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.

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

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

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

Department of Pathology Military University Hospital Prague Prague Czech Republic

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

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Rindi G, Wiedenmann B Neuroendocrine neoplasms of the gut and pancreas: new insights. Nat Rev Endocrinol 8: 54-64, 2011. PubMed DOI

Kojima M, Ikeda K, Saito Net al. Neuroendocrine Tumors of the Large Intestine: Clinicopathological Features and Predictive Factors of Lymph Node Metastasis. Front Oncol 6: 173, 2016. PubMed DOI PMC

Bellizzi AM SATB2 in neuroendocrine neoplasms: strong expression is restricted to well-differentiated tumours of lower gastrointestinal tract origin and is most frequent in Merkel cell carcinoma among poorly differentiated carcinomas. Histopathology 76: 251–264, 2020.

Lin X, Saad RS, Luckasevic TM, Silverman JF, Liu Y Diagnostic value of CDX-2 and TTF-1 expressions in separating metastatic neuroendocrine neoplasms of unknown origin. Appl Immunohistochem Mol Morphol 15: 407-414, 2007. PubMed DOI

Soukup J, Manethova M, Faistova Het al. Pitx2 is a useful marker of midgut-derived neuroendocrine tumours - an immunohistochemical study of 224 cases. Histopathology 81: 799-807, 2022. PubMed DOI

Tseng IC, Yeh MM, Yang CY, Jeng YM NKX6-1 Is a Novel Immunohistochemical Marker for Pancreatic and Duodenal Neuroendocrine Tumors. Am J Surg Pathol 39: 850-857, 2015. PubMed DOI

Zhao LH, Chen C, Mao CYet al. Value of SATB2, ISL1, and TTF1 to differentiate rectal from other gastrointestinal and lung well-differentiated neuroendocrine tumors. Pathol Res Pract 215: 152448, 2019. PubMed DOI

Bellizzi AM Immunohistochemistry in the diagnosis and classification of neuroendocrine neoplasms: what can brown do for you? Hum Pathol 96: 8–33, 2020.

Brechka H, Bhanvadia RR, VanOpstall C, Vander Griend DJ HOXB13 mutations and binding partners in prostate development and cancer: Function, clinical significance, and future directions. Genes Dis 4: 75-87, 2017. PubMed DOI PMC

Zeltser L, Desplan C, Heintz N Hoxb-13: a new Hox gene in a distant region of the HOXB cluster maintains colinearity. Development 122: 2475-2484, 1996. PubMed DOI

Aires R, de Lemos L, Novoa Aet al. Tail Bud Progenitor Activity Relies on a Network Comprising Gdf11, Lin28, and Hox13 Genes. Dev Cell 48: 383–395 e388, 2019.

Sreenath T, Orosz A, Fujita K, Bieberich CJ Androgen-independent expression of hoxb-13 in the mouse prostate. Prostate 41: 203-207, 1999. PubMed DOI

Uhlen M, Fagerberg L, Hallstrom BMet al. Proteomics. Tissue-based map of the human proteome. Science 347: 1260419, 2015.

Varinot J, Cussenot O, Roupret Met al. HOXB13 is a sensitive and specific marker of prostate cells, useful in distinguishing between carcinomas of prostatic and urothelial origin. Virchows Arch 463: 803-809, 2013. PubMed DOI

Kristiansen I, Stephan C, Jung Ket al. Sensitivity of HOXB13 as a Diagnostic Immunohistochemical Marker of Prostatic Origin in Prostate Cancer Metastases: Comparison to PSA, Prostein, Androgen Receptor, ERG, NKX3.1, PSAP, and PSMA. Int J Mol Sci 18, 2017.

Asa SL, Mete O, Schuller U, Ramani B, Mirchia K, Perry A Cauda Equina Neuroendocrine Tumors: Distinct Epithelial Neuroendocrine Neoplasms of Spinal Origin. Am J Surg Pathol, 2022.

Soukup J, Manethova M, Kohout Aet al. Cauda equina neuroendocrine tumors show biological features distinct from other paragangliomas and visceral neuroendocrine tumors. Virchows Arch, 2022.

Bockmayr M, Korner M, Schweizer L, Schuller U Cauda equina paragangliomas express HOXB13. Neuropathol Appl Neurobiol 47: 889-890, 2021. PubMed DOI

Lee JP, Hung YP, O’Dorisio TM, Howe JR, Hornick JL, Bellizzi AM Examination of PHOX2B in adult neuroendocrine neoplasms reveals relatively frequent expression in phaeochromocytomas and paragangliomas. Histopathology 71: 503-510, 2017. PubMed DOI PMC

Volante M, Grillo F, Massa Fet al. Neuroendocrine neoplasms of the appendix, colon and rectum. Pathologica 113: 19-27, 2021. PubMed DOI PMC

Li Z, Yuan J, Wei Let al. SATB2 is a sensitive marker for lower gastrointestinal well-differentiated neuroendocrine tumors. Int J Clin Exp Pathol 8: 7072-7082, 2015. PubMed PMC

Kim JY, Kim KS, Kim KJet al. Non-L-cell immunophenotype and large tumor size in rectal neuroendocrine tumors are associated with aggressive clinical behavior and worse prognosis. Am J Surg Pathol 39: 632-643, 2015. PubMed DOI

Koo J, Zhou X, Moschiano E, De Peralta-Venturina M, Mertens RB, Dhall D The immunohistochemical expression of islet 1 and PAX8 by rectal neuroendocrine tumors should be taken into account in the differential diagnosis of metastatic neuroendocrine tumors of unknown primary origin. Endocr Pathol 24: 184-190, 2013. PubMed DOI

Yang MX, Coates RF, Ambaye Aet al. NKX2.2, PDX-1 and CDX-2 as potential biomarkers to differentiate well-differentiated neuroendocrine tumors. Biomark Res 6: 15, 2018. PubMed DOI PMC

Cheng S, Yang S, Shi Y, Shi R, Yeh Y, Yu X Neuroendocrine prostate cancer has distinctive, non-prostatic HOX code that is represented by the loss of HOXB13 expression. Sci Rep 11: 2778, 2021. PubMed DOI PMC

Beltran H, Tomlins S, Aparicio Aet al. Aggressive variants of castration-resistant prostate cancer. Clin Cancer Res 20: 2846-2850, 2014. PubMed DOI PMC

Abdulfatah E, Fine SW, Lotan TL, Mehra R De novo neuroendocrine features in prostate cancer. Hum Pathol 127: 112-122, 2022. PubMed DOI

Cheng L, Jones TD, McCarthy RPet al. Molecular genetic evidence for a common clonal origin of urinary bladder small cell carcinoma and coexisting urothelial carcinoma. Am J Pathol 166: 1533-1539, 2005. PubMed DOI PMC

Wang G, Xiao L, Zhang Met al. Small cell carcinoma of the urinary bladder: a clinicopathological and immunohistochemical analysis of 81 cases. Hum Pathol 79: 57-65, 2018. PubMed DOI PMC

La Rosa S, Rigoli E, Uccella S, Chiaravalli AM, Capella C CDX2 as a marker of intestinal EC-cells and related well-differentiated endocrine tumors. Virchows Arch 445: 248-254, 2004 PubMed DOI