Loss of Succinate Dehydrogenase Subunit B (SDHB) As a Prognostic Factor in Advanced Ileal Well-differentiated Neuroendocrine Tumors

Overview

Journal Endocrine

Specialty Endocrinology

Date 2016 Dec 2

PMID 27905048

Citations 6

Authors

Massimo Milione

Patrick Maisonneuve

Alessio Pellegrinelli

Sara Pusceddu

Giovanni Centonze

Francesca Dominoni

Cecilia Brambilla

Manila Rubino

Antongiulio Faggiano

Roberto Buzzoni

Laura Concas

Luca Giacomelli

Jorgelina Coppa

Vincenzo Mazzaferro

Filippo De Braud

Affiliations

Soon will be listed here.

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.

Citing Articles

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References

Gill A, Chou A, Vilain R, Clarkson A, Lui M, Jin R . Immunohistochemistry for SDHB divides gastrointestinal stromal tumors (GISTs) into 2 distinct types. Am J Surg Pathol. 2010; 34(5):636-44. DOI: 10.1097/PAS.0b013e3181d6150d. View

Gill A, Benn D, Chou A, Clarkson A, Muljono A, Meyer-Rochow G . Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, and SDHD in paraganglioma-pheochromocytoma syndromes. Hum Pathol. 2010; 41(6):805-14. DOI: 10.1016/j.humpath.2009.12.005. View

Grillo F, Albertelli M, Brisigotti M, Borra T, Boschetti M, Fiocca R . Grade Increases in Gastroenteropancreatic Neuroendocrine Tumor Metastases Compared to the Primary Tumor. Neuroendocrinology. 2015; 103(5):452-9. DOI: 10.1159/000439434. View

Modlin I, Latich I, Kidd M, Zikusoka M, Eick G . Therapeutic options for gastrointestinal carcinoids. Clin Gastroenterol Hepatol. 2006; 4(5):526-47. DOI: 10.1016/j.cgh.2005.12.008. View

Yao J, Hassan M, Phan A, Dagohoy C, Leary C, Mares J . One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008; 26(18):3063-72. DOI: 10.1200/JCO.2007.15.4377. View

Calissendorff J, Maret E, Sundin A, Falhammar H . Ileal neuroendocrine tumors and heart: not only valvular consequences. Endocrine. 2014; 48(3):743-55. DOI: 10.1007/s12020-014-0446-0. View

Boikos S, Stratakis C . The genetic landscape of gastrointestinal stromal tumor lacking KIT and PDGFRA mutations. Endocrine. 2014; 47(2):401-8. PMC: 4729312. DOI: 10.1007/s12020-014-0346-3. View

Capurso G, Lattimore S, Crnogorac-Jurcevic T, Panzuto F, Milione M, Bhakta V . Gene expression profiles of progressive pancreatic endocrine tumours and their liver metastases reveal potential novel markers and therapeutic targets. Endocr Relat Cancer. 2006; 13(2):541-58. DOI: 10.1677/erc.1.01153. View

Amar L, Baudin E, Burnichon N, Peyrard S, Silvera S, Bertherat J . Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. J Clin Endocrinol Metab. 2007; 92(10):3822-8. DOI: 10.1210/jc.2007-0709. View

10.

Ahlman H, Nilsson O, McNicol A, Ruszniewski P, Niederle B, Ricke J . Poorly-differentiated endocrine carcinomas of midgut and hindgut origin. Neuroendocrinology. 2007; 87(1):40-6. DOI: 10.1159/000109976. View

11.

Niemeijer N, Papathomas T, Korpershoek E, de Krijger R, Oudijk L, Morreau H . Succinate Dehydrogenase (SDH)-Deficient Pancreatic Neuroendocrine Tumor Expands the SDH-Related Tumor Spectrum. J Clin Endocrinol Metab. 2015; 100(10):E1386-93. DOI: 10.1210/jc.2015-2689. View

12.

Nilsson O, Van Cutsem E, Delle Fave G, Yao J, Pavel M, McNicol A . Poorly differentiated carcinomas of the foregut (gastric, duodenal and pancreatic). Neuroendocrinology. 2007; 84(3):212-5. DOI: 10.1159/000098013. View

13.

Howitt B, Sun H, Roemer M, Kelley A, Chapuy B, Aviki E . Genetic Basis for PD-L1 Expression in Squamous Cell Carcinomas of the Cervix and Vulva. JAMA Oncol. 2016; 2(4):518-22. DOI: 10.1001/jamaoncol.2015.6326. View

14.

Elston M, Meyer-Rochow G, Conaglen H, Clarkson A, Clifton-Bligh R, Conaglen J . Increased SSTR2A and SSTR3 expression in succinate dehydrogenase-deficient pheochromocytomas and paragangliomas. Hum Pathol. 2015; 46(3):390-6. DOI: 10.1016/j.humpath.2014.11.012. View

15.

Milione M, Pusceddu S, Gasparini P, Melotti F, Maisonneuve P, Mazzaferro V . Succinate dehydrogenase B subunit immunohistochemical expression predicts aggressiveness in well differentiated neuroendocrine tumors of the ileum. Cancers (Basel). 2013; 4(3):808-20. PMC: 3712706. DOI: 10.3390/cancers4030808. View

16.

Niederle M, Hackl M, Kaserer K, Niederle B . 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. 2010; 17(4):909-18. DOI: 10.1677/ERC-10-0152. View

17.

Grillo F, Albertelli M, Annunziata F, Boschetti M, Caff A, Pigozzi S . Twenty years of gastroenteropancreatic neuroendocrine tumors: is reclassification worthwhile and feasible?. Endocrine. 2015; 53(1):58-62. DOI: 10.1007/s12020-015-0734-3. View

18.

ElShamy W, Duhe R . Overview: cellular plasticity, cancer stem cells and metastasis. Cancer Lett. 2013; 341(1):2-8. DOI: 10.1016/j.canlet.2013.06.020. View

19.

Andriani F, Bertolini G, Facchinetti F, Baldoli E, Moro M, Casalini P . 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. 2015; 10(2):253-71. PMC: 5528953. DOI: 10.1016/j.molonc.2015.10.002. View

20.

Bardella C, Pollard P, Tomlinson I . SDH mutations in cancer. Biochim Biophys Acta. 2011; 1807(11):1432-43. DOI: 10.1016/j.bbabio.2011.07.003. View