Ovarian Cancer

1. Ovarian Cancer

2. Ovarian Cancer • Epithelial Tumor, postmenopausal women • Germ cell, younger women • Sex cord-stromal origin, any age

3. Approximately 90% of ovarian cancer is epithelial • significant therapeutic challenges (Epithelial Tumor) • other types of ovarian cancer are often localized ,more amenable to surgical resection, more favorable px • peritoneal serous carcinoma and fallopian tube carcinoma (their clinical and management considerations are similar to those of epithelial ovarian cancer)

4. Epidemiology • leading cause of gynecologic cancer mortality • The lifetime risk :1.7%, • familial predisposition :of 10% to 40% • The median age at diagnosis for sporadic disease is 60 years, • improvement in 5-year survival • A higher risk for nulliparous women • lower risk for those who have had children, who have breastfed, who have undergone tubal ligation, or who have taken oral contraceptives

6. Pathogenesis and Patterns of Metastases • arise from the surface epithelium covering the ovary, which is contiguous with peritoneal mesothelium. It is thought that malignant transformation preferentially occurs within epithelium that becomes trapped within ovarian inclusion cysts during ovulation, where it can develop into a variety of mullerian-type histologies. Thus, ovarian serous carcinomas can resemble the fallopian tube, ovarian mucinous tumors may resemble the endocervix, and ovarian endometrioid carcinomas may resemble the endometrium.

7. Pathogenesis and Patterns of Metastases • Germ cell tumors most likely originate in cells derived from the primitive streak that ultimately migrated to the gonads. • The ovarian stroma consists of granulosa cells, theca cells, and fibroblasts, which give rise to the sex cord- stromal tumors.

8. Several molecular abnormalities in patients with epithelial ovarian cancer, • Cytogenetic analysis may reveal complex abnormalities • Mutation in the p53 proto-oncogene occurs in over 50% of cases, • Mutations in the K-ras proto-oncogene are more common in ovarian borderline tumors (which typically do not undergo p53 mutation). • Amplification of the Her-2/neu gene , 8% • Overexpression of proapoptotic genes such as BAX(Px good) • Expression of (VEGF) (high serum :Px poor)

9. exfoliate from the ovarian surface • The tumor typically spreads to the omentum and to peritoneal surfaces • The lymphatic drainage para-aortic region, pelvic sidewall lymphatics, (external iliac, obturator, and hypogastric chains) inguinal lymph nodes. • 10% to 15% appears to be localized to the ovaries have metastases to para-aortic lymph nodes • retroperitoneal lymph node involvement is found in over 50% of patients with advanced disease.

10. The most common site of extra-abdominal spread is the pleural space (thought to occur via transdiaphragmatic lymphatics), where it causes a malignant pleural effusion in some patients. • Hematogenous metastases to the liver,spleen, or lung • Bone or central nervous system metastases

11. Histologic Classification of Epithelial Tumors • The nomenclature for these tumors reflects the cell type, location of the tumor, and degree of malignancy, ranging from benign lesions to tumors of low malignant potential (LMP) to invasive carcinomas

13. Tumors of LMP (borderline tumors) • epithelial papillae with atypical cell clusters • excellent prognosis • increased mitotic activity • lack stromal invasion

14. Epithelial carcinomas • characterized by histologic cell type and degree of differentiation (tumor grade) • The histologic cell type has limited prognostic significance independent of clinical stage • High tumor grade ,especially in patients with early stage epithelial tumors.

15. papillary serous variety of epithelial ovarian cancer: psammoma bodies • clear cell histology may also be associated with endometriosis, hypercalcemia , relatively resistant to chemotherapy • mucinous ovarian cancers are chemoresistant, sometimes associated with pseudomyxoma peritonei, and may not be associated with dramatic elevations of (CA 125)

16. COMMON EPITHELIAL TUMORS • Malignant serous tumor • Malignant mucinous tumor • Malignant endometrioid tumor

17. SEX CORD - STROMAL TUMORS • Granulosa - stromal cell tumor • Androblastoma: Sertoli-Leydig cell tumor • Germ cell tumor

18. DDx • Gastric, breast (especially ILC), mesothelioma, and colorectal cancers may occasionally present with diffuse peritoneal implants, ascites, and ovarian metastases that mimic primary ovarian cancer. • routine light microscopic histologic evaluation, IHC • cytokeratin CK7 +and CK20 - in most cases of primary serous ovarian cancer, • Staining for gross cystic disease fluid protein (GCDFP) may be positive in up to 50% of patients with breast cancer, whereas this marker should be negative in patients with gastric, colorectal, or ovarian cancer.

