Editors: Rouzan Karabakhtsian, MD, PhD, professor of pathology and director of the Women’s Health Pathology Fellowship, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY; S. Emily Bachert, MD, associate pathologist, Brigham and Women’s Hospital, Boston; Amarpreet Bhalla, MD, assistant professor of pathology, Albert Einstein College of Medicine, Montefiore Medical Center; Divya Sharma, MD, associate professor, Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center; and Paula Toro, MD, gastrointestinal and hepatobiliary fellow, Cleveland Clinic.
Pulmonary solid and granular adenocarcinomas expressing HepPar1
July 2026—Hepatoid lung carcinomas, similar to hepatoid carcinomas of other sites, are defined as extrahepatic tumors exhibiting divergent hepatocellular differentiation. Uniquely, hepatoid carcinomas of the lung are reported to commonly express only HepPar1, which recognizes the mitochondrial enzyme carbamoyl-phosphate synthetase-1 (CPS1). HepPar1/CPS1 was recently found to accumulate in lung adenocarcinomas (LUAD) harboring STK11 mutations, presumably as a genotype-associated metabolic adaptation. The authors conducted a study in which they performed a detailed clinicopathologic and genomic analysis of carcinomas prospectively regarded as hepatoid with isolated HepPar1 expression (n = 17). They found that while robustly positive for HepPar1, these tumors were negative for an extended panel of other hepatocellular markers (AFP, Arginase-1, Glypican-3, and Albumin ISH). Morphologically, the tumors exhibited solid-trabecular architecture with expanded granular-vacuolated-clear cytoplasm, evoking hepatoid morphology. However, focal-to-moderate intracytoplasmic mucin was consistently present and hepatoid resemblance was variable. Pneumocytic markers (TTF1 and Napsin A) were negative, except for cytoplasmic TTF1, and commonly led to diagnostic challenges at metastatic sites. Remarkably, all solid and granular adenocarcinomas tested by next-generation sequencing or STK11 IHC exhibited STK11 mutations or complete loss of expression, or both, compared with a 17 percent STK11 mutation rate in a control group of more than 2,500 unselected LUAD (P<.00001). Patient survival rates were dismal (median, 5.8 months versus 25 months for stage-matched LUAD, P = .0002). Tumors harbored high mitochondrial content by electron microscopy and other methods. When compared to conventional predominantly acinar LUAD with HepPar1 expression (n = 22), the authors found that the tumors also lacked any other hepatocellular markers and had invariable STK11 mutations/loss, increased granular cytoplasm, lower TTF1, and poor prognosis. They concluded that isolated HepPar1 expression in LUAD reflects mitochondrial adaptation to STK11 mutations rather than bona fide hepatocellular differentiation and that HepPar1-expressing solid and granular adenocarcinomas represent an undifferentiated (solid, TTF1-negative) variant in this spectrum of tumors. They proposed that recognizing these tumors is warranted because of their exceptionally aggressive behavior, distinct pathogenomic features, and common association with diagnostic challenges.
Febres-Aldana CA, Vanderbilt CM, Aly R, et al. Pulmonary solid and granular adenocarcinomas expressing HepPar1: highly aggressive tumors exhibiting mitochondrial adaptation to STK11 mutations rather than hepatoid differentiation. Mod Pathol. 2026. doi.org/10.1016/j.modpat.2026.100965
Correspondence: Dr. Natasha Rekhtman at rekhtman@mskcc.org
Gastric neuroendocrine tumors associated with acid-suppressant drugs
Gastric well-differentiated neuroendocrine tumors arising in association with prolonged acid-suppressant drug use, including use of proton pump inhibitors and histamine-2 receptor antagonists (H2RAs), are an emerging gastric well-differentiated neuroendocrine tumor (gNET) subtype presumably arising from drug-related chronic hypergastrinemia. The authors examined the clinicopathologic features of these gNETs in an institutional cohort of 23 patients with 39 instances of the tumor. GNETs were considered acid-suppressant associated in patients with documented proton pump inhibitor or H2RA use, or both, for more than one year or two or more features of drug effect (parietal or enterochromaffin-like cell hyperplasia, or both, or elevated serum gastrin) in those with limited clinical information. Histologic features were assessed, as conventional morphology consisted of tumors with organoid architecture (for example, nested or trabecular) and monomorphic, predominantly epithelioid tumor cells. Unconventional morphologies included secretory cribriform variant (a cribriform or loose reticular network of tumor cells in myxoid matrix), lympho-plasmacytoid variant (small, bland tumor cells resembling inflammatory cells growing in loosely cohesive or solid sheets), and pseudopapillary variant (tumor cells wrapped around fibrocollagenous stromal cores). Tumors were considered pure if there was 80 percent or more of one