PATHOLOGY OF FEMALE GENITAL TRACT Part 1

All images from the Department of Pathology, SZTE except for those otherwise stated Courtesy of Profs. Béla Iványi & Éva Kemény VULVA Vulvitis

• The delicate skin and mucosa of the vulva are vulnerable to many nonspecific microbial and dermatologic conditions.

• Intense itching and scratching often exacerbate the primary disorder. Sexually transmitted vulval infections Common types: • 1. human papillomavirus(HPV): condylomata acuminata vulvar intraepithelial neoplasia (VIN) • 2. herpes genitalis (HSV): vesicular eruption • 3. gonococcal suppurative inflammation of the vulvovaginal glands • 4. syphilis: primary chancre at the site of entry Non-neoplastic epithelial disorders (vulval dystrophies)

• 1. Lichen sclerosus • 2. Lichen simplex chronicus

• Both may appear clinically as white patches or plaques referred to as leukoplakia. Leukoplakia

Similar white patches - leukoplakia - are also seen with: –benign dermatoses –carcinomas Histological examination is therefore indicated in all such lesions! Lichen sclerosus

Epidemiology and pathogenesis:

• Most common in postmenopausal women • Infrequently, the patients may develop squamous cell carcinoma • An autoimmune etiology is implicated. Lichen sclerosus

Macro: • Smooth white plaques that extend and coalesce. When the entire vulva is affected, the labia become atrophic and stiffened and the vaginal orifice is constricted. Micro: • Epidermal atrophy • Dermal fibrosis • Scant perivascular mononuclear infiltrate Lichen simplex chronicus

• Non-specific response to recurrent rubbing or scratching to relieve pruritus Macro: Leukoplakia Micro: • Epidermal hyperplasia, marked hyperkeratosis • Dermal inflammatory infiltrate Clinical features: It rather accompanies than precedes established carcinoma of the vulva Neoplastic epithelial disorders Condyloma acuminatum

Pathogenesis: • Strong association with HPV types 6 and 11 • HPV can be transmitted venereally • Not commonly precancerous but may coexist with intraepithelial neoplasia in the vulva and cervix Morphology • See papillomas (1st semester) Condyloma acuminatum Invasive carcinoma of the vulva and vulvar intraepithelial neoplasia (VIN; Bowen disease) 2 biological forms

1. In younger smoking women • Association with HPV 16,18 • VIN frequently precedes the development of the overt cancer • VIN may exist for many years perhaps for decades 2. In older women • Not associated with HPV • Often preceded by lichen sclerosus Vulvar intraepithelial neoplasia High grade Vulvar intraepithelial neoplasia, carcinoma in situ Invasive carcinoma of the vulva and vulvar intraepithelial neoplasia (VIN; Bowen disease) Macro: • Leukoplakia or exophytic (both VIN & invasive) or ulcerative lesions (invasive) • HPV+ tumors are most often multifocal and appear warty or condylomatous Micro: • Squamous cell carcinoma Invasive carcinoma of the vulva

Prognosis: • In a few years lymphohematogenous spread occurs that correlates with the size of the tumor and the depth of invasion • Tumor < 2 cm in diameter: 90% 5-yr- survival • Larger lesions: 20% 10-yr-survival Rare tumours of the vulva

• Paget’s disease of the vulva: a form of intraepithelial carcinoma similar to that observed in the breast

• Melanoma of the vulva: the microscopical and clinical features are not different from those of other skin melanomas Paget’s disease of the vulva Scattered tumor cells in the epidermis, the tumor cells show perinuclear halos VAGINA VAGINA

CONGENITAL ANOMALIES

• Absence of vagina • Septate vagina • Lateral Gartner’s duct cyst Vaginitis (colpitis) • Common, transient problem, resulting in vaginal discharge (leukorrhea) • Caused by bacteria, fungi and parasites; many of them are normal inhabitants that become pathogenic in predisposed individuals: diabetics systemic antibiotic therapy after abortion or pregnancy elderly persons immunocompromised patients Vaginitis (colpitis)

1. Candidal vaginitis produces a curdy-white discharge. This organism is present in 5% of normal adults. 2. Trichomonas vaginalis produces a watery gray-green discharge in which parasites can be identified. T. vaginalis can be identified in 10% of asymptomatic women. • In both cases active infection usually represents sexually transmitted new strain Vaginal intraepithelial neoplasia and squamous cell carcinoma

• Uncommon • In women over 60 • Can occur with vulval or cervical cancers suggesting a common, probably viral effect (HPV) CERVIX CERVIX

• Acts as a selective barrier and also exposed to various mechanical, chemical and microbial effects. It is often the seat of disease.

