Distinguishing features of autoimmune gastritis depending on previous H. pylori infection or positivity to anti-parietal cell antibodies: results from the Autoimmune gastRitis Italian netwOrk Study grOup (ARIOSO).

OBJECTIVES: To describe the clinical features and the risk of developing gastric tumors in patients with autoimmune gastritis (AIG). METHODS: This was a retrospective, longitudinal, multicenter study conducted at eight Italian tertiary referral centers. We retrieved clinical data from all histologically proven AIG patients. Differences between H. pylori-exposed vs H. pylori-naïve, and anti-parietal cell antibody (PCA)-positive vs PCA-negative patients were investigated. The rate of gastric adenocarcinoma and type 1 gastric neuroendocrine neoplasm (gNEN) was assessed. A multivariable model for factors associated to gNEN was fitted. RESULTS: 1598 patients with AIG (median age 58 years, IQR 46-68; F:M ratio 2.7:1) were included. H. pylori-naïve patients were more likely to have a first-degree family history of AIG (14.7% vs 8.9%; p=0.012), type 1 diabetes mellitus (4.9% vs 2.3%; p=0.025), and pernicious anemia (30.9% vs 21.1%; p=0.003). PCA-positive patients had significantly more associated autoimmune diseases (59.0% vs 42.9%; p<0.001) and were more likely to have been diagnosed by a case-finding strategy (15.3% vs 2.6%; p<0.001). Overall, 15 cases (0.9%) of gastric adenocarcinoma and 153 cases (9.6%) of gNEN occurred, with a global rate of 0.12 (95% CI 0.07-0.20) and 1.22 (95% CI 1.03-1.42) per 100 person/year, respectively. Having a vitamin B12/iron deficiency manifestation at AIG diagnosis was associated with an 16.44 (95% CI 9.94-27.20 p<0.001) hazard ratio of gNEN. CONCLUSIONS: The "pure" AIG pattern has typical features of an autoimmune disease and seems to be unrelated to H. pylori. In a tertiary referral setting, the risk of developing overt gastric adenocarcinoma is low, while patients with vitamin B12 deficiency complications at onset may benefit from a more intense endoscopic follow-up for early gNEN detection.

Pink-on-pink: hepatocellular carcinoma metastatic to oncocytic carcinoma of the thyroid.

Hepatocellular carcinoma typically metastasizes within the liver and may involve extrahepatic sites such as the lungs, adrenal glands, and bones at advanced stages. However, hepatocellular carcinoma metastasis to the thyroid is very uncommon and tumor-to-tumor metastasis from a hepatocellular cancer to a thyroid neoplasm is extremely rare. In this report, we present a case of a 70-year-old man with a hepatocellular carcinoma metastasizing to oncocytic thyroid carcinoma, emphasizing the importance of clinical history and of a multidisciplinary approach, as well as the usefulness of site-specific immunohistochemical markers, in diagnosing and managing cases of Rosai's metastasis, especially when donor and recipient neoplasms share similar histologic features.

Correlation between imaging and histology in benign solitary retroperitoneal nerve sheath tumors: a pictorial review.

BACKGROUND: Benign nerve sheath tumors presenting as solitary retroperitoneal masses (RBNSTs) pose a complex diagnostic challenge for multidisciplinary teams regarding differential diagnosis, staging, and treatment planning. This article reviews the role played by different imaging techniques in assessing RBNSTs and elucidates their typical pathological features with a particular emphasis on the correlation between imaging and histological findings. Furthermore, some examples of retroperitoneal tumors that merit consideration in the process of differential diagnosis based on cross-sectional investigations (CSIs) are reported. The correlation between tissue architecture and appearance on imaging can help increase the accuracy of differential diagnosis with other retroperitoneal neoplasms at CSIs. CRITICAL RELEVANCE STATEMENT: This educational review critically examines the correlation between imaging and histological features in solitary retroperitoneal benign nerve sheath tumors, offering valuable insights for improving the accuracy of differential diagnosis in clinical radiology. KEY POINTS: RBNSTs are challenging to diagnose because they lack specific radiological features. Differential diagnosis of RBNSTs from other retroperitoneal neoplasms on imaging is complex. Surgical removal of RBNSTs is recommended for an accurate diagnosis.

