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Recently discovered DNAJB1-PRKACA oncogenic fusions have been considered diagnostic for fibrolamellar hepatocellular carcinoma. In this study, we describe six pancreatobiliary neoplasms with PRKACA fusions, five of which harbor the DNAJB1-PRKACA fusion. All neoplasms were subjected to a hybridization capture-based next-generation sequencing assay (MSK-IMPACT), which enables the identification of sequence mutations, copy number alterations, and selected structural rearrangements involving ≥410 genes ( n  = 6) and/or to a custom targeted, RNA-based panel (MSK-Fusion) that utilizes Archer Anchored Multiplex PCR technology and next-generation sequencing to detect gene fusions in 62 genes ( n  = 2). Selected neoplasms also underwent FISH analysis, albumin mRNA in-situ hybridization, and arginase-1 immunohistochemical labeling ( n  = 3). Five neoplasms were pancreatic, and one arose in the intrahepatic bile ducts. All revealed at least focal oncocytic morphology: three cases were diagnosed as intraductal oncocytic papillary neoplasms, and three as intraductal papillary mucinous neoplasms with mixed oncocytic and pancreatobiliary or gastric features. Four cases had an invasive carcinoma component composed of oncocytic cells. Five cases revealed DNAJB1-PRKACA fusions and one revealed an ATP1B1-PRKACA fusion. None of the cases tested were positive for albumin or arginase-1. Our data prove that DNAJB1-PRKACA fusion is neither exclusive nor diagnostic for fibrolamellar hepatocellular carcinoma, and caution should be exercised in diagnosing liver tumors with DNAJB1-PRKACA fusions as fibrolamellar hepatocellular carcinoma, particularly if a pancreatic lesion is present. Moreover, considering DNAJB1-PRKACA fusions lead to upregulated protein kinase activity and that this upregulated protein kinase activity has a significant role in tumorigenesis of fibrolamellar hepatocellular carcinoma, protein kinase inhibition could have therapeutic potential in the treatment of these pancreatobiliary neoplasms as well, once a suitable drug is developed.

AimsA synthetic lifting agent, ORISE, used for endoscopic mucosal resections, has been recalled from the market since November 2022 due to clinical complications. Despite this, the impact of ORISE-associated complications is expected to persist in the foreseeable future. We present a large single institutional series of therapeutic resections from patients for whom ORISE was used for initial endoscopic procedures, highlighting the pitfalls and complications associated with its use.MethodsAll specimens showing lifting agent granulomata (LAGs) associated with the use of ORISE were identified. The H&E slides were reviewed to define the morphological characteristics and extent of LAG in the intestinal wall and other organs. The clinical impression and gross findings were compared with the final pathological diagnosis.Results34 cases (28 resections and 6 repeat endoscopic mucosal resection specimens) showed LAG. On microscopy, 20.5% showed no residual disease, 64.7% also showed residual precursor lesion and 14.7% also showed malignancy. In 64.2% of cases, a mass lesion was seen grossly but no malignancy was identified microscopically. ORISE was present in vascular spaces (n=9), lymph nodes (n=2), other organs such as appendix (n=1) and omentum/peritoneum (n=1). The major discordance between clinical impression (mass/neoplasm) and final pathology (no residual malignancy) was seen in 4/34 (11.8%) cases. LAGs were seen up to 10 months after the use of ORISE in the prior endoscopic procedure.ConclusionORISE deposits may mimic residual/disseminated neoplasm and prompt inadvertent changes in surgical decisions. Awareness of this pitfall is essential to prevent unwarranted surgical resections in patients undergoing follow-up for endoscopically resected lesions.

The morphologic spectrum of hepatocellular carcinoma (HCC) is quite broad. While in about one-third of cases, the neoplasms can be categorized into meaningful subtypes based on morphology, a vast majority of these neoplasms are morphologically heterogeneous. With extensive tumor profiling, data has begun to emerge which can correlate specific morphologic features with underlying molecular signatures. A true morphologic subtype not only has reproducible H & E features, further supported by specific immunohistochemical or molecular signatures, but also has specific clinical implications and prognostic associations. Eight such morphologic subtypes are recognized by the 2019 WHO classification of tumors with a few more additional subtypes described in the literature. The goal of this review is to familiarize the reader with the morphologic subtypes and elaborate on the clinical and molecular associations of these neoplasms.

