Discordant DNA mismatch repair protein status between synchronous or metachronous gastrointestinal carcinomas: frequency, patterns, and molecular etiologies

Abstract

The widespread use of tumor DNA mismatch repair (MMR) protein immunohistochemistry in gastrointestinal tract (GIT) carcinomas has unveiled cases where the MMR protein status differs between synchronous/metachronous tumors from the same patients. This study aims at examining the frequency, patterns and molecular etiologies of such inter-tumoral MMR discordances. We analyzed a cohort of 2159 colorectal cancer (CRC) patients collected over a 5-year period and found that 1.3% of the patients (27/2159) had ≥ 2 primary CRCs, and 25.9% of the patients with ≥ 2 primary CRCs (7/27) exhibited inter-tumoral MMR discordance. We then combined the seven MMR-discordant CRC patients with three additional MMR-discordant GIT carcinoma patients and evaluated their discordant patterns and associated molecular abnormalities. The 10 patients consisted of 3 patients with Lynch syndrome (LS), 1 with polymerase proofreading-associated polyposis (PAPP), 1 with familial adenomatous polyposis (FAP), and 5 deemed to have no cancer disposing hereditary syndromes. Their MMR discordances were associated with the following etiologies: (1) PMS2-LS manifesting PMS2-deficient cancer at an old age when a co-incidental sporadic MMR-proficient cancer also occurred; (2) microsatellite instability-driven secondary somatic MSH6-inactivation occurring in only one-and not all-PMS2-LS associated MMR-deficient carcinomas; (3) "compound LS" with germline mutations in two MMR genes manifesting different tumors with deficiencies in different MMR proteins; (4) PAPP or FAP syndrome-associated MMR-proficient cancer co-occurring metachronously with a somatic MMR-deficient cancer; and (5) non-syndromic patients with sporadic MMR-proficient cancers co-occurring synchronously/metachronously with sporadic MMR-deficient cancers. Our study thus suggests that inter-tumoral MMR discordance is not uncommon among patients with multiple primary GIT carcinomas (25.9% in patients with ≥ 2 CRCs), and may be associated with widely varied molecular etiologies. Awareness of these patterns is essential in ensuring the most effective strategies in both LS detection and treatment decision-making. When selecting patients for immunotherapy, MMR testing should be performed on the tumor or tumors that are being treated.

Keywords: Colorectal cancer; Gastrointestinal tract cancer; Hereditary cancer; Lynch syndrome; MMR IHC; Mismatch repair deficiency; Mutational testing.

Figure 1.

Identification of patients with multiple primary colorectal carcinomas and inter-tumoral discordance in mismatch repair protein status utilizing a database of colorectal carcinomas tested by mismatch repair protein immunohistochemistry.

Figure 2.

Distribution of inter-tumoral mismatch repair protein immunohistochemistry discordances among Lynch syndrome patients, patients with non-Lynch syndrome colorectal cancer predisposing syndromes, and patients with sporadic or likely sporadic gastrointestinal tract cancers.

Figure 3.

Inter-tumoral mismatch repair (MMR) protein immunohistochemistry (IHC) discordance in Lynch syndrome (LS). A-F illustrate a PMS2-LS patient with one colonic carcinoma showing normal MMR IHC (A, H&E morphology; B, normal MSH6 IHC; C, normal PMS2 IHC) and another colonic carcinoma showing abnormal MMR IHC (D, H&E morphology; E, clonal loss of MSH6; F, complete loss of PMS2). G-L illustrate another PMS2-LS patient with one colonic carcinoma showing loss of PMS2 only (G, H&E morphology; H, normal MSH6 IHC; I, complete loss of PMS2) and another colonic carcinoma showing loss of both MSH6 and PMS2 (J, H&E morphology; K, complete loss of MSH6; L, complete loss of PMS2). M-R illustrate two small sigmoid colon adenomas from a “compound LS” patient with germline mutation in both MLH1 and MSH2; one adenoma shows abnormality in MLH1/PMS2 (M, H&E morphology; N, normal MSH6 IHC; O, loss of PMS2) and one shows abnormality in MSH2/MSH6 (P, H&E morphology; Q, loss of MSH6; R, normal PMS2 IHC in adenoma). Note that in R, the MSH2/MSH6-deficient adenoma also exhibits a cluster of 3 PMS2-deficient crypts (outlined by small white box and magnified in inset).

Figure 4.

Polymerase proofreading-associated polyposis (PPAP) and familial adenomatous polyposis (FAP) manifesting mismatch repair (MMR)-deficient gastrointestinal tract carcinoma in addition to syndrome-associated MMR-proficient carcinoma. A-F illustrate a PPAP patient having two colorectal carcinomas. One tumor shows morphological features similar to MMR-deficient colonic carcinomas (A-C, H&E morphology: A, conspicuous tumor-infiltrating lymphocytes; B, histologic heterogeneity with gland-forming component juxtaposed with mucinous component that contains signet ring cells; C, non-signet ring mucinous component). But this tumor has normal MMR IHC (not illustrated). The other tumor also shows increased tumor infiltrating lymphocytes, and in this one, it is accompanied by abnormal MMR IHC (D, H&E morphology; E, complete loss of MSH6; F, normal PMS2 IHC). G-L illustrate an MMR-deficient small bowel adenocarcinoma in an FAP patient (G, focal serrated changes seen on mucosal surface in the tumor; H-J, different regions showing different degrees of differentiation with H being moderately differentiated and I and J being poorly differentiated; K, normal MSH6 IHC; L, complete loss of PMS2).

Figure 5.

An apparently sporadic MLH1-methylated MLH1/PMS2-deficient colonic adenocarcinoma coexisting with two mismatch repair (MMR)-proficient primary colonic carcinomas in a 77-year-old patient with negative germline mutation testing. A and B, H&E morphology of the 2 MMR-proficient colonic adenocarcinomas with conventional type histology and no increased tumor-infiltrating lymphocytes. C-E illustrate the patient’s MMR-deficient colonic carcinoma (C, H&E morphology with mucinous features and increased tumor-infiltrating lymphocytes; D, normal MSH6 IHC; E, complete loss of PMS2).