1. T HE F EMALE G ENITAL S YSTEM Manar hajeer, MD University of Jordan, Faculty of Medicine.

2. O UTLINE : Diseases of the vagina. Diseases of the cervix. Diseases of the endomyometrium. Diseases of the ovaries.

3. V AGINAL PATHOLOGIC DISEASES Inflammatory Vaginal Diseases Vaginitis is a common clinical problem that is usually transient, it produces a vaginal discharge (leukorrhea). A large variety of organisms have been implicated, including bacteria, fungi, and parasites. Many represent normal commensals that become pathogenic in conditions such as 1. diabetes. 2. systemic antibiotic therapy that disrupts the normal microbial flora. 3. after abortion or pregnancy. 4. elderly persons with compromised immune function. 5. in patients with the acquired immunodeficiency syndrome.

4. V AGINAL I NFECTIONS Frequent causes are Candida albicans and Trichomonas vaginalis. Candidal (monilial) vaginitis produces a curdy white discharge with severe itching. This organism is present in about 5% of normal adults. T. vaginalis, also a frequent offender, produces a watery, copious gray-green discharge in which parasites can also be identified microscopically.

5. C ERVICAL PATHOLOGY Cervical carcinoma Since the introduction of the Papanicolaou (Pap) smear 50 years ago, the incidence of cervical cancer has dropped. The Pap smear remains the most successful cancer screening test ever developed. In populations that are screened regularly, cervical cancer mortality is reduced by as much as 99%. Many of the cases of cervical carcinoma now occur in women who have not had regular screening. Detection of precursor lesions by the Pap smear at an early stage, permits discovery of these lesions when curative treatment is possible.

6. Cytologic examination can detect CIN (cervical intraepithelial neoplasia) long before any abnormality can be seen grossly. The precancerous epithelial changes (CIN) may precede the development of an overt cancer by many years, or in some cases even decades.

7. On the basis of histology, precancerous changes are graded as follows ( depending on the extent of involvement): * CIN I: Mild dysplasia (<third of full epithelial thickness) * CIN II : Moderate dysplasia (up to 2/3 of full epithelial thickness) * CIN III : Severe dysplasia in full epithelial thickness (carcinoma in situ)

8. D YSPLASIA MEANS INCREASED N/C RATIO, NUCLEAR ENLARGEMENT, HYPERCHROMASIA, AND ABNORMAL NUCLEAR MEMBRANES

10. E PIDEMIOLOGY AND P ATHOGENESIS The peak age incidence of CIN is about 30 years, whereas that of invasive carcinoma is about 45 years. Precancerous changes usually take many years, perhaps decades, to evolve into overt carcinomas. Important risk factors for the development of CIN and invasive carcinoma are: - Early age at first intercourse -Multiple sexual partners -A male partner with multiple previous sexual partners -Persistent infection by "high-risk" papillomaviruses.

11. Those risk factors point to the likelihood of sexual transmission of a causative agent, in this case HPV. HPV can be detected by molecular methods in nearly all precancerous lesions and invasive neoplasms. More specifically, certain high-risk HPV types, including 16, 18, account for the majority of cervical carcinomas.

12. The recently introduced HPV vaccine used in USA and Europe is very effective in preventing HPV infections and hence cervical cancers

13. The most common cervical carcinomas are squamous cell carcinomas (75%), followed by adenocarcinomas and adenosquamous carcinomas. The SCC are increasingly appearing in younger women, now with a peak incidence at about 45 years. The only reliable way to monitor the course of the disease is with careful follow-up and repeat biopsies.

14. C LINICAL A SPECTS O F C ERVICAL C ANCERS Symptomatic tumors can cause: - unexpected vaginal bleeding - leukorrhea - dysuria Mortality is most strongly related to tumor extent (stage) Detection of precursors by cytologic examination(pap smear) and their eradication is the most effective method of cancer prevention.

