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Published on: March 6, 2018
Histopathological and genetic features of mismatch repair-deficient high-grade prostate cancer
Nicolas Wyvekens1, Harrison K Tsai1, Lynette M Sholl1
1Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Aims:
Mismatch repair (MMR) deficiency is commonly caused by functional inactivation of MLH1, PMS2, MSH2 or MSH6. The morphological and molecular correlates of MMR deficiency have been extensively characterized in certain tumour types such as colorectal and endometrial adenocarcinoma. In contrast, the histological and molecular features of MMR-deficient prostate cancer remain incompletely described. In this study, we evaluated 19 MMR-deficient prostate cancers, including 11 cases without prior systemic treatment.
Methods And Results:
All treatment-naive cases (11 of 11, 100%) were grade group 4-5 and had predominant cribriform and/or solid growth patterns. Solid components (any amount) and tumour infiltrating lymphocytes were 7 cases each (7 of 11, 64%). In 68 MMR-proficient grade group 5 prostate cancers, predominant cribriform or solid growth patterns, solid components (any amount) and tumour infiltrating lymphocytes were seen at significantly lower frequencies (31 of 68, 46%; 9 of 68, 13% and 6 of 62, 9%, respectively; P < 0.001 for all comparisons). Molecular evaluation of 19 cases demonstrated that MMR-deficiency was secondary to functional loss of MSH2/MSH6 and MLH1/PMS2 in 15 (79%) and 4 cases (21%), respectively. Definite or probable germline mutations were present in 4 cases (4 of 19, 21%). TMPRSS2::ERG rearrangements were identified in 2 cases (2 of 19, 11%). Recurrent cancer-relevant somatic mutations included (but were not limited to) ATM, TP53, FOXA1, RB1, BRCA2 and PTEN.
Conclusions:
MMR deficiency was most commonly secondary to inactivation of MSH2/MSH6 in this study. Importantly, MMR-deficient high-grade prostatic adenocarcinomas had morphological features that might be useful to identify selected cases for MMR immunohistochemistry.
Insights
Mismatch repair (MMR) deficiency in prostate cancer is often linked to MSH2/MSH6 inactivation. MMR-deficient tumors show distinct high-grade features, aiding identification for further testing.
Area of Science:
- Oncology
- Genetics
- Pathology
Background:
- Mismatch repair (MMR) deficiency, caused by MLH1, PMS2, MSH2, or MSH6 inactivation, is well-studied in other cancers.
- However, the histological and molecular characteristics of MMR-deficient prostate cancer are not well-defined.
Purpose of the Study:
- To evaluate the morphological and molecular features of MMR-deficient prostate cancers.
- To identify potential histological indicators for MMR deficiency in prostate cancer.
Main Methods:
- Reviewed 19 cases of MMR-deficient prostate cancer, including 11 treatment-naive cases.
- Compared morphological features (growth patterns, solid components, tumor-infiltrating lymphocytes) with 68 MMR-proficient cases.
- Performed molecular analysis to determine the cause of MMR deficiency and identify associated mutations.
Main Results:
- All 11 treatment-naive MMR-deficient cases were Grade Group 4-5 with cribriform/solid patterns.
- MMR deficiency was primarily due to MSH2/MSH6 loss (79%) or MLH1/PMS2 loss (21%).
- Germline mutations were found in 21% of cases; common somatic mutations included ATM, TP53, and BRCA2.
Conclusions:
- MMR deficiency in prostate cancer is frequently associated with MSH2/MSH6 inactivation.
- Specific morphological features in high-grade prostatic adenocarcinomas can suggest MMR deficiency, guiding the need for immunohistochemistry testing.
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