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Home , Endometrioid tumor

Female genital tract Vulva:

- Vulva can be affected by many dermatological diseases that affect hairy skin elsewhere (eczema ,Psoriasis …..)

- Bartholin glands:May be involved by acute infection (acute adenitis) that can lead to abscess.

-Bartholin : due to obstruction of the duct. - ~ 3-5cm, lined by transitional or squamous epith. -Produces pain , discomfort , mass.. Rx: Excision or marsupialization (opened permanently). Infectious disease of the vulva: • Viral infections: -HSV. -Molloscum contagiosum (self limiting , by Poxvirus). -HPV. • Bacterial infections: -Syphilis. -Granuloma inguinale (sexual transmitted, by Calymmatobacterium donovani, characterized by papular… ulcerative genital lesion accompanied by abundant granulation tissue with formation of painless mass + LN enlargement, microscopy: non specific, Dx: Gram stain and silver stain+ PCR). -Gonorrhea. • Fungal infections. - Non-Neoplastic Epithelial Disorders: - Lichen Sclerosus:(Chronic atrophic vulvitis): Thin epidermis with loss of rete ridges & sub-epidermal fibrosis(introitus stenosis). -Affects all ages but more in postmenopause. Etiology : ? Autoimune , genetic , hormonal factor. - ~ increased risk of Squamous Cell Ca. - Lichen Simplex Chronicus Results from rubbing or scratching (due to pruritus).Micro:Thick epdermis, expansion of the stratum granulosum, hyperkeratosis. Generally no increase risk of . Vulvar Intraepithelial Neoplasia (VIN)~ CIN  VIN I: Nuclear hyperchromasia and cellular disarray limited to the lower 1/3 of the pithelium.  VIN II: Nuclear hyperchromasia and cellular disarray limited to the lower2/3 of the . Mitoses are often seen.  VIN III: Nuclear hyperchromasia and cellular disarray beyond the lower 2/3 of the epithelium. : Although rare(<1% of female ca. );it represents most the common malignant tumor of vulva (95%). Others : adenocar. , sarcoma. Extramammary Paget’s disease: • Intra-epidermal .

• 1/3 of cases are associated with underlying adenocarcinoma (ex. breast). • Arises from multipotential epidermal cells. • Prognosis depends on presence of underlying carcinoma . Vaginal Malignant Tumors  >95% are SCC  The remaining are: • (mothers: DES ) • • Sarcoma E.g. : (Emberional rhabdomyosarcoma) -Rare but it is the commonest malignant vaginal childhood tumor (in those < 5y). -Grossly: Polypoid grape like mass. Microscopy: -Spindle cell rhabdomyoblasts with characteristic cambium layer formation. Endocervical polyp(s): Reactive “benign” tumor-like lesion affects adult female. -Causes irregular vaginal bleeding. -Polypoid mass arises from the endocervical canal. -Size….~5cm.

-Microscopy: Loose fibromyxoid core coved by mucin secreting endocervical epithelium + squamous metaplasia and inflammation . Cervical polyp Condyloma Acuminatum • Sexually transmitted disease. Benign papillary . • May involve perineum, vulva, anus, vagina, cervix. • Associated with: Sexual activity with multiple partners, DM, pregnancy , immunosuppression... -Microscopy: Hyperplastic & parakeratotic squamous epithethelium with koilocytes (viral cytopathic effects : mild nuclear atypia with perinuclear vacuolization “hallow”).these changes are in the superficial sq.cells. - HPV 6 and 11 are found in most cases. - HPVs infect immature basal squamous epithelium (~ break), or immature metaplastic squamous cells (in squamocolumnar junction of cx), this makes Ca-CX ˃ ..Vulva ,Penis.

Squamous Intraepithelial Lesions of CX:

LSIL CIN I Mild dysplasia HSIL CIN II Moderate dysplasia HSIL CIN III Severe dysplasia HSIL CIN III Cacinoma in-situ CIN: cervical intraepithelial neoplasm LSIL: low grade squamous intraepithelial lesion. HSIL: high grade squamous intraepithelial lesion.

