Pathology of Female Genital Tract

1. Pathology of Female Genital Tract Assoc. Professor Jan Laco, MD, PhD

2. Summary • Vulva • Vagina • Cervix of uterus • Body of uterus • Fallopian tube • Ovary • Diseases of pregnancy

3. 1. Vulva • Malformations and regressive changes • Inflammations • Dystrophies • Pseudotumors • Tumors

4. Malformations and regressive changes • Hypertrophy of clitoris • congenital adrenogenital syndrome (21-hydroxlase) • Senile atrophy • Edema • generalized hydrops • lymphedema – filariosis, lymphogranuloma venereum • Varices • pregnancy, delivery

5. Inflammations – vulvitis/vulvovaginitis • predisposing factors • immunosupression (DM, uremia, malnutrition, ATB) • bacterial • gonorrhea (N. gonorrhoeae) • syphilis (T. pallidum) – chancre (ulcus durum) + condylomata lata • granuloma inguinale (Calymmatobacterium granulomatis) • lymphogranuloma venereum (Chlamydia trachomatis L1-L3) • viral • HSV 2 • HPV (condyloma acuminatum, VIN/SIL) • mycotic • Candida spp. (DM) • parasitic • Trichomonas vaginalis

6. Dystrophies • = non-neoplastic epithelial disorders • clinically leukoplakia – flat whitish lesions • histologically two forms: • Lichen sclerosus (et atrophicus) • postmenopause, autoimmunity ??? • Mi: atrophy of squamous epithelium, loss of adnexa, hyalinosis of upper dermis, chronic inflammation • sclerotic stenosis of vulva / introitus – clinically kraurosis vulvae • 1-4% pts. – squamous cell carcinoma of vulva !!! • Lichen simplex chronicus (hyperplastic dystrophy) • hyperplastic epithelium with hyperkeratosis, NO atypia • NO risk of carcinoma development

7. Pseudotumors • caruncula urethralis • reddish painfull small nodul near external urethral oriffice • recurrent infections • Mi: inflammatory pseudotumor • cysts • skin adnexa (atheromas) • Bartholin gland • retention (up to 5 cm), may be infected (abscess), pain

8. Benign tumors • condyloma acuminatum • ethiology – HPV (low-risk types 6, 11), STD • multiple flat / elevated red-brown lesions (mm-cm) • vulva + perineum, perianal areas • Mi: squamous cell papilloma – papillomatosis, acanthosis, parakeratosis, dyskeratosis - koilocytosis (koilos – empty) • skin adnexal tumors • papillary hidradenoma

9. Benign tumors • Deep “aggressive“ angiomyxoma • young females – 2nd-3rd decades • ~ Bartholin gland cyst • Mi: hypocellular myxoid stroma + vessels • local recurrence • Angiomyofibroblastoma • Cellular angiofibroma

10. Dysplasiavulvar intraepithelial neoplasia (VIN) • 2 etiopathogenetic pathways • differentiated VIN – mutation of TP53 • usual VIN – HPV (high-risk types – 16, 18, 31) • impaired structure / maturation of epithelium • cellular atypia • hyperchromazia, increased N/C ratio, mitoses • grading: d-VIN x u-VIN I-III (LSIL x HSIL)

11. Vulva • precursor lesions = LG squamous intraepithelial lesion (LSIL) u-VIN I, flat condyloma, koilocytosis, atypical koilocytosis, condyloma acuminatum … def.: HPV-positive = HG squamous intraepithelial lesion (HSIL) u-VIN II, u-VIN III, CIS, M. Bowen = differentiated VIN

12. Malignant tumors • squamous cell carcinoma (SCCa) • most common vulvar malignancy • cca 3% tumors of FGT • after 60 Y, currently decrease of age • ethiology • + HR-HPV + young smokers + u-VIN … 30% SCCa • - HR-HPV + old females + d-VIN/LSetA … 70% SCCa • G: leukoplakia x exophytic x endophytic ulcerated • Mi: variably differentiated SCCa • local spread + LN • 5-year survival: 75% (< 2 cm) x 10% (> 2 cm)

13. Malignant tumors • Extramammary Paget disease • intraepithelially spreading carcinoma • apocrinne anogenital glands • primary intraepithelial from progenitor cell • G: map-like lesions ~ dermatitis • Mi: Paget cells in epidermis large cells with PAS+ pale cytoplasm • NO invasion – persistance for several years, NO metastases • invasion - metastases

