Kakar, Sanjay

Noncirrhotic portal hypertension has historically been described using heterogeneous and region-specific terminology—such as idiopathic portal hypertension (IPH), noncirrhotic portal fibrosis (NCPF), obliterative portal venopathy, and nodular regenerative hyperplasia—leading to substantial variability in diagnosis, reporting, and international research collaboration. Differences in guideline definitions from major societies (AASLD, EASL, and APASL), together with the presence of characteristic histologic lesions in patients without clinically overt portal hypertension, have further complicated disease classification. To address these challenges, a large, multisociety, international initiative was convened to harmonize nomenclature and diagnostic criteria. Representatives from liver, pathology, and pediatric hepatology societies across the Americas, Europe, and Asia participated in a structured consensus process that included specialized working groups and external Delphi validation. The initiative produced a globally harmonized and implementable diagnostic framework. Consensus was reached that the terms porto-sinusoidal vascular disorder (PSVD) and NCPF may be used interchangeably when identical diagnostic criteria are applied, and that they should be written as PSVD or NCPF . The diagnosis was defined as fundamentally clinicopathological, requiring integrated assessment. Core principles include the need for a high-quality liver biopsy (≥10 mm), mandatory exclusion of cirrhosis, and systematic exclusion of specific alternative conditions. Importantly, the consensus recognizes that PSVD or NCPF may be diagnosed even without clinical portal hypertension and may coexist with other liver diseases, provided cirrhosis is excluded. Standardized major and minor histologic criteria were developed collaboratively by expert pathologists and externally validated. Features of portal hypertension were harmonized into specific and nonspecific categories applicable to routine clinical practice. An integrated diagnostic scoring system incorporating histology, clinical features, associated conditions, and concommitant etiologies was developed and validated using the Delphi method. This consensus provides the first internationally endorsed, unified framework for the diagnosis of PSVD or NCPF. Its global implementation is expected to reduce diagnostic variability, improve comparability across regions, and facilitate the development of robust, internationally harmonized clinical and translational research cohorts.

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.

CTNNB1- mutated hepatocellular carcinomas are characterized by a distinctive morphology and activation of the Wnt pathway. AXIN1 also plays a key role in the Wnt pathway, but the morphology of AXIN1-mutated tumors has not been examined. In addition, there are ongoing questions on the ability of AXIN1 mutations to activate the Wnt pathway in hepatocellular carcinoma. AXIN1 mutated tumors (N=18) were studied, along with control groups: CTNNB1 (N=17), APC (6), or “Other” genes in the Wnt pathway (5). Wnt pathway activation was studied by immunostains for beta-catenin and glutamine synthetase. Findings were supplemented by gene expression analysis using TCGA data. On histologic examination, the classic morphology associated with beta-catenin mutations was found in all 4 groups: 8/18 AXIN1 (44%), 10/17 CTNNB1 (59%), 4/6 APC (67%), and 1/5 Other (20%). By immunohistochemistry, Wnt pathway activation was found in 11/18 AXIN1 (61%), 15/17 CTTNB1 (88%), 6/6 APC (100%), and 5/5 (100%) of Other. In AXIN1- mutated tumors, the Wnt pathway was weakly activated. Glutamine synthetase stains also highlighted a new “progressed pattern” associated with distinct subnodules of staining. Tertiary lymphoid structures were uncommon except for cases with CTTNNB1 mutations plus additional mutations in the Wnt pathway. In summary, the classic morphology associated with CTNNB1 mutations is found in hepatocellular carcinomas with mutations in AXIN1 , APC , and other Wnt genes. AXIN1 mutated tumors have Wnt activation that is detectable but at lower levels than CTNNB1 mutated tumors. As tumors progress, their level of Wnt activation can change.

