1. Female Reproductive System Kristine Krafts, M.D.

2. Female Reproductive System Outline Cervix Uterus Ovaries Breast

3. Female Reproductive System Outline Cervix Cervical carcinoma

4. Cervical Carcinoma Once the most common cancer in women – now not even in top 10. Decrease due to Pap test! At the same time, precursor lesions are increasing (early detection)

5. Cervical Intraepithelial Neoplasia (CIN) Precursor to carcinoma Almost all carcinomas arise in CIN; but not all cases of CIN progress to carcinoma! Three grades: CIN I: mild dysplasia (half regress, 20% progress) CIN II: moderate dysplasia CIN III: severe dysplasia (30% regress, 70% progress) The higher the grade, the more likely the lesion will progress to carcinoma

6. Cervical Carcinoma Risk Factors Early age at first intercourse Multiple sexual partners A male partner with multiple previous partners Persistent infection with “high-risk” HPV Smoking Immunodeficiency

7. Cervical Carcinoma and HPV HPV is detectable in almost all CIN and cancer. “High-risk” types: 16, 18, 45, 31 Found in carcinomas Integrate into genome, inactivate p53, RB “Low-risk” types: 6, 11 Found in condylomas (benign lesions) Do not integrate into genome

8. Normal cervix, young adult Transformation zone

10. Spectrum of cervical intraepithelial neoplasia (CIN)

11. Normal turning into CIN

12. normalCIN ICIN IICIN III Cytology of CIN (Pap smear)

13. normalCIN ICIN IICIN III “Low-grade dysplasia” “High-grade dysplasia”

14. Invasive Cervical Carcinoma Most cases are squamous, arising from CIN Small number are adenocarcinomas Peak age: 45 (10-15 years after CIN develops!) Spreads slowly Most cases are diagnosed early Mortality is related to stage Stage 0 (preinvasive): 100% 5 year survival Stage 4: 10% 5 year survival

15. Cervical carcinoma

16. Female Reproductive System Outline Cervix Uterus Endometriosis Endometrial hyperplasia Tumors

17. Endometriosis Location of endometrial glands outside uterus Usually peritoneum, rarely lymph nodes Endometrium undergoes cyclic bleeding Causes scarring, pain, sometimes sterility How does endometrium get out?

18. Endometriosis in ovary (“chocolate cyst”)

19. Endometrial Hyperplasia Proliferation of endometrium due to estrogen excess Risk factors: anovulatory cycles, obesity, estrogen- producing ovarian tumors, exogenous hormone use Three categories: simple, complex, and atypical The more severe the hyperplasia, the greater the chance that it will evolve into carcinoma

20. Normal endometrium

21. Endometrial hyperplasia SimpleComplexAtypical

22. Leiomyoma “Fibroid” Benign tumor of smooth muscle Common! Stimulated by estrogen Menorrhagia, metrorrhagia, or asymptomatic

23. Leiomyosarcoma Malignant tumor of smooth muscle Necrotic, with atypical cells and lots of mitoses Often recur after surgery Many metastasize, especially to lungs 5 year survival = 40%

24. LeiomyomaLeiomyosarcoma

25. LeiomyomaLeiomyosarcoma

26. Endometrial Carcinoma Peak age: 55-65 (not before 40) Frequently arises in endometrial hyperplasia Risk factors: obesity, nulliparity, estrogen replacement Symptoms: leukorrhea, irregular bleeding Metastasizes late

27. Endometrial adenocarcinoma

28. Female Reproductive System Outline Cervix Uterus Ovaries Tumors

29. Surface epithelial tumors Cystadenoma Cystadenocarcinoma Germ cell tumors Teratoma Dysgerminoma Yolk sac tumor Choriocarcinoma Granulosa-theca cell tumor Sertoli-Leydig cell tumor Sex cord-stromal tumors Origin of Ovarian Tumors

30. Cystadenoma Benign tumor derived from surface epithelium Repeated ovulation, scarring, infolding of epithelium leads to cysts, which can undergo neoplastic transformation Typically large, occasionally bilateral