• Most lesions are banal inflammations, but cervical squamous cell cancer is a common cancer in women. Transformation zone T r a n s f o r m Cervicitis Common Infecting agents: • Chlamydia trachomatis • Ureaplasma urealyticum • Trichomonas vaginalis • Candida albicans • Neisseria gonorrheae • HSV type II • HPV types Many of the listed microorganisms are transmitted sexually. C. trachomatis is by far the most common and accounts for up to 40% of the cases of cervicitis. Morphology: Mucopurulent to purulent discharge. Cytology, purulent exudate Cytology, fungal infection Acute cervicitis

• Acute nonspecific cervicitis: Postpartum women Staphylococci and streptococci Chronic cervicitis Macro: Swelling, granularity and reddening around the external os

Micro: • Mononuclear infiltrate and Nabothian cysts • The epithelium may show hyperplasia and reactive atypia not to be confused with dysplasia Nabothian cysts Chronic cervicitis Clinical features: • Banal inflammation common in multiparous women. • Severe cervicitis may lead to sterility through deformation and exudative blocking of the cervical canal. Endocervical polyp

• Inflammatory in origin, have no malignant potential Macro: soft smooth, glistening surface, cut surface reveals mucus filled cystic spaces Micro: the surface epithelium and the glands are lined by mucus-secreting columnar cells Clinical features: irregular vaginal bleeding Endocervical polyp Cervical intraepithelial neoplasia (CIN) and invasive carcinoma

Epidemiology and Pathogenesis: • Peak age incidence: CIN - 30 years, invasive carcinoma - 45 years Risk factors of CIN and invasive cancer: • Early age at first intercourse • Multiple sexual partners • Male partner in the group with high risk factors (multiple previous sexual partners) • High risk types of HPV 16, 18 Cervical intraepithelial neoplasia (CIN) and invasive carcinoma

High risk types of HPV: • High risk types of HPV 16, 18, HPV can be detected in 85-90% of precancerous lesions and invasive neoplasms. • In high-grade cervical dysplasias, HPV is incorporated into the genome of the host cell. HPV expresses E6 and E7 proteins that inactivate the p53 and Rb tumor suppressors, respectively, → increased cell proliferation and suppression of DNA damage–induced apoptosis. Loss of LKB1 gene is also involved. Cervical intraepithelial neoplasia (CIN)

Histological grades:

• CIN I: mild dysplasia • CIN II: moderate dysplasia • CIN III: severe dysplasia and carcinoma in situ CIN I, koilocytes in the upper epidermis CIN II

CIN III CIN carcinoma in situ Koilocytes in the upper third of the dysplastic epithelium. Cervical intraepithelial neoplasia (CIN)

Cytologic examination • Papanicolau cytological screening (PAP) can detect CIN long before any abnormality can be seen grossly. • Precancerous epithelial changes may precede an invasive cancer by many years, perhaps by 20 years. Only a fraction of CIN cases progress to invasive carcinoma. Cervical intraepithelial neoplasia (CIN)

Cytological grades: • low-grade squamous intraepithelial lesion (LSIL) • high-grade squamous intraepithelial lesion (HSIL)

Connection between the two grading systems: • low-grade (L-SIL): CIN I • high-grade (H-SIL): CIN II or CIN III PAP smear, koilocytes

IARC, 150 Cours Albert Thomas, 69372 Lyon CEDEX 08, France - © IARC 2015,WHO Groups of atypical cells with enlarged nuclei and nuclear polymorphism

IARC, 150 Cours Albert Thomas, 69372 Lyon CEDEX 08, France - © IARC 2015., WHO Cervical intraepithelial neoplasia (CIN)

Progression of cervical intraepithelial neoplasia (CIN):

• The higher the grade of CIN the greater is the likelihood of progression, but even many high grade lesions do not progress to cancer. Cervical intraepithelial neoplasia (CIN)

Clinical features:

• CIN is usually asymptomatic. The cervix may appear normal to the naked eye, however, colposcopy may disclose abnormalities. • Only careful follow-up, PAP smears and biopsies, if necessary will determine the nature and gravity of the changes. Cervical intraepithelial neoplasia (CIN)

Clinical features: • LSIL is managed conservatively with careful observation, HSIL is treated with surgical excision. • The recently introduced quadrivalent HPV vaccine for types 6, 11, 16, and 18 is very effective in preventing HPV infections, cervical cancer screening is still needed. Invasive carcinoma of the cervix

Macro: • fungating tumor • ulcerative tumor • infiltrative tumor

• Invasive carcinomas of the cervix develop in the transformation zone. Tumors encircling the cervix and penetrating into the underlying stroma produce a barrel cervix. Invasive carcinoma of the cervix

• Local spread: may extend into the rectum, into the base of the urinary bladder or obstruct the ureters! Ascending infection, urosepsis!

• Metastasis: pelvic lymph nodes, lung, bone and liver. Carcinoma of cervix Carcinoma of cervix Carcinoma of cervix Invasive carcinoma of the cervix

Micro: • 80-95% squamous cell carcinoma, generally evolve from precursor CIN • the remainders are adenocarcinomas Invasive squamous carcinoma Invasive carcinoma of the cervix

Clinical features: • Invasive carcinoma irregular vaginal bleeding, leukorrhea, dysuria • Mortality is more often related to its local effects than to distant metastases. Urosepsis! • At least a decade elapses between the in situ and invasive stages. • The 5-year survival is directly proportional to the stage when the lesion is first discovered: carcinoma in situ: 100%, advanced stage with involvement of rectum/bladder: 10% Cervical cancer in advanced stage causing hydronephrosis UTERINE CORPUS Endometritis

• The endometrium is relatively resistant to infections.

Acute endometritis • Occurs after parturition or miscarriage. • Retained products of conception are the usual predisposing factor. • Removal of the retained gestational fragments by curettage is followed by prompt remission. Endometritis Chronic endometritis

• Association with chronic gonorrheal pelvic disease • Tuberculosis, granulomatous inflammation – from drainage of tuberculous salpingitis • Intrauterine contraceptive devices (IUDs) • Spontaneously without apparent cause (15% of the cases) • Histology: irregular proliferation of endometrial glands and mononuclear cell infiltrate with plasma cells Endometritis

Clinically: • Manifests with fever, abdominal pain, and menstrual abnormalities. • There is an increased risk of infertility and ectopic pregnancy as a consequence of damage and scarring of the fallopian tubes. Chr endometritis with polyclonal plasma cell infiltrate

CD79a

kappa lambda Adenomyosis

• Growth of the basal layer of the endometrium down into the myometrium • There are nests of endometrial stroma (CD10+) or glands or both between the muscle bundles • Cyclic bleeding into the glandular nests is very rare as the stratum basalis of the endometrium is nonfunctional Clinically: • Marked involvement may produce menorrhagia and pelvic pain before the onset of the menstruation Adenomyosis

Endometrial glands and stroma in myometrium Adenomyosis Endometrial hyperplasia

• Defined as an increased proliferation of endometrial glands relative to the stroma. Causative factors: Excess of estrogen relative to progestin, sufficiently marked or prolonged • Failure of ovulation, e.g. around the menopause • Prolonged administration of estrogens • Estrogen producing ovarian lesions Endometrial hyperplasia Types (forming a continuum) – non-atypical hyperplasia: • Simple hyperplasia (cystic glands) • Complex hyperplasia with architectural gland crowding without atypia (back-to- back glands)

• Complex hyperplasia with cellular atypia • New terminology: EIN: endometrial intraepithelial neoplasia SIMPLE HYPERPLASIA Endometrial hyperplasia Clinically: • Abnormal uterine bleeding • In time carcinoma may develop, the risk is proportional to the degree of cytological atypia noted • Controll, follow up, in case neccessary curettage, biopsy to determine progression! Risk for the development of adenocarcinoma: • Simple hyperplasia: low (1-3 %) • Atypical hyperplasia: 20-50% • Acquisition of PTEN mutations is believed to be one of several key steps in the transformation of hyperplasias to endometrial carcinomas TUMORS OF THE ENDOMETRIUM Earliest symptom is intrauterine bleedig. Endometrial polyps