Gastric Carcinoma in Autoimmune Gastritis: A Histopathologic and Molecular Study.

Patients with autoimmune gastritis (AIG) have a 13-fold risk of developing type-1 neuroendocrine tumors, whereas the risk for gastric adenocarcinoma is still uncertain. Here we describe the clinicopathologic and molecular features of a series of gastric carcinomas (GC) arising in the context of AIG. A total of 26 AIG-associated GC specimens were collected from 4 Italian Institutions. Immunohistochemistry for MUC1, MUC2, MUC5AC, MUC6, CDX2, HER2, PD-L1, CLDN18, mismatch repair (MMR) proteins, and p53 and EBV-encoded RNA (EBER) in situ hybridization were performed. Histologic and immunohistochemical features were jointly reviewed by 5 expert gastrointestinal pathologists. Next-generation sequencing analysis (TrueSight Oncology 500, Illumina) of 523 cancer-related genes was performed on 19 cases. Most tumors were diagnosed as pT1 (52%) and they were located in the corpus/fundus (58%) and associated with operative link for gastritis assessment stage II gastritis (80.8%), absence of parietal cells, complete intestinal metaplasia, and enterochromaffin-like-cell micronodular hyperplasia. Only 4 (15.4%) GCs were diagnosed during follow-up for AIG. The following histotypes were identified: 20 (77%) adenocarcinomas; 3 (11%) mixed neuroendocrine-non-neuroendocrine neoplasms, and 2 (8%) high-grade solid adenocarcinomas with focal neuroendocrine component, 1 (4%) adenocarcinoma with an amphicrine component. Overall, 7 cases (27%) showed MMR deficiency, 3 (12%) were positive (score 3+) for HER2, 6 (23%) were CLDN18 positive, and 11 (42%) had PD-L1 combined positive score ≥ 10. EBER was negative in all cases. Molecular analysis revealed 5/19 (26%) microsatellite instability (MSI) cases and 7 (37%) tumor mutational burden (TMB) high. The most frequently altered genes were TP53 (8/19, 42%), RNF43 (7/19, 37%), ERBB2 (7/19, 37% [2 amplified and 5 mutated cases]), ARID1A (6/19, 32%), and PIK3CA (4/19, 21%). In summary, AIG-associated GCs are often diagnosed at low stage in patients with longstanding misrecognized severe AIG; they often display a neuroendocrine component or differentiation, have relatively higher rates of MMR deficiency, and TMB high.

Clinical and atopic features of patients with primary eosinophilic colitis: an Italian multicentre study.

Eosinophilic colitis (EC) is the rarest among primary eosinophilic gastrointestinal disorders (EGID). EC is underdiagnosed due to its blurred and proteiform clinical manifestations. To explore the clinical and atopic characteristic of EC adult patients, the diagnostic delay, and relapse-associated factors, by comparison with patients with eosinophilic esophagitis (EoE) and irritable bowel syndrome (IBS). EC patients followed-up at four clinics were included, and clinical, histopathological, and laboratory data were retrieved. As control groups, age-matched patients with EoE and IBS were recruited. Allergy tests included skin prick test and serum specific IgE. Diagnostic delay was assessed. Overall, data from 73 patients were retrieved, including 40 with EC (median age 39 years IQR 22.5-59, F:M 2.1:1), 12 with EoE (F:M ratio: 1:5), and 21 with IBS (F:M ratio: 1:0.9). The most common features in EC patients were female sex (67.5%), atopy (77.5%), abdominal pain/distention (70%), diarrhoea (77.5%), and faecal calprotectin elevation (22.5%). Blood eosinophils were elevated in EoE, but not in EC (p < 0.001), while ECP did not differ across the three groups (p = 0.4). The frequency of allergen sensitization reached 25% of patients. Several frequent pan-allergens for this region were present. The overall diagnostic delay was 10 months (IQR 4-15). Factors contributing to a greater diagnostic delay were atopy, weight loss, and a previous misdiagnosis. EC is mostly a diagnosis of exclusion, burdened by a substantial diagnostic delay. In female patients the presence of allergen sensitization, abdominal symptoms and faecal calprotectin elevation should raise the suspicion of EC.

