Clinicopathological Differences in HER2 Immunohistochemical Expression Between Low-Grade Endometrial Cancer with p53-Abnormal Expression and High-Grade Endometrial Cancer

Background/Objectives: Under the current molecular classification of endometrial cancer, the p53-abnormal group is defined as having the worst prognosis, but the clinicopathological position of low-grade endometrial cancer with p53-abnormal expression relative to high-grade endometrial cancer remains unclear. We previously showed that low-grade endometrial cancer with p53-abnormal expression more closely resembles low-grade endometrial cancer with p53 wild-type expression than high-grade endometrial cancer and that the ERBB2 gene, encoding Human Epidermal Growth Factor Receptor 2 (HER2) protein, is more highly expressed in high-grade endometrial cancer. This study compared HER2 immunohistochemical expression (IHC) among low-grade endometrial cancer with wild-type p53 expression (EClop53wt), low-grade endometrial cancer with p53-abnormal expression (EClop53ab), and high-grade endometrial cancer (EChi), in order to characterize EClop53ab. Methods: We retrospectively analyzed 70 endometrial cancer cases treated at Kyushu University Hospital in 1992–2022. Tumors were classified as EClop53wt, EClop53ab, and EChi based on histopathology and p53 immunohistochemistry, with EChi corresponding to conventional uterine serous carcinoma. HER2 expression was evaluated immunohistochemically using a standardized scoring system (0, 1+, 2+, 3+), and its distribution was compared across the three groups, together with clinicopathological parameters and patient outcomes. Results: EChi showed the highest frequency and intensity of HER2 expression, with a substantially larger proportion of HER2 IHC 3+ cases than EClop53wt and EClop53ab (p < 0.0001 and p = 0.0146, respectively). Meanwhile, there was no significant association between EClop53wt and EClop53ab (p = 0.3794). In addition, HER2 IHC 3+ had significant associations with older age (≥60 years) and substantial lymphovascular space invasion (p = 0.0003 and 0.0174, respectively). Conclusions: EClop53ab exhibits HER2 profiles and clinical behavior more similar to EClop53wt, supporting the more nuanced application of molecular classification and HER2-targeted therapy in endometrial cancer.