Pathology, Molecular Biology, and Tumor Biology
Histotype is a molecular diagnosis
Ovarian carcinoma is no longer one disease. High-grade serous carcinoma carries near-universal TP53 mutation and frequent BRCA1/2 or homologous recombination defects. Low-grade serous carcinoma has KRAS or BRAF alterations and wild-type p53. Endometrioid and clear cell carcinomas are associated with ARID1A, PTEN, and PIK3CA alterations and often arise from endometriosis. Mucinous carcinoma is uncommon and requires excluding a gastrointestinal primary.
Endometrial carcinoma is classified by the TCGA/ProMisE scheme into POLE ultramutated (excellent prognosis), mismatch repair deficient, p53 abnormal, and no specific molecular profile. This classification is now incorporated into staging and increasingly drives adjuvant therapy. Mismatch repair deficiency also flags possible Lynch syndrome and predicts response to immune checkpoint inhibitors. Cervical carcinoma is HPV-driven, with p16 block positivity as a surrogate marker.
Traps
Reading p53 immunohistochemistry incorrectly: abnormal means either diffuse overexpression or complete null pattern, whereas patchy wild-type staining is normal. Low-grade serous carcinoma is not a p53-mutant tumor. A “serous” label on a low-grade tumor should prompt review. p16 positivity does not equal HPV in every site. Serum beta-hCG is the marker for gestational trophoblastic disease, not CA-125.
Worked example
An endometrial curettage shows a tumor with diffuse strong p53 staining and serous morphology. This is p53-abnormal endometrial carcinoma, so treat it as high risk even if the architecture looks deceptively low grade elsewhere in the specimen.