** Koiolocytosis is included in LSIL.

Cervical intraepithelial neoplasia: Cervical intraepithelial neoplasia (CIN) is the term used to describe dysplastic changes in the squamous epithelium of the cervix. Dysplasia often occurs at the squamocolumnar cell junction. Mild dysplasia (CINI) is typified by a slight increase in nuclear/cytoplasmic ratio, hyperchromasia and an abnormal chromatin pattern. However, in severe dysplasia (CIN III) the criteria are high nuclear/cytoplasmic ratio , marked hyperchromasia and abnormal chromatin.

-The epithelial cells fail to mature, there are marked cytological changes and mitotic activity occurs near the surface of the epithelium.

-The three grades of CIN do not imply inevitably progress from CIN I to CIN III or from CIN III to invasive carcinoma. CARCINOMA OF THE CERVIX:

Epidemiology Risk of Ca-cervix is increased in :  Early sexual activity.  Multiple partners.  Cigarette smoking.  History of abnormal Pap smear.  Immunosuppression.  HSV-2 infection.  15 high oncogenic risk HPV types:16, 18, 31, 33, 35... Ca-Cervix, High risk male partner:-

 H/O genital carcinoma (especially penile).  H/O sexually transmitted diseases.  H/O CIN or cervical carcinoma in first wife.  Low socioconomic status.  Multiple sexual partners. Role of HPV in cervical carcinoma ? :- • Consistent presence of certain strains of HPV in carcinoma. • Not all patients infected with the virus develop carcinoma. • HPV may act as an initiator, other factors may act as promoters, these may include: – HSV , smoking , genetic …etc.

Pathogenesis of HPV infection • Uncontrolled transcription of viral E6-E7 oncogenes. • E7 binds and inactivates Rb. • E6 binds p53 and accelerates its degeneration. Human Virus (HPV), type 31, has been demonstrated by means of in-situ DNA hybridisation in many of the cells (arrow). Carcinoma of the Cervix • 80% :SCC • Adenocarcinoma : 10% • Mixture and rare types 10%. Modes of spread: • Direct spread to contiguous sites, may produce: – Hydronephrosis, pyelonephritis, renal failure…. • Lymphatic spread to regional pelvic nodes. • Vascular to lungs and liver Cervical squamous cell carcinoma Uterus (Endo & myometrium) Endometrial cycle • Menstruation (~5 days). • Proliferative phase: Glandular proliferation & compact stroma. • Secretory phase:(14 days) – Cytoplasmic vacuolation (sub –nuclear : 16th day). – Secretions in the lumen (days 19-20) – Stromal edema (days 21, 22) – Decidual changes (large squamous-like) (days 23-27) – Necrosis and sluoghing (day 28)…menses Late secretory shedding Inflammation: The and myometrium are relatively resistant to infections, primarily because the endocervix normally forms a barrier to ascending infection.

ACUTE ENDOMETRITIS : Acute endometritis is uncommon and limited to bacterial infections that arise after delivery or miscarriage. CHRONIC ENDOMETRITIS : Occurs in the following settings: (1) in patients suffering from chronic PID; (2) in postpartum or post-abortion patients with retained gestational tissue; (3) in women with intrauterine contraceptive devices; and (4) in women with tuberculosis, either from miliary spread or, more commonly, from drainage of tuberculous salpingitis. The chronic endometritis in all these cases is secondary to another underlying cause. Some may complain from abnormal bleeding, pain, discharge & infertility. In about 15% of cases no cause is obvious. Histology: plasma cells (which are not present in normal endometrium) are the diagnostic cells together with macrophages and lymphocytes.

Causes of Abnormal Uterine Bleeding by Age Group Dysfunctional Uterine Bleeding Endometrium is constantly engaged in dynamics of shedding and regrowth under fine hormonal control, any alteration may lead to spectrum of disturbances such as atrophy & abnormal proliferative or secretory patterns. The most common problem is the abnormal uterine bleeding. This bleeding is either due to organic lesion (like polyp ,lieomyoma, carcinoma, abortion, ectopic pregnancy….) or due to functional (i.e. in the absence of a well defined organic lesion)the latter called Dysfunctional Uterine Bleeding. Causes of DUB are: 1-Anovulatory Cycle: Etiology : unknown but it is associated with endocrine dz, estrogen secreting & others e.g. DM, obesity, malnutrition….these conditions are associated with unopposed estrogen… accompanied by shedding of endometrium in proliferative phase rather than secretory. Usually occurs at menarche and perimenopause.

