Giovana Torrezan

Subclonal loss of DNA mismatch repair proteins in endometrial carcinomas: an unusual pattern with distinct molecular characteristics

Subclonal loss of mismatch repair (MMR) proteins in endometrial carcinoma has recently been identified through immunohistochemistry (IHC) evaluations, characterized by discrete areas of tumors with complete loss of nuclear expression adjacent to tumor cells with retaining expression. Controversies persist regarding reporting findings and managing such cases. Therefore, we conducted a detailed clinicopathological and molecular analysis on a large cohort of endometrial carcinoma cases with subclonal loss of MMR proteins to explore potential reclassification into different molecular categories that could influence diagnostic and treatment strategies. Eligible endometrial carcinoma cases underwent IHC evaluation for PMS2/MLH1/MSH2/MSH6. Cases showing subclonal loss of MMR proteins underwent macrodissection of both proficient and deficient MMR expression areas, followed by testing for microsatellite instability (Idylla), MLH1 promoter methylation (next-generation sequencing), POLE mutations (next-generation sequencing), and p53 expression (IHC). The proposed molecular evaluation was performed in both proficient and deficient areas. Clinical and pathological data for patients with subclonal loss were also analyzed. We evaluated 356 cases of endometrial carcinoma, identifying subclonal loss in 16 patients (4.4%), predominantly endometrioid (15 cases, 93.75%) and International Federation of Gynecology and Obstetrics stage I (13 cases, 81.25%). Subclonal loss of MSH6 occurred independently in 6 cases (37.5%), and concurrently with subclonal loss of MLH1 in 2 cases (12.5%). Complete loss of MLH1/PMS2 was observed in 2 cases (12.5%). MLH1 promoter methylation was detected in 6 cases (37.5%), with 4 cases showing methylation in both areas analyzed. POLE mutations were found in 3 cases (18.75%), occurring in both deficient and proficient areas. The correlation between IHC findings and molecular results varied, providing valuable predictive and prognostic insights that could guide treatment decisions in some patients. Molecular evaluation should be standard practice in all endometrial carcinoma cases exhibiting subclonal loss of MMR proteins to accurately delineate tumor characteristics. Subclonal loss should be reported distinctly, warranting a more comprehensive diagnostic approach to enhance tumor classification.

Case Report of Small Cell Carcinoma of the Ovary, Hypercalcemic Type (Ovarian Rhabdoid Tumor) with SMARCB1 Mutation: A Literature Review of a Rare and Aggressive Condition

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and aggressive condition that is associated with the SMARCA4 mutation and has a dismal prognosis. It is generally diagnosed in young women. Here, we report a case of a young woman with SCCOHT harboring a rare molecular finding with a highly aggressive biological behavior. The patient had a somatic SMARCB1 mutation instead of an expected SMARCA4 alteration. Even though the patient was treated with high-dose chemotherapy followed by stem cell transplantation, she evolved with disease progression and died 11 months after her first symptoms appeared. We present a literature review of this rare disease and discuss the findings in the present patient in comparison to expected molecular alterations and options for SCCOHT treatment.