14. Malignant tumors • Malignant melanoma • 3-5% of vulvar malignancies • Adenocarcinoma • Basal cell carcinoma (skin)

15. Summary • Vulva • Vagina • Cervix of uterus • Body of uterus • Fallopian tube • Ovary • Diseases of pregnancy

16. Vagina • Malformations / regressive changes • Inflammations • Adenosis • Pseudotumors • Dysplasia • Tumors

17. Malformations / regressive changes • Agenesis, atresia • Vagina septa • Vagina duplex • Cysts of Gartner´s canal • Senile atrophy • Necrosis (radiation) + fistulas • Injury – delivery, criminal abortus • Hematokolpos

18. Inflammations – kolpitis (vaginitis) • + vulvitis + cervicitis • pruritus, discharge (fluor, leukorea) • predisposing factors • hypoestrogenism, DM, pregnancy, loss of normal flora (Lactobacillus Döderleini), alkalisation of vaginal milieu (normal pH  4.5), ATB • colpitis emphysematosa • pregnancy, spontaneously dissappears • dysmicrobia – NO inflammation, abnormal vaginal milieu • bacterial vaginosis – Gardnerella vaginalis

19. Adenosis • presence of glandular instead of squamous epithelium in vagina • endocervical x tubal / endometrial • reddish spots • squamous metaplasia + inflammation • idiopathic x synthetic estrogen diethylstilbesterol • risk: clear cell adenocarcinoma (1 in 1,000)

20. Pseudotumors • endometriosis • implantant cysts from squamous epithelium in episiotomy scar • dysontogenetic cysts • granulation tissue (caro luxurians), e.g. after hysterectomy

21. Dysplasia - VaIN • vaginal intraepithelial neoplasia • LSIL x HSIL • often associated with VIN and CIN • the same ethiology and morphology • VaIN more rare

22. Vagina • precursor lesions = LG squamous intraepithelial lesion (LSIL) VAIN I, flat condyloma, koilocytosis, atypical koilocytosis, condyloma acuminatum … def.: HPV-positive = HG squamous intraepithelial lesion (HSIL) VAIN II, VAIN III, CIS …

23. Tumors • benign • rare, mesenchymal (leiomyoma, fibroma) • malignant • carcinoma • 1-2% of all tumors of FGT • squamous cell carcinoma (90 %) • 6th decade, + VaIN • local spread, fistulas (urinary bladder, rectum) • LN metastases, 5-year survival: 40-50% • adenocarcinoma • endometrioid • clear cell (60% from pregnancies with DES, 17 years) • embryonal rhabdomyosarcoma (sarcoma botryoides) • malignant tumor of childhood (age 5 years)

24. Summary • Vulva • Vagina • Cervix of uterus • Body of uterus • Fallopian tube • Ovary • Diseases of pregnancy

25. Cervix of uterus • ectocervix (squamous epithelium) • endocervix (columnar epithelium) • squamo-columnar junction • between – transformation zone

26. Cervix of uterus • Inflammations • Pseudotumors • Dysplasia • Tumors

27. Inflammations - cervicitis • common, associated with vulvovaginitis • STD • Streptococci (S. agalactiae), staphylococci, enterococci, E. coli • Ch. trachomatis, U. urealyticum • HSV – indication for SC • acute – may be erosions • chronic – chronic inflammation (follicular cervicitis), mucosal hyperplasia (papillary cervicitis)

28. Pseudotumors • cystosis (ovulosis, ovula Nabothi) • ectropium • overgrowth of metaplastic squamous epithelium blocks orifices of EC glands – retention cysts • endometriosis • endocervical polyp • 5% of adult females, bleeding • solitary / multiple, event. protrusion into vagina • up to several cm • hyperplastic and inflammatory changes of endocervical mucosa • NOT precancerosis

29. Dysplasia – cervical intraepithelial neoplasia (CIN) • transformation zone • ethiology – HR-HPV (16, 18, 31, 33), STD • 30 Y, age decreasing !!! • risk factors (+ SCCa) • persistent HR-HPV infection (x immune system) • early age at first intercourse • multiple sexual partners, risk male partner • Mi: cytologic atypia + impaired structure / maturation • squamous - CIN I-III; endoC – LG-CGIN+HG-CGIN • progression to SCCa: CIN I – 2%, CIN II – 5%, CIN III – 20% • regression: CIN I – 50-60%, CIN III – 33%