DUB, continuo: 2-Inadequate luteal phase: Inadequate corpus luteum function resulting in low progesterone output & subsequent early menses. Biopsy : shows secretory endometrium but with lag of more than 2 - days (i.e. Bx= 18th day but really it in the 22nd day). - 3-Irregular shedding: Heavy prolonged menses caused by persistent corpus luteum.

4-Menopausal & postmenopausal changes: Characterized by anovulatory cycles, & architectural alterations in the endometrial glands. 5-Contraceptive induced bleeding. Endometrial polyp: Most endometrial polyps are not (0.5 - 3cm dia) projecting into the uterine cavity. They are covered with endometrial epithelium and composed of non secretory endometrial glands (?) & cellular stroma with thick walled blood vsls.They may be asymptomatic or cause excessive uterine bleeding. Endometrial Hyperplasia Etiology: Excess unopposed estrogen seen in: • Anoulatory cycles – Polycystic ovarian disease – Estrogen producing tumors – Obesity – Classification Simple hyperplasia( glands) complex hyperplasia(back-back) without atypia 1% With cellular atypia 8%

Without atypia with atypia (risk of ca: 3%) (risk of ca:25%)

Endometrial Hyperplasia Simple without

Complex without Complex+atypia Endometrial Adenocarcinoma It is the most common of female • genital tract, mostly affects perimenopausal and postmenopausal women. Predisposing factors: • Endometrial hyperplasia – Obesity – Infertility ,nulli-parity – Diabetes , – hypertension. –

Types of endometrial Adenocarcinoma: 1-endometrioid type. 2-papillary . 3-adenosquamous. 4-clear cell . + others

Endometrioid Papillary serous, clear cell, (>80%) adenosquamous

Estrogen related – Unrelated to estrogen – Associated with hyperplasia – Not associated with hyperplasia – Younger peimenopausal – Older women – women High grade, more aggressive – Low grade –

Endometriosis • Presence of endometrial tissue in remote sites: – , Douglas pouch, uterine ligaments, tubes, peritoneal cavity, umbilicus. • Etiology: – Regurgitation.(of menstruation through Falopian.tubes) – Metaplasia.(of coelomic epith. from which endometrium had been originated) – Vascular or lymphatic dissemination. • Complications: – pain, infertility, dysmenorrhea , misdiagnosed as carcinoma. Gross; • Appears as red-blue areas with hemorrhagic foci. • Fibrosis and adhesion. • Microscopy: Diagnoses is made by presence of 2 out of the following 3: 1-endometrial glands. 2-endometrial stroma. 3-hemosidrin pigment.

Adenomyosis: • Presence of endometrial glands and stroma with in the myometrium. Gross: Brown foci within the myometrium. Clinically: -Usually asymptomatic. -Uterine bleeding. -Dysmenorrhea

Leiomyoma (fibroid) • Most common benign tumor in females. • Found in 30%-50% of women of reproductive age. • Well circumscribed, round, often multiple, firm to hard, gray-white with whorl cut section. • Size is variable 1mm - >3o cm. • Growth is stimulated by pregnancy and hormones • Symptoms related to size and location (intramural , submucosal or subserosal): asymptomatic, mass,bleed… • Histology: Benign smooth muscle bundles with no nuclear atypia , mitosis or necrosis. • There are different variants. • Rx: myomectomy ..hysterectomy Leiomyoma • Malignant smooth muscle tumor. • are equally common before and after menopause, and have a peak incidence at 40 to 60 years • Rare(1/1000) in comparison with leiomyoma. • Histology : invasive spindle cell tumor with nuclear atypia , mitosis and necrosis.

Ovary Commonly presented with neoplastic or non neoplatic varian cyst/mass. Inflammation is rare as a primary dz.

-Non neoplastic ovarian include: -Follicular cysts. -Corpus luteal cyst. -Epithelial inclusion cyst. -Paratubal cyst.

