Gonzalez, Raul S

Enteroblastic, hepatoid, and clear cell carcinomas are rare subtypes of colorectal carcinoma (CRC) with histologic and immunohistochemical (IHC) overlap. We assessed 37 CRCs that possibly represent these subtypes. Provisional criteria for each subtype, along with case photomicrographs and IHC data, were circulated among the authors to provide diagnostic interpretations. Based on plurality consensus, the carcinomas were classified as enteroblastic (n=13), hepatoid (n=6), and clear cell (n=18). Unanimous agreement was reached in 18% (3 clear cell, 3 hepatoid). Interobserver analysis revealed a mean pairwise Cohen κ of 0.63 (range: 0.32 to 0.91), with the hepatoid subtype eliciting the greatest consensus. Clear cell areas were the most likely to intermix with areas of conventional CRC ( P <0.001). Seven patients (20%) had inflammatory bowel disease (mostly linked to enteroblastic CRC). Twenty-three of 34 patients (68%) had nodal metastasis, and 12 (32%) had distant metastasis (mostly to the liver) at presentation. Median recurrence-free survival was 17 months, with enteroblastic cases the most likely to recur (54%, P =0.015). Median follow-up length was 27 months, with 14 patients (40%) dying of disease (representing 7 enteroblastic, 4 hepatoid, and 3 clear cell CRC). Mutations were identified in TP53 (n=8) , APC (n=3) , FBXW7 (n=2), and KRAS (n=1). Inflammatory bowel disease significantly worsened recurrence-free survival on multivariate analysis, while distant metastasis significantly worsened both recurrence-free and overall survival on multivariate analysis. Enteroblastic, hepatoid, and clear cell CRC demonstrate morphologic and IHC overlap, leading to interobserver variability in diagnosis. Given potential differences in clinical correlations and outcomes, more refined criteria are likely necessary.

The WHO 2019 classification of digestive tract tumors introduced a high-grade (G3) category for well-differentiated neuroendocrine tumors (NETs). These neoplasms appear to have a better prognosis than poorly differentiated neuroendocrine carcinomas (NECs) and may not respond to platinum-based chemotherapy, which is the treatment of choice for NECs, justifying the creation of this new category. Most existing data on G3 NETs are derived from pancreatic neuroendocrine neoplasms, as the majority of G3 neuroendocrine neoplasms (NENs) arise there. G3 NETs are rare at extrapancreatic sites, and their prognosis and behavior are not well studied. We collected and analyzed a multi-institutional cohort of 24 extrapancreatic primary gastrointestinal G3 NETs based on mitotic rate and/or Ki67 index (5 gastric, 13 small bowel, 6 colorectal/anal). Mean Ki67 index was 29.3% (range: 10.5% to 50.2%). Cases generally showed typical well-differentiated NET morphology. Nodal metastases were present in 17/17 (100%) patients; 13/24 (45%) had distant metastases at initial presentation, and 7 patients developed them on follow-up. With a median of 29 months of follow-up, only 2 patients (8%) were alive without disease. Outcomes of G3 NETs were compared with a separate cohort of 125 extrapancreatic G1/G2 gastrointestinal NETs. G3 tumors presented at a higher pT-category stage ( P <0.001) and overall stage ( P =0.002), and patients with G3 disease were more likely to die than those with G1/G2 disease ( P <0.001). Our data show that, like pancreatic G3 NETs, rare extrapancreatic gastrointestinal G3 NETs exhibit aggressive behavior compared with their G1/G2 counterparts (although small bowel NETs tend to recur irrespective of grade). In most cases, the G3 designation is driven by Ki67 index, though exceptions exist, emphasizing the need for reviewing mitotic count in every case.

