiple, usually sessile, 0.5 to 3cm.
 Lined by epithelium on three sides w/ central fibrovascular core
 May be asymptomatic or may cause abnormal bleeding if they
ulcerate or undergo necrosis.
 Contain certain chromosomal rearrangements similar to those
found on mesenchymal tumors.
 Glands may be hyperplastic, atrophic, or may demonstrate
secretory changes.
Endometrial Hyperplasia MALIGNANT TUMORS OF THE ENDOMETRIUM
 Important cause of abnormal bleeding and frequent precursor to Carcinoma of the Endometrium
the most common type of endometrial carcinoma.  Most common invasive cancer of the female genital tract.
 Defined as increased proliferation of the endometrial glands
relative to stroma, resulting to increased gland-to-stroma ratio. Pathogenesis
 Associated with prolonged estrogenic stimulation, which can be  Two broad categories: Type I and Type II.
due to anovulation, increased production, or exogenous source.
 Obesity, Menopause, Polycystic ovarian syndrome
 Functioning granulosa cell tumors
 Excessive ovarian cortical function
 Prolonged administration of estrogenic substrates
 Inactivation of PTEN tumor suppressor gene is a common
genetic alteration in both hyperplasia and carcinoma.
 PI3K/AKT pathway becomes overactive.
 Recent classification of endometrial hyperplasia:
1. Simple hyperplasia without atypia
2. Complex hyperplasia without atypia
3. Simple atypical hyperplasia
4. Complex atypical hyperplasia

Morphology
 Non-atypical hyperplasia cardinal features is an increase in the
gland-to-stroma ratio.
 Glands show variation in size and shape and may be dilated
 There may be back to back glands focally; some intervening
Type I Endometrial Carcinoma
stroma is usually retained.
 Most common type, accounts for 80% of cases.
 Reflects endometrial response to persistent estrogen
 Most are well-differentiated, mimics proliferative glands.
stimulation and rarely progress to adenocarcinoma.
 Referred to as endometrioid carcinoma.
 Transforms to cystic atrophy on estrogen withdrawal.
 Typically arise in the setting of endometrial hyperplasia.
 Atypical hyperplasia (endometrial intraepithelial neoplasia)
 Obesity, Diabetes, Hypertension, Infertility, Unopposed estrogen
 Complex pattern of proliferating glands displaying nuclear
atypia, commonly back-to-back and often have complex  Identical PTEN mutations with endometrial hyperplasia.
outline due to branching structures.  Most common mutation increase signaling via PI3K/AKT pathway
 Cells are rounded and lose perpendicular orientation to the  Individual tumors may harbor multiple mutations that increase
basement membrane. PI3K/AKT signaling, suggesting development is fostered by
 Nuclei have vesicular chromatin and conspicuous nucleoli. increased signal strength.
 Among the mutations are the following:
(from old PPT)  PTEN tumor suppressor genes (30-80% of endometrioid CA)
1.) Simple Hyperplasia without atypia  PIK3CA oncogene, plays a role in invasion (40% of cases)
 Mild hyperplasia, 1% may progress to cancer.  KRAS, stimulates PI3K/AKT (25% of cases)
 ARID1A loss of function, a regulator of chromatin structure.
2.) Simple Hyperplasia with atypia
 Cytologic atypia – loss of polarity, prominent nucleoli
 8% may progress to cancer

3.) Complex Hyperplasia without atypia

 Marked gland crowding and branching, back to back with scanty
stroma, no cytologic atypia.
 3% may progress to cancer

4.) Complex Hyperplasia with atypia

 Histologic overlap with well-differentiated endometrioid CA
 23-48% diagnosed by curettage show CA.
 Managed by hysterectomy.
 Young individuals may use Progestin and close follow up.

Page 8 of 16
Morphology
 Endometrioid carcinoma
 Can take the form of a localized polypoid tumor that diffusely
infiltrates the endometrial lining.
 Spread occurs by myometrial invasion followed by direct
extension to the adjacent structures.
 Dissemination to the lymph nodes eventually occur.
 Endometrioid adenocarcinoma
 Demonstrates glandular growth patterns resembling normal
endometrial epithelium, 3 histologic grades:
 Well differentiated (Grade 1) – well-formed glands
 Moderately differentiated (Grade 2) –well-formed glands
mixed with areas of solid sheets of cells, <50%
 Poorly differentiated (Grade 3) – greater than 50% of the
solid sheet growth pattern
 Up to 20% contain foci squamous differentiation, histologically
appears benign when associated with well-differentiated
adenocarcinoma.
 When poorly differentiated adenocarcinoma contain squamous
elements appear frankly malignant.
 Pathologic staging of both type I and type II adenocarcinoma and
malignant mixed mullerian tumors:
 Stage I – Confined to the corpus uteri itself
 Stage II – Involves the corpus and cervix
 Stage III – Extends outside but not outside the true pelvis
 Stage IV – Extends outside the true pelvis, involves the
mucosa of the bladder or the rectum
Type 2 Serous Carcinoma
 Occur in women who are 10 years older than with type I.