Polycystic ovarian disease (stein-leventhal syndrome): -Affects 3-6% of female in reproductive age. -Numerous cystic follicles in both enlarged ovaries. -Obesity , oligomenorrhea , hirsutism + virilization. Etiology: ~ corpus luteum secrete high androgen…converted to estrogen), for years, these endocrine abnormalities were attributed to prim a.269* [- ry ovarian dysfunction because large wedge resections of the ovaries sometimes restore fertility. It is now believed that a variety of enzymes involved in androgen biosynthesis are poorly regulated in PCOD. Corpus luteal cyst: Corpus luteal cyst is derived from the corpus luteum . A normal corpus luteum is slightly cystic, but occasionally it may got a much larger sized cyst (up to 6cm dia) Macroscopically the wall of this cyst has a yellow-brown colour. Histologically the wall of the cyst is composed of broad folded sheets of large luteinized cells with abundant well-defined granular or vacuolated (lipid-rich) cytoplasm. Ovarian Tumors They are numerous, generally they fall into benign, borderline and malignant. About 80% are benign, and these occur mostly in young women (20- 45 years). Borderline tumors occur at slightly older ages. Malignant tumors are more common in older women (above 45 y). Ovarian accounts for 3% of all in females (USA).

Epidemiology: •Familial cases (5% - 10%): Breast - syndrome related to BRCA 1. Ovary, endometrium and colon (Lynch syndrome) •Nulliparity increases risk by 1.5-3.2 folds. •Oral contraceptives decrease the risk by half. •Increased risk among women receiving drugs that induce ovulation but have not become pregnant.

Histological Classification: Ovarian neoplasms are classified according to the most probable tissue of origin, i.e. from one of the three ovarian components: (1) surface epithelium derived from the coelomic epithelium; (2) the germ cells, which migrate to the ovary from the yolk sac and are pluripotent; and (3) the stromal-sex cords (forerunners of the endocrine apparatus of the postnatal ovary).

There is also a group of tumors that defy classification, and finally there are secondary or metastatic tumors to the ovary.

Ovarian Tumors

Cell of origin Overall Proportion of Age frequency malignant affected tumors

Surface epithelium 65-70% 90% 20+ Y

Germ cell 15-20% 3-5% 0-25+ Y

Sex cord - stomal cells 5-10% 2% All ages

Metastases 5% 5% Variable

Ovarian Tumors Surface epithelium

• Main types are : • Serous tumor.

• Mucinous tumor • Endometrioid tumor. • Clear cell tumor. • Brenner tumor: • Cystadenofibroma: • Undifferentiated Surface Ovarian Tumors • Form ~ (90%) of malignant ovarian tumors. • Originate from surface epithelium & recapitulate the components of the Mullerian ducts (Serous ~Tube , Endometrioid ~ endometrium , mucinous ~ cervix).

• Divided into : -Benign, -Borderline (or low malignant potential “LMP”) . -Malignant tumors. • Almost cystic. More complexity and solid components mean more chance for malignancy. Serous Tumors • Age: 30-40 years. • Usually cystic. • Benign() & LMP :70%. • Malignant cases ~ 30% (accounts for approximately 40% of all cancers of the ovary , ~ the most common malignant ovarian tumors). • 25% of benign tumors are bilateral. • 65% of malignant tumors are bilateral. • Psammoma bodies(lamellated calcification) are common findings. • Benign serous tumor : Grossly: Variable sized cystic tumor with smooth and glistening lining. It contains clear fluid “translucent” . Microcopy: Ciliated epithelium with no or mild pleomorphism . No invasion. • Malignant (serous ): Grossly : Variable sized multicystic tumor with papillary/ nodular projections and thickened wall. Microscopically : Malignant cells invading the subepithelial tissue(pleomorphism , mitosis , invasion…). • LMP: ~ malignant but with out definite invasion. **All may have psammoma bodies.

Mucinous Tumors • 30% 0f all ovarian tumor , Age: 30-40 years , • Usually cystic with thick mucinous content • ~ 85% benign and LMP, 15% malignant. • 5% of benign tumors are bilateral. • 20% of malignant tumors are bilateral. • Metastases / rupture may lead to (thick mucous+adhesion). • Microscopy: Benign , malignant & LMP are ~~ serous types but with mucinous lining. • No psammoma bodies

Mucinous LMP Endometrioid Tumors

Benign endometrioid tumors called endometrioid adenofibromas, and borderline endometrioid tumors are uncommon. However, endometrioid account for approximately 20% of all ovarian cancers. Endometrioid tumors are distinguished from serous and mucinous tumors by the presence of tubular glands bearing a close resemblance to benign or malignant endometrium.

