Current Concept in Ovarian Carcinoma: Pathology Perspectives

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1 Current Concept in Ovarian Carcinoma: Pathology Perspectives Rouba Ali-Fehmi, MD Professor of Pathology The Karmanos Cancer Institute, Wayne State University School of Medicine

2 Current Concept in Ovarian Carcinoma: Pathology Perspectives Pathogenesis of Ovarian Carcinoma Type I & II Histology and Grade Prevention

3 Pathogenesis and clinical implications Most ovarian carcinomas present at an advanced stage and survival is poor. Survival for stage I tumors is reported to be greater than 90% Accordingly a great effort has been made to detect ovarian cancer when it is stage I

4 Pathogenesis and clinical implications So far this effort, using CA 125 as a tumor marker and vaginal ultrasound, has been unsuccessful Can something be done to improve this?

5 Dualistic Model Clinical Features Surface epithelial tumors are divided into two groups - Type I and Type II Type I carcinomas are indolent and present as stage I tumors Type II carcinomas are rapidly growing, aggressive tumors and present in advanced stage

6 Dualistic Model Histopathology LG (micropap) serous LG endometrioid Mucinous Clear cell Type I Carcinomas Malignant Brenner Type II Carcinomas HG serous HG endometrioid MMMT (carcinosarcoma) Undifferentiated Shih and Kurman Am J Pathol 164:1511, 2004

7 Dualistic Model Gross Features HG Serous Carcinoma Endometrioid Carcinoma Type II Type I Clear Cell Carcinoma Mucinous Carcinoma Type I Type I

8 Type I LG Serous Morphologically Heterogeneous Mucinous Endometrioid Clear Cell

9 Type II HG Serous Morphologically Homogeneous HG Serous HG Serous HG Endometrioid

10 Dualistic Model Pathogenesis Type I tumors Develop from well established precursor lesions Atypical proliferative (borderline) tumors Endometriosis Type II tumors Precursor not identified

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12 Low-grade serous CA High-grade serous CA

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15 Dual Pathways of Serous Carcinogenesis Type I pathway Low-grade serous carcinoma Type II pathway High-grade serous carcinoma KRAS/BRAF or ERBB2 Mutation TP53 Mutation Not a progression from well to poorly differentiated

16 What is the Pathogenesis of Low grade Carcinoma?

17 Serous Cystadenoma Containing a Small Atypical Proliferative Serous Tumor (APST)

18 Mutation of KRAS and BRAF Precede the Development of APSTs Serous cystadenoma adjacent to APST APST in Serous cystadenoma BRAF mutation Codon 599, T1796A BRAF mutation Codon 599, T1796A

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20 Proposed Progression Model of Endometrioid Adenocarcinoma Endometriosis Courtesy Kathy Cho Atypical Endometriosis Borderline Endometrioid Tumor Genetic Alterations: ARID1A 30% PTEN 15-20% CTNNB1 ( -catenin) % Microsatellite Instability Low-grade Endometrioid Adenocarcinoma

21 What is the Origin of High grade Serous Carcinoma?

22 Cancer Sep 3

23 Kaplan-Meier survival curve demonstrating the survival difference between type I and type II tumors (P>.0001).

24 Ali-Fehmi et al. Cancer Sep 3

25 A Classification of Ovarian Carcinoma Based on Clinical, Pathologic, and Molecular Features Type I Low grade serous carcinoma Mucinous carcinoma Endometrioid carcinoma Clear cell carcinoma Malignant Brenner tumor Type II High-grade serous carcinoma MMMT (carcinosarcoma)

26 The Fallopian Phenomenon

27 Origin of HG Serous CA Among women with pelvic (ovarian) HG serous CA (not with a genetic predisposition) 48% had tubal intraepithelial carcinomas» Kindelberger DW et al. AJSP 2007;31: Similar study 61% with TICs» Pryzbycin CG, et al. AJSP 2010;34: Conclusion - HG sporadic pelvic (ovarian) HG serous CA are probably derived from serous tubal intraepithelial carcinomas (STICs)

28 Serous Tubal Intraepithelial Carcinoma p53 Ki-67

29 Serous Tubal Intraepithelial Carcinoma (STIC) STIC p53 Ki-67 Courtesy Pat Shaw

30 P53 signature P53 positive normal mucosa Coexist with TIC and ovarian carcinoma Location: fimbria Involving secretory cells

31 P53 Signature Crum et al. Clin Med Res Mar;5(1):35-44.

32 Lee et al J Pathol 2007; 211: 26 35

33 Proposed Development of Serous Carcinoma from Normal Tubal Epithelium

34 Tube and Ovary at Ovulation

35 Formation of Cortical Inclusion Cyst (CIC) CIC develops from implanted tubal epithelium not surface OSE Implantation of tubal epithelium on peritoneal surfaces may also account for endosalpingiosis

36 Proposed Development of LG and HG Serous Carcinoma From tubal epithelium LG Serous CA KRAS/BRAF mutation HG Serous CA TP53 mutation inclusion cyst TP53 LG SBT HG Kurman RJ, Shih I-M Am J Surg Pathol 2010;34:433-43

