Abstract
Poorly differentiated neuroendocrine carcinomas (PDNECs) of the gastroenteropancreatic system (GEP) are a heterogeneous group of aggressive malignancies with a high propensity for distant metastases and an ominous prognosis. They have traditionally been divided into small and large cell subtypes on morphological grounds. However, histological diagnosis needs to be supported by immunohistochemistry to avoid possible misdiagnoses either with the more frequent poorly differentiated adenocarcinomas and squamous cell carcinomas or with lymphomas and mesenchymal neoplasms. Although it is well known that GEP PDNECs are associated with a poor prognosis, data from some published studies seem to suggest that there is a fraction of patients with PDNECs who have better survival than expected. GEP PDNECs are currently classified according to the criteria proposed in the 2010 WHO classification. They are simply called neuroendocrine carcinomas (NECs) and are defined by mitotic count >20 × 10 HPF and/or Ki-67 labeling index >20 %. However, a few recent papers have indicated that some NECs, as defined by the 2010 WHO scheme, do not show a poorly differentiated morphology as expected. This category seems to show a better prognosis and, especially, does not respond to cisplatin-based chemotherapy, which represents the goal standard therapeutic approach to high-grade PDNECs. In the present review, the main morphological, immunohistochemical, and prognostic features will be discussed as well as the opportunity to introduce a new category characterized by well to moderately differentiated morphology associated with high proliferation (mitotic count >20 × 10 HPF and/or Ki-67 index >20 %).
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Furlan D, Bernasconi B, Uccella S, Cerutti R, Carnevali I, Capella C (2005) Allelotypes and fluorescence in situ hybridization profiles of poorly differentiated endocrine carcinomas of different sites. Clin Cancer Res 11:1765-1775
Yachida S, Vakiani E, White CM, et al (2012) Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors. Am J Surg Pathol 36:173-184
Yao JC, Shah MH, Ito T, et al (2011) Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364:514-523
Fazio N, Scarpa A, Falconi M (2014) Molecular targeted therapy in enteropancreatic neuroendocrine tumors: from biology to clinical practice. Curr Med Chem 21:1017-1025
Moertel C, Kvols L, O’Connel M, Rubin J (1991) Treatment of neuroendocrine carcinomas with combined etoposide and cisplatin: evidence of major therapeutic activity in the anaplastic variants of these neoplasms. Cancer 68:227-232
Smith J, Reidy-Lagunes D (2013) The management of extrapulmonary poorly differentiated (high grade) neuroendocrine carcinomas. Semin Oncol 40:100-108
La Rosa S, Marando A, Sessa F, Capella C (2012) Mixed adenoneuroendocrine carcinomas (MANECs) of the gastrointestinal tract: an update. Cancers 4:11-30
Solcia E, Klöppel G, Sobin LH, et al (2000) Histological typing of endocrine tumours. WHO International Histological Classification of Tumours, 2nd Edition. Springer, Berlin
Rindi G, Arnold R, Bosman FT, et al (2010) Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: Bosman FT, Carneiro F, Hruban RH, Theise ND (eds). WHO classification of tumours of the digestive system. IARC Press, Lyon, pp 13-14
Jiang SX, Mikami T, Umezawa A, Saegusa M, Kameya T, Okayasu I (2006) Gastric large cell neuroendocrine carcinomas: a distinct clinicopathologic entity. Am J Surg Pathol 30:945-953
Shia J, Tang LH, Weiser MR, et al (2008) Is nonsmall cell type high-grade neuroendocrine carcinoma of the tubular gastrointestinal tract a distinct disease entity? Am J Surg Pathol 32:719-731
La Rosa S, Marando A, Furlan D, Sahnane N, Capella C (2012) Colorectal poorly differentiated neuroendocrine carcinomas and mixed adenoneuroendocrine carcinomas: insights into the diagnostic immunophenotype, assessment of methylation profile, and search for prognostic markers. Am J Surg Pathol 36:601-611
Basturk O, Hruban RH, Adsay NV, et al (2014) Poorly differentiated neuroendocrine carcinomas of the pancreas: a clinicopathologic analysis of 44 cases. Am J Surg Pathol 38:437-447
Volante M, Birocco N, Gatti G, Duregon E, Lorizzo K, Fazio N, Scagliotti GV, Papotti M (2014) Extrapulmonary neuroendocrine small and large cell carcinomas: a review of controversial diagnostic and therapeutic issues. Hum Pathol 45:665-673
Rindi G, Bordi C, La Rosa S, Solcia E, Delle Fave G (2011) Gastroenteropancreatic (neuro)endocrine neoplasms: the histology report. Dig Liver Dis 43(Suppl 4):S356-S360
Corrin B, Gilby ED, Jones NF, Patrick J (1973) Oat cell carcinoma of the pancreas with ectopic ACTH secretion. Cancer 31:1523-1527
Wick MR (2000) Immunohistology of neuroendocrine and neuroectodermal tumors. Semin Diagn Pathol 17:194-203
DeLellis RA, Shin SJ, Treaba DO (2010) Immunohistology of endocrine tumors. In: Dabbs DJ (ed). Diagnostic Immunohistochemistry: Theranostic and genomic applications. Saunders Elsevier, Philadelphia, pp 291-339
