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Loss of succinate dehydrogenase subunit B (SDHB) as a prognostic factor in advanced ileal well-differentiated neuroendocrine tumors

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Abstract

Purpose

Abnormal expression of succinate dehydrogenase, (SDH), in particular of the B subunit (SDHB), is implicated in the pathogenesis of neuroendocrine tumors. This study evaluates the distribution of SDHB in WHO grading G1 and G2 intestinal, well-differentiated neuroendocrine tumors and corresponding lymph node or liver metastases.

Methods

We collected ileal well-differentiated neuroendocrine tumors specimens from consecutive patients with prior primary resection and distant synchronous or metachronous liver metastases. We obtained 195 specimens from primary tumors (n = 106) and metastases (n = 89). The expression (E) of SDHB and the immunostaining intensity (I) were evaluated semiquantitatively and combined into a single score. SDHB score was evaluated in primitive tumor and metastatic specimens.

Results

SDHB was found in all tumor cells. Mean SDHB expression was 72.7 % ± 17.1 % in primitive specimens and 27.9 % ± 24.6 % in metastatic specimens (p < 0.0001). SDH intensity was higher in primitive specimens (p < 0.0001). SDHB score was 9–12 in 96 specimens of the primitive group and 2 metastatic specimens (p < 0.0001). None of the analyzed parameters was predictive of overall survival in the primitive subset. In the metastatic subset, loss of SDHB expression, intensity, and score were prognostic factors for survival. Lower expression and intensity of SDHB in metastatic lesions were associated with longer overall survival. When combining SDHB score and Ki-67 % in the metastatic subset, a lower SDHB score was associated with prolonged overall survival, independently from Ki-67 %.

Conclusions

SDHB score was different in primitive and metastatic specimens. The combination of SDHB score and Ki-67 % was a stronger predictor of overall survival than Ki-67 % alone. This stratification might help predict survival.

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References

  1. C. Dagohoy, C. Leary, J.E. Mares, E.K. Abdalla, J.B. Fleming, J.N. Vauthey, A. Rashid, D.B. Evans, J.C. Yao, M. Hassan, A. Phan, One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J. Clin. Oncol. 26, 3063–3072 (2008)

    Article  PubMed  Google Scholar 

  2. J. Calissendorff, E. Maret, A. Sundin, H. Falhammar, Ileal neuroendocrine tumors and heart: not only valvular consequences. Endocrine 48, 743–755 (2015)

    Article  CAS  PubMed  Google Scholar 

  3. M.B. Niederle, M. Hackl, K. Kaserer, B. Niederle, Gastroenteropancreatic neuroendocrine tumours: the current incidence and staging based on the WHO and European neuroendocrine tumour society classification: an analysis based on prospectively collected parameters. Endocr. Relat. Cancer. 17, 909–918 (2010)

    Article  PubMed  Google Scholar 

  4. I.M. Modlin, I. Latich, M. Kidd, M. Zikusoka, G. Eick, Therapeutic options for gastrointestinal carcinoids. Clin. Gastroenterol. Hepatol. 4, 526–547 (2006)

    Article  CAS  PubMed  Google Scholar 

  5. F. Grillo, M. Albertelli, F. Annunziata, M. Boschetti, A. Caff, S. Pigozzi, D. Ferone, L. Mastracci, Twenty years of gastroenteropancreatic neuroendocrine tumors: is reclassification worthwhile and feasible? Endocrine. 53(1), 58–62 (2016)

  6. H. Ahlman, O. Nilsson, A.M. McNicol, P. Ruszniewski, B. Niederle, J. Ricke, R. Jensen, B. Kos-Kudla, K. Oberg, J.M. O’Connor, M.E. Pavel, M.P. Vullierme, Poorly-differentiated endocrine carcinomas of midgut and hindgut origin. Neuroendocrinology 87, 40–46 (2008)

    Article  CAS  PubMed  Google Scholar 

  7. O. Nilsson, C.E. Van, F.G. Delle, J.C. Yao, M.E. Pavel, A.M. McNicol, M.I. Sevilla Garcia, W.H. Knapp, F. Kelestimur, A. Sauvanet, S. Pauwels, D.J. Kwekkeboom, M. Caplin, Poorly differentiated carcinomas of the foregut (gastric, duodenal and pancreatic). Neuroendocrinology. 84, 212–215 (2006)

    Article  CAS  Google Scholar 

  8. M. Milione, S. Pusceddu, P. Gasparini, F. Melotti, P. Maisonneuve, V. Mazzaferro, F.G. de Braud, G. Pelosi, Succinate dehydrogenase B subunit immunohistochemical expression predicts aggressiveness in well differentiated neuroendocrine tumorsof the ileum. Cancers (Basel) 4, 808–820 (2012)

    Article  CAS  Google Scholar 

  9. A.J. Gill, D.E. Benn, A. Chou, A. Clarkson, A. Muljono, G.Y. Meyer-Rochow, A.L. Richardson, S.B. Sidhu, B.G. Robinson, R.J. Clifton-Bligh, Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, and SDHD in paraganglioma- pheochromo-cytoma syndromes. Hum. Pathol. 34, 636–644 (2010)

    Google Scholar 

  10. A.J. Gill, A. Chou, R. Vilain, A. Clarkson, M. Lui, R. Jin, V. Tobias, J. Samra, D. Goldstein, C. Smith, L. Sioson, N. Parker, R.C. Smith, M. Sywak, S.,B. Sidhu, J.M. Wyatt, B.G. Robinson, R.P. Eckstein, D.E. Benn, R.J. Clifton-Bligh, Immunohistochemistry for SDHB divides gastrointestinal stromal tumors (GISTs) into 2 distinct types. Am. J. Surg. Pathol. 34, 805–814 (2010)

