Female genital system Vulva disorders are not too frequent Vulvitis many non specific microbe-induced inflammations intense itching (pruritus), scratching 4 specific infectious agents: HPV - condylomata acuminata, vulvar intraepithelial neoplasia (VIN) HSV - vesicular eruption gonococci - suppurative infection T. pallidum - syphilis (primary chancre) Vulvar dystrophies non-neoplastic epithelial disorders atrophy (thinning) or hypertrophy (thickening) 2 major forms: lichen sclerosus squamous hyperplasia Lichen sclerosus thinning of epithelium, disappearance of rete pegs superficial hyperkeratosis dermal fibrosis + mononuclear inflammatory infiltrate clinically - smooth, white plaques - stiffened labia all age groups, most frequent in postmenopausal women pathogenesis uncertain (autoimmune?); in 1-4% cancer ! Squamous hyperplasia area of leukoplakia epithelium - increased mitotic activity, no atypia! no increased predisposition to cancer Tumors Benign Condylomas anogenital warts - tend to be large two distinctive forms Condylomata lata rarely seen today - secondary syphilis Condylomata acuminata mm-cm pink-red-brown histology - papilomas, distinctive features (koilocytosis) HPV 6 and 11 - closely related to common warts veneral transmission (also around anus and on the penis) not precancerous, but frequently coexistent with VIN (different types of HPV) Malignant VIN and carcinoma 3% of all gyn cancers, mostly the age over 60Y dramatic increase in the past few decades, younger age 90% = squamous cell ca 10% = adenoca, melanoma, basal cell ca two principal forms HPV-related (HPV 16, 18 and 31) - 90% preceded by VIN I.-II.-III.), younger age, sometimes coexistent with cervical ca HPV-non-related older age, 10%, preceded for years by lichen sclerosus exophytic and endophytic forms multifocality Histology HPV+ = poorly differentiated HPV- = well diffferentisated slow progression - direct invasion, regional LN (inguinal), hematogenous spread size dependent - under 2 cm 75% 5Y survival, over 2 cm only 10% 10Y survival Paget's disease (extramammary) intraepithelial spread of carcinomatous cells (single or in small clusters) origin from anogenital glands (adnexal) clinical appearance - areas of red-crusted inflammatory-like areas extension into skin appandages, metastasizing Melanoma 3-5% of vulvar cancers similar to skin frequently fatal outcome Vagina seldom site of primary disease in adults congenital anomalies, vaginitis, tumors Congenital anomalies agenesis - total absence (extremely rare) hypoplasia - smaller size vagina duplex (double v.) - assoc. with malformations of other parts of the gyn tract lateral Gardner's duct cyst - persistent embryonic remnants Vaginitis relatively common clinical problem - transient vaginal discharge (leukorrhea) large variety of microorganisms (bacteria, fungi, parasites) - some are sexually transmitted immunosuppressed patients are predisposed (DM, pregnancy, abortion, AIDS) Candida albicans curdy-white discharge about 5% of adult females appearance of symptomatic infection = predisposing influences or more aggressive strain (sex.transm.) Trichomonas vaginalis copious watery gray-green discharge sometimes asymptomatic infection! Nonspecific atrophic vaginitis postmenopausal women Malignant tumors Embryonal rhabdomyosarcoma (sarcoma botryoides) soft polypoid masses rare infants and children under 5Y Clear cell adenocarcinoma in pubertal girls - daughters of mothers using diethylstilbestrol during pregnancy Uterine cervix barrier against infection, escape of menstrual flow, trauma during childbirth Cervicitis erosions versus true inflammations Erosions shifting of transformation zone during life span squamous cell metaplasia retention cysts (nabothian - ovula Nabothi) Inflammations extremely common mucopurulent-purulent vaginal discharge infectious or non-infectious vaginal aerobes and anaerobes, streptoc., staphyloc, enteroc., E.coli more important - true pathogenes - Ch. trachomatis, U. urealyticum, T. vaginalis, Candida sp., N. gonorrhoeae, HSV II., HPV many sexually transmitted (STD) most important Ch. trachomatis (40% of STD cervicitis) HSV - infection of the infant during passage throughthe birth canal! Cervicitis acute or chronic reddening, swelling and granularity of the cervical mucosa nabothian cyst (inflamm. occlusion) micro: hyperplasia, reactive atypia (not dysplasia!) deformation of cervical canal + unfavorable enviroment for the sperm - sterility Tumors Endocervical polyp not a true tumor - focal tumor-like hyperplasia (post-inflammatory) cysts, squamous metaplasia of surface epithelium stromal oedema Cervical intraepithelial neoplasia (CIN) and squamous cell ca once the most frequent form of female cancer since 50th - cytological screening (Papanicolaou) dramatic decrease of incidence of ca, significant increase of precancerous lesions (CIN) - better diagnostics almost all cases of cervical ca develope from CIN × not every case of CIN must necessarily progress into ca almost all cases of both CIN and squamous ca - HPV related (high risk subtypes 16, 18, 31 and 33) CIN I.