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Radiogenomics of Ovarian cancer
Srini Prasad MD
Univ Texas MD Anderson Cancer Center
Ovarian Epithelial Carcinoma: Facts and Figures
• Most lethal gynecological malignancy; 90% of adult
ovarian cancers; Second most common GYN cancer (US)
• Estimated 22,430 new cancers with 15,280 deaths in 2007
• Lifetime-risk is 1-2% (United States)
• Approx. 80% of cancers: Stage 2-4 @ Diagnosis
– 70% die within 5 years of diagnosis
Kurman RJ. Am J Surg Pathol 2010;34(3):433-443
Ovarian cancer is not a single disease
Ovarian Carcinoma: Current Concepts
• Histologically and biologically diverse disease
• Characteristic histology, cytogenetics & metabolic
pathways determine biology, treatment response & prognosis
Ovarian Epithelial Tumors: Histological Spectrum*
Type
High-Grade Serous
Carcinoma
Low-Grade Serous
Carcinoma
Endometrioid Carcinoma
Frequency
60-65%
Clear cell Carcinoma
10%
Histology
5%
10-15%
*2014 World Health Organization Classification of Ovarian Tumors
Ovarian Epithelial Tumors: Histological Spectrum*
Type
Frequency
Transitional Carcinoma
5%
Mucinous Carcinoma
<5%
Histology
*2014 World Health Organization Classification of Ovarian Tumors
10% ovarian cancers are hereditary
Ovarian Carcinoma: Hereditary syndromes
• Hereditary forms: Distinct clinicopathological features
• Mutations of tumor-suppressor genes BRCA 1 & 2 (90%)
– Ovarian cancer syndrome
– Breast & Ovarian cancer syndrome
• Mutations of DNA MisMatch Repair (MMR) genes hMLH1 &
hMSH2 (10%)
– Hereditary non-polyposis colorectal cancer HNPCC (Lynch-II)
Finch et al. Gynecol Oncol 2006;100:58-64
Ovarian Carcinoma: Risk Stratification
Lifetime
risk for
Ovarian Ca
Sporadic
HNPCC
Syndrome
BRCA1
mutation
BRCA2
Mutation
1-2%
12%
40-50%
20-30%
Finch et al. Gynecol Oncol 2006;100:58-64
Ovarian Cancer: BRCA 1 / 2 associated syndromes
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Predominantly serous carcinomas; High-grade, high-stage
Better response to platinum chemotherapy; longer survival
OC pill prophylaxis, prophylactic salpingo-oophorectomy?
Annual GYN surveillance
Finch et al. Gynecol Oncol 2006;100:58-64
Ovarian cancers develop from microscopic &
macroscopic precursor lesions
Ovarian Carcinoma: Carcinogenesis
Histology
High-grade Serous
Carcinoma
Precursor lesions
Serous tubal intraepithelial carcinoma
Low-grade Serous
Carcinoma
Serous cystadenoma, adenofibroma
Serous Borderline Tumor
Mucinous Carcinoma
Mucinous cystadenoma
Mucinous Borderline Tumor
Ovarian Carcinoma: Carcinogenesis
Histology
Precursor lesions
Endometrioid Carcinoma
Endometriosis
Endometrioid borderline tumor or
adenofibroma
Clear cell Carcinoma
Endometriosis
Clear cell adenofibroma, Borderline
Tumor
Malignant Brenner neoplasm
Brenner neoplasm
Borderline Brenner Tumor
Each ovarian cancer subtype shows distinctive
genetics & biology
Molecular Genetics in Clinical Practice
“The Devil is in the DNA”
*Chanock, Thomas. Nat Genet 2007;39(3):283-4
Ovarian Carcinoma: Carcinogenesis
Histology
Precursor lesions
Mutations
High-grade Serous
Carcinoma
Serous tubal
intraepithelial carcinoma
TP-53 (60-80%)
HER2/neu gene (10-20%)
AKT2 gene (12-18%)
Low-grade Serous
Carcinoma
Serous cystadenoma,
adenofibroma
Serous Borderline Tumor
B-raf, K-ras (>2/3
tumors)
Mucinous Carcinoma
Mucinous cystadenoma
Mucinous Borderline
Tumor
K-ras (>60%)
Nik NN et al. Annu. Rev. Pathol. Mech. Dis. 2014
Ovarian Carcinoma: Carcinogenesis
Histology
Precursor lesions
Mutations
Endometrioid Carcinoma Endometriosis
Endometrioid borderline
tumor or adenofibroma
CTNNB-1 (>1/3 cancers)
PTEN/PI3KCA (40%)
MSI ( Up to 20%)
Clear cell Carcinoma
Endometriosis
Clear cell adenofibroma,
Borderline Tumor
PI3KCA (33%)
HNF-1β/IL6-STAT/HIF-1α
HER2/neu gene
Malignant Brenner
neoplasm
Brenner neoplasm
Borderline Brenner Tumor
Not well characterized
Ovarian Carcinoma: HNPCC syndrome
• Autosomal dominant disorder; mutations of DNA
MisMatch Repair (MMR) genes hMLH1 & hMSH2 (70%)
• Defective MMR genes lead to microsatellite instability &
inactivation of genes that regulate cell cycle
• Characterized by right colon cancers (without polyps),
endometrial and ovarian cancers
• Stage I/II ovarian cancers at an early age
• Serous or endometrioid histopathology
Prat J. Hum Pathol. 2005;36(8):861-70
Endometriosis Associated Ovarian Carcinoma
• 1-2% of endometriosis shows malignant change
• Sequential genetic changes cause malignant transformation
• EAOC is typically low stage/low grade, predominantly
clear-cell (most common subtype) or endometrioid type, &
portend a better prognosis
Endometriosis Associated Ovarian Carcinoma
Endometrium
β-catenin,IL-6
ER,PR
Endometriosis
PTEN,hMLH1
LOH 9p,11q,22q
Atypical Endometriosis
PTEN, TP53
β-catenin, LOH 6q,5q
Endometrioid / Clear Cell Cancer
Ovarian Carcinoma: Clinical Implications
• Histology determines tumor biology/stage, prognosis &
response to chemotherapy
– Mucinous, low-grade serous & clear cell cancers: chemoresistant
• High grade & low-grade serous cancers respond differently
– Platinum vs Pathway specific chemotherapy
• Endometriosis predisposes to endometrioid & clear cell Ca
• Endometrioid carcinoma is associated with endometrial Ca
• 85% of patients with serous carcinoma have advanced disease;
5-year survival is a dismal 10-20%
Kurman RJ. Am J Surg Pathol 2010;34(3):433-443
Ovarian Carcinoma: Clinical Implications
• Screening
– Type I vs Type II cancers (Low stage vs low volume disease)
• Prophylactic salpingectomy vs salpingo-oophorectomy
– Hereditary cancer syndromes
• Treatment
– Pathway specific vs platinum chemotherapy
– Her2/Neu upregulated in clear cell carcinoma: may respond to
anti- Her2/Neu antibody (Herceptin) therapy
– Drugs aimed at MAPK/BRAF: ?Help in low-grade serous Ca
Kurman RJ. Am J Surg Pathol 2010;34(3):433-443
Ovarian Carcinoma: Conclusions
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Most ovarian ‘cancers’ likely arise from outside the ovary
?Changes in screening, prophylaxis and treatment paradigms
Imaging: A major role in diagnosis, staging & management
Molecular imaging: Help in early/recurrent disease, drug
development?
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