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Immunoreactivity of HOXB13 in Neuroendocrine Neoplasms Is a Sensitive and Specific Marker of Rectal Well-Differentiated Neuroendocrine Tumors

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Abstract

HoxB13 is a transcription factor involved in defining of posterior endodermal derivatives, including prostate and rectum. While it is used as a marker of prostatic adenocarcinoma, it has not been studied systematically in neuroendocrine neoplasms. Thus, we performed HoxB13 immunohistochemistry in tissue microarrays and the whole sections of 232 neuroendocrine neoplasms. These included 34 paragangliomas (PGs), 20 cauda equina neuroendocrine tumors (CENETs), 123 well-differentiated neuroendocrine tumors (WDNETs), and 55 neuroendocrine carcinomas (NECs). WDNETs were additionally analyzed with SATB2, and colorectal WDNETs with CDX2 and serotonin immunohistochemistry. In total, HoxB13 immunoreactivity was observed in 95% (19/20) CENETs, 10.6% (13/123) WDNETs, and 12.9% (7/54) NECs. No PGs were positive. Large intestine WDNETs expressed HoxB13 in 68.4% (13/19); five negative tumors originated in cecum and one in rectum. In rectum, 92.9% (13/14) WDNETs expressed HoxB13. HoxB13 was 92.9% sensitive and 100% specific, showing 100% positive predictive value for the rectal origin of WDNET. In NECs, HoxB13 was positive in 15.4% (2/13) GIT tumors and 80% (4/5) prostatic NECs, but in none of urinary bladder NECs (0/8). SATB2 was positive in 17.1% (21/123) WDNETs, including 78.9% (15/19) of colorectal WDNETs, 71.4% (5/7) appendiceal WDNETs, and 2.9% (1/34) small intestine WDNETs. All 4 SATB2-negative large bowel tumors originated in the cecum. When both markers combined, HoxB13+/SATB2+ immunoprofile was seen exclusively in rectal WDNETs (positive predictive value 100%), while HoxB13−/SATB2+ immunoprofile was highly suggestive of the appendiceal origin (positive predictive value 71.4%). Therefore, HoxB13 can be useful as an immunohistochemical marker of rectal WDNETs and prostatic NECs.

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Data Availability

The results of immunohistochemistry of individual tumors together with the clinical data and histology images (in the form of “*.svs” formatted image files) used and analyzed during the current study are available from the corresponding author on reasonable request. The results of immunohistochemistry of all analyzed colorectal tumors are included as Supplementary Table 1.

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Acknowledgements

We would like to thank Dr. Boris Rychly (Unilabs sro., Bratislava, SK), Dr. Marketa Trnkova (AeskuLab k.s., Prague, CR), Dr. Ludmila Michnova (Military University Hospital Prague, Prague, CR), and Maria Wozniakova (University Hospital Ostrava and Faculty of Medicine, University of Ostrava) for kindly providing cases of CENETs from the archives of their institutions.

Funding

This study was supported by the project BBMRI-CZ LM2023033, Charles University Cooperation Program, research area DIAG and METD, and Project of Czech Ministry of Defense MO 1012. The work was supported by the European Regional Development Fund-Project BBMRI-CZ Biobank network—a versatile platform for the research of the etiopathogenesis of diseases, No: EF16_013/0001674.

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Authors and Affiliations

  1. Department of Pathology, Military University Hospital Prague, Prague, Czech Republic

    Jiri Soukup

  2. The Fingerland Department of Pathology, Charles University, Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové, Sokolska 581, Prague, 500 05, Czech Republic

    Jiri Soukup, Monika Manethova, Vaclav Stejskal, Helena Hornychova & Ales Ryska

  3. Department of Neurosurgery, Charles University, Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové, Prague, Czech Republic

    Tomas Cesak

  4. Department of Neurosurgery and Neurooncology, 1st Medical Faculty, Military University Hospital Prague, Charles University, Prague, Czech Republic

    David Netuka

  5. 4th Department of Internal Medicine, Charles University, Faculty of Medicine in Hradec Králové and University Hospital Hradec Králové, Prague, Czech Republic

    Filip Gabalec

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Contributions

JS, AR, and FG conceived and designed the study; JS, MM, and VS procured and reviewed the cases included in the study; TC and DN procured clinical data of the tumors and histological material of CENETs and helped with the study design; FG procured clinical data; HH implemented, validated, and performed the immunohistochemical procedures; MM, JS, and VS analyzed the results of the study; JS performed statistical analysis. All authors contributed to writing and reviewing the manuscript.

Corresponding author

Correspondence to Jiri Soukup.

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Ethics Approval

The study was conducted in accordance with the Declaration of Helsinki and with the approval of the Ethics Committee of University Hospital Hradec Kralove (reference no. 202101P06 and no. 202109P01).

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The authors declare no competing interests.

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Soukup, J., Manethova, M., Stejskal, V. et al. Immunoreactivity of HOXB13 in Neuroendocrine Neoplasms Is a Sensitive and Specific Marker of Rectal Well-Differentiated Neuroendocrine Tumors. Endocr Pathol 34, 333–341 (2023). https://doi.org/10.1007/s12022-023-09779-9

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