19. Common Histologic Types of Epithelial Ovarian Cancer • Papillary serous • Endometrioid • Mucinous • Clear cell

20. Papillary serous • The most common type of epithelial ovarian cancer. • May contain psammoma bodies • often associated with CA 125 elevation. • Identical histology is observed for primary peritoneal serous cancer (PPSC).

21. Endometrioid • Sometimes associated with endometriosis or an independent uterine cancer of similar histology. May occur with early stage disease in younger patients, although advanced disease is also possible.

22. Mucinous • May rarely be associated with pseudomyxoma peritoneii. CA 125 levels may not be markedly elevated. Relatively chemoresistant. Differential diagnosis of a mucinous ovarian tumor includes metastatic disease from an appendiceal primary.

23. Clear cell • The most chemoresistant type of ovarian cancer. Often contains hobnail cells with cleared out cytoplasm due to glycogen. Sometimes associated with endometriosis or humorally mediated hypercalcemia.

24. Diagnosis • asymptomatic • Symptomatic of spreads to the upper abdomen • Approximately 70% with stage III or IV whereas the majority of patients with borderline, germ cell, and sex cord -stromal tumors present with early stage disease limited to the pelvis • mass on routine pelvic examination or because of pelvic pain caused by ovarian torsion. • ovarian germ cell malignancies tend to stretch and twist the infundibulopelvic ligament, causing severe pain

25. Abdominal discomfort, bloating, and early satiety (ascites and a pelvic mass on physical examination) • (Sister Mary Joseph's node) or a pleural effusion • The mass on pelvic examination is frequently firm and fixed, with multiple nodularities palpable in the cul-de-sac.

26. The CA 125 serum level is elevated in more than 80% of serous epithelial ovarian cancers. • not a reliable diagnostic test, since it can also be elevated in a variety of benign gynecologic conditions (such as endometriosis,pelvic inflammatory disease, or pregnancy) and nongynecologic malignancies (such as breast, lung, and GI). • the CA 125 level is elevated in 50% of patients with early stage epithelial ovarian cancer, • CA 19-9, which is elevated in some mucinous ovarian carcinomas, and carcinoembryonic antigen (CEA) are less frequently useful.

27. It is typical for a patient with epithelial ovarian cancer to have a normal CEA level in the setting of a significantly elevated CA 125 level. • Postoperatively, the CA 125 level provides a sensitive way to monitor treatment response and development of disease recurrence. Because relapsed epithelial ovarian cancer is usually incurable, however, there is currently no evidence that early detection of recurrence through CA 125 levels confers a survival advantage in this disease.

28. International Federation of Gynecology and Obstetrics Staging System for Epithelial Ovarian Cancer

29. STAGE I Tumor limited to ovary or ovariesa IA One ovary, without ascites, positive peritoneal washings, surface involvement, or rupture. IB Both ovaries, without ascites, positive peritoneal washings, surface involvement, or rupture. IC Ascites, positive peritoneal washings, surface involvement, or rupture present.

30. STAGE II Ovarian tumor with pelvic extensiona IIA Involvement of the uterus or fallopian tubes. IIB Involvement of other pelvic organs (e.g., bladder, rectum, or pelvic sidewall). IIC Pelvic extension, plus findings indicated for IC.

31. STAGE III Tumor involving the upper abdomen or lymph nodes IIIA Microscopic disease outside of the pelvis, typically involving the omentum. IIIB Gross deposits less than or equal to 2 cm in diameter.b IIIC Gross deposits greater than 2 cm in diameter, or nodal involvement.b

32. STAGE IV Distant organ involvement, including pleural spacec or hepatic/splenic parenchyma.

33. aPatients with disease that appears to be confined to the ovaries or pelvis require nodal biopsy for complete staging, in order to exclude the possibility of occult stage IIIC. • bDisease measurements for staging purposes are made before debulking has been attempted. • cPleural effusion must be cytologically proven to be malignant if used to define stage IV disease.

34. TVU • diagnostic tool • TVU is more sensitive (CTS) • The classic sonographic finding of malignancy is a complex‌ cyst, defined as containing both solid and cystic components, sometimes with septations and internal echogenicity . • Finding a complex cyst on sonography, especially in the presence of signs and symptoms consistent with ovarian cancer, often requires surgery for further evaluation. It is best to avoid percutaneous biopsy during the initial evaluation, which can result in cyst rupture and spillage of malignant cells into the peritoneal cavity. Bilateral ovarian involvement and ascites are sometimes detected by sonography as well. • Color Doppler imaging

35. Simple cysts • Simple cysts in asymptomatic postmenopausal do not always require surgical evaluation if they are associated with normal CA 125 levels, • Postmenopausal women with simple cysts in association with elevated serum CA 125 levels, simple cysts that exceed 5 to 10 cm in diameter, or simple cysts in association with abnormal color Doppler flow studies are often referred for surgery.