    Google Scholar 

  11. S.A. Boikos, C.A. Stratakis, The genetic landscape of gastrointestinal stromal tumor lacking KIT and PDGFRA mutations. Endocrine 47, 401–408 (2014)

    Article  CAS  PubMed Central  Google Scholar 

  12. N.D. Niemeijer, T.G. Papathomas, E. Korpershoek, R.R. de Krijger, L. Oudijk, H. Morreau, J.P. Bayley, F.J. Hes, J.C. Jansen, W.N. Dinjens, E.P. Corssmit, Succinate dehydrogenase (SDH)-deficient pancreatic neuroendocrine tumor expands the SDH-related tumor spectrum. J. Clin. Endocrinol. Metab. 100, E1386–E1393 (2015)

    Article  CAS  PubMed  Google Scholar 

  13. G. Capurso, S. Lattimore, T. Crnogorac-Jurcevic, F. Panzuto, M. Milione, V. Bhakta, N. Campanini, S.M. Swift, C. Bordi, G. Delle Fave, N.R. Lemoine, Gene expression profiles of progressive pancreatic endocrine tumours and their liver metastases reveal potential novel markers and therapeutic targets. Endocr. Relat. Cancer. 13, 541–558 (2006)

    Article  CAS  PubMed  Google Scholar 

  14. F. Andriani, G. Bertolini, F. Facchinetti, E. Baldoli, M. Moro, P. Casalini, R. Caserini, M. Milione, G. Leone, G. Pelosi, U. Pastorino, G. Sozzi, L. Roz, Conversion to stem-cell state in response to microenvironmental cues is regulated by balance between epithelial and mesenchymal features in lung cancer cells. Mol. Oncol. 10, 253–271 (2016)

    Article  CAS  PubMed  Google Scholar 

  15. B.E. Howitt, H.H. Sun, M.G. Roemer, A. Kelley, B. Chapuy, E. Aviki, C. Pak, C. Connelly, E. Gjini, Y. Shi, L. Lee, A. Viswanathan, N. Horowitz, D. Neuberg, C.P. Crum, N.L. Lindeman, F. Kuo, A.H. Ligon, G.J. Freeman, F.S. Hodi, M.A. Shipp, S.J. Rodig, Genetic basis for PD-L1 expression in squamous cell carcinomas of the cervix and vulva. JAMA Oncol 2, 518–522 (2016)

    Article  PubMed  Google Scholar 

  16. F. Grillo, M. Albertelli, M.P. Brisigotti, T. Borra, M. Boschetti, R. Fiocca, D. Ferone, L. Mastracci, Grade increases in gastro-entero-pancreatic neuroendocrine tumor metastases compared to the primary tumor. Neuroendocrinology. 103(5), 452–9 (2016)

  17. W.M. Elshamy, R.J. Duhé, Overview: cellular plasticity, cancer stem cells and metastasis. Cancer Lett. 341, 2–8 (2013)

    Article  CAS  PubMed  Google Scholar 

  18. C. Bardella, P.J. Pollard, I. Tomlinson, SDH mutations in cancer. Biochim. Biophys. Acta 1807, 1432–1443 (2011)

    Article  CAS  PubMed  Google Scholar 

  19. L. Amar, E. Baudin, N. Burnichon, S. Peyrard, S. Silvera, J. Bertherat, X. Bertagna, M. Schlumberger, X. Jeunemaitre, A.P. Gimenez-Roqueplo, Succinate dehy- drogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. J. Clin. Endocrinol. Metab. 92, 3822–3828 (2007)

    Article  CAS  PubMed  Google Scholar 

  20. M.S. Elston, G.Y. Meyer-Rochow, H.M. Conaglen, A. Clarkson, R.J. Clifton-Bligh, J.V. Conaglen, A.J. Gill, Increased SSTR2A and SSTR3 expression in succinate dehydrogenase-deficient pheochromocytomas and paragangliomas. Hum. Pathol. 46, 390–396 (2015)

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. 1st Division of Pathology, Department of Pathology and Laboratory Medicine, IRCCS, Milan, Italy

    Massimo Milione, Alessio Pellegrinelli, Giovanni Centonze, Francesca Dominoni & Cecilia Brambilla

  2. Division of Epidemiology and Biostatistics, European Institute of oncology (IEO), Milan, Italy

    Patrick Maisonneuve

  3. Departement of Medical Oncology, IRCCS Foundation National Cancer Institute, Milan, Italy

    Sara Pusceddu, Roberto Buzzoni, Laura Concas & Filippo de Braud

  4. Istituto Nazionale per lo studio e la cura dei tumori “Fondazione G. Pascale”—IRCCS, Naples, Italy

    Manila Rubino & Antongiulio Faggiano

  5. University of Genoa, Genoa, Italy

    Luca Giacomelli

  6. Department of Surgery, G.I. Surgery and Liver Transplantation, Istituto Nazionale Tumori (National Cancer Institute), Milan, Italy

    Jorgelina Coppa & Vincenzo Mazzaferro

Authors
  1. Massimo Milione
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  2. Patrick Maisonneuve
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  3. Alessio Pellegrinelli
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  4. Sara Pusceddu
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  15. Filippo de Braud
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Corresponding author

Correspondence to Massimo Milione.

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The authors declare that they have no competing interests.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Milione, M., Maisonneuve, P., Pellegrinelli, A. et al. Loss of succinate dehydrogenase subunit B (SDHB) as a prognostic factor in advanced ileal well-differentiated neuroendocrine tumors. Endocrine 57, 512–517 (2017). https://doi.org/10.1007/s12020-016-1180-6

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  • DOI: https://doi.org/10.1007/s12020-016-1180-6

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