Current Concept in Ovarian Carcinoma: Pathology Perspectives Rouba Ali-Fehmi, MD Professor of Pathology The Karmanos Cancer Institute, Wayne State University School of Medicine
Current Concept in Ovarian Carcinoma: Pathology Perspectives Pathogenesis of Ovarian Carcinoma Type I & II Histology and Grade Prevention
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
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?
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
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
Dualistic Model Gross Features HG Serous Carcinoma Endometrioid Carcinoma Type II Type I Clear Cell Carcinoma Mucinous Carcinoma Type I Type I
Type I LG Serous Morphologically Heterogeneous Mucinous Endometrioid Clear Cell
Type II HG Serous Morphologically Homogeneous HG Serous HG Serous HG Endometrioid
Dualistic Model Pathogenesis Type I tumors Develop from well established precursor lesions Atypical proliferative (borderline) tumors Endometriosis Type II tumors Precursor not identified
Low-grade serous CA High-grade serous CA
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
What is the Pathogenesis of Low grade Carcinoma?
Serous Cystadenoma Containing a Small Atypical Proliferative Serous Tumor (APST)
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
Proposed Progression Model of Endometrioid Adenocarcinoma Endometriosis Courtesy Kathy Cho Atypical Endometriosis Borderline Endometrioid Tumor Genetic Alterations: ARID1A 30% PTEN 15-20% CTNNB1 ( -catenin) - 15-40% Microsatellite Instability Low-grade Endometrioid Adenocarcinoma
What is the Origin of High grade Serous Carcinoma?
Cancer. 2010 Sep 3
Kaplan-Meier survival curve demonstrating the survival difference between type I and type II tumors (P>.0001).
Ali-Fehmi et al. Cancer. 2010 Sep 3
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)
The Fallopian Phenomenon
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;31:161-169 Similar study 61% with TICs» Pryzbycin CG, et al. AJSP 2010;34:1407-1416 Conclusion - HG sporadic pelvic (ovarian) HG serous CA are probably derived from serous tubal intraepithelial carcinomas (STICs)
Serous Tubal Intraepithelial Carcinoma p53 Ki-67
Serous Tubal Intraepithelial Carcinoma (STIC) STIC p53 Ki-67 Courtesy Pat Shaw
P53 signature P53 positive normal mucosa Coexist with TIC and ovarian carcinoma Location: fimbria Involving secretory cells
P53 Signature Crum et al. Clin Med Res. 2007 Mar;5(1):35-44.
Lee et al J Pathol 2007; 211: 26 35
Proposed Development of Serous Carcinoma from Normal Tubal Epithelium
Tube and Ovary at Ovulation
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
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
Type II Type I Crum et al. Clin Med Res. 2007 Mar;5(1):35-44.
Histology
Rationale for histotyping Distinct disease entities Diagnostic criteria for carcinoma Carcinoma grading Personal and family cancer risk Therapeutic relevance
WHO classification Serous Mucinous Endometrioid Clear cell Transitional Squamous Mixed epithelial Undifferentiated
Take Home Message Distinct disease entities Diagnostic criteria for carcinoma Carcinoma grading Personal and family cancer risk Therapeutic relevance
Ovarian cancer. distinct disease entities Stage Grade Survival @ 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
Some Problems.. Mucinous carcinoma Clear cell carcinoma Poorly differentiated endometrioid carcinoma Mixed epithelial carcinoma
Serous Carcinoma
Endometrioid Carcinoma
Mucinous Carcinoma
CK20
CK7
Clear Cell Carcinoma
Diagnosis?
P16
P53
WT1
Serous carcinoma: immunophenotype WT1 (>75%, all grades) Histologic subtype assignment Primary site P53 (>70%, high grade) Other: PAX-8 P16
H&E PAX8 WT1 Serous Endometrioid Clear Mucinous Nonaka et al, Am J Surg Pathol 2008;32:1566 1571
Grading
Grading ovarian carcinoma Historically there has been no uniformly accepted grading system
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
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
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
Low Grade Serous Carcinoma - mild to moderate nuclear atypia - low mitotic index ( 12 mitoses per 10 HPFs)
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)
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
Is Ovarian Serous Carcinoma Ever Stage I? Hardly ever!
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
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
Surgery in Advanced Ovarian Cancer Diagnosis Primary Chemotherapy ( Neoadjuvant Chemotherapy ) Remission Recurrence *Also, setting for first cytoreduction after neoadjuvant chemotherapy
Ovarian Carcinogenesis Clinical Implications Looking to the future
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
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
Prevention Women >40 undergoing hysterectomy for benign uterine disease Has been argued should undergo bilateral salpingo oophorectomy to prevent ovarian cancer in the future
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;113:1027-37
Prevention Olmstead County, MN population-based study 2390 women undergoing TAH for benign uterine disease from 1950-87 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
What matters the most Histologic type and Tumor grade Histologic type and Tumor grade with characteristic genetic alterations. Prevention