Abstract
Gastroenteropancreatic neuroendocrine neoplasms grade 3, all of them with >20% Ki-67, can be heterogeneous on the basis of their morphological features, comprising well and poorly differentiated neoplasms; the former are named tumors and the latter carcinomas. Several papers about gastroenteropancreatic neuroendocrine neoplasms grade 3 heterogeneity have been reporting over the last years by clinicians and pathologists, indicating that the differential diagnosis between named tumors grade 3 and named carcinomas grade 3 may be relevant in defining a different approach in terms of characterization of disease, staging, and treatment. To well define the sub-type of gastroenteropancreatic neuroendocrine neoplasms grade 3 pathologist’s expertise in recognizing tumor morphology, immunohistochemical, and molecular techniques were reported remarkable. Although current evidence about grade 3 gastroenteropancreatic neuroendocrine neoplasms heterogeneity is still far from producing validated specific therapies for specific subcategories, the hypotheses generated from the several retrospective analyses published so far on this topic represent solid bases for designing prospective therapeutic clinical trials in homogenous clinical settings.
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References
E. Leoncini, P. Boffetta, M. Shafir, K. Aleksovska, S. Boccia, G. Rindi, Increased incidence trend of low-grade and high-grade neuroendocrine neoplasms. Endocrine (2017). doi:10.1007/s12020-017-1273-x
A. Dasari, C. Shen, D. Halperin, B. Zhao, S. Zhou, Y. Xu et al., Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. (2017). doi:10.1001/jamaoncol.2017.0589
A.W. Group, S. Busco, C. Buzzoni, S. Mallone, A. Trama, M. Castaing et al., Italian cancer figures—report 2015: the burden of rare cancers in Italy. Epidemiol. Prev. 40(1 Suppl 2), 1–120 (2016). doi:10.19191/EP16.1S2.P001.035
O. Basturk, Z. Yang, L.H. Tang, R. Hruban, C. McCall, V. Adsay et al., Increased (>20%) Ki67 proliferation index in morphologically well differentitated pancreatic neuroendocrine tumors (PanNETs) correlates with decreased overall survival. Mod. Pathol. 26(Abstract #1761), 463A (2013)
O. Basturk, Z. Yang, L.H. Tang, R.H. Hruban, V. Adsay, C.M. McCall et al., The high-grade (WHO G3) pancreatic neuroendocrine tumor category is morphologically and biologically heterogenous and includes both well differentiated and poorly differentiated neoplasms. Am. J. Surg. Pathol. 39(5), 683–690 (2015). doi:10.1097/PAS.0000000000000408
M. Heetfeld, C.N. Chougnet, I.H. Olsen, A. Rinke, I. Borbath, G. Crespo et al., Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms. Endocr. Relat. Cancer 22(4), 657–664 (2015). doi:10.1530/ERC-15-0119
M. Milione, P. Maisonneuve, A. Pellegrinelli, S. Pusceddu, G. Centonze, F. Dominoni et al., Loss of succinate dehydrogenase subunit B (SDHB) as a prognostic factor in advanced ileal well-differentiated neuroendocrine tumors. Endocrine (2016). doi:10.1007/s12020-016-1180-6
H. Sorbye, S. Welin, S.W. Langer, L.W. Vestermark, N. Holt, P. Osterlund et al., Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann. Oncol. 24(1), 152–160 (2013). doi:10.1093/annonc/mds276
F.L. Velayoudom-Cephise, P. Duvillard, L. Foucan, J. Hadoux, C.N. Chougnet, S. Leboulleux et al., Are G3 ENETS neuroendocrine neoplasms heterogeneous? Endocr. Relat. Cancer. 20(5), 649–657 (2013). doi:10.1530/ERC-13-0027
F. Grillo, M. Albertelli, F. Annunziata, M. Boschetti, A. Caff, S. Pigozzi et al., Twenty years of gastroenteropancreatic neuroendocrine tumors: is reclassification worthwhile and feasible? Endocrine 53(1), 58–62 (2016). doi:10.1007/s12020-015-0734-3
D.S. Klimstra, Reassessing the grade of gastroenteropancreatic neuroendocrine neoplasms. Endocrine 53(1), 4–6 (2016). doi:10.1007/s12020-016-0966-x
G.A.R. Rindi, F.T. Bosman, C. Capella, D.S. Klimstra, G. Klöppel, P. Komminoth, E. Solcia. Nomenclature and classification of digestive neuroendocrine tumors. in WHO Classification of tumours of the Digestive System. Lyon ed. by F.C.F. Bosman, R. Hruban, N. Theise (International Agency for Research on Cancer (IARC), Lyon, 2010)
G. Klöppel. On the value of Ki-67 in the prognostic grading of pancreatic neuroendocrine neoplasms: an update. (USCAP, 2017) San Antonio, Texas. Accessed 4–10 March 2017
M. Milione, P. Maisonneuve, F. Spada, A. Pellegrinelli, P. Spaggiari, L. Albarello et al., The clinicopathologic heterogeneity of grade 3 gastroenteropancreatic neuroendocrine neoplasms: morphological differentiation and proliferation identify different prognostic categories. Neuroendocrinology 104(1), 85–93 (2017). doi:10.1159/000445165
N. Fazio, M. Milione, Heterogeneity of grade 3 gastroenteropancreatic neuroendocrine carcinomas: New insights and treatment implications. Cancer Treat. Rev. 50, 61–67 (2016). doi:10.1016/j.ctrv.2016.08.006
R. Garcia-Carbonero, H. Sorbye, E. Baudin, E. Raymond, B. Wiedenmann, B. Niederle et al., ENETS consensus guidelines for high-grade gastroenteropancreatic neuroendocrine tumors and neuroendocrine carcinomas. Neuroendocrinology 103(2), 186–194 (2016). doi:10.1159/000443172
M. Milione, P. Maisonneuve, F. Spada, A. Pellegrinelli, P. Spaggiari, L. Albarello et al., The clinicopathologic heterogeneity of grade 3 gastroenteropancreatic neuroendocrine neoplasms: morphological differentiation and proliferation identify different prognostic categories. Neuroendocrinology 104(1), 85–93 (2016). doi:10.1159/000445165
L.H. Tang, O. Basturk, J.J. Sue, D.S. Klimstra, A practical approach to the classification of WHO grade 3 (G3) well-differentiated neuroendocrine tumor (WD-NET) and poorly differentiated neuroendocrine carcinoma (PD-NEC) of the pancreas. Am. J. Surg. Pathol. 40(9), 1192–1202 (2016). doi:10.1097/PAS.0000000000000662
D.M. Girardi, A.C.B. Silva, J.F.M. Rego, R.A. Coudry, R.P. Riechelmann, Unraveling molecular pathways of poorly differentiated neuroendocrine carcinomas of the gastroenteropancreatic system: A systematic review. Cancer Treat. Rev. 56, 28–35 (2017). doi:10.1016/j.ctrv.2017.04.002
N. Sahnane, D. Furlan, M. Monti, C. Romualdi, A. Vanoli, E. Vicari et al., Microsatellite unstable gastrointestinal neuroendocrine carcinomas: a new clinicopathologic entity. Endocr. Relat. Cancer 22(1), 35–45 (2015). doi:10.1530/ERC-14-0410
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Massimo Milione and Nicola Fazio equally participated in the discussion of evidence and letter preparation.
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Milione, M., Fazio, N. G3 GEP NENs category: are basic and clinical investigations well integrated?. Endocrine 60, 28–30 (2018). https://doi.org/10.1007/s12020-017-1365-7
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DOI: https://doi.org/10.1007/s12020-017-1365-7