Invasive lobular carcinoma metastasis to pancreas mimicking pancreatic signet ring cell carcinoma: A case report and systematic review of the literature.

Metastasis to the gastrointestinal tract is a rare instance in the natural history of breast cancer, usually in association with lobular histology and widespread dissemination of disease. We report the case of a 74-year-old woman with a history of invasive lobular carcinoma presenting with a pancreatic metastasis mimicking a primary pancreatic adenocarcinoma; we also present a systematic review of the relevant literature. The presentation of pancreatic metastasis in the setting of breast cancer is unspecific, and histology is of paramount importance for a correct diagnosis; surgical metastasectomy could be of some benefit in the correct clinical setting.

Claudin-18.2 testing and its impact in the therapeutic management of patients with gastric and gastroesophageal adenocarcinomas: A literature review with expert opinion.

Claudin-18.2 (CLDN18.2) is a member of the tight junction protein family and is a highly selective biomarker with frequent abnormal expression during the occurrence and development of various primary malignant tumors, including gastric cancer (GC) and esophago-gastric junction adenocarcinomas (EGJA). For these reasons, CLDN18.2 has been investigated as a therapeutic target for GC/EGJA malignancies. Recently, zolbetuximab has been proposed as a new standard of care for patients with CLDN18.2-positive, HER2-negative, locally advanced and metastatic GC/EGJA. The use of CLDN18 IHC assays to select patients who might benefit from anti-CLDN18.2 therapy is currently entering clinical practice. In this setting, pathologists play a central role in therapeutic decision-making. Accurate biomarker assessment is essential to ensure the best therapeutic option for patients. In the present review, we provide a comprehensive overview of available evidence on CLDN18.2 testing and its impact on the therapeutic management of patients with GC/EGJA, as well as some practical suggestions for CLDN18.2 staining interpretation and potential pitfalls in the real-world setting.

A Clinicopathologic Comparison Between Early-Onset and Late-Onset Small Bowel Adenocarcinoma: A Multicenter International Study.

INTRODUCTION: Early-onset small bowel adenocarcinoma (EO-SBA) is a rare and poorly characterized entity. METHODS: This retrospective study conducted on an international multicenter cohort of 208 patients with SBA aimed at comparing clinicopathologic features of EO-SBA (age younger than 50 years at SBA diagnosis) and late-onset SBA (age 50 years or older at SBA diagnosis). RESULTS: The presence of predisposing pathologic conditions was significantly more common in the EO-SBA group compared with that in the late-onset SBA group ( P = 0.003, Fisher exact test; relative risk: 1.50, 95% confidence interval: 1.20-1.86). This difference is mainly due to the significantly higher prevalence of celiac disease among patients with EO-SBA. DISCUSSION: EO-SBA is strongly associated with predisposing conditions, particularly with celiac disease, highlighting the importance of routine screening for celiac disease in patients with EO-SBA.

Application of a pattern-based approach to histological diagnosis in very early onset IBD (VEO-IBD) in a multicentric cohort of children with emphasis on monogenic disease with IBD-like morphology.

