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 firstname.lastname@example.org
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 email@example.com
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.
Correspondence: Dr. Taofic Mounajjed at firstname.lastname@example.org
Role of columnar cell lesions in breast carcinogenesis
Columnar cell lesions have been proposed as precursor lesions of low-grade breast cancer. The molecular characteristic of low-grade breast neoplasia is whole-arm loss of chromosome 16q. The authors conducted a study in which they analyzed copy number changes of six genes on 16p and 20 genes on 16q by multiplex ligation-dependent probe amplification of 165 lesions in 103 patients. The analysis included 23 columnar cell lesions and 19 atypical ductal hyperplasia lesions arising in columnar cell lesions, as well as cases of usual ductal hyperplasia, blunt duct adenosis, ductal carcinoma in situ, lobular neoplasia, and invasive carcinoma. Usual ductal hyperplasia and blunt duct adenosis lacked whole-arm losses of 16q. In contrast, columnar cell lesions without atypia, columnar cell lesions with atypia, atypical ductal hyperplasia, and low-grade ductal carcinoma in situ and low-grade invasive carcinomas increasingly harbored whole-arm losses of 16q (17, 27, 47, and 57 percent, respectively). However, no recurrent losses in specific genes could be identified. In several patients, columnar cell lesions and atypical ductal hyperplasia harbored similar losses as related ductal carcinoma in situ or invasive carcinomas within the same breast. There were indications for 16q breakpoints near the centromere. Whole-arm gains on 16p were relatively scarce, and no relation was found between whole-arm gains of 16p and progression of lesions of the low-grade breast neoplasia family. The authors concluded that columnar cell lesions, with and without atypia, often harbor whole-arm losses of 16q, which underlines their role as precursors in low-grade breast carcinogenesis, in contrast with usual ductal hyperplasia and blunt duct adenosis. However, no recurrent losses in specific genes could be identified, which points to minor events in multiple tumor-suppressor genes, rather than major events in a single 16q gene, contributing to low-grade breast carcinogenesis.
De Boer M, Verschuur-Maes AHJ, Buerger H, et al. Role of columnar cell lesions in breast carcinogenesis: analysis of chromosome 16 copy number changes by multiplex ligation-dependent probe amplification [published online ahead of print July 5, 2018]. Mod Pathol. doi:10.1038/s41379-018-0099-2.
Correspondence: Dr. Paul J. van Diest at email@example.com
Development of a point-based scoring system for HCC to stratify risk of posttransplant recurrence
Eligibility for liver transplant is most commonly decided by measuring tumor size and number on radiographic imaging. However, this method often underestimates the extent of disease. Evaluation of tumor histology has been shown to improve risk stratification when compared with imaging-based transplant criteria, but the World Health Organization (WHO) guidelines for grading hepatocellular carcinoma (HCC) are imprecise and require subjective interpretation by the pathologist. The authors performed a retrospective analysis of 190 explanted livers containing HCC and correlated histologic features with posttransplant recurrence to formulate a three-tiered, point-based scoring system that categorizes tumors as having a low, intermediate, or high risk of recurrence. The recurrence risk assessment score (RRAS) evaluates tumor architecture and specific cytologic features—nuclear pleomorphism, cytoplasmic amphophilia, and nuclear-to-cytoplasmic ratio—and shows superior stratification of HCC recurrence risk compared with imaging criteria and grade assigned by WHO methodology. Stratifying tumors using RRAS criteria, the rate of recurrence after transplant was zero for low-risk tumors (compared with three percent for well-differentiated tumors), 12 percent for intermediate-risk tumors (compared with 15 percent for moderately differentiated tumors), and 54 percent for high-risk tumors (compared with 29 percent for poorly differentiated tumors). Receiver operating characteristic analysis showed that RRAS criteria were significantly better at predicting HCC recurrence than WHO grade (area under the curve, 0.841 and 0.671, respectively; P = .0061). The results indicate that evaluation of tumor histology is superior to radiographic criteria for predicting recurrence risk following liver transplantation and that the RRAS system better stratifies recurrence risk compared with HCC grading by WHO methodology.
Roberts DE, Kakar S, Mehta N, et al. A point-based histologic scoring system for hepatocellular carcinoma can stratify risk of posttransplant tumor recurrence. Am J Surg Pathol. 2018;42:855–865.
Correspondence: Dr. Daniel E. Roberts at firstname.lastname@example.org