While we have traditional classified major histopathologic subtypes of ovarian carcinoma (serous, mucinous, endometrioid, clear cell) by morphology, recent studies demonstrate that these subtypes can be distinguished by gene mutations and gene expression patterns. I suppose the "good news" (for us pathologists) is that morphology does fairly well predicting distinctive, albeit not unique, genetic/molecular signatures that are likely to be present in a given tumor. For example, serous carcinoma-P53 mutations, mucinous carcinoma--KRAS mutations, endometrioid carcinoma--CTNNB1 (β-catenin) mutations, clear cell--PIK3CA mutations. But so what?
The implication is that instead of generically treating all histological subtypes essentially the same, specific constituitively activated pathways might be targeted regardless of histology.
Characteristic signaling pathways defects are present in subsets of ovarian endometrioid adenocarcinoma.
- Constitutive activation of canonical Wnt signaling pathway by missense mutations of CTNNB1 are one such example that occurs in about 25% of ovarian endometrioid carcinoma. Endometrioid carcinomas with CTNNB1 missense mutations are associated with low tumor stage, low histologic grade, and prominent squamous differentiation. Immunohistochemistry for β-catenin can be used to assess for activation of the Wnt signaling pathway. Deregulated Wnt signaling by activating CTNNB1 mutations (or inactivating APC mutations) are detected by nuclear staining of β-catenin, while intact Wnt signaling is identified by a membranous β-catenin staining pattern.
- Deregulation of the PI3K/Akt pathway occurs in about 15% of endometrioid carcinomas by inactivating mutations of PTEN or activating mutations of PIK3CA. Many also have defects in the Wnt signaling pathway.
- Presumptive mutations in exons 5 through 8 of TP53 are also identified in about 50% of endometrioid carcinomas. TP53 mutations negatively correlate with Wnt and PI3K/Akt pathway defects. Note the overlap in TP53 mutations with ovarian serous carcinomas by gene expression profiling and principal component analysis as well as an association between TP53 mutations and high grade (FIGO 2/3) and high stage tumors.
A revised classification of ovarian carcinoma can be based of the pattern of tumor progression and molecular or genetic changes and not on specific histopathologic diagnostic categories.
- generally develop in a stepwise manner from well-recognized precursor "borderline" tumors
- includes: low-grade serous carcinoma, low-grade endometrioid carcinoma, mucinous carcinoma and a subset of clear cell carcinoma
- slow-growing, large but confined to ovary
- FIGO grade 1
- somatic mutations of PKs: KRAS, BRAF, PIK3CA, ERBB2
- mutations of CTNNB1 and PTEN
- TP53 mutations rare
- includes: high-grade serous and endomtrioid carcinoma, undifferentiated carcinoma, a subset of clear cell carcinoma, carcinosarcoma
- rapidly growing, early dissemination
- rarely association with precursor lesions
- increased changes in DNA copy number
- high frequency TP53 mutations