Macro: sessile or pedunculated lesions

Clinical features: • Most common at the time of menopause, cause abnormal uterine bleeding, and very rarely give rise to cancer Endometrial polyp Endometrial polyp, vessels with thick wall Endometrial carcinoma

Epidemiology and Pathogenesis: • On the basis of clinical and molecular data, two major types are recognized:

Endometrioid carcinoma Serous carcinoma Endometriod carcinoma

• Frequently arises on a background of endometrial hyperplasia. • Breast carcinoma occurs in women with endometrial cancer (and vice versa) more frequently. Estrogen effect • Mutations in mismatch repair genes and the tumor suppressor gene PTEN. Endometriod carcinoma

Risk factors: • Obesity: increased synthesis of estrogen in fat depots from adrenal and ovarian precursors • Diabetes • Hypertension • Infertility: nulliparous women, often have nonovulatory cycles • Prolonged estrogen replacement therapy • Estrogen secreting ovarian tumors Endometriod carcinoma

Macro: • Infiltrative • Exophytic

Micro: • Resemble the endometrial glands Endometrioid carcinoma

ER Serous carcinoma

• Arises in older women • Usually is associated with endometrial atrophy • Mutations in the TP53 gene. • They behave aggressively Grossly: Tumors are usually large and bulky and deeply invasive. Microscopically: papillary or glandular growth pattern with marked cellular atypia Serous carcinoma Endometrial carcinoma

Clinical features for both: • Local spread: tumor extends through the uterine wall and infiltrates the periuterine structures • Metastases to pelvic lymph nodes and to distant organs, lung, liver • Patients typically present with uterine bleeding. Stage is the major determinant of survival in both types. • Serous tumors tend to manifest more frequently with extrauterine extension and therefore have a worse prognosis than endometrioid carcinomas. Pathology of the female genital tract - Part 2

All images from the Department of Pathology, SZTE except for those otherwise stated Courtesy of Profs. Béla Iványi & Éva Kemény UTERINE CORPUS MYOMETRIUM Leiomyoma

• Benign tumor of smooth muscle cells • They are the most common benign tumor in females • Found in nearly half of women during reproductive life • Estrogens stimulate their growth, they shrink postmenopausally Leiomyoma

Macro: • Sharply circumscribed, firm, gray-white masses with a whorled cut surface. • Frequently multiple. • After menopause they may become densely collagenous or even calcified. Micro: • Whorling bundles of smooth muscle cells, degenerative changes are often present Leiomyoma

Clinical features: • May be entirely asymptomatic • They may manifest with menorrhagia or metrorrhage as a pelvic mass or may be detected as a cause of infertility • No malignant transformation Leiomyoma Leiomyoma Leiomyosarcoma

• Malignant tumour of smooth muscle cells. • Often occur in postmenopausal women.

Macro: soft, hemorrhagic, necrotic masses Micro: criteria of malignancy include necrosis, cytologic atypia, and mitotic activity. Leiomyosarcoma Leiomyosarcoma

Clinical features: • Arise directly from the mesenchymal cells of myometrium, not from preexisting leiomyomas • Almost always solitary tumors • Recurrence after removal and metastases are common (lung) • The more anaplastic the tumor, the poorer the outlook is FALLOPIAN TUBE (including ectopic pregnancy) Fallopian tubes: Salpingitis • Often as part of pelvic inflammatory disease (etiologies:) – Gonorrhea, – Non-gonococcal: Chlamydia, Mycoplasma, coliform bacteria, Staphylococcus… • Acute purulent inflammation > chronic • Can lead to blood-borne infections, tuboovarian abscess, adhesions predisposing to tubal pregnancy, sterility – Tuberculous salpingitis (rare); with endometritis Fallopian tubes • Other diseases mentioned: – Endometriosis (discussed with the ovaries) – Ectopic pregnancy – Tumors: • Ovarian surface epithelial tumors (HG serous carcinomas) often arise from the fimbrial edge of the tubes (discussed with the ovaries) Ectopic pregnancy

• Implantation of the fertilized ovum in any site other than the normal uterine location, occurrence: in 1% of pregnancies. Types: • Tubal pregnancy (90% of the cases) • Ovary • Abdominal cavity • Intrauterine portion of the tube (interstitial pregnancy) Ectopic pregnancy