30. Cervix • precursor lesions = LG squamous intraepithelial lesion (LSIL) CIN I, flat condyloma, koilocytosis, atypical koilocytosis, condyloma acuminatum … def.: HPV-positive = HG squamous intraepithelial lesion (HSIL) CIN II, CIN III, CIS … = adenocarcinoma in situ… HG-CGIN • LG-CGIN no longer used

31. Cervical intraepithelial neoplasia • prebioptic diagnostics – screening • kolposcopy • + Schiller´s test – application of Lugol´s solution • normal epithelium (glycogen) brown • dysplastic epithelium white • cytology (smears) • staining according Papanicolaou • evaluation acc. Bethesda classification • L-SIL (low-grade squamous intraepithelial lesion) = CIN I • H-SIL (high-grade squamous intraepithelial lesion) = CIN II-III

32. Benign tumors • condyloma acuminatum • mostly on ectocervix • slightly elevated whitish lesions • Mi: see vulva • mesenchymal • mostly leiomyoma – problems during delivery

33. Malignant tumors • squamous cell carcinoma – 75% of C tumors • on the basis of CIN in TZ • 45 Y, age decreasing !!! • G: exophytic x endophytic (ulceration, deformation) • local spread to body of uterus, vagina, parametria, rectum, urinary bladder – fistulas, stenosis of ureters (hydronephrosis) • metastases – LN, distant late • 5-year survival: I – 90%, II – 82%, III – 35%, IV – 10% • adenocarcinoma (adenosquamous) – 20% of C tumors • usual, mucinous, endometrioid, clear cell • adenoma malignum, villoglandular adenoCa • neuroendocrine carcinoma (small cell) – 5%

34. Summary • Vulva • Vagina • Cervix of uterus • Body of uterus • Fallopian tube • Ovary • Diseases of pregnancy

35. Body of uterus • Inflammations • Endometriosis • Dysfunctional endometrium • Endometrial Hyperplasia • Pseudotumors • Tumors

36. Inflammations • endometrial inflammation (endometritis) • acute • after delivery / abortus (placental residua, blood clots) • pyogenic bacteria (streptococci) – ascendent spread • purulent, discharge blockage – pyometra • sepsis puerperalis • chronic • pathologic bleeding, pain, infertility • ethiology – gonorrhea, after delivery /abortus, IUD – actinomycosis, Chlamydia spp., TBC • lymphoplasmacellular inflammation in endometrium, granulomatous (TBC)

37. Inflammations • myometrial inflammation – myometritis • + endometritis – endomyometritis • after delivery / abortus • thrombophlebitis of uterine veins • perimetrial inflammation - perimetritis • from myometrium to peritoneum upon uterus • part of pelveoperitonitis if the source is fallopian tube • parametrial inflammation – parametritis (uterine ligg.) • phlegmone • cause – penetrating injury, gangrenous tumors

38. Endometriosis • = endometrial mucosa (glands+stroma) in abnormal localization • endometriosis interna, adenomyosis • in myometrium of uterus • from bazal zone • menorrhagia, pelvialgia • endometriosis externa • peritoneum of pelvis, fall. tube, vagina, ovarium, vulva, GIT, urinary bladder, abdominal wall, LN, lungs, heart, skeleton • from functional zone • active during menstrual cycle – chocolate cysts • infertility, dysmenorrhea, pelvialgia • pathogenesis • regurgitation – implantation of pieces of endometrium (in tube, scar) • metaplastic – endometrial differentiation of coelomic epithelium (secondary Müllerian system) • vascular / lymphatic dissemination

39. Uterinebleeding • pathologic uterine bleeding • quantitative (hyper- or hypo-menorrhea) • time-inappropriate (poly- or oligo-menorrhea) • menorrhagia + metrorrhagia • premenarchal and postmenopausal bleeding • causes – bleeding disorder, inflammations, endometriosis, polyps, benign and malignant tumors … + dysfunctional endometrium • dysfunctional endometrium – impaired hormonal regulations, sometimes associated with uterine bleeding

