Pathology of Ovarian Tumours. Dr. Jyothi Ranganathan MD ( Path) AFMC Pune PDCC (Cytopathology) PGI Chandigarh

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1 Pathology of Ovarian Tumours Dr. Jyothi Ranganathan MD ( Path) AFMC Pune PDCC (Cytopathology) PGI Chandigarh

2 Outline Incidence Risk factors Classification Pathology of tumours Tumour markers Prevention quiz

3 Incidence Highest in central and eastern Europe Bulgaria-14.2/100,000 Fifth leading cause of cancer-related death in women Indian-6.6/100,000 (Institution based studies) Women aged years, median 63

4 Risk factors Nulliparity and low parity Family history: heritable mutations BRCA-1(Breast carcinoma gene-1) and BRCA-2 germline pathogenic mutations cause10-12% of ovarian cancers Lynch syndrome ( HNPCC)1-2% of ovarian cancers Gonadal dysgenesis in children

5 BRCA1/BRCA2 Tumor suppressor gene Mutations cause hereditary breast and ovarian cancers, (1 in 300 to 800 women) Cumulative life-time risks of ovarian cancer with these gene mutations is estimated, 40 53% : BRCA1 carriers 20 30% : BRCA2 carriers

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7 Common neoplasms 80% are benign young (20-45) 20% are Malignant - older (>40) 50% deaths due to late detection.

8 Surface epithelial tumors : 65-70% benign/borderline/malignant Germ cell tumors : 15-20% Stromal tumors : 5-10% Metastatic tumors : 5%

9 WHO Classification Surface epithelial tumors 1. Serous tumors: Benign (cystadenoma) Borderline tumors (serous borderline tumor) Malignant (serous adenocarcinoma) 2. Mucinous tumors( endocervical-like and intestinal type) Benign (cystadenoma) Borderline tumors (mucinous borderline tumor) Malignant (mucinous adenocarcinoma)

10 Classification 3. Endometrioid tumors: Benign (cystadenoma) Borderline tumors (endometrioid borderline tumor) Malignant (endometrioid adenocarcinoma) 4. Clear cell tumors: Benign Borderline tumors Malignant (clear cell adenocarcinoma) 5. Transitional cell tumors: Brenner tumor Brenner tumor of borderline malignancy Malignant Brenner tumor Transitional cell carcinoma (non-brenner type)

11 Epithelial-stromal tumors : Adenosarcoma Carcinosarcoma (formerly mixed Mullerian tumors)

12 Classification Sex cord - stromal tumors Granulosa cell tumors (Juvenile & Adult type) Fibromas Fibrothecomas Thecomas Sertoli cell tumors Leydig cell tumors Sex cord tumor with annular tubules Gynandroblastoma Steroid (lipid) cell tumors

13 Classification Germ cell tumors Teratomas Immature Mature Solid Cystic (dermoid cyst) Monodermal (struma ovarii, carcinoid) Dysgerminoma Yolk sac tumor (endodermal sinus tumor) Choriocarcinoma Mixed germ cell tumors

14 Metastatic cancer from non ovarian primary: Colonic, appendix Gastric Breast

15 Pathologist role Frozen sections FNAC/ fluid cytology Histopathology specimen Surgical specimens: should be preserved within one hour of surgery in a fixative-10% buffered formalin and sent intact without mutilation. Large specimen should be partially sliced to enhance penetration by formalin Gross Microscopy Immunohistochemistry (IHC)whenever required

16 Serous tumours Frequently bilateral(30-66%) 75% are benign 25% malignant Unilocular or multiloculated cysts Tubal epithelial lining Papillae,solid areas and necrosis is seen with malignancy

17 Serous cystadenoma

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19 Serous Cystadenoma:

20 Serous Cystadenoma single layer of columnar ciliated Fine papillae

21 Papillary serous cystadenoma (solid/cystic)-borderline

22 Papillary cystadenoma (bor) Papillary complexity Nuclear stratification& atypia No stromal invasion

23 S

24 Papillary complexity Nuclear stratification& atypia Psammoma bodies stromal invasion Serous cystadenocarcinoma

25 Mucinous Tumors Uni or multiloculated cysts Rarely bilateral : 5-20% Tall columnar, apical mucin Associated with Pseudomyxoma peritoneii (pools of mucin with epithelial cells)

26 Mucinous cystadenoma Multilocular cyst lined by single layer of columnar cells with basally placed nuclei and apical mucin.