 Usually arise in the setting of endometrial atrophy.
 Poorly differentiated (grade 3) tumors.
 Most common subtype is Serous carcinoma, which overlap with
morphologically and biologically with ovarian serous carcinoma.
 Less common subtypes: Clear Cell, Malignant Mixed Mullerian
 Mutations in TP53 are present in 90% of cases.
 Majority are missense mutations resulting in an
accumulation of the altered protein.
 Precursor lesion (serous endometrial intraepithelial carcinoma)
consists of cells identical to the serous carcinoma but lacks
identifiable stromal invasion.
 Serous carcinoma presumably begins as a surface epithelial
neoplasm that extends into adjacent gland structure and later
invades the stroma.
 Poorer prognosis due to propensity to exfoliate and travel
through the fallopian tubes and implant on peritoneal surfaces.
Morphology
 Arise in small atrophic uteri and are often large bulky tumors or
deeply invasive into the myometrium.
 Precursor lesion consists of malignant cells similar to the
carcinoma but is confined to the epithelial surfaces.
 Invasive lesions may have papillary pattern of growth.
 Cells have marked atypia with high N:C ratio, atypical mitotic
figures, hyperchromasia, and prominent nucleoli.
 Can have glandular growth pattern, distinguished from type I by
the marked cytologic atypia.
 Classified as grade 3, irrespective of histologic pattern.
Page 9 of 16
Clinical Features
 Uncommon in women younger than 40 years old.
 Peak incidence in postmenopausal women, 55-65 years old.
 No currently available screening.
 Usually produces irregular, or postmenopausal bleeding with
excessive leukorrhea.
 Prognosis depends on clinical stage, histologic grade, subtype
 Stage I (grade 1 and 2) – 90% 5 year survival
 Stage I (grade 3) – 75%
 Stage II, III – 50% less
Malignant Mixed Mullerian Tumors
 MMMTs also referred to as carcinosarcomas are endometrial
adenocarcinomas with a malignant mesenchymal component.
 The mesenchymal component take number of forms:
 Some contain uterine mesenchymal elements (stromal
sarcoma, leiomyosarcoma).
 Others contain heterologous malignant cell types
(rhabdomyosarcoma, chondrosarcoma).
 Mutations involve same genes with endometrial carcinoma.
 Outcome is determined primarily by depth of invasion and stage.
 Patients with tumors that have heterologous mesenchymal
components do worse than those whose tumors do not.
 25-30% 5-year survival rate.
Morphology
 Often bulky and polypoid, may protrude to the cervical os.
 Usually consist of adenocarcinoma mixed with malignant
mesenchymal (sarcomatous) elements.
 The tumor may contain 2 distinct separate epithelial and
mesenchymal components.
 Sarcomatous components may also mimic extrauterine tissues.
 Metastasis only contains epithelial components.
TUMORS OF THE ENDOMETRIAL STROMA
 Uncommon, less than 5% of endometrial cancers.
Adenosarcomas
 Present as large, broad-based endometrial polypoid growths that
may prolapse through the cervical os.
 Diagnosis is based on presence of malignant-appearing stroma,
which coexist with benign but abnormal endometrial glands.
 Predominant in 40-0 years old, low-grade malignancy.
 Principal diagnostic dilemma is distinguishing from large benign
polyps, because adenosarcoma is estrogen sensitive and
responds to oophorectomy.
Stromal Tumors
 Resembles normal stromal cells.
 Divided into 2 categories:
 Benign stromal nodules
 Endometrial stromal sarcomas
 May be further divided into low- or high-grade types.
 Low-grade usually have translocations in which portions of the
JAZF1 gene encoding for transcriptional repressor is fused with a
gene belonging to the polycomb gene family such as SUZ12 that
participates in complex that introduce repressive histone marks
silencing genes.
 The fusion proteins act by disrupting the polycomb complex,
leading to misexpression of oncogenic genes.
 High-grade contain different chromosomal translocations,
currently unknown function.
 50% recur, relapse rates range from 36% (Stage I) to more than
80% (Stage III/IV), unpredicted by either mitotic index or atypia.
TUMORS OF THE MYOMETRIUM
Leiomyomas
 Uterine leiomyoma (fibroids) is the most common tumor in
women, they are benign smooth muscle neoplasms may occur
single but more often multiple.
 Normal karyotypes, 40% have simple chromosomal abnormality.
 Several cytogenetic subgroups:
 Rearrangements of 12q14 and 6p involving HMGIC and
HMGIY genes respectively.
 MED12 in 70% of leiomyomas encodes a component of
Mediator, a multiprotein complex that stimulates gene
expression by bridging long-range enhancers and promoters.
Morphology
 Sharply circumscribed, discrete, round, firm, gray-white tumors
varying in size from small to massive tumors that fill the pelvis.
 They are found within the myometrium of corpus.