General: • In ectopic pregnancy the early development of the embryo is fairly normal, including the formation of placental tissue, amniotic sac and decidual changes. • Abdominal pregnancy can occasionally carried to term Ectopic pregnancy

Predisposing factors: any factors retarding the passage of the ovum • Chronic salpingitis (half of the cases) • Intrauterine tumors • Endometriosis • In almost half of the tubal cases no anatomic cause can be demonstrated Ectopic pregnancy

DG: • Elevated level of hCG similar to that seen in normal pregnancy, however lack of elevation does not exclude the diagnosis. • Curettage: decidual change, Arias-Stella reaction in endometrial glands, but no chorionic villi or other fetal parts. Ectopic pregnancy

Tubal pregnancy, morphology: • The tube is locally distended up to 3-4 cm containing of freshly clotted blood in which placental tissue and fetal parts may be seen. • The histological diagnosis depends on the visualization of placental villi. ECTOPIC PREGNANCY • Curettage: decidual change, Arias-Stella reaction in endometrial glands • but no chorionic villi or other fetal parts

Decidual change in the endometrium Arias-Stella reaction in endometrial glands Tubal pregnancy The tube is locally distended, the lumen contains, freshly clotted blood and chorionic villi

T TUBA

Chorionic villi.

Decidual change

Hemorrhage Tubal pregnancy

Clinically: • The invading placenta causes intratubal hemorrhage (hematosalpinx) → may rupture → hemoperitoneum. • Rupture of an ectopic pregnancy may be catastrophic, needing prompt surgical intervention. OVARIES Non-tumorous diseases of ovaries

Follicle and luteal cyst • Common • Originate from unruptured Graafian follicles • Usually multiple, subcortical, filled with serous fluid • Lining: granulosa or luteal cells • Rarely may rupture: intraperitoneal bleeding and acute abdomen Ovary

É. Kemény Wall of follicle cyst / follicular cyst Non-tumorous diseases of ovaries Polycystic ovaries (Stein-Leventhal syndrome): Pathogenesis, principal biochemical abnormalities: • Excessive production of androgens which are converted to estrogens in peripheral fatty depots → inhibit the secretion FSH • High levels of luteinizing hormone (LH) • Low levels of follicle stimulating hormone (FSH) • The basis of excess ovarian androgen secretion is mysterious. Non-tumorous diseases of ovaries

Polycystic ovaries: Stein-Leventhal syndrome

Macro: ovaries are enlarged, many subcortical small cyst Micro: cortical stromal fibrosis + many follicular cysts, absence of corpora lutea Clinically: • Generally in young females following menarchae with symptoms of oligomenorrhea, hirsutism, infertility, sometimes obesity, type II diabetes. Endometriosis

• Endometriosis is an important clinical condition as it often causes infertility, pelvic pain and other problems. Pathogenesis: • Frequently multifocal. • Foci of functioning endometrial tissue in the ovaries, pelvis, less frequently at other sites of abdomen, rarely lymph nodes, lung; Caesarean section scars Endometriosis Theories of origin (not mutually exclusive): • Regurgitation theory: menstrual backflow through the Fallopian tubes and subsequent implantation. • Metaplastic theory: endometrial differentiation of coelomic epithelium. • Vascular or lymphatic dissemination theory: explaining extrapelvic and intranodal implants. • Stem cell / progenitor cell theory: bone marrow derived cell differentiate into endometrial tissue Endometriosis

• Endometriotic tissue is not just misplaced but is also abnormal; • exhibits increased levels of inflammatory mediators +(increased) estrogen production by stromal cells (aromatase)→ enhance the survival and persistence of the endometriotic tissue at a foreign location Endometriosis

Macro: • Almost always contains functioning endometrium, which undergoes cyclic bleeding. • As a result of the accumulating blood the foci are red-blue to yellow-brown. • In the ovaries the lesions may form large blood filled cysts: chocolate cysts. Seepage of blood may lead to widespread pelvic fibrosis. Micro: • Endometrial glands, stroma and hemosiderin in disordered localisation i.e. ovaries. Chocolate cysts in the ovari

Brown pigment, haemosiderin Prussian-blue

CD10+ stroma CK + endometrial glands É. Kemény Endometriosis

Clinical features: • Manifestations depend on the distribution of the lesions. – Pelvic scarring often causes pain and sterility – Intrapelvic bleeding results in severe dysmenorrhea Tumors of the ovary

