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, pathology resident, Cleveland Clinic.
Comprehensive characterization of intraductal oncocytic papillary neoplasm of pancreas
July 2025—Intraductal oncocytic papillary neoplasm of the pancreas is a recently recognized pancreatic tumor. The authors conducted a study to generate a comprehensive and quantitative summary of various aspects of intraductal oncocytic papillary neoplasms (IOPN). They searched the PubMed, Scopus, and Embase databases for studies reporting on pancreatic IOPN. Clinicopathologic, immunohistochemical, and molecular data were extracted from the studies and summarized. A comparative analysis of the molecular alterations of IOPN in juxtaposition with the typical molecular profile of conventional pancreatic ductal adenocarcinoma and intraductal papillary mucinous neoplasm from reference cohorts was subsequently conducted. The study cohort was composed of 409 patients with 414 IOPN. The male-to-female ratio was 1.5:1. Pancreatic head was the most common site (131 of 237; 55.3 percent), but a diffuse tumor extension involving more than one pancreatic segment was described in approximately one in five (49 of 237; 20.6 percent) cases. The mean tumor size was 45.5 mm. The tumors were characterized by florid arborizing papillae, intraepithelial lumina formation, and oncocytic cells that lack evidence of intestinal differentiation (MUC2 and CDX2 negative) but appear to have pyloric lineage. An associated invasive carcinoma was present in 50 percent (168 of 336) of cases. In those cases, most tumors were pT1 or pT2 and pN0 (more than 80 percent), and vascular invasion was uncommon (20.6 percent). More than 90 percent of patients were alive after surgical resection. The most commonly expressed mucins were MUC5AC (110 of 112; 98.2 percent) and MUC6 (78 of 84; 92.8 percent). Compared with pancreatic ductal adenocarcinoma and intraductal papillary mucinous neoplasm, the classic pancreatic drivers KRAS, TP53, CDKN2A, SMAD4, and GNAS were less altered in IOPN (P<.01). Moreover, fusions involving the PRKACA or PRKACB gene were detected in all 68 cases examined, with PRKACB::ATP1B1 being the most common (27 of 68 cases; 39.7 percent). These genomic events emerged as a defining molecular alteration of IOPN (P<.01). Therefore, such fusions represent a promising biomarker for diagnostic purposes. Recent evidence also suggests that they influence the acquisition of oncocytic morphology. IOPN is a distinct pancreatic neoplasm with specific clinicopathologic and molecular features and excellent prognosis. The authors concluded that given its clinical and prognostic implications, recognizing IOPN is essential for accurate patient diagnosis and management.
Paolino G, Basturk O, Esposito I, et al. Comprehensive characterization of intraductal oncocytic papillary neoplasm of the pancreas: A systematic and critical review. Mod Pathol. 2024;37. doi.org/10.1016/modpat.2024.100554
Correspondence: Dr. Claudio Luchini at claudio.luchini@univr.it
Clinicopathologic study of large-cell basaloid adenocarcinoma of lung
A distinctive form of lung adenocarcinoma that closely mimics large-cell neuroendocrine carcinoma has been described. The authors conducted a study in which they assessed the clinicopathologic, immunohistochemical, ultrastructural, and molecular genetic features of these tumors. They identified 12 tumors from six women and six men aged 46 to 86 years (mean, 58.4 years) using the surgical pathology files at their institutions or, in one instance, personal consultation files. The tumors presented as peripheral subpleural masses measuring 2 to 12 cm (mean, 6.5 cm). They were histologically characterized by islands or anastomosing and serpiginous strands of large, atypical cells showing striking peripheral palisading of nuclei, with high mitotic activity and prominent comedo-like areas of necrosis. Because of their striking resemblance to neuroendocrine tumors, some of the studied tumors were initially diagnosed as large-cell neuroendocrine carcinoma, despite the absence of neuroendocrine markers. Immunohistochemistry showed that the tumors were positive for TTF1 and napsin-A, and it showed negative p40 staining. The tumors were also uniformly negative for multiple neuroendocrine markers, including chromogranin, synaptophysin, CD56, and INSM1. Electron microscopy performed in two cases was negative for membrane-bound dense core neurosecretory granules. Pathogenic alterations were detected in five of eight tumors tested by next-generation sequencing. Point mutations in KRAS and TP53 were identified in five patients. Low-level amplification of GNAS, KIT, and FGFR1 was present in two patients. No RB1 mutations were identified. Clinical follow-up in 10 cases showed that two patients died from their tumors, two experienced distant metastases, and six were alive and well from one to 13 years after diagnosis (median, 7.1 years). The authors concluded that large-cell basaloid adenocarcinoma is an unusual variant of lung cancer that is easily confused with large-cell neuroendocrine carcinoma. Awareness of this unusual variant of lung adenocarcinoma is important for determining treatment and prognoses and avoiding misdiagnoses.
