Choi, Won‐Tak

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.

AimThe aim of this study was to compare the histopathologic features of MMF‐induced colitis and colonic GVHD and develop a digital tool using deep learning convolutional neural networks (CNNs) to semi‐automate the quantification of eosinophils.MethodsMMF and GVHD colitis cases were retrieved. A cohort of transplant patients who were at risk for developing GVHD and were on MMF at the time of biopsy was also identified. Cases were reviewed for histologic features and a deep learning CNN was trained to quantify lamina propria eosinophils. Clinical history was collected.ResultsNinety‐five patients were included in the study group: GVHD (n = 37), MMF (n = 25) and GVHD vs. MMF (n = 33). Within the GVHD vs. MMF group, one patient was thought to have definitive MMF colitis and one possible MMF colitis. The GVHD group had a significantly higher apoptotic count compared to the MMF group (median: 7 vs. 2, P = 0.03). Neuroendocrine aggregates were present in the GVHD (N = 12) and GVHD vs. MMF (N = 4) groups while absent in the MMF group. The MMF group had a higher semi‐quantitative eosinophil score and a higher automated eosinophil count as detected by the deep learning CNN (median eos/HPF: MMF 19.2, GVHD vs. MMF 3.6, GVHD 3.4, P < 0.001).ConclusionsLower eosinophil counts, higher apoptotic counts and neuroendocrine cell aggregates favour the diagnosis of GVHD. AI models for eosinophil quantification may serve as an ancillary tool for assessing this differential diagnosis. Given the rarity of MMF‐induced colitis in SCT patients, pathologists should have a high threshold for making this diagnosis in this population.

AimsThere are no standardized histologic criteria for diagnosing serrated epithelial change (SEC) in inflammatory bowel disease (IBD), but two commonly used definitions are currently in use. The first definition (DEF1) is a simpler definition but requires endoscopic correlation. It encompasses all endoscopically invisible or non‐targeted serrated lesions without morphologic evidence of dysplasia that do not meet the diagnostic criteria of sessile serrated lesion (SSL) or traditional serrated adenoma (TSA). In contrast, the second definition (DEF2) incorporates more complex morphologic criteria (i.e., disorganized crypt architecture with some crypts no longer perpendicular or extending down to the muscularis mucosae, irregular serration spanning the entire thickness of the mucosa, and goblet cell‐rich epithelium), but does not necessitate endoscopic correlation. The reproducibility of SEC diagnoses using these definitions among gastrointestinal (GI) pathologists has not yet been evaluated.Methods and resultsSeven GI pathologists independently evaluated 38 GI cases, including 21 digitally scanned biopsy slides and 17 previously published images, demonstrating various types of serrated changes and their morphologic mimics. The diagnostic categories included: (1) SEC, (2) hyperplastic polyp (HP), (3) SSL, (4) TSA, (5) hypermucinous dysplasia (HMD), and (6) no serrated change or dysplasia (NSD). All cases were selected by a single pathologist (WTC) who did not participate in the interobserver study. The pathologists initially assessed each case as if it were endoscopically normal and provided a diagnosis using DEF1. Next, they re‐evaluated each case, this time considering it as a nodular or polypoid lesion, and again made a diagnosis using DEF1. The same process was then repeated for each case but using DEF2. A total of 532 diagnoses were made for each definition (7 pathologists × 38 cases × 2 endoscopic appearances). Fleiss' kappa statistics were used to assess the level of agreement among the seven pathologists. The total number of SEC diagnoses using DEF1 (n = 110 of 532) was more than twice that of DEF2 (n = 50 of 532). Also, the number of SEC diagnoses per pathologist was higher using DEF1 (mean: 16, range: 12–18) compared to DEF2 (mean: 7, range: 0–14). Furthermore, the instances where four or more pathologists agreed on the diagnosis of SEC were more frequent with DEF1 (16 of 38 cases) than with DEF2 (1 of 38 cases). The overall agreement in diagnosing SEC (vs. no SEC) using DEF1 was substantial (k = 0.69, P < 0.001), whereas the agreement using DEF2 was only slight (k = 0.18, P < 0.001). Among potential SEC mimics, there was substantial agreement in diagnosing HP (k = 0.69 using DEF1), SSL (k = 0.68), TSA (k = 1.00), HMD (k = 0.79), and NSD (k = 0.61) (P < 0.001).ConclusionsThe diagnosis of SEC using DEF1 is significantly more reproducible than using DEF2. Utilizing DEF1 is also less likely to miss potentially important cases of SEC. Therefore, DEF1 could be adopted to separate SEC from other serrated lesions and morphologic mimics in IBD.