37 Type II Type I Crum et al. Clin Med Res Mar;5(1):35-44.

38 Histology

39 Rationale for histotyping Distinct disease entities Diagnostic criteria for carcinoma Carcinoma grading Personal and family cancer risk Therapeutic relevance

40 WHO classification Serous Mucinous Endometrioid Clear cell Transitional Squamous Mixed epithelial Undifferentiated

41 Take Home Message Distinct disease entities Diagnostic criteria for carcinoma Carcinoma grading Personal and family cancer risk Therapeutic relevance

42 Ovarian cancer. distinct disease entities Stage Grade 5 years Chemosensitive Hi grade serous Lo grade serous III, IV Hi (2, 3) 40% (20%) Yes III Low (1) 80% No Endometrioid I Low (1) 95% Yes Clear cell I, II Intermediate (2) 75% No Mucinous I Low (1, 2) >90% No

43 Some Problems.. Mucinous carcinoma Clear cell carcinoma Poorly differentiated endometrioid carcinoma Mixed epithelial carcinoma

44 Serous Carcinoma

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50 Endometrioid Carcinoma

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54 Mucinous Carcinoma

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58 CK20

59 CK7

60 Clear Cell Carcinoma

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64 Diagnosis?

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68 P16

69 P53

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74 Serous carcinoma: immunophenotype WT1 (>75%, all grades) Histologic subtype assignment Primary site P53 (>70%, high grade) Other: PAX-8 P16

75 H&E PAX8 WT1 Serous Endometrioid Clear Mucinous Nonaka et al, Am J Surg Pathol 2008;32:

76 Grading

77 Grading ovarian carcinoma Historically there has been no uniformly accepted grading system

78 Grading of Ovarian Cancer The WHO system Based on the pathologist s impression of both architectural and cytologic features Categories not defined according to a quantitative method Well, Moderately, and Poorly differentiated

79 Grading of Ovarian Cancer M.D. Anderson grading system Applicable only to serous carcinoma Segregate serous carcinomas that have different molecular, pathogenetic, histologic, immunohistochemical, and clinical features

80 M.D. Anderson grading system The two-tier grading system is based primarily on the assessment of nuclear atypia with the mitotic rate used as a secondary feature Two grades: Low High

81 Low Grade Serous Carcinoma - mild to moderate nuclear atypia - low mitotic index ( 12 mitoses per 10 HPFs)

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84 High Grade Serous Carcinoma - pleomorphic cells with marked nuclear atypia ( 3:1 variation in size and shape) - high mitotic index (>12 mitoses per 10 HPFs)

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87 Low vs. High Grade Serous Carcinoma: Immunohistochemical Differences Antibody Low Grade Serous Ca p53 18% 64% BcI-2 5% 26% High Grade Serous Ca MIB1 23.0% 55.4% Her-2 neu 4.5% 36% C-Kit 4.5% 30% O Neill CJ et al, 2005

88 Is Ovarian Serous Carcinoma Ever Stage I? Hardly ever!

89 Carcinomas Stage Distribution Cell Type stage I Stage II-IV Serous 4% Mucinous 83% Endometrioid 53% Clear cell 36% Brener 100% 36% 17% 47% 64% 0% Seidman et al Int J Gynecol Pathol 23:41,2003

90 Carcinomas Stage Distribution Cell Type stage I Stage II-IV Serous 4% Mucinous 83% Endometrioid 53% Clear cell 36% Brener 100% 36% 17% 47% 64% 0% Seidman et al Int J Gynecol Pathol 23:41,2003

91 Surgery in Advanced Ovarian Cancer Diagnosis Primary Chemotherapy ( Neoadjuvant Chemotherapy ) Remission Recurrence *Also, setting for first cytoreduction after neoadjuvant chemotherapy

92 Ovarian Carcinogenesis Clinical Implications Looking to the future

93 Prevention The traditional approach to reducing the mortality of ovarian cancer has been early Dx and Rx Given the lack of effectiveness of treatment and screening in improving overall survival a better approach may be prevention

94 Prevention If it can be unequivocally shown that HG serous CA develops in the fallopian tube (fimbria) and involves the ovary secondarily Women at high risk (Family Hx or those with hereditary BRCA mutations) Salpingectomy or fimbriectomy only

95 Prevention Women >40 undergoing hysterectomy for benign uterine disease Has been argued should undergo bilateral salpingo oophorectomy to prevent ovarian cancer in the future

96 Prevention Nurses Health Study 30,000 women undergoing TAH for benign uterine disease Compared with ovarian conservation oophorectomy was associated with increased risk of mortality from all causes increased nonfatal coronary heart disease Approximately 300,000 women in the U.S. undergo elective oophorectomy each year Parker WH, et al. Obstet Gynecol 2009;113:

97 Prevention Olmstead County, MN population-based study 2390 women undergoing TAH for benign uterine disease from Compared with ovarian conservation oophorectomy was associated with significantly increased risk of mortality only for women <45 years Rocca WA, et al. Lancet Oncology 2006;7:821-28

98 What matters the most Histologic type and Tumor grade Histologic type and Tumor grade with characteristic genetic alterations. Prevention