morphologic pattern and mixed if there was more than 20 percent of a secondary morphologic pattern. Tumor growth was categorized as nodular (round aggregates of tumor expanding radially and destroying adjacent mucosa) and lateral (irregular networks of tumor cells spreading parallel to the mucosal surface and infiltrating between normal structures in adjacent mucosa). Patients were a median age of 65 years (range, 37–84 years) and predominantly female (female-to-male ratio, 1.6:1). Hypergastrinemia was present in 69 percent (11 of 16) of tested patients (median serum gastrin level, 232 pg/mL; range, 130–407 pg/mL). Fifty percent (eight of 16) of patients with documented acid-suppressant drug use had used such drugs for 10 or more years. Most gNETs were 1 cm or less and restricted to the mucosa. Regional lymph node metastasis was rare (two of 21; nine percent). Secretory cribriform morphology was observed in 15 percent of tumors, and mixed pseudopapillary and conventional/nested morphology was found in three percent. Thirty percent of patients had multiple tumors diagnosed over 0.75 to nine years, though none developed distant disease (median follow-up, three years; range, 0–15 years), including two patients with lymph node metastasis (10- and 13-year follow-up). The background oxyntic mucosa commonly showed parietal cell hyperplasia or enterochromaffin-like cell hyperplasia, or both, and, importantly, lacked the atrophy and metaplasia characteristic of autoimmune metasplastic atrophic gastritis. The authors concluded that acid-suppressant–associated gNETs are typically small, arise in the gastric body or fundus, are confined to mucosa and predominantly low to intermediate grade (G1/G2), have an indolent course, are often multiple, and are frequently associated with very prolonged use (10 years or more) of proton pump inhibitors or H2RAs, or both, suggesting that very long-term hypergastrinemia may be required for these tumors to develop. Prospective, multicenter studies with detailed clinical and medication histories and consistent measurement of gastrin levels would provide more definitive insights and help standardize diagnostic criteria for acid-suppressant–associated gNETs.
Azimpouran M, Waters KM, Hendifar AE, et al. Gastric neuroendocrine tumors associated with acid suppressant drugs are frequently associated with very prolonged drug use and may show unconventional morphologies. Hum Pathol. 2025. doi.org/10.1016/j.humpath.2025.106013
Correspondence: Dr. Danielle A. Hutchings at danielle.hutchings@cshs.org
Ossifying spindled and epithelioid tumor: a novel soft tissue tumor
The authors conducted a study in which they described the clinicoradiologic, pathologic, and molecular features of a unique soft tissue tumor characterized by a peripheral shell of bone and composed of bland myoid spindle and epithelioid cells that were keratin positive. The study cohort consisted of six men and six women who were a mean age of 32 years. The tumors arose in the extremities (n = 9) and proximal limb girdle (n = 3) and were equally distributed between deep and superficial soft tissue. Patients reported dull painless masses of several months’ to more than 10 years’ duration (mean, 2.9 years). Imaging demonstrated a complete or partial peripheral shell of bone that could extend centrally, and the tumors were a mean size of 5.7 cm. The tumors were composed of uniform, eosinophilic myoid spindle cells growing in sheets and intersecting fascicles and surrounded by mature lamellar or woven bone, or both of the latter. An admixed component of intermediate-sized epithelioid cells with eosinophilic cytoplasm was also present. Mitotic activity was consistently low. Immunohistochemistry showed strong multifocal staining for keratins, and 50 percent (five of 10) of cases showed focal S100 staining of tumor cells. However, all were negative for SMA, desmin, SOX10, ERG, and CD34. Genetic analysis by multiple targeted RNA sequencing panels was negative (n = 10), but whole transcriptome sequencing (n = 8) revealed a recurrent and novel in-frame SRSF7::NFATC3 fusion in four tumors. Dual fluorescence in situ hybridization probes for SRSF7::NFATC3 confirmed this fusion and identified a fifth case, which had not undergone whole transcriptome sequencing but was negative by a targeted RNA fusion panel. Methylation profiling (n = 8) demonstrated a shared epigenetic profile that was distinct from other entities. Clinical follow-up (n = 11) showed no evidence of recurrence after primary excision (mean, 41.6 months). In summary, the authors described a novel soft tissue tumor designated ossifying spindled and epithelioid tumor, a descriptive histologic term that also emphasizes the tumor’s close radiologic mimic, ossifying fibromyxoid tumor. All cases behaved in a benign fashion without recurrence following simple excision. It is important to be aware of this entity so it can be distinguished from neoplasms that have more aggressive biological potential.