15. E NDOMYOMETRIAL PATHOLOGY ENDOMETRITIS: Inflammation of the endometrium (acute or chronic) is seen as part of: 1- The spectrum of pelvic inflammatory disease, a condition with consequences for the integrity of the fallopian tubes and subsequent infertility. 2- Associated with retained products of conception subsequent to miscarriage or delivery. 3- Due to a foreign body such as an intrauterine device, acting as a nidus for infection and removal of the offending tissue or foreign body typically results in resolution.

16. C LINICAL FEATURES : All forms of endometritis may present with fever, abdominal pain, menstrual abnormalities, infertility and ectopic pregnancy due to damage to the fallopian tubes.

17. ADENOMYOSIS Refers to the growth of the basal layer of the endometrium down into the myometrium. Nests of endometrial stroma, glands, or both, are found well down in the myometrium between the muscle bundles. The uterine wall often becomes thickened and the uterus is enlarged and globular. Because these glands derive from the stratum basalis of the endometrium, they do not undergo cyclical bleeding. Marked adenomyosis may produce menorrhagia, dysmenorrhea, and pelvic pain before the onset of menstruation.

18. ENDOMETRIOSIS Endometriosis is characterized by endometrial glands and stroma in a location outside the endomyometrium. It occurs in as many as 10% of women in their reproductive years and in nearly half of women who have infertility. It is a common cause of dysmenorrhea, and pelvic pain, and may present as a pelvic mass filled with degenerating blood (chocolate cyst). It is frequently multifocal and may involve multiple tissues in the pelvis (ovaries, uterine ligaments, fallopian tubes, and rectovaginal septum…..etc).

19. “C HOCOLATE “ CYST IN AN OVARY

20. In contrast to adenomyosis, endometriosis almost always contains functionalis endometrium, which undergoes cyclic bleeding. Because blood collects in these aberrant foci, they usually appear grossly as red-blue to yellow-brown nodules or implants of variable size and lie on or just under the affected serosal surface. Often individual lesions coalesce to form larger masses. When the ovaries are involved, the lesions may form large, blood-filled cysts that are transformed into the characterstic so-called chocolate cysts as the blood ages.

21. Consequences: widespread fibrosis, adherence of pelvic structures, sealing of the tubal fimbriated ends, and distortion of the oviducts and ovaries. The histologic diagnosis at all sites depends on finding two of the following three features within the lesions: endometrial glands, endometrial stroma, or hemosiderin pigment.

22. E NDOMETRIAL H YPERPLASIA An excess of estrogen relative to progestin, if sufficiently prolonged or marked, will induce exaggerated endometrial proliferation (hyperplasia), which can be preneoplastic. The severity of hyperplasia is classified based on architectural crowding and cytologic atypia, ranging from: 1- Simple hyperplasia to 2- Complex hyperplasia, and finally 3- Atypical hyperplasia. These three categories represent a continuum based on the level and duration of the estrogen excess. In time the hyperplasia may become autonomously proliferating, no longer needing estrogenic influence, eventually giving rise to carcinoma.

23. The risk of developing carcinoma is dependent on the severity of the hyperplastic changes and associated cellular atypia. Simple hyperplasia carries a negligible risk, while a person with atypical hyperplasia with has a 20% risk of developing endometrial carcinoma. Any estrogen excess may lead to hyperplasia. Potential contributors include; unovulatory cycles, prolonged administration of estrogenic steroids without counterbalancing progestin; estrogen-producing ovarian lesions and tumors. A common risk factor is obesity, because adipose tissue processes steroid precursors into estrogens. When atypical hyperplasia is discovered, it must be carefully evaluated for the presence of cancer and must be monitored by repeated endometrial biopsy.

24. TUMORS OF THE ENDOMETRIUM AND MYOMETRIUM Endometrial Polyps These are sessile, usually hemispheric (rarely pedunculated) lesions that are 0.5 to 3 cm in diameter. Larger polyps may project from the endometrial mucosa into the uterine cavity. Benign tumors with no risk of endometrial cancer.

25. E NDOMETRIAL C ARCINOMA Endometrial carcinoma is the most frequent cancer occurring in the female genital tract. Endometrial cancer appears most frequently in 50s and 60s and is distinctly uncommon in women younger than 40 years of age. There are two clinical settings in which endometrial carcinomas arise: 1)in perimenopausal women with estrogen excess 2)in older women with endometrial atrophy. These scenarios are correlated with differences in histology: endometrioid and serous carcinoma of the endometrium, respectively.