Suster D, Mejbel HA, Mackinnon AC, et al. Large-cell basaloid adenocarcinoma of the lung: A clinicopathologic study of 12 cases of a distinctive form of lung cancer often mistaken for large-cell neuroendocrine carcinoma. Am J Surg Pathol. 2025;49(1):83–93.
Correspondence: Dr. David Suster at dis49@njms.rutgers.edu
Spectra of well-differentiated neuroendocrine lesions in the extrahepatic biliary system
Neuroendocrine tumors in the extrahepatic biliary system are exceedingly rare. They typically manifest as mass lesions, and the authors have not found documentation of the occurrence of microscopic neuroendocrine cell proliferation at this location. The authors conducted a study to characterize the clinicopathological features of a series of well-differentiated neuroendocrine lesions involving the extrahepatic biliary tree, including mass-forming neuroendocrine tumors (NETs) and microscopic nonmass-forming neuroendocrine cell proliferation, designated neuroendocrine cell micronests (NCMs). Surgical resections of NETs/NCMs involving the extrahepatic bile ducts and gallbladder were identified in the electronic pathology databases of seven institutions from January 2011 to September 2023. Clinical and histological findings were recorded. Ten patients (four female and six male; age, 34–75 years) were included in the study. Histopathological examination revealed visible mass-forming lesions (1.6–14.0 cm in size) in four patients. The lesions were found in the gallbladder (n = 2) or extrahepatic bile duct (n = 2) and were diagnosed as well-differentiated NETs. The remaining six cases revealed incidental nonmass-forming NCMs in the cystic duct (n = 2), common bile duct (n = 3), and gallbladder (n = 1). The NCMs ranged from less than 0.1 to 0.4 cm in size. Four were associated with biliary lithiasis. No evidence of metastasis or recurrence was seen in the follow-up period of 0.1 to 11.2 years. The authors concluded that this study highlights the spectra of extrahepatic biliary well-differentiated neuroendocrine lesions, ranging from incidental microscopic NCMs to grossly apparent mass-forming NETs, potentially requiring different forms of clinical management. Noteworthy is the frequent association of incidental microscopic neuroendocrine cell proliferations with biliary lithiasis, indicating a potential neuroendocrine metaplastic pathogenesis that merits further exploration.
Liu Y, Esnakula AK, Jain S, et al. Spectra of well-differentiated neuroendocrine lesions in the extrahepatic biliary system: a case series. Histopathology. 2025;86:285–293.
Correspondence: Dr. Dipti Karamchandani at dipti.karamchandani@utsouthwestern.edu
Characteristics of HER2-altered non-small cell lung cancer: implications for precision medicine
The heterogeneous relationship between protein expression, amplification, and mutations in HER2-altered non-small cell lung cancer remains unclear. The authors conducted a study to elucidate the clinicopathological and molecular characteristics of HER2-altered non-small cell lung cancer (NSCLC) and investigate practical approaches for identifying patients who might benefit from HER2-targeted therapies. Using next-generation sequencing data, they identified 1,680 patients with NSCLC, 105 of whom had HER2 amplification or an oncogenic mutation. Clinicopathological data and tissue slides were reviewed. Immunohistochemistry and silver in situ hybridization were performed according to American Society of Clinical Oncology/College of American Pathologists guidelines. The authors identified 89 (5.3 percent) patients with HER2-altered NSCLC, comprising 30 (1.8 percent) patients with amplification and 59 (3.6 percent) with mutations, and compared them with 165 control patients. Of the 59 HER2-mutated cases, 52 harbored tyrosine kinase domain (TKD) mutations, primarily HER2 exon 20 insertions. HER2 TKD alterations were associated with younger age, female sex, nonsmoking status, adenocarcinoma with a micropapillary pattern, lung-to-lung metastasis, and poor overall survival. Thirty-three of the 52 patients with TKD mutations and three with non-TKD point mutations showed incomplete or complete membranous HER2 immunoreactivity (1+ and 2+, 61.07 percent). Six patients exhibiting amplifications had an IHC score of 2+ despite their high copy numbers and had concurrent HER2 exon 20 insertion or other driver gene alterations, such as EGFR, KRAS, or SMARCA4. HER2-altered NSCLC with molecular co-alterations showed heterogeneous patterns through HER2 IHC and silver in situ hybridization. Therefore, next-generation sequencing should be used to identify HER2 mutations in patients with NSCLC who present with concomitant alterations. Furthermore, the aforementioned clinicopathological characteristics and HER2 IHC results can be valuable in identifying patients with HER2-altered NSCLC. Additional research in this area may provide insights relative to developing more effective diagnostic and therapeutic strategies for this complex subset of NSCLC patients.
Lee Y, Lee B, Choi YL, et al. Clinicopathologic and molecular characteristics of HER2 (ERBB2)-altered non-small cell lung cancer: implications for precision medicine. Mod Pathol. 2024;37. doi.org/10.1016/j.modpat.2024.100490
Correspondence: Dr. Yoon-La Choi at ylachoi@skku.edu or Dr. Boram Lee at boram.lee.1103@gmail.com