Gross JM, Zou YS, Michal M, et al. Ossifying spindled and epithelioid tumor: a novel soft tissue tumor. Mod Pathol. 2025. doi.org/10.1016/j.modpat.2025.100840
Correspondence: Dr. John M. Gross at jgross28@jhmi.edu
Diagnostic potential of a novel IHC marker to differentiate mesothelioma from its morphological mimics
Diagnosis of mesothelioma remains challenging due to the tumor’s nonspecific clinical, radiological, and histopathological features, compounded by its morphological diversity and overlapping IHC profiles with other tumors. Building on their previous finding that glutamine-fructose-6-phosphate transaminase 2 (GFPT2) is highly expressed in mesothelioma tissue (cytoplasmic or membranous, or both), the authors evaluated its diagnostic utility in distinguishing mesotheliomas from histological mimics. They conducted an IHC analysis of GFPT2 in 101 mesotheliomas and 266 histological mimics, including 100 nonsmall cell lung cancers, 40 high-grade serous ovarian cancers, six epithelioid hemangioendotheliomas, 33 solitary fibrous tumors, 23 aggressive fibromatoses, six synovial sarcomas, seven dedifferentiated liposarcomas, six leiomyosarcomas, four malignant peripheral nerve sheath tumors, eight sarcomatoid carcinomas, 20 reactive mesothelial hyperplasias, and 13 well-differentiated papillary mesothelial tumors. GFPT2 positivity was detected in 85.15 percent (86 of 101) of mesothelioma cases, a rate comparable to that of calretinin (93.07 percent; 94 of 101) and higher than that of WT1, D2-40, and CK5/6. GFPT2 exhibited consistently high sensitivity among all subtypes: 85.14 percent in epithelioid, 81.82 percent in sarcomatoid, and 87.50 percent in biphasic mesothelioma, with positivity in epithelial and sarcomatoid components. In contrast, HEG1 showed high sensitivity (94 percent) in epithelioid mesothelioma but decreased markedly (44 percent) in sarcomatoid cases, underscoring the more uniform performance of GFPT2. Furthermore, GFPT2 was detected in 80.49 percent (33 of 41) of biopsy specimens, emphasizing its reliability in small samples. The positivity of GFPT2 in mesothelioma (85.15 percent; 86 of 101) was significantly higher than in reactive mesothelial hyperplasia (zero of 20), well-differentiated papillary mesothelioma tumor (zero of 13), nonsmall cell lung cancer (zero of 100), high-grade serous ovarian cancer (zero of 40), epithelioid hemangioendothelioma (16.7 percent; one of six), solitary fibrous tumor (zero of 33), aggressive fibromatosis (21.74 percent; five of 23), synovial sarcoma (zero of six), leiomyosarcoma (zero of six), malignant peripheral nerve sheath tumor (25 percent; one of four), and sarcomatoid carcinoma (12.5 percent; one of eight). However, dedifferentiated liposarcoma showed high GFPT2 positivity (85.7 percent; six of seven). The authors concluded that this study demonstrated the diagnostic utility of GFPT2 in mesothelioma and its ability to mitigate challenges associated with tumor heterogeneity. While it is a promising novel antibody, further validation through larger multi-institutional studies is needed to confirm its clinical utility.
Wei J, Ma X, Chen G, et al. Diagnostic potential of a novel immunohistochemical marker, GFPT2, in differentiating mesothelioma from its morphological mimics. Histopathology. 2025. doi.org/10.1111/his.70062
Correspondence: Dr. Qixing Gong at gongqixing@hotmail.com
Usefulness of the OLGIMA system for gastric cancer risk assessment
The risk stratification of gastric cancer is primarily based on assessing well-established precursor lesions, glandular atrophy, and intestinal metaplasia and has resulted in the Operative Link on Gastritis Assessment (OLGA) and Operative Link on Gastric Intestinal Metaplasia (OLGIM) classification systems. While pathologists can reproduce OLGIM stage, use of the OLGA system on a daily basis is laborious, and the system has poor reproducibility. In addition, the system does not comprehensively address the severity of glandular atrophy and intestinal metaplasia as recommended by Updated Sydney System consensus. The authors proposed the Operative Link on Gastric Intestinal Metaplasia and Glandular Atrophy Assessment (OLGIMA) system, which identifies OLGIM III–IV and upstages 0–II with advanced glandular atrophy. They designed a cross-sectional study of consecutive diagnostic gastroscopies in adults to demonstrate the noninferiority of the OLGIMA system compared with OLGIM for identifying patients at high risk for gastric cancer. Gastric biopsies were taken. The Updated Sydney System guidelines were used for histological grading of glandular atrophy and intestinal metaplasia. Higher risk of gastric cancer was defined as OLGIM III–IV and advanced glandular atrophy. OLGIMA stage was assessed based on the most severe glandular atrophy or intestinal metaplasia findings in the antrum and corpus. The study included 998 patients (median age, 57 years; 64 percent women; 35 percent with Helicobacter pylori infection). Thirty-nine (3.9 percent) patients had higher gastric cancer risk: 17 (1.7 percent) with OLGIM III–IV; 12 (1.2 percent) with advanced glandular atrophy; and 10 (one percent) meeting both criteria. Among OLGIM 0–II patients, 12 (1.2 percent) had advanced glandular atrophy. The OLGIMA system upstaged 39 (3.9 percent) patients to III–IV, as it is more sensitive than OLGIM. The authors concluded that the OLGIMA system identifies patients at higher risk of gastric cancer (OLGIMA III–IV), encompassing all OLGIM III–IV patients, and upstages those OLGIM 0–II patients with advanced gastric atrophy. This approach addresses the limitations of OLGA and OLGIM by integrating gastric atrophy and intestinal metaplasia severity as recommended by the Updated Sydney consensus.
Guillena PGD, Cuatrecasas M, Montori S, et al. The OLGIMA system for gastric cancer risk assessment. A useful method based on the histological Sydney consensus. Histopathology. 2026. doi.org/10.1111/his.70042
Correspondence: Dr. Miriam Cuatrecasas at mcuatrec@clinic.cat