Sigmoid Colon Adenocarcinoma with Isolated Loss of PMS2 Presenting in a Patient with Synchronous Prostate Cancer with Intact MMR: Diagnosis and Analysis of the Family Pedigree

Abstract

Lynch syndrome (LS) patients with isolated PMS2 loss in the colon cancer, while intact MMR in the prostate cancer, are exceedingly rare. Herein, we report such a case. A 71-year-old male was found to have increased serum PSA (10 ng/ml) after treatment for his urinary tract infection. Prostate biopsies showed foci of prostate cancer with Gleason score 7 (3+4) (grade grope 2) involving 10% of two cores. Through work up for treatment of the prostate cancer, he was found to have focal thickening of his sigmoid colon with adjacent lymphadenopathy in CT scans. Colon biopsy showed a tubular adenoma with high-grade dysplasia and deep invasive carcinoma could not be excluded. A low anterior resection of the rectosigmoid colon was performed and a sigmoid colon adenocarcinoma (pT2N1b, AJCC 8th edition) was confirmed. Immunostaining showed that the colon cancer was positive for CDX2, SATB2, had a loss of PMS2 and intact expression of MLH1, MSH2 and MSH6, negative for AMACR, while the prostate cancer was positive for AMACR, had intact expression of PMS2, MLH1, MSH2 and MSH6, and negative for CDX2 and SATB2. MSI-H phenotype and PMS2 mutation in the colon cancer were confirmed by microsatellite instability (MSI) PCR and next-generation sequencing (NGS), respectively. Through genetic counseling and analysis of the family pedigree, LS was confirmed with colon cancer present in multiple maternal family members and his brother also had metachronous colon and prostate cancers. To the best of our knowledge, this is the first documented case of synchronous colon and prostate cancers, with isolated PMS2 loss present in the colon cancer while intact DNA mismatch repair (MMR) protein expressions present in the prostate cancer, in the English literature. The pathogenesis, diagnosis and prognosis of this entity are discussed.

Discordance between immunochemistry of mismatch repair proteins and molecular testing of microsatellite instability in colorectal cancer

“…50 Isolated loss of one MMR protein (PMS2, MSH2, or MSH6) with a weaker impact of impairment on MMR function (dMMR/MSS status), in addition to germline missense mutations (pMMR/MSI status), may explain the high percentage of discordance cases observed in LS. 51 Consequently, most discordant cases were confirmed or suspected LS (7 cases). Double somatic inactivation of one MMR gene could be the mechanism underlying MMR inactivation in suspected LS with no germline MMR mutation, as has been reported for MSH6.…”

Microsatellite Instability: Diagnosis, Heterogeneity, Discordance, and Clinical Impact in Colorectal Cancer

“…However, the contrary is not true insofar as MLH1 and MSH2 proteins, in their monomeric forms, can interact with other proteins of the MMR system, i.e., MSH3, and thereby avoid degradation [21]. Indeed, isolated loss of PMS2 expression (≈5% to 10% of dMMR CRC [22]) or isolated loss of MSH6 expression (≈5% to 15% of dMMR CRC [23]) is not rare. In view of both economy and time saving, some pathologists have analyzed MMR expression of two proteins (MLH1 and MSH2) instead of four but have not been able to detect isolated loss of PMS2 or MSH6 expression.…”

“…Moreover, an isolated loss of MSH6 is not always responsible for MMR system deficiency, and hence not always detected by MSI technique [27,28]. Indeed, there exists functional redundancy of MMR proteins (PMS2 and PMS1, MSH6 and MSH3) with MMR protein expression loss at IHC loss, while MSS status is retained due to partial activity of the MMR system [22]. Moreover, MMR protein IHC can be difficult or misleading as it depends on staining processes, which are not standardized from one laboratory to another (antigen demasking, optimal antibody dilution, incubation time, etc.).…”

Liver Metastasis of Hepatoid Colonic Adenocarcinoma: A Rare and Unusual Entity With Poor Prognosis and Review of the Literature

“…Molecular testing of the biopsy liver mass did not display any detectable microsatellite instability (MSI) using a panel of microsatellite marker BAT25, BAT26, NR-21, NR-24, and MONO-27 [1]. The tumor was interpreted as being microsatellite stable (MSS).…”