Tumors may arise from:

• 1) Coelomic surface epithelium • 2) Totipotent germ cells • 3) Multipotential sex cord-stromal cells Surface epithelial tumors

Types according to biological behavior: • Benign: cystadenoma • Borderline: tumor of low malignant potential • Malignant: cystadenocarcinoma or carcinoma Types according to histology: serosus, mucinosus and endometrioid tumors Malignant forms of surface epithelial origin account for almost 90% of all ovarian cancers Surface epithelial tumors

Important risk factors for ovarian cancer: • Nulliparity • Family history and germline mutations: familial, mutations of BRCA1 and BRCA2 tumor suppressor genes, that are also associated with hereditary breast cancer, too. Serous tumors

Serous cystadenoma: • 25% are bilateral • Inner surface is smooth • Serosal covering is smooth and glistening • Lined by single layer of tall columnar ciliated or secretory cells • Papillary formations, psammoma bodies are common in the tips of papillae Serous tumors

• Borderline tumor / tumor of low malignant potential • No significant stromal invasion Serous carcinoma

Serous cystadenocarcinoma • 66% of aggressive forms are bilateral • The inner surfaces show irregular papillary projections, solid areas may also be seen • Serosal covering with nodular irregularities indicates penetration of capsule • Complex, multilayered papillary formations • Cytologiacal atypia of the lining cells • Invasion of the stroma Serous carcinoma

Types: • Low-grade serous carcinomas that arise from benign or borderline lesions progress slowly are associated with KRAS, BRAF or ERBB2 mutations. • High-grade serous carcinomas develop rapidly, and most of them have mutations in TP53. Serous cystadenocarcinoma Serous cystadenocarcinoma Serous cystadenocarcinoma Serous carcinoma

Spread: • Commonly contiguous spread within the pelvis and peritoneal dissemination, peritoneal carcinosis • Spread to regional lymph nodes is frequent • Distant metastases are infrequent: lung, liver • Prognosis is poor and depends on the stage at the time of the diagnosis. Mucinous tumors

Differences compared to serous tumors: • Most are benign mucinous cystadenomas (80%) • The epithelium consists of mucin-secreting cells • Cyst content is mucinous • Only 5% of malignant tumors are bilateral Mucinous tumors

• „Pseudomyxoma peritonei” results from rupture of mucinous cystadenocarcinoma or that of carcinoma with low malignant potential. (Appendix!) • The peritoneal cavity is filled with mucinous material multiple tumor implants are found on all serosal surfaces. Mucinous cystadenoma, multicystic Mucinous cystadenoma Endometrioid tumors

• Linings of the cysts are similar to those of the endometrium • Endometrioid tumors are usually malignant, although benign and borderline forms exist • They are bilateral in 30% of the cases • In 15-30% of these patients there is a „concomitant” endometrial carcinoma – these are almost always transtubal metastases from endometrial carcinoma • Similar to endometrioid-type carcinoma of the endometrium, endometrioid carcinomas of the ovary have mutations in the PTEN tumor suppressor gene Germ cell tumors, teratoma

Most common: benign mature teratoma Dermoid cyst

Rarely, similarly to testicular germ cell tumors Dysgerminoma (counterpart of testicular seminoma) Embryonal carcinoma Choriocarcinoma Yolc sac carcinoma Teratoma

DERMOID CYST • Ectodermal differentiation of the totipotent germ cells • The cyst is lined by epidermis with large number of adnexal appendages, • Most are in young women • The cyst is often filled with sebaceous material and matted hair • Nodular thickening in the wall from which teeth protrude, bone, cartilage, nests of bronchial or gastrointestinal epithelium may also occur • Rarely there is malignant transformation, squamous cell carcinoma DERMOID CYST DERMOID CYST DERMOID CYST

DERMOID CYST Sex cord-stromal tumors

• Sex cord–stromal tumors may display differentiation toward granulosa, Sertoli, Leydig, or ovarian stromal cell type.