AimsWe compiled two cohorts of colorectal adenosquamous carcinoma (ASC) to describe its histologic and molecular aspects using modern parameters to compare them with literature reports using meta‐analysis of cohorts and individual case series.Methods and ResultsWe identified 53 colorectal ASC from 19 North American academic medical centres, in addition to national database reports on 94 Dutch cases. We analysed available clinical, histologic, and immunohistochemical features and patient outcome. ASC comprised 0.02% of colorectal cancers in the Dutch database. The median cohort patient ages at resection were 65 and 69 years (North American and Dutch cohorts, respectively), with a roughly equal male:female ratio. The squamous component represented between 5% and 95% of each tumour, with a median of 50%. Tumour‐infiltrating lymphocytes (TILs) were generally low (66%), and tumour budding was often Bd1 (64%). Most cases were pT3 (55%) or pT4 (40%), with nodal metastases in more than half (58%). Twenty‐three cases (43%) metastasized distantly, most commonly to the liver. Mismatch repair (MMR) deficiency was identified in 34% of the cases. Follow‐up was available for 48 patients; 13 (27%) had recurrent disease and 29 (60%) died. A total of 31 patients progressed, with median time to progression of 18 months. Available data for the Dutch cohort revealed largely similar findings, as did review of cases in the literature.ConclusionColorectal ASC usually presents at an advanced stage. Despite high rates of MMR deficiency and low tumour budding, TILs were generally low, and there is a high recurrence rate and poor prognosis.

Aims The current American Joint Committee on Cancer (AJCC) staging manual and the College of American Pathologists (CAP) colorectal carcinoma (CRC) protocol specify use of a four‐tiered grading system (i.e. grades 1–4; well‐differentiated–undifferentiated) for CRC, based on percentage of gland formation. The World Health Organization (WHO) 5th edition grades CRC into low‐grade (well‐ and moderately differentiated) and high‐grade (poorly and undifferentiated), based on the least differentiated component. We studied interobserver agreement and practice patterns among pathologists when grading CRC by these two grading systems. Methods and results Five gastrointestinal pathologists reviewed 100 scanned CRC slides and graded the tumour on each slide, per provided criteria in (a) WHO 5th edition book, (b) AJCC manual/CAP CRC protocol and (c) their clinical practice. A questionnaire for grading selected CRC subtypes was also provided. Statistical analysis was performed using Pearson's χ 2 test and Fleiss multi‐rater kappa analyses. Overall, agreement among the five reviewers when grading via WHO and AJCC criteria for low‐grade and high‐grade CRC was moderate ( κ = 0.568, P < 0.001) and good ( κ = 0.611, P < 0.001), respectively. All reviewers graded significantly more tumours as high‐grade when using WHO (median = 46) versus AJCC/CAP criteria (median = 20). Conclusions Interobserver agreement was higher using the AJCC grading criteria as a two‐tiered system. Significantly more tumours were called high‐grade using the WHO criteria. This raises concerns regarding upgrading tumours, as well as potential differences in grading tumours among pathologists worldwide, based on regional preferred grading systems. Synchronisation of these two grading systems is necessary for uniform grading of CRCs throughout institutions.

AimsMassive gastric polyposis is a rare entity that is often associated with juvenile polyposis syndrome (JPS). The aim of this study was to evaluate the clinicopathological features of 22 patients with abundant gastric juvenile‐type or hyperplastic‐like polyps.Methods and resultsThe study included 12 males and 10 females with a median age of 48 years (range: 13–79 years). Fourteen (64%) patients carried a diagnosis of JPS, and three had prior gastrointestinal adenocarcinomas. Patients without known JPS presented at an older median age (60 years versus 40 years; P = 0.0068). Clinical symptoms included nausea, vomiting, and abdominal pain; 23% of patients were asymptomatic. Eighteen cases showed complete or near‐complete carpeting of the gastric mucosa by innumerable polyps, ranging from a few millimetres to ~100 mm. Most polyps formed long, bulbous projections and had characteristic histological features, including a smooth outer contour, prominent stromal oedema, and widely spaced, often cystically dilated glands lined by foveolar epithelium; some polyps had less stroma and more hyperplastic foveolar epithelium. All had normal underlying or adjacent mucosa. Four (18%) cases harboured adenocarcinoma, and seven (32%) others showed dysplasia. SMAD4 immunohistochemical staining showed patchy loss in polyps from 19 of 20 cases tested. Five of six (84%) patients tested had a germline SMAD4 mutation.ConclusionsMassive gastric juvenile‐type polyposis can occur in patients with and without known JPS, and may mimic different conditions, such as other polyposis syndromes and Ménétrier disease. Pathologists play an important role in disease classification, as some patients lack a family or personal history of JPS, have few if any colonic polyps, and may not harbour diagnostic germline mutations.