Markedly Elevated HE4 in Hepatic Neuroendocrine Neoplasm: A Report of Two Cases and Literature Review

 Human epididymis protein 4 (HE4) is a secretory protein encoded by the whey-acidic four-disulfide core domain protein 2 (WFDC2) gene. Clinically, HE4 is an important serological biomarker used to detect and monitor epithelial ovarian cancer. Although elevated in a high percentage of patients with ovarian and endometrial cancer, high serum HE4 levels may also be detected in patients with other various non-gynecologic malignant disorders such as lung adenocarcinoma and breast cancer. However, the association between high HE4 and hepatic neuroendocrine neoplasms (HNENs) remains unknown.

 Herein, two patients with HNENs and elevated serum HE4 are presented. Both cases were old women who underwent pelvic examination and ultrasonography and the results were normal. Immunohistochemistry assays demonstrated high HE4 expression in neuroendocrine carcinoma, whereas no HE4 expression was observed in hepatocellular carcinoma and clear cell renal cell carcinoma liver metastases.

 This preliminary observation suggested HE4 concentrations may be elevated in neuroendocrine neoplasm patients with no ovarian cancer. Thus, HE4 results should be interpreted cautiously in female patients with HNENs. In addition, this preliminary observation suggested the need to perform further studies to assess the implications of our results in terms of the potential role of HE4 as a serum biomarker in the diagnosis and prognosis of HNEN patients.