The differential diagnosis of hepatic mass lesions is broad and arriving at the right diagnosis can be challenging, especially on needle biopsies. The differential diagnosis of liver tumors in children is different from adults and is beyond the scope of this review. In adults, the approach varies depending on the age, gender, and presence of background liver disease. The lesions can be divided broadly into primary and metastatic (secondary), and the primary lesions can be further divided into those of hepatocellular origin and nonhepatocellular origin. The first category consists of benign and malignant lesions arising from hepatocytes, while the second category includes biliary, mesenchymal, hematopoietic, and vascular tumors. Discussion of nonepithelial neoplasms is beyond the scope of this review. The hepatocytic lesions comprise dysplastic nodules, focal nodular hyperplasia, hepatic adenoma, and hepatocellular carcinoma, and the differential diagnosis can be challenging requiring clinicopathological correlation and application of immunohistochemical (IHC) markers. Liver is a common site for metastasis, sometimes presenting with an unknown primary site, and proper workup is the key to arriving at the correct diagnosis. The correct diagnosis in this setting requires a systematic approach with attention to histologic features, imaging findings, clinical presentation, and judicious use of IHC markers. The list of antibodies that can be used for this purpose keeps on growing continually. It is important for pathologists to be up to date with the sensitivity and specificity of these markers and their diagnostic role and clinical implications. The purpose of this review is to outline the differential diagnosis of hepatic masses in adults and discuss an algorithmic approach to make a right diagnosis.

Risk stratification of gastrointestinal stromal tumors (GISTs) is based on experience with tumors of the stomach, small bowel, and rectum, which are far more common than GISTs of other sites. In this study from 47 institutions, we analyzed GISTs of the esophagus ( n  = 102), colon ( n  = 136), and appendix ( n  = 27) for their size, mitotic rate, morphology, and outcome to determine which criteria predict their behavior. Esophageal GISTs were small (median: 2.5 cm) with spindle cell morphology and a low mitotic rate (mean: 3.6/5 mm 2 ). Twelve (12%) tumors progressed, including 11 with a mitotic rate >5/5 mm 2 and one large (6.8 cm) GIST with a mitotic rate of 2/5 mm 2 . Colonic GISTs were smaller (median: 1.4 cm) and presented with abdominal pain or bleeding in 29% of cases. Most (92%) were composed of spindle cells with a mean mitotic rate of 4.6/5 mm 2 . Sixteen (12%) tumors progressed: 14 had mitotic rates >5/5 mm 2 , and two were >5.0 cm with a mitotic rate <5/5 mm 2 . All but one appendiceal GIST measured <2.0 cm. These tumors were composed of spindle cells with low mitotic rates (<5/5 mm 2 ), and none progressed. Our results suggest that progression risk among esophageal and colonic GISTs is associated with increased mitotic activity (>5/5 mm 2 ) and size >5.0 cm. These findings support the use of size and mitotic rate for prognostication of GISTs in these locations, similar to tumors of the stomach, small bowel, and rectum.

Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare but distinct disease that remains poorly understood, especially at proteome level. We report comprehensive mass spectrometry-based proteomic analyses of SPN ( n  = 13) and characterize differences from other pancreatic neoplasms, pancreatic ductal adenocarcinoma ( n  = 11) and neuroendocrine tumor ( n  = 10). We discovered that the SPN proteome is uniquely distinct from that of other pancreatic neoplasms. Lysosome-related proteins are enriched and upstream lysosomal processes transcriptional regulators, MITF and TFE3, are overexpressed in SPN. MITF protein expression is more specific for SPN than TFE3, previously considered the most specific immunohistochemical marker. Since lysosomal-related processes are connected to biological energy generation processes, we profiled metabolic pathways and found that SPN is characterized by higher fatty acid oxidation and lower glycolysis than PDAC and high proteasome pathway activity with many proteasomal proteins upregulated, suggesting a possible link to metabolic adaptation mechanisms in low-nutrient environments. Proteomics characterizes SPN as an immune-cold tumor with low MHC class I expression. Proteome-based receptor tyrosine kinase (RTK) pathway profiling suggests PDGFRA and ERBB2 (HER2) as potential candidates for targeted therapy. Our results provide unique proteomic contribution to the understanding of SPN biology and highlight differences from other pancreatic tumors. Graphical abstract