 Characteristic whorled pattern of smooth muscle bundles on cut
section makes it readily identifiable.
 The individual muscle cells are uniform in size and shape.
 Benign variants include atypical tumors with atypia and giant
cells, and cellular leiomyomas both have low mitotic index.
 Benign metastasizing Leiomyoma is a uterine leiomyoma that
extends to the vessels and spreads hematogenously to other
sites, most commonly the lungs.
 Disseminated Peritoneal Leiomyomatosis presents as multiple,
small peritoneal nodules.
 Both are considered benign despite their unusual behavior.
 Leiomyomas in pregnancy can cause spontaneous abortion, fetal
malpresentation, uterine inertia, and post-partum hemorrhage.
Leiomyosarcoma
 Uncommon malignant neoplasms, arise from myometrium or
endometrial stromal precursor cells.
 Have complex, highly variable karyotypes, frequently include
deletions, a subset contains MED12 mutations.
Morphology
 Grow within the uterus into 2 patterns:
 Bulky fleshy masses that invade the uterine wall
 Polypoid masses that project into the uterine lumen
 Wide range of atypia, well-differentiated to highly anaplastic.
 Distinction from leiomyoma is based on nuclear atypia, mitotic
index, and zonal necrosis.
 Presence of 10 or more mitoses per 10 HPF indicates
malignancy, particularly if accompanied by atypia or necrosis.
 If tumor contains atypia or large cells, 5 mitoses per hpf,
sufficient enough to justify diagnosis of malignancy.
 Peak incidence at 40-60 years old, recur following surgery,
disseminates hematogenously, 5-year survival is 40%., anaplastic
lesions have 10-15%.
Page 10 of 16
Fallopian Tubes
INFLAMMATIONS
 Suppurative salpingitis may be cause by any pyogenic organism.
 Gonococcus is the causative organism in more than 60% of the
disorders, Chlamydia in the remaining cses.
 Tuberculous salpingitis common where tuberculosis is prevalent
TUMORS AND CYSTS
 Paratubal cysts – most common primary lesions, minute,
translucent cysts filled with clear serous fluid.
 Hydatids of Morgagni – larger varieties found near the
fimbriated ends of the tube or in the broad ligament.
 These cysts are lined by serous epithelium, presumed to arise in
remnants of the mullerian ducts and of little significance.
 Adenomatoid tumors – benign, mesothelioma occurs
subserosally on the tube or in the mesosalpinx.
 Primary adenocarcinoma is rare, presents as dominant tubal
mass detected by pelvic examination
Ovaries
NON-NEOPLASTIC AND FUNCTIONAL CYSTS
Follicular and Luteal Cysts
 Cystic follicles are very common, originate from unruptured
Graafian follicle or those that ruptured and immediately sealed.
Morphology
 Usually multiple, filled with clear serous fluid lined by gray,
glistening membrane, range in size up to 2 cm in diameter.
 Larger cysts (follicle cysts) may be diagnosed on palpation / US.
 Granulosa lining cells are present if the intraluminal pressure has
not been so great as to cause their atrophy.
 The outer theca cells may be conspicuous due to increased
amount of pale cytoplasm (luteinization).
 Luteal Cysts (corpora lutea) are present in the normal ovaris,
lined by rim of bright yellow tissue containing luteinized
granulosa cells.
 May rupture and cause peritoneal reaction.
Polycystic Ovaries and Stromal Hyperthecosis
 PCOS is a complex endocrine disorder characterized by
hyperandrogenism, menstrual abnormalities, polycystic
ovaries, chronic anovulation, and decreased fertility.
 Formerly called Stein Leventhal syndrome, affects 6-10% of
reproductive age women.
 Associated with Type 2 DM, Obesity (insulin resistance) and
premature atherosclerosis, indicative of a metabolic disorder.
 PCOS are at risk of endometrial hyperplasia.
 Stromal Hyperthecosis also called cortical stromal hyperplasia
 A disorder of the ovarian stroma seen in postmenopausal
women, overlaps with PCOS in younger women.
 Uniform enlargement of the ovary (up to 7 cm), has a white tan
appearance on sectioning.
 Involvement is usually bilateral shows hypercellular stroma and
luteinization of the stromal cells, visible as discrete nests of cells
with vacuolated cytoplasm.
 Similar manifestations to PCOS with prominent virilization.
 Theca lutein hyperplasia is a physiologic condition that mimics
the above syndromes.
OVARIAN TUMORS
 80% are benign, mostly in young women (20-45 years old)
 Borderline tumors occur at slightly older ages.
 Malignant tumors common in older women (45-60 years old).
 Most have spread beyond the ovary at time of diagnosis.
 Most tumors of the ovary arise from one of 3 components:
 Surface epithelium
 Germ cells – migrate to the ovary from yolk sac
 Stromal cells – including sex cords
 Can also be metastatic from non-ovarian primary tumor
EPITHELIAL TUMORS
 Most primary ovarian neoplasms arise from mullerian epithelium
 Three major histologic subtypes:
 Serous
 Mucinous
 Endometrioid
 Classified as benign, borderline, or malignant.
