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Ovarian carcinomas (molecular pathology)

Wednesday 10 September 2014

epithelial ovarian cancer

Each of the major histologic types of EOC is associated with a different set of cell signaling pathways abnormalities, which for the type I tumors are shared with their respective precursor lesions (borderline tumors and endometriosis) supporting their stepwise progression.

In contrast, the type II tumors, aside from a very high frequency of TP53 mutations and molecular alterations of BRCA1/2, are characterized by marked genetic instability and lack other mutations.

Recent morphologic, immunohistochemical, and molecular genetic studies have led to the development of a new paradigm for the pathogenesis and origin of epithelial ovarian cancer based on a dualistic model of carcinogenesis that divides epithelial ovarian cancer into 2 broad categories designated types I and II.

Type I tumors comprise low-grade serous, low-grade endometrioid, clear cell and mucinous carcinomas, and Brenner tumors. They are generally indolent, present in stage I (tumor confined to the ovary), and are characterized by specific mutations, including KRAS, BRAF, ERBB2, CTNNB1, PTEN, PIK3CA, ARID1A, and PPP2R1A, which target specific cell signaling pathways. Type I tumors rarely harbor TP53 mutations and are relatively stable genetically.

Type II tumors comprise high-grade serous, high-grade endometrioid, malignant mixed mesodermal tumors (carcinosarcomas), and undifferentiated carcinomas. They are aggressive, present in advanced stage, and have a very high frequency of TP53 mutations but rarely harbor the mutations detected in type I tumors.

In addition, type II tumors have molecular alterations that perturb expression of BRCA either by mutation of the gene or by promoter methylation. A hallmark of these tumors is that they are genetically highly unstable.

Recent studies strongly suggest that fallopian tube epithelium (benign or malignant) that implants on the ovary is the source of low-grade and high-grade serous carcinoma rather than the ovarian surface epithelium as previously believed.

Similarly, it is widely accepted that endometriosis is the precursor of endometrioid and clear cell carcinomas and, as endometriosis, is thought to develop from retrograde menstruation; these tumors can also be regarded as involving the ovary secondarily.

The origin of mucinous and transitional cell (Brenner) tumors is still not well established, although recent data suggest a possible origin from transitional epithelial nests located in paraovarian locations at the tuboperitoneal junction.

Thus, it now appears that type I and type II ovarian tumors develop independently along different molecular pathways and that both types develop outside the ovary and involve it secondarily.

If this concept is confirmed, it leads to the conclusion that the only true primary ovarian neoplasms are gonadal stromal and germ cell tumors analogous to testicular tumors.

This new paradigm of ovarian carcinogenesis has important clinical implications. By shifting the early events of ovarian carcinogenesis to the fallopian tube and endometrium instead of the ovary, prevention approaches, for example, salpingectomy with ovarian conservation, may play an important role in reducing the burden of ovarian cancer while preserving hormonal function and fertility.


The dualistic model of pathogenesis accommodates and confirms the heterogeneous nature of EOC and places the major histologic types into two groups (type I and type II) based on their distinctive clinicopathologic and molecular genetic features. It also links specific histologic types with their putative precursor lesions.

Thus, type I tumors are comprised of low-grade serous carcinomas, low-grade endometrioid, clear cell and mucinous carcinomas which develop in a stepwise fashion from well-established precursor lesions, such as borderline tumors and endometriosis.

They typically present as large masses that are confined to one ovary (stage Ia), are indolent and have a good prognosis.

The type I tumors are relatively genetically stable and typically display a variety of somatic sequence mutations that include KRAS, BRAF, PTEN, PIK3CA CTNNB1 (the gene encoding beta catenin), ARID1A and PPP2R1A but very rarely TP53.

In contrast, type II tumors are comprised of HGSC (usual type of serous carcinoma), high-grade endometrioid carcinoma, malignant mixed mesodermal tumors (carcinosarcomas) and undifferentiated carcinomas, which present in advanced stage (stages II-IV) in over 75% of cases; they grow rapidly and are highly aggressive.

Type II tumors, of which HGSC is the prototypic type, are chromosomally highly unstable and harbor TP53 mutations in >95% of cases; they rarely display the mutations found in the type I tumors.

BRCA inactivation, either by mutation or inactivation of expression of BRCA and its downstream genes via promoter methylation occurs in up to 40-50% of HGSC. BRCA inactivation has not been reported in the type I tumors.

Actionable mutations

CCNE1 20% : CCNE1-CDK2 inhibitors
PIK3CA 18% : PI3K/AKT/mTOR inhibitors
NF1 12% : PI3K/AKT/mTOR inhibitors , MPAK inhibitors , HSP90 inhibitors
PTEN 8% ; PI3K/AKT/mTOR inhibitors


- Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer—shifting the paradigm. Kurman RJ, Shih IeM. Hum Pathol. 2011 Jul;42(7):918-31. doi : 10.1016/j.humpath.2011.03.003 PMID: 21683865 (Free)

Open references

- Integrated analysis of germline and somatic variants in ovarian cancer.
Kanchi KL, Johnson KJ, Lu C, McLellan MD, Leiserson MD, Wendl MC, Zhang Q, Koboldt DC, Xie M, Kandoth C, McMichael JF, Wyczalkowski MA, Larson DE, Schmidt HK, Miller CA, Fulton RS, Spellman PT, Mardis ER, Druley TE, Graubert TA, Goodfellow PJ, Raphael BJ, Wilson RK, Ding L.
Nat Commun. 2014;5:3156. doi : 10 1038/ncomms4156
PMID: 24448499

- Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer—shifting the paradigm. Kurman RJ, Shih IeM. Hum Pathol. 2011 Jul;42(7):918-31. doi : 10.1016/j.humpath.2011.03.003 PMID: 21683865 (Free)