AimsInflammatory bowel disease (IBD)‐associated serrated lesions are categorized into three distinct subtypes: traditional serrated adenoma (TSA)‐like lesion, sessile serrated lesion (SSL)‐like lesion, and serrated lesion, not otherwise specified (NOS). Although the risk of neoplastic progression of serrated lesions without dysplasia has not been shown to exceed that of sporadic cases, the clinicopathologic features of the three serrated subtypes with dysplasia remain poorly understood in the context of IBD.Methods and ResultsWe analysed 87 serrated lesions with dysplasia (collectively referred to as serrated dysplasia) identified endoscopically in 58 IBD patients, including 51 (59%) TSA‐like dysplasia, 24 (28%) SSL‐like dysplasia, and 12 (14%) serrated dysplasia NOS. Inclusion criteria required all three serrated subtypes to show morphologic evidence of dysplasia and to be located within areas of colitis. We also compared the clinicopathologic features of serrated dysplasia with those of 239 conventional (adenomatous) dysplastic lesions from 149 IBD patients. The cohort included 39 (67%) men and 19 (33%) women, with a mean age of 54 years and a mean IBD duration of 20 years. Most patients had ulcerative colitis (n = 41; 71%) and pancolitis (n = 48; 83%). The majority of serrated lesions with dysplasia had a polypoid or visible endoscopic appearance (n = 73; 84%), with a mean size of 1.4 cm, and were found in the left colon (n = 66; 76%). Most lesions (n = 73; 84%) demonstrated low‐grade dysplasia at the time of biopsy diagnosis, whereas high‐grade dysplasia (HGD) was identified in the remaining 14 (16%) lesions. SSL‐like dysplasia was more frequently associated with ulcerative colitis (94%) compared to TSA‐like dysplasia (67%) and serrated dysplasia NOS (56%) (P = 0.042). Although only seven (12%) patients had a concurrent history of primary sclerosing cholangitis, it was exclusively identified in the TSA‐like dysplasia group (19% versus 0% in both the SSL‐like dysplasia group and the serrated dysplasia NOS group; P = 0.017). Serrated dysplasia NOS more commonly demonstrated HGD at the time of biopsy diagnosis (42%) compared to TSA‐like dysplasia (12%) and SSL‐like dysplasia (13%) (P = 0.022). Serrated dysplasia NOS was also more frequently associated with synchronous and/or metachronous nonconventional dysplasia (60%) compared to TSA‐like dysplasia (16%) and SSL‐like dysplasia (9%) (P = 0.037). Serrated dysplasia, regardless of subtype, was associated with high rates of advanced neoplasia (HGD or colorectal cancer) at the previous biopsy site or in the same colonic segment during follow‐up. Within a mean follow‐up time of 13 months, advanced neoplasia was detected in 50% of the TSA‐like dysplasia group, 67% of the SSL‐like dysplasia group, and 100% of the serrated dysplasia NOS group (P = 0.622). Moreover, at least one‐third of patients in each group (58% in the TSA‐like dysplasia group, 44% in the SSL‐like dysplasia group, and 33% in the serrated dysplasia NOS group; P = 0.332) developed synchronous/metachronous dysplasia, with at least 50% of these lesions progressing to advanced neoplasia within a mean follow‐up time of 11 months (P = 1.000). The serrated dysplasia group showed nearly six times the incidence of advanced neoplasia upon follow‐up (59%) compared to the conventional dysplasia group (10%) (P < 0.001).ConclusionTSA‐like dysplasia, SSL‐like dysplasia, and serrated dysplasia NOS show distinct clinicopathologic features. However, all three serrated subtypes were associated with high rates of advanced neoplasia (50%–100%) during follow‐up, suggesting that these lesions could potentially be combined into one diagnostic category, such as serrated dysplasia.