 Benign is classified further based on the component of the tumor
 Cystic areas (Cystadenoma)
 Cystic and fibrous (Cytadenofibromas)
 Predominantly fibrous (Adenofibromas)
Page 11 of 16
 Borderline and malignant tumors can also have cystic
component, sometimes referred to as cystadenomas.
 Schematic diagram of pathogenesis of epithelial ovarian tumors.
 Type I tumors progress from benign tumors through borderline
tumors that may give rise to low-grade carcinoma (low-grade
serous, endometrioid, mucinous).
 Type II tumors arise from inclusion cysts via intraepithelial
precursors, demonstrate high grade features commonly of
serous histology, arise from serous intraepithelial CA.
Serous Tumors
 These cystic neoplasm include the most common malignant
ovarian tumors and account for 40% of all cancers in the ovary.
Pathogenesis
 Risk factors are:
 Nulliparity
 Family history
 Heritable mutations (BRCA1, 5% of < 70y/o, and BRCA2)
 Higher frequency in women with low parity.
 Women at 40-59 years old who took OCP or undergone tubal
ligation have reduced risk
 2 major groups based on nuclear atypia:
1.) Low grade (Well-differentiated)
 KRAS, BRAF, ERBB2 mutations
 From borderline serous tumors.
2.) High grade (Moderate to poorly differentiated)
 TP53 mutation, from in situ lesions in the fallopian tube or
serous inclusion cysts.
Morphology
 Either multicystic in which the papillary epithelium is contained
within few fibrous walled cysts, or as mass projecting to the
surface of the ovary.
 Benign have smooth glistening wall with no thickening or papilla
 Borderline tumors have increased number of papillary projection
 Bilaterality is common.
 Serous borderline tumors exhibit increased complexity of the
stromal papilla, stratification of epithelium, mild nuclear atypia.
 The epithelial proliferation often grows in a delicate, papillary
pattern called micropapillary carcinoma a precursor to low-
grade serous carcinoma.
 High-grade serous carcinoma distinguished from low-grade by
having complex growth patterns and widespread infiltration.
 Concentric calcifications (psamommas bodies) characterize
serous tumors but are not specific for neoplasia.
Mucinous Tumors
 Account for 20-25% of all neoplasms.
 Principally in middle adult life and are rare before puberty and
after menopause.
 Vast majority are benign or borderline.
Pathogenesis
 Mutation in KRAS proto-oncogene.
 Majorities of benign mucinous cystadenomas (58%), mucinous
borderline tumors (75-86%), and ovarian mucinous CA (85%).
Morphology
 Differ from serous, the surface of the ovary is rarely involved,
only 5% are bilateral.
 Tend to produce large cystic masses, multiloculated tumors filled
with sticky, gelatinous fluid rich in glycoproteins.
 Lining of tall, columnar epithelial cells with apical mucin that lack
cilia, demonstrate gastric and intestinal type of differentiation.
 Mucinous borderline are distinguished from cystadenomas by
epithelial stratification, tufting, papillary intraglandular growth.
 10 year survival rate for Stage I, non invasive is 95%
 Malignant tumors have 90% survival rate.
 Pseudomyxoma peritonei is characterized by extensive
mucinous ascites, cystic epithelial implants on peritoneal
surfaces, adhesions, and frequent involvement of ovaries.
Endometrioid Tumors
 Accounts for 10-15% of all ovarian cancers.
 Benign endometrioid tumors called endometrioid adenofibroma
and borderline tumors occur but uncommon.
 May arise in the setting of endometriosis and associated with
areas of borderline tumor.
 15-20% may coexist with endometriosis, occur a decade earlier
than lesions that are not endometriosis-associated.
 Similar pathogenesis with Type I endometrial carcinoma.
Morphology
 Present with solid and cystic areas of growth.
 40% are bilateral, implies extension beyond the genital tract.
 Low-grade tumors that reveal glandular patterns.
 5-year survival rate with stage I tumors is 75%.
Clear Cell Carcinoma
 Similar genetic aberrations with endometrioid adenocarcinoma.
 Now thought to be a variant of the said neoplasm.
 90% survival rate if confined to the ovary.
 Uncommon.
 Genetic aberration (PIK3CA, ARID1A, KRAS, PTEN, TP53)
Page 12 of 16
Cystadenofibroma
 Uncommon, benign.
 More pronounced proliferation of the fibrous stroma than the
overlying epithelium.
 Small, multilocular with simple papillary processes
 May contain serous, mucinous, endometrioid, or transitional
epithelium
 Borderline lesions with cellular atypia.
 Metastatic spread is uncommon.
Transitional Cell Tumors
 Contain neoplastic epithelial cells resembling urothelium.
 Usually benign, comprise 10% of ovarian tumors.
 Also referred as Brenner tumors.
