Characterization of Rectal Cancer in Patients With Lynch Syndrome

Abstract

Lynch syndrome (LS) resulting from a germline mutation in a DNA mismatch repair (MMR) gene is the most common form of hereditary colorectal cancer syndrome accounting for 3-5% of all colorectal cancer (CRC) cases. Mismatch repair deficient (dMMR) CRC is more commonly located in the proximal colon with decreasing incidence distally; thus, dMMR rectal cancer has not been well characterized. Our study aimed to describe the clinicopathologic features and outcomes of patients with LS-associated rectal cancer. Clinical genetics database review (1998–2014) identified all probands with CRC and a deleterious germline mutation in a MMR gene (MLH1, MSH2, MSH6, PMS2) diagnostic of LS. Clinical history and pedigree was extracted from medical records and Progeny. The Dworak classification was used for tumor regression grade (TRG) from grade 0 (no regression) to grade 4 (total regression). Of 192 LS patients with CRC, 27(14.1%) had RC. Mean age at RC diagnosis was 39.7 years (range, 22-59) with 18.5% having synchronous (n = 3) or metachronous (n = 2) colon cancer. In 85% of cases, the RC was the first LS-associated malignancy. While all RC patients met Revised Bethesda, only 48% met Amsterdam II criteria. Twenty-three rectal tumors were analyzed for MSI or defective MMR protein expression by immunohistochemistry; results were abnormal and concordant with germline test results in all cases. Nineteen (70%) patients harbored either an MSH2 or MSH6 gene mutation, with only 8 (30%) being MLH1 or PMS2 carriers. Of 25 RC patients with clinical data, 12 proceeded directly to surgery (7 stage 0/I; 5 stage II/III). Thirteen RC patients received preop neoadjuvant treatment for clinical stage II/III (n = 11) or IV (n = 2) disease, including 12 receiving chemoradiation and 6 also receiving FOLFOX chemotherapy. Downstaging of the primary tumor occurred in 69.2% (9/13) and of lymph nodes in 75% (9/12) of cases. All 13 RC patients underwent R0 resections and 10 patients had TRG available. Two (20%) patients had TRG 1, 7 (70%) had TRG 2 or 3 and 1 (10%) had TRG 4. One patient received preop FOLFOX for cT3N+ disease without chemoradiation with excellent clinical response initially; however, surgical pathology showed ypT4N2 disease with subsequent rapid development of metastatic disease. Another patient with cT4N2M1 (non-regional lymph node) progressed through induction FOLFOX, but after receiving chemoradiation was downstaged to ypT3N0M0. With a median follow-up of 4.6 years (range, 0.08-17.0), 2 had local and distant recurrences and 4 developed a subsequent LS-associated cancer. Although less common than colon cancer, rectal cancer may be the index cancer leading to a diagnosis of LS and appears to be overrepresented in MSH2/MSH6 gene mutation carriers. Further analysis to compare outcomes and prognosis with non-Lynch and sporadic dMMR rectal cancers is needed.