-II.-III. - depending on the relative thickness of involved epithelium (1/3 - 2/3 - more than 2/3) alteration of maturation, atypical nuclei, mitotic activity I. - low grade lesion (60% regress, 30% persist, 10% progress to CIN III., 1-5% become invasive) - flat condyloma III. - high grade lesion (33% regress, 6-74% progress) peak incidence of CIN = 30Y (× invasive ca = 45Y) risk factors: early age of first intercourse; multiple sexual partners; male partner with multiple previous sex. partners Invasive ca of the cervix 80-95% = squamous cell ca (evolution from CIN) - keratinizing or non-keratinizing remainder = adenoca, adenosquamous ca, small cell ca, other rare types peak incidence 45Y 3 distinct macroscopic forms: 1. fungating - most frequent (cauliflower-like mass) 2. ulcerative - sloughing of the central surface 3. infiltrative - least frequent - growth into the stroma spread into cervical canal, lower uterine segment and parametria involvement of LN, distant metastases (lungs, bones, liver) clinical symptoms: irreg. vaginal bleeding, leukorrhea, painfull coitus, dysuria - late symptoms! mortality depends on stage Body of uterus inflammation - endometritis adenomyosis + endometriosis dysfunctional bleeding endometrial hyperplasia tumors of endometrium tumors of myometrium Endometritis endom. relatively resistant to infections Acute rare! bacterial infections post partum or post abortum retained products of conception = predisposing factor (removal by curettage!) Chronic chronic gonorrhoeal pelvic disease miliary TBC chronic retention of gestational tissue IUD spontaneous (15%) Adenomyosis growth of the basal layer of endometrium into the myometrium stroma and glands between muscle bundles thickening of the uterine wall bleeding into tissue extremely unusual! (no cyclic changes) menorrhagia, dysmenorhea, pelvic pain Endometriosis clinically far more important than adenomyosis infertility, dysmenorrhea, pelvic pain foci of endometrial tissue in the pelvis (ovaries, pouch of Douglas, uterine ligaments, oviducts, rectovaginal septum) or in the remote sites (peritoneal cavity, appendix, umbilicus, post-surg. scars, LN, lungs, other) 3 possible explanations: 1. regurgitation theory (menstrual backflow) 2. metaplastic theory (endometrial differentiation of coelomic epithelium) 3. vascular or lymphatic dissemination theory almost always functioning endometrium - cyclic bleeding blood collection - red-blue nodules (1-2 cm) or blood filled cysts (decomposition of blood - hemosiderin - "chocolate cysts") organization - fibrosis - pelvic adhesions - distortion of oviducts and ovaries - infertility histology: endometrial glands, stroma, hemosiderin Dysfunctional uterine bleeding and endometrial hyperplasia most common problem in gyn monorrhagia (profuse or prolonged bleeding at the time of the period) metrorrhagia (irregular bleeding between the periods) ovulatory bleeding common causes polyps leiomyomas endometrial carcinoma cervical carcinoma endometritis endometriosis dysfunctional bleeding and endometrial hyperplasia Dysfunctional uterine bleeding absence of an organic lesion various causes in various ages of the patients Failure of ovulation (anovulatory cycle) common at both ends of reproductive life, dysfunction of hypotalamic-pituitary axis, adrenal or thyroid; malnutrition, obesity, physical or emotional stress => hormonal imbalance (excess of estrogen) proliferative phase is not followed by a secretory phase mild cystic changes, poorly supported endometrium - collapse, rupture of spiral arteries, bleeding Endometrial hyperplasia excess of estrogen hyperplasia simple or complex typical or atypical based on the level and duration of estrogen excess risk of carcinoma (atypical hyperplasia in 20-25%) Tumors of endometrium Endometrial polyps sessile, hemispheric, 0,5-3 cm focal hyperplasia of mucosa, stroma monoclonal (focal adenomatous proliferation of stroma) any age, most