36. Simple cysts In premenopausal • may be functional (i.e., a corpus luteum cyst) • a benign process such as a serous cystadenoma. • simple cysts that are persistent or enlarging, especially in the setting of a rising CA 125 level, are reasonable candidates for surgical evaluation to exclude malignancy. • several benign conditions in premenopausal women may also be associated with elevated CA 125 levels, such as pregnancy or endometriosis, and there is no absolute CA 125 cutoff to distinguish benign from malignant pathologies

37. CT or (MRI) in defining the extent of peritoneal disease • However, for the patient with a complex ovarian cyst and clinical signs and symptoms to suggest ovarian cancer, these studies generally do not obviate the need for surgical exploration. • CT may sometimes be helpful in distinguishing a gynecologic malignancy from a metastatic pancreatic neoplasm, for instance, for which an exploratory laparotomy may not be warranted. In selected patients, CT may also assist in surgical planning by locating the site of suspected bowel obstruction.

38. MRI has not been shown to have a clear advantage over CT in patients with an ovarian mass, except for pregnant patients when ultrasonography is inconclusive and there is a desire to avoid radiation exposure.

39. PET:there is currently no proven role for PET in the diagnosis or subsequent follow-up of patients with ovarian cancer. • CXR may sometimes be performed to evaluate the presence of pleural effusions, which occur in 10% of patients with epithelial ovarian cancer at diagnosis.

40. Screening and Early Detection • identifying the majority of patients with precancerous lesions or early disease • major surgery • Costs • mortality • the false-positive rate • positive predictive value (PPV)

41. screening procedure • serum tumor marker levels • ultrasonography • both

42. CA 125 serum level • alone, is not a useful • not specific for ovarian cancer cirrhosis, peritonitis, pleuritis, pancreatitis, endometriosis, uterine leiomyomata, benign ovarian cysts, and pelvic inflammatory disease • elevated in other malignancies such as breast, lung, colorectal, pancreatic, and gastric cancers. • CA 125 level is elevated in the majority of patients with advanced epithelial ovarian cancer, it is abnormal in only 50 % of patients with early stage disease.

43. candidate markers • show promise for enhancing the accuracy of CA 125 levels, • HE4 (human epididymis 4) • osteopontin • mesothelin • osteoblast-stimulating factor-2. • OVX-1 • Lysophosphatidic acid

44. these markers may be complementary to CA 125 None of these tests has been proven to have sufficient sensitivity and specificity for routine screening at the current time.

45. CA 125+ TVU • an attempt to improve screening. • TVU suggested a sensitivity of close to 100% but a specificity of 98%, which is insufficient to achieve a PPV of 10%. • color Doppler imaging improves the specificity of TVU ,PPV? • using a morphologic index?

46. Two randomized controlled trials measurement of CA 125 level (single threshold elevation of more than 35 U/mL) and TVU together, performed annually, as a first-line screen will require an average of 10 years of follow-up

47. The second randomized screening trial is currently being conducted in the United Kingdom and uses CA 125 levels (or rate of rise of CA 125) as a trigger for performing TVU.

48. Hereditary Ovarian Carcinoma • 5% to 10% epithelial ovarian carcinoma carry a germline mutation • The breast -ovarian cancer syndrome 90% of hereditary ovarian cancer and is often suspected whenever the pedigree reveals multiple affected family members with ovarian cancer, bilateral or early onset breast cancer, both breast and ovarian cancer in the same individual, or a male relative with breast cancer.Fallopian tube cancer and primary peritoneal serous cancer (PPSC)

49. Breast and ovarian cancers • inherited germline mutations in the BRCA1 or BRCA2 genes, • transferred by either parent, • these genes act as tumor suppressors and play a critical role in the repair of double-stranded DNA breaks.32

50. The lifetime risk of ovarian cancer is 20% to 60% for patients with BRCA1 mutations, and 10% to 35% for BRCA2 mutation carriers. • Ovarian cancer with germline mutations of BRCA1 appears to present with distinct clinical and pathologic features compared with sporadic ovarian cancer. • The majority of BRCA1-associated cancers are serous adenocarcinomas, with an average age at diagnosis of 48 years, whereas the mean age for BRCA2-associated ovarian cancers is 60 years.