27 Mucinous cystadenoma-borderline Nuclear stratification& atypia No stromal invasion

28 Mucinous cystadenocarcinoma Complexity of glands Nuclear stratification& atypia stromal invasion

29 Endometrioid tumors Mostly unilateral (40% bilateral) Resemble the endometrium About 20% of all ovarian tumors Associated with endometrial cancer (30%) Concurrent endometriosis may exist

30 Solid / cyst filled by hemorrhage & necrosis Endometrioid tumors

31 Endometrioid adenocarcinoma stromal invasion by irregular malignant endometrial glands

32 Germ cell tumor- classification

33 Cystic Teratoma (Dermoid Cyst)

34 Dermoid Cyst

35 Immature Teratoma Solid/ necrosis &hemorrhage

36 Immature Teratoma primitive neuroepithelium with multiple neural tubes

37 Dysgerminoma The ovarian counterpart of the testicular seminoma 2% of all ovarian malignancies Affects younger females (second and third decades) An excellent prognosis Highly radiosensitive

38 Solid/ lobulated mass with foci of hemorrhage Dysgerminoma

39 sheets of monotonous rounded cells with pale cytoplasm and central nuclei Dysgerminoma

40 Endodermal sinus tumor (Yolk sac Tumour) Highly malignant & clinically aggressive neoplasm children and young females 20% of malignant germ cell tumors Respond well to surgery and chemotherapy 5 year survival stage I : %

41 Endodermal sinus tumor (Yolk sac carcinoma) Schiller-Duval body BV

42 Granulosa Cell Tumor Hormonally active(estrogenic neoplasm) Adult type : in postmenopausal women, associated with endometrial hyperplasia and carcinoma Juvenile type :first two decades, causes precocious sexual development

43 Sheets of granulosa cells containing spaces lined by the cells to give a folliclelike appearance (Call-Exner bodies). Granulosa Cell Tumor

44 Thecoma Functional tumors producing estrogen It occur in postmenopausal women Endometrial hyperplasia or carcinoma may develop

45 Solid tumor with variegated yellow - orange appearance. Thecoma

46 sheets of round to oval cells with pale cytoplasm containing lipid. Thecoma

47 Sertoli-Leydig cell tumors 1% of ovarian neoplasms occurs pred in young women Commonly androgenic causes defeminization of women : breast atrophy, amenorrhea, loss of hair and hip fat, virilization with hirsutism

48 Sertoli-Leydig cell tumors Tubules lined by Sertoli cells and sheet of Leydig cells

49 Metastases to ovary About 3% of malignant tumors in the ovary are metastatic Most common primary sites: breast followed by the large intestine, stomach, and genital tract organs Krukenberg tumor

50 Screening for ovarian cancers Physical examination Transvaginal USG Serum CA 125 levels: elevated in 80% epithelial tumors but in only 50% of early stage tumors Poor specificity as can be elevated in benign conditions like endometriosis, fibroids etc. Specificity and PPV is higher in post-menopausal women

51 HE-4(Human epididymis protein-4) Expressed in one third of tumors which lack CA 125 expression Monitor disease progression and recurrence Normal less than 150 pm Sensitivity and specificity is increased when combined with CA 125

52 ROMA Risk of ovarian malignancy algorithm Combination of CA 125 and HE-4 Esp useful in preoperative diagnosis in postmenopausal women with pelvic masses Risk prediction Premenopausal >13% high probability Postmenopausal >27.7%high probability

53 Novel test: OVA-1 Combination biomarkers-transthyretin, Apo A1,beta 2 microglobulin, transferrin and CA 125 Premenopausal: score of 5 high probability Post menopausal: scores 4.4 are high probability 100% sensitivity for ovarian cancers stage II-IV 90% sensitivity for stage I

54 Biomarkers for non epithelial tumors Inhibin A/B for sex cord stromal tumors Serum AFP and beta HCG for germ cell tumors

55 Prevention bilateral salpingo-oophorectomy is the most effective prophylactic treatment for BRCA mutation carriers Ovarian cancer risk is reduced by % Small risk of peritoneal carcinomatosis still remains

56 TAKE HOME MESSAGE Early diagnosis and screening important in ovarian tumours : later stages assoc with high morbidity and mortality Tumor markers play an imp role in diagnosis & prognosis BRCA 1/2 testing /MMR mutations with family history of breast and ovarian cancer/ Lynch syndrome Proper pathological diagnosis with staging is important for treatment and follow up

57 QUIZ Name a Bollywood celebrity who has had ovarian cancer?

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59 Which are the commonest ovarian tumours? Which are the genes associated with heriditary breast and ovarian cancer? Which are the oestrogen producing tumours?

60 Answers 1.Commonest ovarian tumours are surface epithelial tumours-mostly benign and the commonest malignant tumour is serous papillary cystadenocarcinoma 2.Oestrogen producing tumours Granulosa cell tumours, Thecomas 3. BRCA1/2 Germline mutations and mutations in MMR genes for Lynch syndrome

61 Gross

62 Microscopy

63 DIAGNOSIS Mature cystic teratoma

64 Benign or malignant?

65 Benign or malignant

66 Thank you