common at menopause Endometrial carcinoma most common cancer of female genital tract (USA, western Europe) age 55-65Y, uncommon under 40Y risk factors: obesity, DM, hypertension, infertility increased estrogen stimulation background of endometrial hyperplasia 20% of cases without estrogen-dependent background (elder patients, higher grade, poorer prognosis) grossly - infiltrative or exophytic; firm to soft, partially necrotic invasion into endometrial wall, serosa, periuterine structures meta regional LN, distant organs microscopically - adenoca resembling uterine mucosa (endometrioid type), sometimes squamous metaplasia (adenoacanthoma), sometimes true sq. diff - adenosquamous carcinoma rare histological variants (clear cell, serous papillary) Tumors of myometrium Leiomyoma (=fibroid) most common benign tumors in females (30-50%!) more frequent in blacks than in white hormonally dependent (stimulated by estrogen) shink in size after menopause asymptomatic, bleeding, palpable grossly - multiple, sharply circumscribed, firm, gray-white submucosal, intramural, subserosal microscopically - whorling bundles of smooth muscle cells; regressive changes - fibrosis, bleeding, myxoid degeneration, calcification no risk of malignant transformation Leiomyosarcoma origin de novo (not from preexisting leiomyoma) almost always solitary grossly - similar to leiomyomas or infiltrative growth microscopically - wide range of differentiation frequent mitoses, cellular atypia, apoptosis local recurrence, metastatic spread 5Y survival rate - 40% Fallopian tubes very rarely site of disease inflammations - bacterial (gonorrhea, Chlamydia, Mycoplasma hominis, streptococci, staphylococci) fever, lower abdominal or pelvic pain, stenosis-obstruction, dilatation extrauterine (tubal) pregnancy - dilatation, rupture, bleeding - hemorrhagic shock (hemoperitoneum) Ovaries inflammations, cysts, tumors (benign and malignant) Inflammations usually not primary (spread of salpingitis - salpingo-oophoritis) tuboovarial abscess - simulating tumor Cysts non-neoplastic vs. neoplastic endometriosis - hemorrhagic cysts (chocolate cysts) follicle and luteal cysts - physiologic variants, innocuous unruptured graafian follicles 1-1,5 cm, serous risk of rupture Polycystic ovaries (Stein-Leventhal syndrome) oligomenorrhea, hisrutism, infertility, obesity multiple cystic follicles, excessive production of estrogen and androgens grossly - ovaries 2× normal in size, gray-white, smooth cortex micro - cortical stromal fibrosis, cysts lined by granulosa cells; absence of corpora lutea Tumors of ovary great diversity 3 cell types - coelomic covering (surface) epithelium (90% of cancers!) - germ cells - sex cord-stromal cells (all together 10% of cancers) Surface epithelial-stromal tumors strictly epithelial (e.g. cystadenoma) or epithelial-stromal (e.g. adenofibroma) benign, intermediate (borderline, low malignant potential), malignant Serous tumors most frequent ovarian tumors, ages 30-40Y cystic or solid - cystadenomas, cystadenocarcinomas 60% benign, 15% borderline, 25% malignant borderline+malignant = 60% of all ovarian cancers most 5-10 cm, up to 40 cm in 25% bilateral! benign smooth, malignant nodular cut section - benign predominantly cystic (serous content), malignant solid parts micro - benign-single layer; malignant-papillae, multilayered, psammoma bodies, infiltrative growth meta spread - pelvic peritoneum, regional LN poor prognosis (late diagnosis!) Mucinous tumors analogous to serous tumors (categories, ages) mucin secreting epithelium (endocervix-like or intestinal-like) less likely to be malignant (10% of ovarian cancers) 80% benign, 10% borderline, 10% malignant 5-20% bilateral (benign less often than malignant) larger than serous, multilocular, no psammoma bodies rupture of malignant (or borderline) tumors - pseudomyxoma peritonei (jelly-like material on peritoneal surface, floating tumors cells) - similar to appendiceal origin mucinous tumors have better prognosis than serous ones Endometrioid tumors solid or cystic sometimes originate within endometriotic cyst tubular glands usually malignant, bilaterality in 30% Cystadenofibroma variant of benign cystadenoma pronounced proliferation of fibrous stroma small, multilocular Brenner tumor uncommon, solid, unilateral abundant stroma, nests of transitional epithelium (resembling that of urinary tract) cystic transformation of the nests grossly - smooth, gray-white, 2-20 cm mostly benign, malignant cases are rare Germ cell and