• Depending on differentiation, they may produce estrogens or androgens. Sex cord-stromal tumors

Granulosa cell tumors • Two thirds occur in postmenopausal women • Are potentially malignant • Clinical features: • Have the potential of producing large amounts of estrogen! • Consequence: precocious sexual development, endometrial hyperplasia and predispose to endometrial carcinoma. Granulosa-theca cell tumor Granulosa cell component: Call-Exner body reminds of immature follicle.

Call-Exner body Metastatic tumors

• Metastases of abdominal and breast tumors to the ovary are common. Krukenberg tumor: • metastatic bilateral ovarian cancer • primary tumor: signet ring cell carcinoma of stomach Krukenberg tumor: ovarian metastasis of stomach signet ring cell carcinoma

H-E

PAS

CK7 Summary of lesions • Non tumorous Tumors – Salpingitis - Epithelial (ben-bord-mal):

– Tubal pregnancy Serous (LG vs HG) TUBES – Endometriosis Mucinous Endometrioid… – Cysts – Polycystic ovarian sy - Germ cell tumors:

OVARIES – Endometriosis Dermoid cyst (teratoma) Others

- Sex cord stroma tumors

- Metastatic DISEASES OF PREGNANCY Placental inflammations and infections

Two pathways: 1. Ascending infection through the birth canal • Most common • Caused by bacteria, Mycoplasma and Candida • Can cause premature birth and premature rupture of the membranes • Chorioamnionitis: chorioamnion shows leukocytic infiltrate with edema and congestion, infection may involve the cord and placental villi Placental inflammations and infections

2. Hematogenous spread, rare • Histologically the villi are most often affected (villitis). Underlying conditions: – syphilis – tuberculosis – listeriosis – toxoplasmosis – various viral infections (rubella, cytomegalovirus, HSV) Ectopic pregnancy

• Discussed previously Gestational trophoblastic disease

• Gestational trophoblastic disease is a spectrum of tumor-like conditions, and tumors characterized by proliferation of trophoblastic tissue. Hydatiform mole

There are two types, they result from abnormal fertilization. Complete moles Partial moles • No fetal parts Contains fetal parts • All chorionic villi Has some normal abnormal chorionic villi • Diploid (46,XX >46,XY) Always triploid (empty ovum + 1 or 2 sperm) (ovum + 2 sperm) Hydatiform mole

Macro: the uterine cavity is filled with thin walled translucent cystic grapelike structures, cystic chorionic villi. Micro: • Complete mole: hydropic swelling of chorionic villi and virtual absence of vascularization + cytotrophoblast and syncytial trophoblast proliferation. • Partial mole: affects only some of the villi and the trophoblastic proliferation is focal. Hydatiform mole Hydatiform mole Hydatiform mole

Clinically. • They are much more common before age 20 and after age 40. The usual presentation is painless vaginal bleeding, 12-14 weeks after conception. The uterus may be too large for dates and no fetal parts or heart sounds are present, hCG levels are elevated Clinical course: • Complete mole becomes invasive: 10%, • Give rise to choriocarcinoma: 2-3% • HCG monitoring in the blood and urine permits detection of incomplete removal or complications • Chemotherapy is almost always curative Invasive mole

• Hydropic villi deeply penetrate the uterine wall • Hydropic villi may embolize to distant organs, such as lungs or brain, but these are not true metastases and may regress spontaneously • Clinically: invasive moles are associated with persistently elevated hCG. The tumor responds well to chemotherapy but can result in uterine rupture and life-threatening hemorrhage Choriocarcinoma

• Malignant tumor arising from gestational chorionic epithelium • 50% follow a complete hydatiform mole, about 25% arise after abortion • Most of the remainder occur in a previously normal pregnancy Choriocarcinoma

Macro and micro: • Very hemorrhagic and necrotic masses within the uterus, vascular invasion is a characteristic feature • Chorionic villi are not present, the tumor is purely epithelial, the chorioepithelium is atypical Choriocarcinoma

Clinical features: • Bloody, brownish discharge • Rising titer of hCG, the titers are much higher than in the case of a mole • At the time of initial discovery, there is usually widespread dissemination via the blood Choriocarcinoma

Prognosis: • Chemotherapy: nearly 100% of cases localized to uterus have been cured, • Maternal immune response against the foreign (paternal) antigens helps. • Important: By contrast there is poor response to chemotherapy in choriocarcinomas that arise in the gonads (ovary or testis) from totipotential cells. Choriocarcinoma