 Borderline (atypical proliferative Brenner tumor).
 Tumors with benign Brenner nests admixed with malignant
tumor cells are referred to as malignant Brenner tumors.
 If more than 50% are malignant epithelium are considered
transitional cell carcinoma of the ovary.
Morphology
 These neoplasms may be solid or cystic.
 Usually unilateral (90%) and vary in size (1-30cm)
 The fibrous stroma, is marked by sharply demarcated nests of
epithelial cells resembling the epithelium of the urinary tract,
often with mucinous glands in the center.
 Infrequently, the stroma is composed of plump fibroblasts
resembling theca cells, may have hormonal activity.
CLINICAL COURSE, DETECTION & PREVENTION
 All carcinomas produce similar clinical manifestations, most
commonly lower abdominal pain and abdominal enlargement.
 GI complains, urinary frequency, dysuria, pelvic pressure.
 Benign lesions are easily resected and cured.
 Malignant forms tend to cause progressive weakness, weight
loss, and cachexia.
 If carcinomas extend through the capsule to seed to the
peritoneal cavity, massive ascites is common.
 Ascitic fluid is filled with exfoliated tumor cells.
 Most present with high stage disease
 Poor 5- to 10 year survival rate.
 No tumor marker has good sensitivity and specificity.
 CA-125 – used to monitor recurrence or progression.
GERM CELL TUMORS
 Constitute 15-20% of all ovarian tumors.
 Most are benign cystic teratomas, found principally in children
and young adults, may show malignant behavior.

Teratomas
 Divided into 3 categories:
 Mature (Benign)
 Immature (Malignant)
 Monodermal or Highly specialized
Mature Benign Teratomas
 Most common germ cell tumor.
 Young reproductive women.
 Most are cystic, often referred to as dermoid cyst, because they
are almost always lined by skin-like structures.
 Associated with paraneoplastic syndromes such as inflammatory
limbic encephalitis.
 Karyotype of almost all benign teratomas is 46 XX.
Morphology
 Benign teratomas are bilateral (10-15%), unilocular cysts
containing hair and sebaceous material.
 Thin wall lined by an opaque, gray-white, wrinkled epidermis,
frequently with protruding hair shafts.
 Common to find areas of calcification.
 Microscopically, cyst wall is composed of stratified squamous
epithelium with underlying sebaceous glands, hair shafts, and
other skin adnexal structures.
 In most cases, tissues from other germ layers are present.
 1% of the dermoid undergo malignant transformation, most
commonly to squamous cell carcinoma.
st
 Arise from ovum after the 1 meiotic division.
 May be found together with mucinous cystadenoma.
Immature Malignant Teratomas
 Component resembles embryonal and immature fetal tissue
 Found in prepubertal adolescent, young women, mean age 18.
 Grow rapidly, frequently penetrate the capsule.
 Spread locally or distantly.
Morphology
 Bulky, smooth external surface and tend to be slid.
 Hair, sebaceous material, cartilage, bone, and calcification may
be present along with areas of necrosis and hemorrhage.
 Varying amounts of neuroepithelium, cartilage, bone, etc.
 Histologic grade (I to III) is based on proportion of the tissue
containing the immature neuroepithelium.
Monodermal or Specialized Teratomas
 Rare group of tumors.
 Most common are: stuma ovarii and carcinoid.
 Always unilateral, although contralateral teratoma may be
present.
Page 13 of 16
 Struma ovarii is composed entirely of mature thyroid tissue,
which may be functional and cause hyperthyroidism.
 Carcinoid is from intestinal tissue in teratoma, may produce
carcinoid syndrome (produce 5HT) if more than 7 cm.
 Strumal Carcinoid combination of the two.
 Only 2% of carcinoids metastasize.
Dysgerminoma
 Ovarian counterpart of testicular seminoma.
 2% of ovarian cancers, 50% of malignant ovarian germ cell tumor
nd rd
 Occur in childhood, 75% occur in 2 -3 decade of life.
 Occur in patients with gonadal dysgenesis, including
pseudohermaphroditism.
 Express OCT-3, OCT-4, and NANOG like seminomas.
 Implicated in the maintenance of pluripotency.
 Have syncytiotrophoblasts that are (+) for hCG
 Also express KIT receptors.
 All dysgerminomas are malignant.
Morphology
 Most are unilateral, ranging from nodules to masses.
 Have solid, yellow-white to gray-pink appearance, often soft and
fleshy, composed of large vesicular cells with clear cytoplasm.
 Well-defined cell boundaries, and centrally placed nuclei.
 Grows in sheets or cords separated by scant fibrous stroma,
infiltrated by mature lymphocytes and may contain granulomas.
Yolk Sac Tumor
nd
 2 most common malignant germ cell tumor.
 Most are children or young women, 80% survival rate.
 Derived from malignant germ cells that are differentiating along
the exraembryonic yok sac lineage.
 Expresses α-fetoprotein.
