Addressing HER2 IHC scoring discrepancies in endometrial serous carcinoma: a comparative analysis with reflex ISH

HER2 overexpression and amplification occur in a subset of endometrial serous carcinomas (ESC) and carcinosarcomas, but HER2 testing remains unsettled due to the lack of tumor-specific guidelines. We retrospectively evaluated 113 tumors with serous morphology (95 ESC, 4 mixed carcinomas, 13 carcinosarcomas) diagnosed between 2001 and 2022 at two tertiary centers. HER2 immunohistochemistry was assessed using four scoring systems: ASCO/CAP 2007 breast, ASCO/CAP 2023 breast, ASCO/CAP/ASCP 2016 gastric, and an ESC-specific algorithm. All equivocal and discordant cases underwent in situ hybridization (ISH). HER2 positivity ranged from 15% with the 2007 breast and ESC-specific systems to 20% with the 2023 breast and 24% with the gastric criteria, and it was significantly associated with patient age > 70 years (p = 0.016). Concordance was excellent between the 2007 breast and ESC-specific systems (K = 0.98), good between the 2023 breast and 2007/ESC systems (K = 0.71-0.73), and excellent between the 2023 breast and gastric criteria (K = 0.95). Eight discordant tumors were resolved by ISH, confirming ERBB2 amplification in five. Intratumoral heterogeneity was observed in 13 cases (12%), including one carcinosarcoma with focal gene amplification. The prevalence of HER2-low tumors varied markedly, from 16 (14%) with gastric criteria to 26 (23%) with ESC-specific scoring. These findings demonstrate that the choice of scoring system substantially impacts HER2 classification in ESC. While 2007 breast and ESC-specific criteria remain the only ones validated for trastuzumab, gastric criteria are required for trastuzumab-deruxtecan eligibility. Standardized, therapy-specific algorithms integrating IHC and ISH are essential to optimize patient selection, including candidates with HER2-low tumors.