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. To assess the utility of C4d immunohistochemistry for esophageal pemphigus vulgaris. Methods and results. We searched for patients with a history of esophageal pemphigus vulgaris who had esophageal biopsies for routine hematoxylin and eosin (H&E) staining. A total of 8 biopsies from 7 patients were available. We also identified 18 non-pemphigus esophageal biopsies for controls. C4d immunohistochemistry was performed on each biopsy. Five of 6 (83%) biopsies with classic pemphigus vulgaris histologic findings were positive for intercellular staining at the basal layer. The negative biopsy was in a patient that had recently received high-dose corticosteroid treatment for a flare. Two biopsies with atypical histologic features for pemphigus vulgaris had negative C4d staining but positive direct immunofluorescence (DIF) studies. Various nonspecific C4d staining patterns were observed in the controls, but none showed the intercellular staining pattern that was observed in pemphigus vulgaris. Conclusions. Suprabasal clefting with acantholysis and “tombstone effect” are described histologic features of pemphigus vulgaris on H&E. However, procedural artifact may mimic these findings. Currently, the gold standard for pemphigus vulgaris is DIF, which is not always available because it cannot routinely be performed on formalin-fixed paraffin embedded tissue. Our study shows that C4d immunohistochemistry may be a useful adjunct in evaluating esophageal pemphigus vulgaris.

Various subtypes of nonconventional dysplasia have been recently described in inflammatory bowel disease (IBD). We hypothesized that goblet cell deficient dysplasia and serrated dysplasia may be the primary precursor lesions for goblet cell deficient (GCDAC) and serrated (SAC) variants of colonic adenocarcinoma, respectively. Clinicopathologic features of 23 GCDAC and 10 SAC colectomy cases were analyzed. All dysplastic lesions found adjacent to the colorectal cancers (n = 22 for GCDACs and n = 10 for SACs) were subtyped as conventional, nonconventional, or mixed-type dysplasia. As controls, 12 IBD colectomy cases with well to moderately differentiated adenocarcinoma that lacked any mucinous, signet ring cell, low-grade tubuloglandular, or serrated features while retaining goblet cells throughout the tumor (at least 50% of the tumor) were evaluated. The cohort consisted of 19 (58%) men and 14 (42%) women, with a mean age of 53 years and a long history of IBD (mean duration: 18 y). Twenty-seven (82%) patients had ulcerative colitis. GCDACs (57%) were more often flat or invisible than SACs (10%) and controls (25%; P = 0.023). The GCDAC and SAC groups were more likely to show lymphovascular invasion (GCDAC group: 52%, SAC group: 50%, control group: 0%, P = 0.001) and lymph node metastasis (GCDAC group: 39%, SAC group: 50%, control group: 0%, P = 0.009) than the control group. Notably, GCDACs and SACs were more frequently associated with nonconventional dysplasia than controls (GCDAC group: 77%, SAC group: 40%, control group: 0%, P < 0.001). Goblet cell deficient dysplasia (73%) was the most prevalent dysplastic subtype associated with GCDACs (P = 0.049), whereas dysplasias featuring a serrated component (60%) were most often associated with SACs (P = 0.001). The GCDAC group (75%) had a higher rate of macroscopically flat or invisible synchronous dysplasia compared with the SAC (20%) and control (33%) groups (P = 0.045). Synchronous dysplasia demonstrated nonconventional dysplastic features more frequently in the GCDAC (69%) and SAC (40%) groups compared with the control group (0%; P = 0.016). In conclusion, goblet cell deficient dysplasia and dysplasias featuring a serrated component could potentially serve as high-risk markers for GCDACs and SACs, respectively.