sex cord-stromal tumors rare, extremely variable morphology, many entities most important = teratoma Teratomas germ cell origin 15-20% of ovarian tumors mostly during first two decades the younger the patient, the higher likelyhood of malignancy benign (mature), malignant (immature), carcinoma arising in teratoma, specialized teratomas Mature cystic teratoma marked ectodermal differentiation - dermoid cysts (epidermis + skin appendages) 90% unilateral, up to 10 cm cut section - sebaceous secretion, hairs cyst wall with a nodule (Rokitanski nodule) or nidus with teeth mixture of mature tissues (bone, cartilage, gut mucosa, bronchial mucosa, glial tissue, ganglion cells, thyroid tissue, salivary glands in 10-15% torsion - acute surgical emergency in 15% of cases - malignant transformation - squamous cell carcinoma Immature malignant teratoma early in life, mean age 18Y grossly - bulky, solid, foci of necrosis micro - immature tissues - cartilage, bone, muscle, nerve prognostic importance - foci of neuroepithelial differentiation - poor prognosis Specialized teratomas struma ovarii - mature thyroid tissue - hyperthyroidism, source of papillary cancer ovarian carcinoid - carcinoid syndrome Diseases of pregnancy causes of intrauterine or perinatal death, premature birth, congenital malformations, growth retardation, maternal death, maternal and fetal morbidity Placental inflammations ascending infection - most common, bacterial (Chlamydia, vaginal flora) and Candida associated with premature birth leucocytic infiltration of chorioamnion, edema congestion of the vessels - spread into umbilical cord and chorionic villi hematogenous (transplacental) infection most commonly infiltration of villi (villitis) syphilis, TBC, listeriosis, toxoplasmosis viruses (rubella, CMV, HSV) involvement of the fetus Ectopic pregnancy any site other than normal uterine location 1% of pregnancies 90% - oviducts (tubal pregnancy) ovaries, abdominal cavity, intrauterine portion of oviducts any obstruction of oviducts (chronic inflammation, postinflammatory fibrosis, intrauterine tumors, endometriosis) 50% of cases - no anatomic lesion demonstrable normal development of early embryo (placental tissue, amniotic sac, decidual changes) abdominal pregnancy very rarely carried to term! tubal pregnancy - size of max. 3-4 cm, bleeding (intratubal hematoma - hematosalpinx), rupture, intraperitoneal hemorrhage clinically initially indistinguishable from normal pregnancy acute abdomen, sudden onset, shock! Gestational trophoblastic disease 3 ovelapping morphological categories hydatidiform mole invasive mole choriocarcinoma elevated levels of hCG - blood, urine - control of effect of treatment Hydatidiform mole voluminous mass - swollen villi - grape-like structure complete (never fetal parts, all villi abnormal, diploid 46, XX) - empty egg + 2 spermatozoa or diploid sperm partial (fetal parts, some normal villi, almost always triploid 69, XXY) - normal egg + 2 spermatozoa or diploid sperm hCG - complete - extremely high, partial - only slightly abnormal risk of choriocarcinoma - usually from complete mole (2% of cases), rare in partial complete mole - 1:1000 pregnancies in the USA, much higher in Asia (???); under 20Y and after 40Y grossly - delicate friable mass of translucent cystic structures micro - absence of vascularization, loose myxoid stroma, chorionic epithelium - diffuse proliferation, atypia Invasive mole intermediate between h. mole and choriocarcinoma locally aggressive, no metastatic potential penetration of villi with proliferating trophoblast deeply into uterine wall sometimes rupture - life-threatening hemorrhage removal not possible by curretage - chemotherapy! Choriocarcinoma very aggressive malignant tumor origin from gestational chorionic epithelium or from pluripotent germ cells within gonads (e.g. choriocarcinoma in males!) rare in US and western Europe (1:30,000 pregnancies), frequent in Asia and Africa (1:2,000 pregnancies) 50% develop after complete mole, 25% after abortion, remainder after normal pregnancy bloody or brownish discharge, rising titer of hCG (much higher than in mole), absence of uterine enlargement grossly - hemorrhagic, necrotic (self-destruction of primary lesion!) micro - no villi, both syncytiotrophoblast + cytotrophoblast - both highly atypical, mitotic activity, early invasion into myometrium and vessels - hematogenous metastases (lungs, vagina, brain, liver, kidneys) in the past - always fatal, today - 100% are cured (chemotherapy)