31. Patient with ovarian cystadenoma

33. Ovarian cystadenoma

36. Teratoma Benign tumor with differentiation along all three germ cell layers (ectoderm, endoderm, mesoderm) Usually cystic, with skin inside (“dermoid cyst”) Sebaceous material, matted hair, teeth, bone… Malignant variant has immature tissues

37. Teratoma

39. Ovarian Cancer 22,000 new cases / 14,000 deaths in 2014 5 th commonest, 5 th most deadly cancer in women Danger: no definitive signs until advanced Peak age: 50 Most are cystadenocarcinomas

40. Papillary cystadenocarcinoma

42. Ovarian Cancer Symptoms Feeling of fullness or bloating Pelvic pain Back pain Abnormal menses Risk factors Nulliparity Family history (BRCA gene mutation) NOT using oral contraceptives!

43. Ovarian Cancer Treatment: surgery, radiation, chemotherapy Prognosis depends on stage Cancer confined to the ovary: 5y survival 70% Cancer through ovarian capsule: 5y survival 13%

44. Female Reproductive System Outline Cervix Uterus Ovaries Breast Fibrocystic change Tumors

45. Breast Many breast diseases present as lumps Most lumps represent benign things… …but a lump always needs to be evaluated Ultrasound, mammography, fine needle aspiration, and biopsy are the usual methods

46. Most breast lumps are benign

47. Fibrocystic Change Two kinds: nonproliferative and proliferative change Cause: exaggeration of normal breast cycles Rarely associated with increased cancer risk Very common (present in most women at autopsy) Called fibrocystic change, not fibrocystic disease

48. Fibrocystic change

49. Normal breast

50. Nonproliferative fibrocystic change

51. Proliferative fibrocystic change

52. Fibroadenoma Most common benign breast tumor Stimulated by estrogen Peak incidence in 20s Solitary, discrete, moveable mass Fibrous tissue with compressed ducts and lobules

53. Fibroadenoma

55. Breast Carcinoma 233,000 new cases / 40,000 deaths in 2014 Most common, 2 nd deadliest cancer in women Lifetime risk: 1 in 8 75% of patients are >50 Rate was increasing but now stable

56. Breast Carcinoma Risk Factors Age Family history Increased estrogen exposure Obesity Alcohol consumption High-fat diet

57. Breast Carcinoma Family History 5-10% of all cases are hereditary Worry if first degree relative with breast cancer Most have BRCA-1 or BRCA-2 mutations Tumor suppressor genes; help repair DNA Genetic testing difficult Most carriers get cancer by age 70

58. Breast Carcinoma Clinical Findings If discovered by palpation Solitary, painless, moveable mass 2-3 cm in diameter Axillary nodes positive in 50% of patients If discovered by mammography 1 cm in size Axillary nodes positive in only 15% of patients As disease progresses Fixation to chest wall Adherence to overlying skin Peau d’orange

60. Advanced breast carcinoma: fixation to skin

61. Peau d’orange

62. Breast Carcinoma Histologic Types Non-invasive Ductal carcinoma in situ (DCIS) Lobular carcinoma in situ (LCIS) Invasive Ductal Lobular Inflammatory Others

63. Normal breast

64. Lobular carcinoma in situ

65. Invasive breast carcinoma

66. Low-grade invasive ductal carcinoma

67. High-grade invasive ductal carcinoma

68. Inflammatory breast carcinoma

69. Breast Carcinoma Prognostic Factors Size of tumor Lymph node involvement Distant metastases Grade of tumor Histologic type of tumor

70. Sentinel node biopsy

71. Stage 0 Stage I Stage II Stage III Stage IV TNM* staging system for breast cancer DCIS <2 cm <5 cm >5 cm <5 cm >5 cm Any T 0 <3 0 4+ 1+ 10+ Any N M0 skin or chest wall M1 92% 87% 75% 46% 13% * Tumor (size), nodes (# positive), metastases StageTNM5-year survival