26. E NDOMETRIOID CARCINOMA These tumors are termed endometrioid because of their similarity to normal endometrial glands. There is a constellation of well-defined risk factors for endometrioid carcinoma: Obesity: increased synthesis of estrogens in fat depots and from adrenal and ovarian precursors; Diabetes Hypertension (mostly an association and not a true risk factor) Infertility: women tend to be nulliparous, often with nonovulatory cycles. Prolonged estrogen replacement therapy Estrogen-secreting ovarian tumors.

27. Many of these risk factors are the same as those for endometrial hyperplasia endometrial carcinoma frequently arises on a background of endometrial hyperplasia. Mutations in DNA mismatch repair genes and PTEN are common. Graded into 3 grades (1, 2, 3)

28. S EROUS CARCINOMA Serous carcinoma of the endometrium is pathophysiologically distinct. It typically arises in a background of atrophy, sometimes in the setting of an endometrial polyp (no relation with endometrial hyperplasia). Mutations in DNA mismatch repair genes and PTEN are rare in serous carcinoma; however, nearly all cases have mutations in the p53 tumor suppressor gene.

29. They behave as poorly differentiated cancers and are not graded, and are particularly aggressive. since even very small or superficial serous tumors may nonetheless spread via the fallopian tube to the peritoneal cavity, leading to an advanced stage at time of diagnosis.

30. T UMORS OF THE MYOMETRIUM L IEOMYOMAS Benign tumors that arise from the smooth muscle cells in the myometrium, however, because they are firm, they are more often referred to as fibroids. They are the most common benign tumor in females and are found in 30% to 50% of women during reproductive life. Estrogens and possibly oral contraceptives stimulate their growth; conversely, they shrink postmenopausally.

32. May be single, but most often multiple firm tumors within the uterus. range in size from small to massive neoplasms. most commonly are embedded within the myometrium (intramural), whereas others may lie directly beneath the endometrium (submucosal) or directly beneath the serosa (subserosal )

34. Leiomyomas of the uterus may be entirely asymptomatic and be discovered only on routine pelvic or post mortem examination. The most frequent manifestation, when present, is menorrhagia. Large masses in the pelvic region may become palpable to the woman or may produce a dragging sensation. Benign leiomyomas almost never transform into sarcomas, and the presence of multiple lesions does not increase the risk of harboring a malignancy.

35. P ATHOLOGY OF THE OVARIES FOLLICLE AND LUTEAL CYSTS are so common as almost to constitute physiologic variants. often multiple and develop immediately subjacent to the serosal covering of the ovary. Usually, they are small (1-1.5 cm in diameter) and are filled with clear serous fluid. Sometimes these cysts rupture, producing intraperitoneal bleeding and acute abdominal symptoms

36. POLYCYSTIC OVARIES Oligomenorrhea, hirsutism, infertility, and sometimes obesity may appear in young women (usually in girls after menarche) secondary to excessive production of estrogens and androgens (mostly the latter ) by multiple cystic follicles in the ovaries. The ovaries are usually twice normal in size, are gray-white with a smooth outer cortex, and are studded with subcortical cysts 0.5 to 1.5 cm in diameter. There is a conspicuous absence of corpora lutea.

37. O VARIAN TUMORS Ovarian tumors can be categorized into 1- surface epithelial tumors (65-70%). 2- germ cell tumors(15-20%). 3- sex cord stromal tumors (5-10%). 4- metastasis (5%). The malignant forms of epithelial tumors also account for almost 90% of ovarian cancers.

38. S URFACE EPITHELILA TUMORS Serous (most common). Mucinous. Endometrioid. Each can be benign, malignant or border line.

39. Several risk factors for epithelial ovarian cancers have been recognized. Two of the most important are nulliparity and family history. Although only 5% to 10% of ovarian cancers are familial. A majority of hereditary ovarian cancers seem to be caused by mutations in the BRCA genes, BRCA1 and BRCA2