AIMS: Very early-onset inflammatory bowel disease (VEO-IBD) is a clinical umbrella term referring to IBD-like symptoms arising in children before the age of 6 years, encompassing both 'pure' IBD, such as ulcerative colitis (UC) and Crohn's disease (CD) and monogenic diseases (MDs), the latter often involving genes associated with primary immunodeficiencies. Moreover, histological features in gastrointestinal (GI) biopsies in MD can also have IBD-like morphology, making differential diagnosis difficult. Correct diagnosis is fundamental, as MDs show a more severe clinical course and their inadequate/untimely recognition leads to inappropriate therapy. METHODS AND RESULTS: Biopsy samples from the lower and upper GI tract of 93 clinically diagnosed VEO-IBD children were retrospectively selected in a multicentre cohort and histologically re-evaluated by 10 pathologists blinded to clinical information. Each case was classified according to morphological patterns, including UC-like; CD-like; enterocolitis-like; apoptotic; eosinophil-rich; and IBD-unclassified (IBD-U). Nine (69%) MD children showed IBD-like morphology; only the IBD-U pattern correlated with MD diagnosis (P = 0.02) (available in 64 cases: 51 non-MD, true early-onset IBD/other; 13 MD cases). MD patients showed earlier GI symptom onset (18.7 versus 26.9 months) and were sent to endoscopy earlier (22 versus 37 months), these differences were statistically significant (P < 0.05). Upper GI histology was informative in 37 biopsies. CONCLUSIONS: The diagnosis of the underlying cause of VEO-IBD requires a multidisciplinary setting, and pathology, while being one of the fundamental puzzle pieces, is often difficult to interpret. A pattern-based histological approach is therefore suggested, thus aiding the pathologist in VEO-IBD reporting and multidisciplinary discussion.

IDH1-mutated Crohn's disease-associated small bowel adenocarcinomas: Distinctive pathological features and association with MGMT methylation and serrated-type dysplasia.

AIMS: Patients with Crohn's disease (CrD) have an elevated risk for the development of small bowel adenocarcinomas (SBAs). Actionable isocitrate dehydrogenase 1 (IDH1) mutations have been reported to be more frequent in CrD-SBAs than in sporadic SBAs. The present study aimed to investigate the clinicopathological and immunophenotypical features, as well as methylation profiles, of IDH1-mutated CrD-SBAs. METHODS AND RESULTS: An international multicentre series of surgically resected CrD-SBAs was tested for IDH1 mutation. Clinicopathological features, immunophenotypical marker expression and O6-methylguanine-DNA methyltransferase (MGMT) and long interspersed nuclear element-1 (LINE-1) methylation were compared between IDH1-mutated and IDH1 wild-type CrD-SBAs. Ten (20%) of the 49 CrD-SBAs examined harboured an IDH1 mutation and all the mutated cancers harboured the R132C variant. Compared to IDH1 wild-type cases, IDH1-mutated CrD-SBAs showed significantly lower rates of cytokeratin 7 expression (P = 0.005) and higher rates of p53 overexpression (P = 0.012) and MGMT methylation (P = 0.012). All three dysplastic growths associated with IDH1-mutated SBAs harboured the same IDH1 variant (R132C) of the corresponding invasive cancer, and all were of non-conventional subtype (two serrated dysplastic lesions and one goblet cell-deficient dysplasia). In particular, non-conventional serrated dysplasia was significantly associated with IDH1-mutated CrD-SBAs (P = 0.029). No significant cancer-specific survival difference between IDH1-mutated CrD-SBA patients and IDH1 wild-type CrD-SBA patients was found (hazard ratio = 0.55, 95% confidence interval = 0.16-1.89; P = 0.313). CONCLUSIONS: IDH1-mutated CrD-SBAs, which represent approximately one-fifth of total cases, are characterised by distinctive immunophenotypical features and methylation profiles, with potential therapeutic implications. Moreover, IDH1-mutated non-conventional, serrated dysplasia is likely to represent a precursor lesion to such CrD-SBAs.

Long-Term Natural History of Autoimmune Gastritis: Results From a Prospective Monocentric Series.