 Histologic feature is glomerulus-like structure composed of
central blood vessel enveloped by tumor cells within a space
lined by tumor cells (Schiller Duval Bodies).
 Hyaline droplets are present in all tumors.
Choriocarcinoma
 More commonly of placental origin, example of an
extraembryonic differentiation of malignant germ cells.
 Germ cell origin can only be conformed in prepubertal patients.
 Mostly exist with other germ cell tumor, rarely pure.
 Elaborates high hCG.
Other Tumors
 Embryonal Carcinoma – highly malignant of primitive embryonal
elements that is similar to that arising from the testes.
 Polyembryoma – containing so-called embryoid bodies.
 Mixed germ-cell tumor – containing various combinations of
dysgerminoma, teratoma, yolk sac tumor, and choriocarcinoma.
SEX CORD STROMAL TUMORS
 Derived from ovarian stroma, in turn derived from sex cords.
 Undifferentiated gonadal mesenchyme produce both male
(sertoli and leydig) and female (granulosa and theca).

Granulosa Cell Tumors
 Composed of cells that resemble granulosa cells of developing
ovarian follicle, divided into adult and juvenile.
 Account for 5% of all ovarian tumors, 95% of all granulosa tumor
 95% are adult tumors.
Morphology
 Usually unilateral, vary from foci to large, solid, cystic
encapsulated masses.
 Hormonally active has yellow coloration due to intracellular lipid
 Small cuboidal to polygonal cells may grow in anastomosing
cords, sheets, or strands.
 Small, distinctive, gland-like structures filled with acidophilic
material recall immature follicles (Call-Exner bodies).
 Clinical importance for 2 reasons:
 Elaborate large amounts of estrogen
 They may behave like low-grade malignancy
 Functionally active tumors in prepubertal girls (juvenile) may
produce precocious sexual development.
 Other produce androgens, masculinizing the patient.
 All are potentially malignant.
 Elevated tissue and serum levels of inhibin are associated, may
be useful for identifying and monitoring patients.
Fibrothecomas, Thecomas, and Fibromas
 Arise from the ovarian stroma that are composed of either
fibroblasts (fibromas) or plump spindle cells with lipid droplets
(thecomas).
 Account for 4% of all ovarian tumors.
 Many tumor contain mixture of both termed fibrothecomas.
 Pure thecomas are rare.
 Fibromas are hormonally inactive, thecomas are active.
 Unilateral, usually solid, spherical, slightly lobulated,
encapsulated, hard, gray-white masses covered by intact serosa
 Composed of well-differentiated fibroblasts and a scant
interspersed collagenous stroma.
 Associated with:
 Meigs syndrome – ovarian tumor, ascites, hydrothorax
 Basal cell nevus syndrome
 Vast majority are benign, but cellular fibromas with mitotic
activity, increased N:C ratio are identified since they may pursue
malignant course, termed fibrosarcomas.
Sertoli-Leydig Cell Tumor
 Often function and commonly produce masculinization.
 Few have estrogenic effects.
 Occur in women of all ages, peak incidence (20-30 years old).
 Half of cases have DICER1 mutations, encodes for endonuclease
 Presence of DICER suggests genesis of male-directed stromal cell
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Morphology
 Unilateral, resemble granulosa cell tumors grossly.
 Well-differentiated tumors show tubules with sertoli cells or
leydig cells interspersed with stroma.
 Intermediate forms show only outlines of immature tubules and
large eosinophilic Leydig cells.
 Poorly differentiated have sarcomatous pattern with disorderly
disposition of epithelial cell cords.
Other Sex Cord-Stromal Tumors
 Hilus cell tumors (Purely Leydig cell tumors) usually derived from
clusters of polygonal cells arranged around hilar vessels.
 Rare, unilateral comprised of large lipid-laden Leydig cells
with distincy borders and cytoplasmic structure called Reinke
crystalloids.
 Present with masculinization, hirsutism, voice change, clitoral
enlargement, tumors produce testosterone.
 Pregnancy Luteoma closely resembles the corpus luteum of
pregnancy, may produce virilization in pregnant patients and
their female infants.
 Gonadoblastoma uncommon tumor composed of germ cells and
sex cord-stroma resembling immature Sertoli and granulosa cells
 Abnormal sexual development.
 80% are females, 20% are males with undescended testis
 Coexistent dysgerminoma occur in 50% of cases
METASTATIC TUMORS
 Most common derived from tumors of mullerian origin: Uterus,
Fallopian tube, Contralateral ovary, or pelvic peritoneum.
 Most common extramullerian tumor metastatic to the ovary are
carcinomas of the breast and GIT.
 Classic GIT Carcinoma involving the ovaries is termed
Krukenberg tumor, characterized by bilateral metastases
composed of mucin-producing, signet-ring cancer cells most
often of gastric origin.
Gestational and Placental Disorders
 The placenta is composed of chorionic villi that sprout from the
chorion to provide large contact area between the fetal and
maternal circulations.