Validated nonbiopsy methods to assure duodenal mucosal healing in celiac disease are lacking, yet ongoing mucosal injury is associated with anemia, osteoporosis, and lymphoma. Most providers utilize clinical data as surrogates of mucosal status to avoid additional esophagogastroduodenoscopy. The reliability of such surrogates to predict mucosal recovery has been incompletely evaluated. The aim of this study was to rigorously assess patterns of histologic mucosal recovery at follow-up in celiac disease and to correlate findings with clinical data. Gastrointestinal pathologists from 13 centers evaluated initial and follow-up duodenal biopsies from 181 celiac disease patients. Marsh scores and intraepithelial lymphocytes (IELs)/100 enterocytes were assessed blindly. Histology at follow-up was correlated with symptoms, immunoglobulin A anti–tissue transglutaminase titers and gluten-free diet adherence. Fifty-six/181 (31%) patients had persistent villous blunting and 46/181 (25%) patients had just persistently elevated IELs at follow-up, with only 79/181 (44%) patients having complete histologic remission. IEL normalization (82/181; 45%) lagged villous recovery (125/181;69%). In a minority of patients, villous blunting was limited to proximal duodenal biopsies. No correlation was found between Marsh scores and symptoms, normalization of immunoglobulin A anti–tissue transglutaminase serology, or diet adherence. Children showed greater recovery of Marsh score (P<0.001) and IELs (P<0.01) than adults. Persistent mucosal injury is common in celiac disease, with discordant villous/IEL normalization. Pathologist awareness of expected findings in celiac disease follow-up biopsies, including their frequent lack of correlation with clinical data, is important for patient management, and has implications for eligibility criteria for therapeutics currently in development.

SummaryBackgroundColitis is a significant complication of immune checkpoint inhibitors (ICI). Currently, clinical and endoscopic severity are used to guide therapy.AimsTo investigate associations between clinical, endoscopic, and histological features with outcomesMethodsWe identified 149 patients from seven institutions with biopsy‐proven ICI colitis. Biopsies were evaluated for histological features including the Geboes score, and the Robarts histopathological index (RHI) was calculated. Clinical, endoscopic, and histological data were tested for associations with biological use and adverse colitis outcomes (biological‐refractory colitis, colectomy or death from colitis).ResultsThree mutually exclusive histological patterns were identified: acute colitis, chronic active colitis and microscopic colitis. Microscopic colitis was associated with older age (68.5 vs 61 years for acute colitis pattern, P = 0.02) and longer time to colitis (5.5 vs 3 months for the other patterns, P = 0.05). Biological use was associated with earlier time to colitis (2 vs 3 months, P = 0.04) and higher RHI (18 vs 12, P = 0.007). On multivariate analysis, RHI ≥14 was associated with biological use with an odds ratio of 4.5 (95% CI 1.4‐13.8; P = 0.01). Adverse colitis outcomes were associated with shorter time to colitis (2 vs 3 months, P = 0.008) and higher RHI (24 vs 14, P = 0.001). On multivariate analysis, RHI ≥24 was associated with adverse colitis outcomes with an odds ratio 9.5 (95% CI 2.1‐42.3 P = 0.003).ConclusionHistological activity as measured by RHI is the only factor independently associated with biological use and adverse colitis outcomes. Prospective studies are needed to validate these findings to determine if histological activity should be incorporated into therapeutic algorithms.

LINKED CONTENTThis article is linked to Pai et al and Buckle & Christensen papers. To view these articles, visit https://doi.org/10.1111/apt.16142 and https://doi.org/10.1111/apt.16203