Abstract
Human epididymis protein 4 (HE4) is originally described as an epididymis specific protein and now clinically used as a serum marker for ovarian carcinoma. However, the expression of HE4 in neuroendocrine neoplasms (NENs) has not been studied. By immunohistochemistry, the expressions of HE4 in 94 normal tissues and 484 NENs which included 242 well-differentiated NENs and 242 poorly differentiated NENs were studied. HE4 was positive in 90/94 (95.7%) of the neuroendocrine cells in normal tissues, 228/242 (94.2%) of well-differentiated NENs, and 206/242 (85.1%) of poorly differentiated NENs, and the expression of HE4 decreased progressively with loss of histological differentiation, with the positive rate of 96.2%, 92.7%, 92.3%, 85.4%, and 84.4% in NET-G1/carcinoid, NET-G2/atypical carcinoid, NET-G3, NEC-LC, and NEC-SC respectively. In NET-G1 and NET-G2, HE4 staining showed a peculiar polarized distribution, with an extraordinarily strong granular staining in subnuclear cytoplasm. A diffuse and uniform cytoplastic HE4 staining was observed in NET-G3 and poorly differentiated NENs. The positive rate of HE4 in primary tumors (91.1%, 387/425) was significantly higher than that of metastases (79.7%, 47/59) (p < 0.05). In a series of 70 pure non-NENs poorly differentiated carcinomas, the specificity rate of HE4 was 92.9% (65/70), which was in line with that of Syn. The negative rate of HE4 was 87.0% (40/46) in the non-neuroendocrine components of the MiNEN cases, which was lower than that of the pure non-neuroendocrine carcinomas (92.9%, 65/70) but without statistical significance (p > 0.05). HE4 may prove to be a useful immunohistochemical marker of neuroendocrine differentiation, although comparative studies and a more extensive analysis of other tissue types are necessary.
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References
Bellizzi AM (2020) Immunohistochemistry in the diagnosis and classification of neuroendocrine neoplasms: what can brown do for you. Hum Pathol 96:8–33
Czeczok TW, Stashek KM, Maxwell JE et al (2018) Clusterin in neuroendocrine epithelial neoplasms: absence of expression in a well-differentiated tumor suggests a jejunoileal origin. Appl Immunohistochem Mol Morphol 26(2):94–100
Kaemmerer D, Träger T, Hoffmeister M et al (2015) Inverse expression of somatostatin and CXCR4 chemokine receptors in gastroenteropancreatic neuroendocrine neoplasms of different malignancy. Oncotarget 6(29):27566–27579
Heetfeld M, Chougnet CN, Olsen IH et al (2015) Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer 22(4):657–664
Li B, Li X, Mao R, Liu M, Fu L, Shi L, Zhao S, Fu M (2021) Overexpression of ODF1 in gastrointestinal tract neuroendocrine neoplasms: a novel potential immunohistochemical biomarker for well-differentiated neuroendocrine tumors. Endocr Pathol 32(2):301–308
Alexander RE, Cheng L, Grignon DJ, Idrees MT (2014) Cytoplasmic OCT4 staining is a sensitive marker of neuroendocrine differentiation. Hum Pathol 45(1):27–32
Kővári B, Turkevi-Nagy S, Báthori Á, Fekete Z, Krenács L (2020) Syntaxin 1: a novel robust immunophenotypic marker of neuroendocrine tumors. Int J Mol Sci 21(4):1213.
