CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
Editors: Rouzan Karabakhtsian, MD, PhD, professor of pathology and director of the Women’s Health Pathology Fellowship, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY; Rachel Stewart, DO, PhD, assistant professor, Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington; Nicole Panarelli, MD, associate professor of pathology, Albert Einstein College of Medicine, Montefiore Medical Center; and Shaomin Hu, MD, PhD, pathology resident, Albert Einstein College of Medicine, Montefiore Medical Center.
Distinguishing patients with double somatic mismatch-repair mutations from those with Lynch syndrome
January 2019—Lynch syndrome is the most common form of hereditary colon cancer. Germline mutations in the mismatch-repair (MMR) genes MLH1, MSH2 (EPCAM), MSH6, and PMS2, followed by a second hit to the remaining allele, lead to cancer development. Universal tumor screening for Lynch syndrome is routinely performed on colon cancer. Screening has identified patients with unexplained MMR deficiency that lack MLH1 methylation and a germline mutation. Tumor sequencing has since identified double somatic (DS) mutations in the MMR gene corresponding with the absent protein in 69 percent of these patients. The authors assessed whether histomorphology could distinguish patients with DS mutations from those with Lynch syndrome. Colorectal cancer patients with DS mutations were identified from population-based cohorts from Iceland (2000–2009), Columbus, Ohio (1999–2005), and the state of Ohio (2013–2016). Next-generation sequencing was performed on tumors with unexplained MMR deficiency. Patients with Lynch syndrome from Ohio cohorts were the comparison group. The authors evaluated the histologic features associated with MMR deficiency—tumor-infiltrating lymphocytes, Crohn-like reaction, histologic subtype, and necrosis. They identified 43 tumors with DS mutations and 48 from patients with Lynch syndrome. The authors found no significant difference in histologic features between tumors in Lynch syndrome patients and tumors with DS mutations. They concluded that because the histology of tumors with DS mutations is indistinguishable from those caused by Lynch syndrome, tumor sequencing to evaluate DS mutations should be considered to help clarify sporadic versus hereditary causes of unexplained MMR deficiency.
Hemminger JA, Pearlman R, Haraldsdottir S, et al. Histology of colorectal adenocarcinoma with double somatic mismatch-repair mutations is indistinguishable from those caused by Lynch syndrome. Hum Pathol. 2018;78:125–130.
Correspondence: Dr. W. L. Frankel at wendy.frankel@osumc.edu
Features and prognosis of mucinous intrahepatic cholangiocarcinoma
Mucinous variant of intrahepatic cholangiocarcinoma is rare, and its clinicopathological features and prognosis are not clear. The authors conducted a study to investigate the clinicopathological features and prognosis of mucinous intrahepatic cholangiocarcinomas (iCCs). They included in the study six cases classified as mucinous iCC, in which the extracellular mucin consisted of at least 50 percent of tumor volume, and 79 conventional iCCs. The mean size of mucinous and conventional iCCs was 6.2 and 6.0 cm, respectively. Eighty-three percent of patients with mucinous iCC presented at T3 stage or above compared with 28 percent of patients in the conventional group (P < .01). Three patients with mucinous iCC (50 percent) died within one year. The average survival time of patients with mucinous iCCs was significantly reduced compared with that of patients in the conventional group (nine months versus two years; P < .001). Immunohistochemistry was performed on six mucinous and 12 conventional iCCs with matched age, gender, and stage, which revealed positive immunoreactivity in MUC1 (83 versus 58 percent), MUC2 (33 versus 17 percent), MUC5AC (100 versus 42 percent), MUC6 (50 percent versus zero), CK7 (83 versus 83 percent), CK20 (zero versus 17 percent), CDX2 (17 percent versus zero), p53 (67 versus 67 percent), Smad4 (67 versus 58 percent), and EGFR (83 versus 42 percent) in mucinous and conventional iCCs, respectively. Molecular studies showed one mucinous iCC with KRAS G12C mutation and no BRAF or IDH1/2 mutations. Mucinous iCC is a unique variant that constitutes seven percent of iCCs. It is more immunoreactive for MUC1, MUC2, MUC5AC, and MUC6. Unlike adenocarcinomas of colorectal primary, mucinous iCCs are often CK7+/CK20−/CDX2− and microsatellite stable. Mucinous iCC likely presents at advanced stage upon diagnosis, with shorter survival time compared with conventional iCCs.
Chi Z, Bhalla A, Saeed O, et al. Mucinous intrahepatic cholangiocarcinoma: a distinct variant. Hum Pathol. 2018;78:131–137.
Correspondence: Dr. J. Lin at jinglin@iupui.edu
Colonic adenomatous polyps involving submucosal lymphoglandular complexes
Lymphoglandular complexes are lymphoid nodules containing intestinal mucosa and are present in close apposition to muscularis mucosae or submucosa. Colorectal adenomas rarely involve submucosal lymphoglandular complexes (LGCs), simulating invasive adenocarcinoma with associated submucosal lymphoid aggregates. The authors conducted a study to identify distinctive histologic features between submucosal LGCs and true invasion. Seven adenomas (tubular/tubulovillous adenomas [n = 6], including four with high-grade dysplasia and one with focal intramucosal adenocarcinoma, and sessile serrated adenoma [n = 1]) were in the right (n = 5) and left colon (n = 2). Seven adenocarcinomas were in the right (n = 3), left (n = 2), and rectum/rectosigmoid colon (n = 2). Adenomatous glands involving submucosal LGCs were invested in lamina propria, showed continuity with surface adenoma, were well rounded and contained within lymphoid tissue, and predominantly lacked classic features of pseudoinvasion. One case showed a herniation pattern carrying muscularis mucosae. Adenocarcinomas had at least one of the following features: infiltrating single cells/small clusters (n = 5), poorly formed, fused, and irregular glands (n = 2), solid tumor nests (n = 1), desmoplastic reaction (n = 5), intraluminal necrosis (n = 3), or lymphovascular invasion (n = 1). In contrast, none of the adenomas had these features. Adenocarcinomas showed no herniation, but connection to surface tumor (n = 5) was seen. Five invasive adenocarcinomas extended into the submucosa beyond the lymphoid aggregate. The authors concluded that adenomas involving LGCs are a rare, clinicopathologically distinct form of pseudoinvasion that mimics invasive adenocarcinoma. Histologic features that distinguish them are a well-rounded contour contained within the lymphoid tissue, as well as lack of infiltrating single cells/small clusters, solid tumor nests, desmoplastic reaction, lymphovascular invasion, and poorly formed, fused, and irregular glands.
Lee HE, Wu TT, Chandan VS, et al. Colonic adenomatous polyps involving submucosal lymphoglandular complexes: a diagnostic pitfall. Am J Surg Pathol. 2018;42(8):1083–1089.