Multiregion genomic analysis of pancreatic mucinous cystic neoplasms
Mucinous cystic neoplasms account for approximately 25 percent of resected neoplastic cysts in the pancreas. However, only about 15 percent of resected mucinous cystic neoplasms (MCNs) harbor high-grade dysplasia or invasive carcinoma, and survival with invasive disease seems to be better than with intraductal papillary mucinous neoplasm-associated pancreatic ductal adenocarcinoma. To gain insights into the molecular mechanisms of MCN tumorigenesis, the authors performed multiregion genetic analyses of MCN samples. They sampled epithelial tissue from 18 surgically resected MCNs and performed dedicated multiregion analysis of somatic genetic alterations by targeted next-generation sequencing of 25 driver genes. They also performed whole exome sequencing and IHC on selected samples to supplement their analyses. In total, 128 samples of epithelial MCN tissue were sequenced and analyzed, including samples from 13 small MCNs with low-grade dysplasia, one small MCN with high-grade dysplasia, and four large MCNs with high-grade dysplasia. Eight of 13 (61.5 percent) comprehensively sampled small low-grade MCNs lacked somatic driver gene mutations in all tissue blocks. These MCNs were lined by predominantly flat epithelia. In contrast, the majority of MCNs with driver gene mutations were predominantly lined by mucin-rich epithelia. No heterogeneity in KRAS mutations was seen across the sampled regions. Multiregion genetic analysis of four large MCNs with high-grade dysplasia provided insights into neoplastic progression, with shared somatic alterations suggesting that high-grade dysplasia arises from low-grade mucin-rich epithelia. These findings were supported by complementary whole exome sequencing studies of 26 MCN epithelia samples. The neoplastic epithelia in the majority of small MCNs did not harbor somatic mutations in pancreatic driver genes. The genetic findings from multiregion analysis of MCNs contrast with previous investigations of other mucin-producing pancreatic cysts, indicating distinct mechanisms in early tumorigenesis. The authors proposed that their findings necessitate a more nuanced risk assessment of MCNs, using improved preoperative assessment tools. They concluded that more than half of the small MCNs in their study lacked somatic driver gene mutations, providing a molecular mechanism for low risk of malignant progression and suggesting the use of surveillance over surgical resection in select patients.
Pflüger MJ, Fujikura K, Braxton AM, et al. Multiregion genomic analysis of human pancreatic mucinous cystic neoplasms. Mod Pathol. 2025. doi.org/10.1016/j.modpat.2025.100759
Correspondence: Dr. Laura D. Wood at ldwood@jhmi.edu
HER2-positive breast cancers: intratumoral heterogeneity, HER2 amplification, and neoadjuvant therapy response
Human epidermal growth factor receptor 2-positive breast cancers are frequently treated with neoadjuvant anti-HER2 and chemotherapy (NACT). However, treatment response varies, with a subset of tumors showing high residual cancer burden. The authors investigated the relationship between HER2 IHC intratumoral heterogeneity (ITH), low-level HER2 amplification, and tumor response to NACT. A total of 205 post-NACT HER2-positive breast carcinomas with residual cancer burden results were classified into the following HER2 groups: IHC3+ (HER2 IHC positive, no FISH performed); group one-high (FISH HER2 copies greater than 8 or HER2/CEP17 ratio greater than 4); group one-intermediate (HER2 copies greater than 6–8 or HER2/CEP17 ratio greater than 3–4); group one-low (HER2 copies of 4–6 and HER2/CEP17 ratio of 2–3); and group three (HER2 copies of 6 or greater and HER2/CEP17 ratio of less than 2). Low-level HER2 amplification (collectively designated as HER2 copies of 4–8 or HER2/CEP17 ratio of less than 4) was associated with reduced response to HER2-targeted therapy and higher residual cancer burden post-NACT. HER2 IHC ITH, defined as the presence of at least three distinct staining intensities with at least 10 percent of tumor cells exhibiting weak or no staining, was significantly more prevalent in low-level HER2 amplification groups (group one-intermediate, 93.3 percent; group one-low, 87.5 percent; and group three, 80.0 percent) compared with high-level amplification groups (IHC 3+, 24.7 percent and group one-high, 28.6 percent) (P<.001). Both low-level HER2 amplification and HER2 IHC ITH, regardless of hormone receptor status, were independently associated with poor treatment response, and tumors demonstrating both features had the highest likelihood of low therapeutic efficiency. These findings suggest that both low-level HER2 amplification and HER2 IHC ITH contribute to poor NACT response and may warrant alternative therapeutic strategies. Additional prospective studies are needed to refine the clinical significance of low-level HER2 amplification and IHC ITH, particularly in the context of novel HER2-targeted therapies such as antibody-drug conjugates.
Dai W, Navolotskaia O, Fine JL, et al. Not all HER2-positive breast cancers are the same: intratumoral heterogeneity, low-level HER2 amplification, and their impact on neoadjuvant therapy response. Mod Pathol. 2025;38(7). doi.org/10.1016/j.modpat.100785
Correspondence: Dr. Jing Yu at yuj@upmc.edu or Dr. Beth Z. Clark at clarkbz@upmc.edu
Intraoperative evaluation of pediatric bone and soft tissue lesions
Frozen section evaluation of pediatric bone and soft tissue lesions is performed infrequently and may pose considerable diagnostic challenges. There are limited data addressing accuracy and diagnostic difficulties. The authors conducted a study to identify and analyze discrepancies between frozen section diagnoses and final diagnoses to increase awareness of common diagnostic pitfalls in frozen section evaluation of pediatric bone and soft tissue (BST) lesions. They retrospectively reviewed 595 consecutive frozen sections of pediatric BST lesions from 373 patients and analyzed accuracy and causes of interpretation errors. Discrepant diagnoses were found in 23 of 595 (3.9 percent) frozen sections. Discrepancy rates were slightly higher in benign soft tissue lesions and frozen sections requested for diagnosis/adequacy, although no statistically significant difference was observed. Pathologist misinterpretation contributed to discrepancies in 17 of 23 (73.9 percent) frozen sections, which were classified into six patterns of error. Three of the six were margin patterns: normal hematopoietic elements versus malignant cells in Ewing sarcoma bone marrow margin (n=3), prominent sinonasal vasculature and stroma versus sinonasal tract angiofibroma (n=3), and atrophic skeletal muscles versus malignant cells in rhabdomyosarcoma and Ewing sarcoma (n=2). And three of the six were diagnosis patterns: misclassification of benign bone tumors (n=5), misclassification of benign spindle neoplasms (n=2), and vascular malformation versus normal tissue (n=2). The authors concluded that frozen section is a valuable tool for guiding surgical management of pediatric BST lesions, which can be challenging entities and represent significant diagnostic pitfalls. Awareness of these frozen section pitfalls may help in further increasing diagnostic accuracy.
Coiner BL, Correa H, Johnson JE, et al. Intraoperative evaluation of pediatric bone and soft tissue lesions: Retrospective analysis of 595 frozen sections with emphasis on discrepancy and diagnostic pitfalls. Arch Pathol Lab Med. 2025;149(9):838–845.
Correspondence: Dr. Huiying Wang at huiying.wang@vumc.org