-Endometrioid carcinomas may arise in the setting of . About 15% to 20% of cases with endometrioid carcinoma coexist with endometriosis.

-Morphology. Grossly endometrioid carcinomas present as a solid /cystic mass. - 40% involve both ovaries Ovarian Tumors • Dysgeminoma (~testis Surface epithelium Seminoma ). • Yolk sac tumor. Germ cell: • :

Sex cord-stomal cell -Mature. -Monodermal.

Metastases -Immature(malignant)

• . • Mixed germ cell tumors • 15%- 20% of all ovarian tumors. • Usually in first 2 decades of life. • >90% are benign, more cystic..(dermoid cyst). • Malignant (immature) teratoma tends to occur in younger individuals, more solid and contains immature tissue (neural , cartilage….) . • 90% are unilateral. • Microscopy: somatic differentiation from the 3 germ layers :skin ,teeth. Brain , bone , liver.... • Sruma ovarii (thyroid).

Immature teratoma Dysgeminoma Schiller-Duval body in yolk sac carcinoma Ovarian Tumors

• Granulosa cell tumor Surface epithelium • • Germ cell • Sertoli-Leydig cell tumor Sex cord-stromal cell

Metastases Granulosa–Theca Cell Tumors Ovarian neoplasms composed of varying proportions of granulosa and theca cell differentiation. Collectively, these neoplasms account for about 5% of all ovarian tumors. The granulosa cell component of these tumors takes many histologic patterns (small, cuboidal to polygonal cells). In occasional cases small follicles filled with an acidophilic material recall immature follicles (Call-Exner bodies). Granulosa cell tumors have clinical importance for two reasons: 1-Granulosa cell tumors are potentially malignant. 2- Can elaborate large amounts of estrogen…..endomet. Hyperplasia….

Fibrothecomas Tumors arising in the ovarian stroma that are composed of either fibroblasts () or plump spindle cells with lipid droplets () or mixture. These tumors usually presented as a pelvic mass, sometimes accompanied by ascites and hydrosalpinx and this is known as Meigs syndrome.

fibrothecoma

Call-Exner bodies Diseases of pregnancy • Ectopic pregnancy : Implantation of fertilized ovum in any site other than normal uterine location. It occurs in about 1% of pregnancies. - 90% occurs in the Fallopian tube. - Other sites include ovaries , abdominal cavity … - The underlying causes include : chronic inflammation & fibrosis of the tube , tumor and endometriosis. However in about half of the cases the underlying is unknown. - Clinically ~ normal pregnancy until rupture that could cause severe abdominal pain. Decidua in F.tube

Chorionic villi

Ectopic tubal gestation Gestational trophoplastic diseases • A spectrum of tumor and tumor like conditions characterized by proliferation of pregnancy-associated trophoblastic tissue of progressive malignant potential. • They include : 1-Hydatidiform mole (complete & partial forms). 2-Invasive mole. 3- Frank malignant dz : Choriocarcinoma. Complete Hydatidiform Mole • Empty ovum fertilized by either 2 sperms or one diploid sperm (paternal material). While in Partial m. 2 sperms (or 1 dipoloid sperm) fertilize 1 ovum. • Grossly, mass of grape like vesicles. • Histology: - Large avascular villi with central edema (cisterns) and circumferential proliferation of trophoblasts. - Absent fetus. Clinically: Vaginal bleeding , large for date and high HCG • 10-20% risk of persistent trophoblastic disease. • 2%-3% risk of choriocarcinoma.

Complete Versus Partial Hydatidiform Mole Feature Complete mole Partial mole

Karyotype Diploid(paternal) Triploid

Villous edema All villi Some villi

Trophoblastic Circumferential Focal proliferation

Atypia Present ~Absent

Serum hCG Elevated Less elevated

Risk of 2-3% rare choriocarcinoma Choriocarcinoma

• Geographic variation: 1/30,000 pregnancies in the West, 1/2,000 in East Asia. • Age: high risk below 20Y and above 40Y. – 50% follow complete mole – 25% follow abortions. – 24% follow normal pregnancy – 1% follow ectopic pregnancy. • Very high titers of bhCG. • Hemorrhagic tumor with anaplasic sycytiotrophblasts and cytotrophoblasts. • V. bleeding …..Wide spread dissemination(liver, lung…)