Hepatic adenoma: evolution of a more individualized treatment approach.

BACKGROUND: Hepatic adenomas (HAs) are benign, solid liver lesions, which carry a risk of hemorrhage and malignant transformation. This review article highlights the advances in the diagnosis and management of HAs. METHODS: A comprehensive review was performed using MEDLINE/PubMed and Web of Science databases with a search period ending on September 30, 2023. Using PubMed, the terms "hepatocellular," "hepatic," and "adenoma" were searched. RESULTS: HA has been classified into at least 8 subtypes based on molecular pathology, each exhibiting unique histopathologic features, clinical considerations, and risk of malignant transformation. The most common subtype is inflammatory HA, followed by hepatocyte nuclear factor 1α-inactivated HA, ß-catenin exon 3-mutated HA (ßex3-HA), ß-catenin exon 7- or 8-mutated HA, sonic hedgehog HA, and unclassified HA. Magnetic resonance imaging is the best imaging method for diagnosis and can distinguish among HA subtypes based on fat and telangiectasia pathologic characteristics. The risk of malignant transformation varies among molecular subtypes, ranging from <1% to approximately 50%. Up to 42% of HAs present with spontaneous intratumoral hemorrhage and peritoneal hemorrhage. In general, only 15% to 20% of patients require surgery. HA larger than 5 cm are more likely to be complicated by bleeding and malignant transformation, regardless of subtype, and should generally be resected. In particular, ßex3-HA carries a high risk of malignant transformation and can be considered a true precancerous lesion. CONCLUSION: The management of HAs is based on a multidisciplinary approach. Clinical decision-making should integrate information on gender, tumor size, and HA subtyping. In the future, patients with HA will benefit from novel medical therapies tailored to the individual molecular subtypes.

Strong Annexin A10 Expression Supports a Pancreatic Primary and Combined Annexin A10, Claudin 18, and SOX2 Expression Supports an Esophagogastric Origin in Carcinomas of Unknown Primary.

Primary tumor site determination for gastrointestinal (GI) tract and pancreaticobiliary (PB) tree carcinomas that present as metastasis of unknown primary can be problematic. Annexin A10 (ANXA10), claudin 18 (CLDN18), and trefoil factor 1 (TFF1) have been identified through expression profiling as markers of gastric lineage commitment; sex-determining region Y (SRY)-box transcription factor 2 (SOX2) expression has been reported in several tumor types, including gastric adenocarcinomas. We evaluated the diagnostic utility of immunohistochemistry for ANXA10, CLDN18, SOX2, and TFF1 for determining the site of origin for GI/PB adenocarcinomas. Immunohistochemistry for all 4 markers was performed on tissue microarrays including 559 GI/PB tumors and 421 other tumors. H-scores were calculated as the product of the intensity (0 to 3) and extent (percentage, 0% to 100%) of staining. Positive staining was defined as >5% staining. ANXA10 expression was most frequent in pancreatic adenocarcinomas when compared with all other GI/PB tumors (96.4% vs. 43.5%, P <0.001). Strong staining for ANXA10 (H-score ≥200) distinguished pancreatic ductal adenocarcinoma from intrahepatic cholangiocarcinoma and adenocarcinomas of the gallbladder and colorectum (69.6% vs. 0%, P <0.001). Triple positivity for ANXA10, CLDN18, and SOX2 was more frequent in esophagogastric tumors than in other GI/PB tumors (22.6% vs. 4.1%; P <0.001). TFF1 expression was observed in nearly all tumor types. Staining for ANXA10, CLDN18, and SOX2 as part of a panel may aid in distinguishing esophagogastric adenocarcinomas from lower GI/PB tumors. ANXA10 staining may be particularly useful in distinguishing pancreatic adenocarcinomas from intrahepatic cholangiocarcinoma and adenocarcinomas of the gallbladder and colorectum.

Co-occurrence of VHL and SDHA Pathogenic Variants: A Case Report.

Von Hippel Lindau(VHL)syndrome presents with cerebellar and spinal hemangioblastomas, renal cell cancer, neuroendocrine pancreatic tumor, and pheochromocytoma and it is caused by germline mutations in the VHL gene. Pathogenic germline variants in the succinate dehydrogenase A (SDHA) gene are associated with paraganglioma and pheochromocytoma. Here we report co-occurrence of germline pathogenic variants in both VHL and SDHA genes in a patient who presented with pancreatic neuroendocrine tumor. As these genes converge on the pseudo-hypoxia signaling pathway, further studies are warranted to determine the significance of co-occurrence of these variants in relation to tumor penetrance, disease severity, treatment response and clinical outcomes in this selected group of patients.

Ki-67 Proliferation Index Assessment in Gastroenteropancreatic Neuroendocrine Tumors by Digital Image Analysis With Stringent Case and Hotspot Level Concordance Requirements.

OBJECTIVES: The Ki-67 proliferation index is integral to gastroenteropancreatic neuroendocrine tumor (GEP-NET) assessment. Automated Ki-67 measurement would aid clinical workflows, but adoption has lagged owing to concerns of nonequivalency. We sought to address this concern by comparing 2 digital image analysis (DIA) platforms to manual counting with same-case/different-hotspot and same-hotspot/different-methodology concordance assessment. METHODS: We assembled a cohort of GEP-NETs (n = 20) from 16 patients. Two sets of Ki-67 hotspots were manually counted by three observers and by two DIA platforms, QuantCenter and HALO. Concordance between methods and observers was assessed using intraclass correlation coefficient (ICC) measures. For each comparison pair, the number of cases within ±0.2xKi-67 of its comparator was assessed. RESULTS: DIA Ki-67 showed excellent correlation with manual counting, and ICC was excellent in both within-hotspot and case-level assessments. In expert-vs-DIA, DIA-vs-DIA, or expert-vs-expert comparisons, the best-performing was DIA Ki-67 by QuantCenter, which showed 65% cases within ±0.2xKi-67 of manual counting. CONCLUSIONS: Ki-67 measurement by DIA is highly correlated with expert-assessed values. However, close concordance by strict criteria (>80% within ±0.2xKi-67) is not seen with DIA-vs-expert or expert-vs-expert comparisons. The results show analytic noninferiority and support widespread adoption of carefully optimized and validated DIA Ki-67.