40. Dysfunctional endometrium • dysfunctional non-secretory endometrium • abnormal levels of estrogens • decreased levels – hypoproliferative / atrophic endometrium • increased levels – hyperproliferative / hyperplastic endometrium • cause – anovulatory cycles • dysfunctional secretory endometrium • abnormal levels of gestagens • decreased levels – hyposecretory endometrium • cause – inadequate luteal phase • increased levels - hypersecretory endometrium (like pregnancy) • dysfunctional irregulatory endometrium • imbalance between estrogens and gestagens • e.g.: stromoglandular dissociation • hormonal therapy, hormonal contraception

41. Endometrial hyperplasia • cause – hyperestrogenism • exogennous administration • anovulatory cycles • estrogen-producing tumors (ovary), polycystic ovaries • G: high endometrium (diffuse x focal) • simplex x complex – no longer used • simplex – hyperplasia of glands and stroma (glandular cystic h.) • complex – reduction of stroma, structural abnormalities • without atypia x atypical … atypia = dysplasia • precancerosis – atypical complex hyperplasia 20-25% risk for endometrial adenocarcinoma

42. Pseudotumors • polyps • placental polyp • placental residua • corporal polyp • circumscribed hyperplasia of proliferative glands with fibrous stroma • solitary / multiple (mm-cm), perimenopause • adenomyoma • smooth muscle tissue stroma • atypical polypous adenomyoma • benign x local recurrence

43. Malignant tumors of endometrium • endometrial adenocarcinoma (type I vs. type II) • most frequent malignant tumor of FGT • peak 55th-65th Y • risk factors (type I) • hypertension, diabetes mellitus, obesity • early menarché, late menopause, infertility, anovulatory cycles • hyperestrogenism (atypical complex hyperplasia) • Lynch syndrome • clinically – postmenopausal bleeding (dg. curettage) • Grossly: • polypous – late invasion • diffuse – early invasion • spread – myometrium, cervix, adnexa, pelvis • late metastases – regional LN, hematogennous rare • 5-year survival: I – 90%, II – 30-50%, III a IV – 20%

44. Endometrial carcinoma • endometrioid • mucinous • serous • clear cell • undifferentiated

45. Endometrial carcinoma

46. Tumors of endometrial stroma • 45 Y, bleeding • Mi: uniform small cells encircling vessels • Endometrial stromal nodul • Grossly: well circumscribed yellowish nodule • benign • Endometrial stromal sarcoma • infiltration in myometrium and into lymphatic vessels • low-grade – local recurrence, late metastases • high-grade – aggressive tumor

47. Myometrial tumors - leiomyoma • most common benign tumor in females, 30-50% fertile females • 40-50 Y • hormonal dependent • progression during pregnancy, regression in postmenopause • clinically – acc. position and size • pain, bleeding, infertility, problems during delivery • G: firm circumscribed whitish-pink nodule, fascicular • mm-cm (up to 10 cm) • solitary / multiple (uterus myomatosus) • localization • submucosal • bleeding, polypoid on stalk – into cervical canal = myoma nascens, infarction • intramural • subserosal (sometimes polypoid)

48. Myometrial tumors - leiomyoma • Mi: • elongated spindle-shaped cells with eosinophilic cytoplasm and cigarette-shaped nuclei • regressive changes (edema, hemorrhage, hyalinization, calcification) • rarer variants • epithelioid (polygonal cells with pale cytoplasm) • bizarre • cellular • mitotically active • intravenous leiomyomatosis • benign metastasizing leiomyoma

49. Myometrial tumors - leiomyosarcoma • rare • de novo, NOT from leiomyoma • peak – 60 Y • Mi: malignant smooth muscle tumor mitoses, nuclear atypia, infiltrative growth, necroses • variants • epithelioid • myxoid • 5-year survival: 40%

50. Mixed tumors • carcinosarcoma (MMMT) • postmenopause • extremely aggressive, myometrial invasion, metastases • epithelial c. – poorly diff. endometrioid/serous Ca • mesenchymal c. • fibro-, leiomyo-sarcomatous - homologous mixed tumor – carcinosarcoma • rhabdomyo-, lipo-, chondro-, osteo-sarcomatous - heterologous mixed tumor - MMMT • 5-year survival: 30% • adenosarcoma