 In mature placenta, blood enters the intervilous space via the
spiral arteries and circulate around the villi to allow exchange.
 Deoxygenated fetal blood enters the placenta via 2 umbilical
arteries that branch radially to form chorionic arteries.
 In the villi, they form extensive capillary system.
 Gas and nutrient diffusion occurs via endothelial cells and
thinned-out syncytiotrophoblast and cytotrophoblast.
 No mixing or little mixing between maternal and fetal blood.
DISORDERS OF EARLY PREGNANCY
Spontaneous Abortion
 Miscarriage is defined as pregnancy loss before 20 weeks of
gestation, most of these occur before 12 weeks.
 10-15% terminate in spontaneous abortion.
 20% of early pregnancies terminate without notice.
 Most important causes of spontaneous abortion:
 Fetal Chromosomal anomalies – aneuploidy, polyploidy,
translocations.
 Maternal Endocrine factors – luteal-phase defect, DM
 Physical defects of the uterus – myomas, polyps, malformed
 Systemic disorders of maternal vasculature – APAS, HTN
 Infections – Toxoplasma, Mycoplasma, Listeria, Viruses.
nd
Ascending infection is common in 2 trimester losses.
Ectopic Pregnancy
 Refers to implantation of fetus in a site other than the normal
intra uterine location, most common is fallopian tube (90%).
 Other sites include the ovary, abdominal cavity, intrauterine
portion of fallopian tube (cornual).
 Most important predisposing condition is PID resulting in
intraluminal fallopian tube scarring.
 Use of intrauterine contraceptive device is associated.
 Ovarian pregnancy results from fertilization and trapping of the
ovum just at the time of rupture.
 Abdominal pregnancy occurs when the ovum fails to enter or
drops out of the fimbriated end of the tube.
Morphology
 Second most common cause of hematosalpinx, should always be
suspected if tubal hematoma is present.
 Embryonal sac, surrounded by chorionic villi implants within the
lumen of the fallopian tube.
 Trophoblasts and chorionic villi invade the wall.
 Gestational sac distends the tube causing thinning and rupture.
 Results to massive intraperitoneal hemorrhage.
 Less commonly, may undergo regression and extruded to the
fimbriated end of the tube (tubal abortion)
Clinical Features
 Rupture is a medical emergency.
 Onset of moderate to severe abdominal pain, vaginal bleeding of
6-8 weeks after LMP.
 Patient may rapidly develop hemorrhagic shock with signs of an
acute abdomen.
 Diagnosis is based on hCG titers, pelvic sonography, endometrial
biopsy or laparoscopy.
DISORDERS OF LATE PREGNANCY
rd
 Occurs in the 3 trimester are related to the complex anatomy
of the maturing placenta.
 Ascending infections involving the chorioamnionic membranes
may lead to premature rupture of membranes and delivery.
 Retroplacental hemorrhage at the placenta and myometrium
(abruptio placentae) threatens both mother and fetus.
 Disruption of fetal vessels may lead to fetal blood loss.
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Twin Placentas
 Twin pregnancies arise from fertilization of two ova (dizygotic) or
from division of one ovum (monozygotic).
 Three basic types:
 Diamnionic dichorionic
 Diamnionic monochorionic
 Monoamnionic monochorionic
 Monochorionic placenta implies monozygotic twins.
 Dichorionic may occur with either monozygotic or dizygotic.
 Once complication is twin-twin transfusion syndrome.
 Monochorionic twins have vascular anastomoses that
connect the circulations, in some cases include one or more
venous shunts.
 If these increase blood flow from one twin to another, one
twin will be underperfused, and one will be fluid overloaded.
Abnormalities of Placental Implantation
 Placenta previa is a condition where the placenta implants in the
rd
lower uterine segment or cervix, leading to serious 3 trimester
bleeding.
 Complete placenta previa covers the internal cervical os thus
requires delivery via caesarian section.
 Placenta accreta is caused by partial or complete absence of the
decidua, such that the villous adheres directly to the
myometrium, leads to failure of placental separation at birth.
Placental Infections
 Two pathways:
 Ascending via the birth canal
 Hematogenous (transplacental)
 Ascending is the most common, always bacterial.
 Localized infection of the membrane produces premature
rupture and preterm delivery, amniotic fluid may be cloudy with
purulent exudate.
 Several hematogenous infections, classically the TORCH group,
(toxoplasmosis, rubella, CMV, herpes), others such as syphilis,
tuberculosis, listeriosis, gives rise to chronic inflammation.
Preeclampsia and Eclampsia
 Preeclampsia is a systemic syndrome characterized by
widespread maternal endothelial dysfunction presents as (PRE):
 Proteinuria
 Rising blood pressure (HTN)
 Edema
 Occurs usually in the last trimester, common in primiparas,
 Eclampsia is when convulsion already occurs.
 10% develop HELLP Syndrome presents with Hemolytic anemia,
elevated liver enzymes, and low platelets.
Pathogenesis
 Still under investigation.
 Symptoms disappear after placental delivery.