Rooper LM, Sharma R, Li QK, Illei PB, Westra WH (2017) INSM1 demonstrates superior performance to the individual and combined use of synaptophysin, chromogranin and CD56 for diagnosing neuroendocrine tumors of the thoracic cavity. Am J Surg Pathol 41(11):1561–1569
Mukhopadhyay S, Dermawan JK, Lanigan CP, Farver CF (2019) Insulinoma-associated protein 1 (INSM1) is a sensitive and highly specific marker of neuroendocrine differentiation in primary lung neoplasms: an immunohistochemical study of 345 cases, including 292 whole-tissue sections. Mod Pathol 32(1):100–109
González I, Lu HC, Sninsky J et al (2019) Insulinoma-associated protein 1 expression in primary and metastatic neuroendocrine neoplasms of the gastrointestinal and pancreaticobiliary tracts. Histopathology 75(4):568–577
Lilo MT, Chen Y, LeBlanc RE (2018) INSM1 is more sensitive and interpretable than conventional immunohistochemical stains used to diagnose Merkel cell carcinoma. Am J Surg Pathol 42(11):1541–1548
Xin Z, Zhang Y, Jiang Z et al (2018) Insulinoma-associated protein 1 is a novel sensitive and specific marker for small cell carcinoma of the prostate. Hum Pathol 79:151–159
Švajdler M, Mezencev R, Šašková B, Ondič O, Mukenšnábl P, Michal M (2019) Triple marker composed of p16, CD56, and TTF1 shows higher sensitivity than INSM1 for diagnosis of pulmonary small cell carcinoma: proposal for a rational immunohistochemical algorithm for diagnosis of small cell carcinoma in small biopsy and cytology specimens. Hum Pathol 85:58–64
Takase Y, Naito Y, Okabe Y et al (2019) Insulinoma-associated protein 1 expression in pancreatic neuroendocrine tumours in endoscopic ultrasound-guided fine-needle aspiration cytology: an analysis of 14 patients. Cytopathology 30(2):194–200
Kuji S, Watanabe R, Sato Y et al (2017) A new marker, insulinoma-associated protein 1 (INSM1), for high-grade neuroendocrine carcinoma of the uterine cervix: Analysis of 37 cases. Gynecol Oncol 144(2):384–390
Rooper LM, Bishop JA, Westra WH (2018) INSM1 is a sensitive and specific marker of neuroendocrine differentiation in head and neck tumors. Am J Surg Pathol 42(5):665–671
Kirchhoff C, Habben I, Ivell R, Krull N (1991) A major human epididymis-specific cDNA encodes a protein with sequence homology to extracellular proteinase inhibitors. Biol Reprod 45(2):350–357
Drapkin R, von Horsten HH, Lin Y et al (2005) Human epididymis protein 4 (HE4) is a secreted glycoprotein that is overexpressed by serous and endometrioid ovarian carcinomas. Cancer Res 65(6):2162–2169
Galgano MT, Hampton GM, Frierson HF Jr (2006) Comprehensive analysis of HE4 expression in normal and malignant human tissues. Mod Pathol 19(6):847–853
O’Neal RL, Neal RL, Nam KT et al (2013) Human epididymis protein 4 is up-regulated in gastric and pancreatic adenocarcinomas. Hum Pathol 44(5):734–742
Kamei M, Yamashita S, Tokuishi K et al (2010) HE4 expression can be associated with lymph node metastases and disease-free survival in breast cancer. Anticancer Res 30(11):4779–4783
Bignotti E, Ragnoli M, Zanotti L et al (2011) Diagnostic and prognostic impact of serum HE4 detection in endometrial carcinoma patients. Br J Cancer 104(9):1418–1425
Hough CD, Cho KR, Zonderman AB, Schwartz DR, Morin PJ (2001) Coordinately up-regulated genes in ovarian cancer. Cancer Res 61(10):3869–3876
Hellström I, Raycraft J, Hayden-Ledbetter M et al (2003) The HE4 (WFDC2) protein is a biomarker for ovarian carcinoma. Cancer Res 63(13):3695–3700
Hough CD, Sherman-Baust CA, Pizer ES et al (2000) Large-scale serial analysis of gene expression reveals genes differentially expressed in ovarian cancer. Cancer Res 60(22):6281–6287
Moore RG, McMeekin DS, Brown AK et al (2009) A novel multiple marker bioassay utilizing HE4 and CA125 for the prediction of ovarian cancer in patients with a pelvic mass. Gynecol Oncol 112(1):40–46
Ribeiro JR, Gaudet HM, Khan M et al (2017) Human epididymis protein 4 promotes events associated with metastatic ovarian cancer via regulation of the extracelluar matrix. Front Oncol 7:332
Rindi G, Klimstra DS, Abedi-Ardekani B (2018) A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol 31(12):1770–1786
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This work was supported by grants from the Natural Science Foundation of Shandong Province (ZR2020MH081).
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Qiuyao Li and Wenjing Su designed the experiments and reviewed the cases. Kun Yang, Huifeng Jiang, Haiyun Song, and Kun Feng performed the experiments. Kun Yang and Huifeng Jiang analyzed the data. Wenjing Su prepared the manuscript.
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Su, W., Yang, K., Jiang, H. et al. Human epididymis protein 4 (HE4) is a novel immunohistochemical marker of neuroendocrine differentiation. Virchows Arch 481, 433–441 (2022). https://doi.org/10.1007/s00428-022-03387-4
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DOI: https://doi.org/10.1007/s00428-022-03387-4