Abstract Objective β-Catenin–mutated hepatocellular adenomas (HCAs) carry an increased malignant transformation risk and are screened by interpreting glutamine synthetase (GS) and β-catenin by immunohistochemistry (IHC). Our study aims to assess GS and β-catenin interpretation guidelines for applicability and reproducibility in predicting high-risk HCA and other relevant molecular alterations. Methods Hematoxylin and eosin (H&E), β-catenin, GS, and CD34 stains from 75 HCAs were interpreted by three pathologists using Method A (GS interpretation: negative, perivenular patchy, map-like, diffuse, and indeterminate) and Method B criteria (similar GS interpretation scheme based on a recent publication, with and without CD34 expression patterns). Ease of application and interpretation confidence level were assessed. High-risk IHC was defined as nuclear β-catenin and/or diffuse homogeneous GS. Molecular testing was performed on a subset of HCAs and controls. Results There were 57 resections and 18 biopsy specimens examined. Methods A and B (GS only) were rated as easy to apply, with high interpretation confidence (≥90% using both methods). Consensus rate was comparable in biopsy specimens (100% for both methods) and resections (88% for Method A, 93% for Method B). While the same cases were stratified into high-risk GS categories using both systems, clinically significant genetic alterations (TERT promoter, EGFR, MTOR, and TP53) were identified in 25% of cases stratified as not high risk by IHC. Conclusions Both methods have a similar ease of application and level of interpretation confidence, and they also detected β-catenin mutations as expected. Other relevant molecular alterations associated with risk of neoplastic progression and/or bleeding were detected in 25% of HCAs with the non-high-risk IHC phenotype, suggesting the value of molecular testing in this subset.

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.

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.

Liver biopsies have consistently contributed to our understanding of the pathogenesis and aetiologies of acute liver disease. As other diagnostic modalities have been developed and refined, the role of biopsy in the management of patients with acute liver failure (ALF), acute‐on‐chronic liver failure (ACLF) and acute hepatitis, including acute liver injury (ALI), has changed. Liver biopsy remains particularly valuable when first‐line diagnostic algorithms fail to determine aetiology. Despite not being identified as a mandatory diagnostic tool in recent clinical guidelines for the management of ALF or ACLF, many centres continue to undertake biopsies given the relative safety of transjugular biopsy in this setting. Several studies have demonstrated that liver biopsy can provide prognostic information, particularly in the context of so‐called indeterminate hepatitis, and is extremely useful in excluding conditions such as metastatic tumours that would preclude transplantation. In addition, its widespread use of percutaneous biopsies in cases of less severe acute liver injury, for example in the establishment of a diagnosis of acute presentation of autoimmune hepatitis or confirmation of a probable or definite drug‐induced liver injury (DILI), has meant that many centres have seen a shift in the ratio of specimens they are receiving from patients with chronic to acute liver disease. Histopathologists therefore need to be equipped to deal with these challenging specimens. This overview provides an insight into the contemporary role of biopsies (as well as explant and autopsy material) in diagnosing acute liver disease. It outlines up‐to‐date clinical definitions of liver injury and considers recent recommendations for the diagnosis of AIH and drug‐induced, autoimmune‐like hepatitis (DI‐AIH).

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.

Subtyping hepatic adenomas is important for patient management due to differing complication risks. Immunohistochemical staining with C-reactive protein (CRP) and serum amyloid-A (SAA) is widely accepted as a surrogate for molecular classification to identify inflammatory hepatocellular adenomas. Limited data, however, has been published on how these 2 stains compare for sensitivity. We conducted a large, multicenter, retrospective study to examine the sensitivity and staining characteristics of CRP and SAA in inflammatory hepatic adenomas, with focal nodular hyperplasia (FNHs) as a control group. Inflammatory adenomas were identified in 133 patients (average age 37 years, 109 were female). In all, 69.9% of cases were resection specimens and 90.2% of all cases showed positive staining for both CRP and SAA; 10 (7.5%) were positive for CRP only and 3 (2.3%) were positive for SAA only. CRP was more sensitive than SAA (97.74% vs. 92.48%, P-value = 0.0961) and showed more extensive and intense staining, with a significantly higher modified H-score (P<0.001). Focal nodular hyperplasia can also show positive CRP and SAA staining but with a lower modified H-score (P<0.0001). Based on beta-catenin and glutamine synthetase staining, 26 of inflammatory adenomas also had beta-catenin activation (19.5%). All 3 cases with positive SAA and negative CRP staining were beta-catenin activated. In contrast, the proportion of cases that were CRP positive and SAA negative was similar regardless of beta-catenin activation. The data affirms the strategy of using both CRP and SAA immunostains for hepatic adenoma subtyping and raises the awareness of the highly variable nature of SAA staining characteristics.