Clinicopathological Differences in HER2 Immunohistochemical Expression Between Low-Grade Endometrial Cancer with...

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 (EC^lop53^wt), low-grade endometrial cancer with p53-abnormal expression (EC^lop53^ab), and high-grade endometrial cancer (EC^hi), in order to characterize EC^lop53^ab. Methods: We retrospectively analyzed 70 endometrial cancer cases treated at Kyushu University Hospital in 1992-2022. Tumors were classified as EC^lop53^wt, EC^lop53^ab, and EC^hi based on histopathology and p53 immunohistochemistry, with EC^hi 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: EC^hi showed the highest frequency and intensity of HER2 expression, with a substantially larger proportion of HER2 IHC 3+ cases than EC^lop53^wt and EC^lop53^ab (p < 0.0001 and p = 0.0146, respectively). Meanwhile, there was no significant association between EC^lop53^wt and EC^lop53^ab (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: EC^lop53^ab exhibits HER2 profiles and clinical behavior more similar to EC^lop53^wt, supporting the more nuanced application of molecular classification and HER2-targeted therapy in endometrial cancer.