INTRODUCTION: The natural history of autoimmune gastritis (AIG) has been poorly described. In this study, we report the long-term natural history and clinical clustering of the full spectrum of AIG, from the potential to the complicated stage. METHODS: Prospective single-center study conducted in a tertiary referral center. Patients with AIG at any stage (0 = potential; 1 = early; 2 = florid; 3 = severe; and 4 = complicated) were enrolled (January 2000-December 2022). The histopathological evolution, the clinical presentation, and the correlates of evolution of potential AIG were assessed. RESULTS: Four hundred ninety-eight patients with AIG (mean age 56.7 ± 15.2 years, F:M ratio 2.5:1) were included, of whom 93 experienced potential AIG. The maximum disease duration was 27 years (median 18, interquartile range 14-23), while the overall median follow-up was 52 months (interquartile range 12-95). Age was significantly lower in stage 0 compared with that in the other stages. Accidental histologic evidence and hematologic findings were the most common clusters of diagnosis. The overall median rate of progression was 7.29 per 100 persons/yr (95% confidence interval [CI] 6.19-8.59), while the stage-specific rates of progression were 10.85 (stage 0; 95% CI 7.75-15.18), 14.83 (stages 1-2; 95% CI 11.89-18.49), and 2.68 (stage 3; 95% CI 1.88-3.84). Newly onset neoplastic complications at follow-up occurred in 41/483 patients (8.5%; 23 neuroendocrine tumors and 18 epithelial dysplasia). No cases of adenocarcinoma were noticed. Male sex was associated with a greater likelihood of evolving from potential AIG to overt AIG. DISCUSSION: AIG is a progressive disorder, with a virtually absent risk of gastric adenocarcinoma. Patients with potential AIG should be monitored because they carry a high risk of evolving into overt AIG.

Prevalence and type of MMR expression heterogeneity in colorectal adenocarcinoma: therapeutic implications and reporting.

Mismatch repair (MMR) immunohistochemical (IHC) evaluation has entered pathology routine practice as the first-line screening method to identify patients with MMR deficient (MMRd)/microsatellite instability (MSI) colorectal cancer (CRC), and its misdiagnosis may significantly impact the personalization of CRC patient care. To determine the prevalence of MMR protein intratumor heterogeneity in real-world practice, we collected a series of 8282 CRCs tested for MMR proteins in the setting of Lynch syndrome universal screening. Four heterogenous cases were also investigated for tumor infiltrating lymphocytes count, MSI status, and consensus molecular subtypes by Nanostring nCounter® Platform. Overall, 1056 (12.8%) CRCs showed a MMR altered status, with 46 cases showing a heterogeneous MMR profile (0.56% of the total, and 4.36% of all MMRd cases). To conclude, the authors make some critical remarks regarding the approach to MMR heterogeneity in clinical practice and routine diagnostics.

Gastritis Cystica Profunda: A Rare Disease, a Challenging Diagnosis, and an Uncertain Malignant Potential: A Case Report and Review of the Literature.

Gastritis cystica profunda (GCP) has been defined as a rare submucosal benign gastric lesion with cystic gland growth. Due to its unclear etiopathogenesis, this lesion is often misdiagnosed and mistaken for other gastric masses. Currently, a standardized treatment for GCP lesions is still missing. Here, we illustrate a case of a patient admitted to our general surgery department for melena and general discomfort. No history of peptic ulcer or gastric surgery was present. Upper GI endoscopy was performed, showing a distal gastric lesion with a small ulceration on the top. CT-scan and endoscopic ultrasound confirmed the presence of the lesion, compatible with a gastric stromal tumor, without showing any eventual metastasis. Surgical gastric resection was performed. Histological findings were diagnostic for GCP, with cistically ectasic submucosal glands, chronic inflammation, eosinophilic infiltration and foveal hyperplasia. GCP is a very exceptional cause of upper-GI bleeding with specific histological features. Its diagnosis as well as its therapy are challenging, resulting in several pitfalls. Even though it is a rare entity, GCP should always be considered in the differential diagnosis of gastric submucosal lesions.