Gastric polyps are frequently encountered on endoscopic examinations. While many of these represent true epithelial lesions, some of the polyps may result from underlying stromal or lymphoid proliferations or even heterotopic tissue. Histologic examination is essential for accurate typing of the polyps to predict malignant potential and underlying possible genetic abnormalities. The focus of this review is on gastric hamartomatous polyps, which are relatively rare and diagnostically challenging. Though most of the gastric hamartomatous polyps are benign, certain types are associated with increased malignant potential. These include certain polyps associated with specific genetic familial polyposis syndromes and gastric inverted hamartomatous polyps. Identification of these polyps can result in the prevention or early diagnosis of gastric carcinoma and also help in the identification of family members with polyposis syndromes. The aim of this review is to categorize gastric hamartomatous polyps and aid in the identification of high-risk categories.

Background: Sciatic nerve is a mixed nerve which provide sensory and motor supply for skin and muscles of the lower limb by tibial and common peroneal nerve. Anatomical variations of sciatic nerve at high division have been reported by various authors. The path of the sciatic nerve is important while administration of intramuscular injection to prevent nerve injury and nerve blockage failure during anesthesia. This knowledge of high division helps in different surgical approach for sciatic nerve injury or hip dislocation. Aims and Objectives: The aim of the study was to describe incidences of high division variation of Sciatic nerve and different types in cadavers during routine dissection schedule. Materials and Methods: The study was conducted during routine dissection schedule in anatomy department for first MBBS students to observe sciatic nerve course in 30 gluteal regions from 15 adult cadavers fixed by formalin. Location of sciatic nerve in relation to piriformis muscle and its division whether in single nerve sheath or separate sheath and types was recorded. Results: In 12 cadavers (80%), sciatic nerve course found normal which leaves pelvis at inferior border of piriformis muscle and bifurcate in terminal branches tibial nerve and common peroneal nerve as it approaches at the apex of popliteal fossa. In 3 cadavers (20%), two male and one female, we found high division of sciatic nerve where terminal branches, tibial nerve, and common peroneal nerve leave the pelvis below piriformis separately in different sheaths. Conclusion: Knowledge of variations-related high division of sciatic nerve would help surgeons during different interventions related to sciatic nerve and for preventing further complications.

Double somatic mismatch-repair-gene mutation/alteration is a recently recognized molecular mechanism that underlies microsatellite instability-high in some colorectal carcinomas. It remains to be determined whether and how microsatellite instability-high tumors with this molecular defect differ from their counterparts caused by other mechanisms, specifically, Lynch syndrome-associated and MLH1 -promoter hypermethylated. In this study, we evaluated the clinical and pathological characteristics of a series of 15 double somatic mutation/alteration-associated microsatellite instability-high colorectal carcinomas identified from our genetics service and 68 such cases reported in the literature. We observed that these cases presented at an age similar to MLH1 -promoter hypermethylated ( n  = 20) and microsatellite-stable ( n  = 39) cases but older than Lynch syndrome-associated cases ( n  = 20, p  < 0.05). While these tumors simulated other microsatellite instability-high tumors in their prevalent right-sided location, they appeared to differ in TNM stages at presentation (73% stage III/IV versus 25% stage III/IV in other microsatellite instability-high tumors, p  = 0.04). Histologically, 40% of them had a dominant solid growth pattern. Inter-tumoral heterogeneity was a striking feature, spanning the spectrum from medullary type (with a tumor-infiltrating-lymphocyte/high-power-field count as high as 59) to conventional-type with only few tumor-infiltrating-lymphocytes (1/high-power-filed). As a group, these tumors seemed less likely to show robustly high lymphocytic infiltration than other microsatellite instability-high tumors (only 20% had ≥10 tumor-infiltrating-lymphocytes/high-power-filed, whereas this rate in Lynch syndrome-associated and MLH1 -promoter hypermethylated tumors was 60% and 75%, respectively). Three double somatic mutation/alteration-associated tumors were treated with a PD1/PD-L1 checkpoint inhibitor. While all three had an elevated tumor-mutation-burden (>47 mut/megabase), only one had tumor-infiltrating-lymphocytes >10/high-power-field, yet all three exhibited measurable response. In summary, microsatellite instability-high colorectal carcinomas caused by double somatic mismatch-repair-gene mutation/alteration may have varied clinical and pathological characteristics, and some may have relatively low tumor-infiltrating-lymphocytes; response to immune checkpoint inhibitors can be achieved in this group even when the lymphocytic infiltration is not abundant.