Barbareschi M, Roldo C, Zamboni G, Capelli P, Cavazza A, Macri E, Cangi MG, Chilosi M, Doglioni C (2004) CDX-2 homeobox gene product expression in neuroendocrine tumors: its role as a marker of intestinal neuroendocrine tumors. Am J Surg Pathol 28:1169-1176
La Rosa S, Rigoli E, Uccella S, Chiaravalli AM, Capella C (2004) CDX2 as a marker of intestinal EC-cells and related well-differentiated endocrine tumors. Virchows Arch 445:248-254
La Rosa S, Chiaravalli AM, Placidi C, Papanikolaou N, Cerati M, Capella C (2010) TTF1 expression in normal lung neuroendocrine cells and related tumors: Immunohistochemical study comparing two different monoclonal antibodies. Virchows Arch 457:497-507
Hermann G, Konukiewitz B, Schmitt A, Perren A, Klöppel G (2011) Hormonally defined pancreatic and duodenal neuroendocrine tumors differ in their transcription factor signatures: expression of ISL1, PDX1, NGN3, and CDX2. Virchows Arch 459:147-154
Schmitt AM, Riniker F, Anlauf M, Schmid S, Soltermann A, Moch H, Heitz PU, Klöppel G, Komminoth P, Perren A (2008) Islet 1 (Isl1) expression is a reliable marker for pancreatic endocrine tumors and their metastases. Am J Surg Pathol 32:420-425
Koo J, Zhou X, Moschiano E, De Peralta-Venturina M, Mertens RB, Dhall D (2013) 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
Agaimy A, Erlenbach-Wünsch K, Konukiewitz B, Schmitt AM, Rieker RJ, Vieth M, Kiesewetter F, Hartmann A, Zamboni G, Perren A, Klöppel G (2013) ISL1 expression is not restricted to pancreatic well-differentiated neuroendocrine neoplasms, but is also commonly found in well and poorly differentiated neuroendocrine neoplasms of extrapancreatic origin. Mod Pathol 26:995-1003
La Rosa S, Marando A, Gatti G, Rapa I, Volante M, Papotti M, Sessa F, Capella C (2013) Achaete-scute homolog 1 as a marker of poorly differentiated neuroendocrine carcinomas of different sites: a validation study using immunohistochemistry and quantitative real-time polymerase chain reaction on 335 cases. Hum Pathol 44:1391-1399
La Rosa S, Sessa F, Capella C, Riva C, Leone BE, Klersy C, Rindi G, Solcia E (1996) Prognostic criteria in nonfunctioning pancreatic endocrine tumors. Virchows Arch 429:323-333
Power DG, Asmis TR, Tang LH, Brown K, Kemeny NE (2011). High-grade neuroendocrine carcinoma of the colon, long-term survival in advanced disease. Med Oncol Suppl1:S169-S174
Akintola-Ogunremi O, Pfeifer JD, Tan BR, et al (2003) Analysis of protein expression and gene mutation of c-kit in colorectal neuroendocrine carcinomas. Am J Surg Pathol 27:1551-1558
Ishikubo T, Akagi K, Kurosumi M, Yamaguchi K, Fujimoto T, Sakamoto H, Tanaka Y, Ochiai A (2006) Immunohistochemical and mutational analysis of c-kit in gastrointestinal neuroendocrine cell carcinoma. Jpn J Clin Oncol 36:494-498
Gross DJ, Munter G, Bitan M, et al (2006) The role of imatinib mesylate (Glivec) for treatment of patients with malignant endocrine tumors positive for c-kit or PDGF-R. Endocr Relat Cancer 13:535-540
Pages F, Galon J, Dieu-Nosjean MC Tartour E, Sautès-Fridman C, Fridman WH (2010) Immune infiltration in human tumors: a prognostic factor that should not be ignored. Oncogene 29:1093-1102
Rindi G, Klöppel G, Alhman H, et al. TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virschows Arch 2006; 449:395-401
DeLellis RA, Lloyd RV, Heitz PU, Eng C (2004) Pathology and genetics of tumours of endocrine organs. World Health Organization Classification of Tumours. IARC Press, Lyon
La Rosa S, Inzani F, Vanoli A, Klersy C, Dainese L, Rindi G, Capella C, Bordi C, Solcia E (2011) Histologic characterization and improved prognostic evaluation of 209 gastric neuroendocrine neoplasms. Hum Pathol 42:1373-1384
Volante M, Daniele L, Asioli S et al (2013) Tumor staging but not grading is associated with adverse clinical outcome in neuroendocrine tumors of the appendix: a retrospective clinical pathologic analysis of 138 cases. Am J Surg Pathol 37:606-612
Basturk O, Yang Z, Tang LH, et al (2013) Increased (>20 %) Ki67 proliferation index in morphologically well differentiated pancreatic neuroendocrine tumors (PanNETs) correlates with decreased overall survival. Mod Pathol 26(Suppl 2):423A
Vélayoudom-Céphise FL, Duvillard P, Foucan L, et al (2013) Are G3 ENETS neuroendocrine neoplasms heterogeneous? Endocr Relat Cancer 20:649-657
Travis WD (2010) Advances in neuroendocrine lung tumors. Ann Oncol Suppl 7:vii65-71
Sorbye H, Welin S, Langer SW, et al (2013) Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann Oncol 24:152-160
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The authors dedicate this paper to Prof. Capella who has been our teacher for such a long time.
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La Rosa, S., Sessa, F. High-Grade Poorly Differentiated Neuroendocrine Carcinomas of the Gastroenteropancreatic System: from Morphology to Proliferation and back. Endocr Pathol 25, 193–198 (2014). https://doi.org/10.1007/s12022-014-9316-9
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DOI: https://doi.org/10.1007/s12022-014-9316-9