 Diffuse endothelial dysfunction, vasoconstriction and increased
vascular permeability.
 Pathophysiologic aberrations:
 Abnormal placental vasculature
 Endothelial dysfunction and imbalance of angiogenic and
anti-angiogenic factors
 Coagulation abnormalities
Morphology
 Placenta reveals various microscopic changes, most reflect
malperfusion, ischemia, and vascular injury
 Infarcts, larger and more numerous
 Exaggerated ischemic changes, increased syncytial knots.
 Retroplacental hematomas
 Abnormal decidual vessels, show thrombi
 Liver lesions
 Irregular, focal, subcapsular, intraparenchymal hemorrhage
 Fibrin thrombi in the portal capillaries
 Kidney lesions
 Glomeruli show marked swelling of endothelial cells.
 Amorphous dense deposits on endothelial side of BM
 Mesangial cell hyperplasia
 Brain may have hemorrhage with small-vessel thrombosis.
 Similar changes are found in the heart and anterior pituitary.
Clinical Features
 Most commonly starts, 34 weeks of gestations.
 Begins earlier in women with hydatidiform mole or preexisting
kidney disease, HTN, or coagulopathies.
 Onset is insidious, HTN, edema with proteinuria.
 Eclampsia is heralded by CNS involvement (convulsions, coma)
 Management differs depending on the gestational age and
severity of the disease.
 Delivery is the treatment of choice regardless of severity.
 In preterm, patients with mild disease is closely monitored.
 Eclampsia, severe preeclampsia with end-organ dysfunction,
fetal comproise, or with HELLP syndrome are indicative of
delivery regardless the gestational age.
 Anti HTN therapy does not affect the disease course.
Gestational Trophoblastic Disease
Hydatidiform Mole
 Associated with increased risk of persistent trophoblastic disease
(invasive mole) or choriocarcinoma.
 Characterized by cystic swelling of the chorionic villi,
accompanied by variable trophoblastic proliferation.
 Diagnosed during early pregnancy, ~9weeks, via ultrasound.
Complete Mole
 Results from fertilization of an egg that has lost its female
chromosomes, resulting to a genetic material that is completely
paternally derived, embryo usually dies early.
 90% have 46, XX karyotype stemming from duplication of genetic
material of one sperm (androgenesis), 10% is due to fertilization
of an empty egg by 2 sperms (46XX, or 46XY).
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Partial Mole
 Results from fertilization of an egg with 2 sperm.
 Karyotype is triploid (69XXY), occasionally tetraploid (92XXXY).
 Increased risk of persistent molar disease, but they are not
associated with choriocarcinoma.
Morphology
 Delicate, friable mass of thin-walled, translucent, cystic,
grapelike structures consist of swollen edematous hydropic villi
 In complete mole, it involves all or most of the villous tissue.
 The chorionic villi are enlarged, scalloped with central cavitation
(cisterns), covered by extensive trophoblast proliferation.
 In partial moles, only a fraction is enlarged, trophoblastic
hyperplasia is focal and less marked.
Clinical Features
 Present with spontaneous miscarriage or undergo curettage.
 In complete moles, hCG is highly elevated.
 Patient is subsequently monitored for 6 months to a year to
ensure that the hCG levels decrease to non-pregnant levels.
 Continuous elevation may be indicative of persistent or invasive
mole, develops in 15% of molar pregnancies, more in complete.
Invasive Mole
 Penetrates or even perforates the uterine wall.
 There is invasion of the myometrium accompanied by
proliferation of both cytotrophoblasts and syncytiotrophoblast.
 Tumor is locally destructive and may invade other tissues.
 Hydropic villi may embolize, but do not grow in these organs.
 Manifests as vaginal bleeding and irregular uterine enlargement.
 Persistently elevated serum hCG.
Choriocarcinoma
 Gestational choriocarcinoma is a malignant neoplasm of
trophoblastic cells derived from previous pregnancy.
 Rapidly invasive and metastasizes widely.
 esponds well to chemotherapy.
 Soft, fleshy, yellow-white tumor, have large pale areas of
necrosis and extensive hemorrhage.
 Do not produce chorionic villi, consists of proliferating
syncytiotrophoblasts and cytotrophoblasts.
 Irregular vaginal spotting of bloody brown fluid.
 hCG levels are typically elevated.
 Most common sites of metastasis:
 Lungs (50%)
 Vagina (30-40%)
 Brain, liver, bone, kidney
 Treatment depends on stage of the tumor in gestational
choriocarcinoma. Non-gestational resistant to therapy
Placental Site Trophoblastic Tumor (PSST)
 Less than 2% of gestational trophoblastic neoplasms.
 Neoplastic proliferation of extravillous trophoblasts called
intermediate trophoblasts normally found in non-villous sites.
 PSTT presents as uterine mass with bleeding or amenorrhea,
moderately elevated hCG.
 Composed of malignant trophoblastic cells diffusely infiltrating
the endomyometrium.