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Endocrine Pathology
Published in: Endocrine Pathology 2/2021

Open Access 01-06-2021 | Carcinoid Tumor

Challenges in High-grade Neuroendocrine Neoplasms and Mixed Neuroendocrine/Non-neuroendocrine Neoplasms

Author: Stefano La Rosa

Published in: Endocrine Pathology | Issue 2/2021

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Abstract

The growth in knowledge of the pathogenesis, molecular background, and immunohistochemical profile of neuroendocrine neoplasms (NENs) has led not only to an increased awareness of these diseases but also to several changes of the nomenclature. In particular, the concept and terminology of high-grade (grade 3) NENs and mixed neoplasms have changed considerably over the last 20 years, creating some confusion among pathologists and clinicians. The aim of this review is to elucidate the diagnostic criteria, including the most important differential diagnoses of high-grade NENs and mixed neuroendocrine/non-neuroendocrine neoplasms (MiNENs). The role of the Ki67 labelling index and morphology, used to define grade 3 NENs of the digestive system and lungs, is also discussed. The evolution of the concepts and terminology of MiNENs is revised, including the most important differential diagnoses.
Literature
1.
Oberndorfer S (1907) Karzinoïde Tumoren des Dunndarms. Frankf Z für Pathol 1:426e9
2.
Capella C, Heitz PU, Höfler H, Solcia E, Klöppel G (1994) Revised classification of neuroendocrine tumors of the lung, pancreas and gut. Digestion 55(Suppl 3):11-23PubMedCrossRef
3.
Rindi G, Klöppel G, Alhman H, et al. (2006) TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch 449:395-401PubMedPubMedCentralCrossRef
4.
Rindi G, Klöppel G, Couvelard A, Komminoth P, Körner M, Lopes JM, McNicol AM, Nilsson O, Perren A, Scarpa A, Scoazec JY, Wiedenmann B (2007) TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch 451:757-762PubMedCrossRef
5.
Klöppel G, La Rosa S (2018) Ki67 labeling index: assessment and prognostic role in gastroenteropancreatic neuroendocrine neoplasms. Virchows Arch 472:341-349PubMedCrossRef
6.
Rindi G, Arnold R, Bosman FT, Capella C, Klimstra DS, Klöppel G, Komminoth P, Solcia E (2010) Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: Bosman FT, Carneiro F, Hruban RH, Theise ND (eds) WHO classification of tumors of the digestive system. IARC, Lyon, pp 13-14
7.
Sorbye H, Welin S, Langer SW, Vestermark LW, Holt N, Osterlund P, Dueland S, Hofsli E, Guren MG, Ohrling K, Birkemeyer E, Thiis-Evensen E, Biagini M, Gronbaek H, Soveri LM, Olsen IH, Federspiel B, Assmus J, Janson ET, Knigge U (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.PubMedCrossRef
8.
Basturk O, Yang Z, Tang LH, Hruban RH, Adsay V, McCall CM, Krasinskas AM, Jang KT, Frankel WL, Balci S, Sigel C, Klimstra DS (2015) The high-grade (WHO G3) pancreatic neuroendocrine tumor category is morphologically and biologically heterogeneous and includes both well differentiated and poorly differentiated neoplasms. Am J Surg Pathol 39:683-690PubMedPubMedCentralCrossRef
9.
Milione M, Maisonneuve P, Spada F, Pellegrinelli A, Spaggiari P, Albarello L, Pisa E, Barberis M, Vanoli A, Buzzoni R, Pusceddu S, Concas L, Sessa F, Solcia E, Capella C, Fazio N, La Rosa S (2017) The clinicopathologic heterogeneity of grade 3 gastroenteropancreatic neuroendocrine neoplasms: morphological differentiation and proliferation identify different prognostic categories. Neuroendocrinology 104:85-93PubMedCrossRef
10.
Vélayoudom-Céphise FL, Duvillard P, Foucan L, Hadoux J, Chougnet CN, Leboulleux S, Malka D, Guigay J, Goere D, Debaere T, Caramella C, Schlumberger M, Planchard D, Elias D, Ducreux M, Scoazec JY, Baudin E (2013) Are G3 ENETS neuroendocrine neoplasms heterogeneous? Endocr Relat Cancer 20:649–657PubMedCrossRef
11.
Heetfeld M, Chougnet CN, Olsen IH, et al (2015) Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer 22:657–664PubMedCrossRef
12.
Klöppel G, Couvelard A, Hruban RH, Klimstra DS, Komminoth P, Osamura RY, Perren A, Rindi G (2017) Neuroendocrine neoplasms of the pancreas: introduction. In: Lloyd RV, Osamura RY, Klöppel G, Rosai J (eds) WHO classification of tumours of endocrine organs. IARC, Lyon, pp 211-214
13.
Klimstra DS, Klöppel G, La Rosa S, Rindi G (2019) Classification of neuroendocrine neoplasms of the digestive system. In: WHO Classification of Tumours Editorial Board editors. WHO classification of tumours, 5th edn. Digestive system tumours. IARC, Lyon, pp 16–19
14.
Pelosi G, Bianchi F, Hofman P, Pattini L, Ströbel P, Calabrese F, Naheed S, Holden C, Cave J, Bohnenberger H, Dinter H, Harari S, Albini A, Sonzogni A, Papotti M, Volante M, Ottensmeier CH (2019) Recent advances in the molecular landscape of lung neuroendocrine tumors. Expert Rev Mol Diagn 19:281-297PubMedCrossRef
15.
Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG (2015) WHO classification of tumours of the lung, pleura, thymus and heart. IARC, Lyon
16.
Uccella S, Sessa F, La Rosa S (2015) Diagnostic approach to neuroendocrine neoplasms of the gastrointestinal tract and pancreas. Turk Patoloji Derg 31(Suppl 1):113-127PubMed
17.
Uccella S, La Rosa S, Metovic J, Marchiori D, Scoazec JY, Volante M, Mete O, Papotti M (2021) Genomics of high-grade neuroendocrine neoplasms: well-differentiated neuroendocrine tumor with high-grade features (G3 NET) and neuroendocrine carcinomas (NEC) of various anatomic sites. Endocr Pathol Jan 12. https://​doi.​org/​10.​1007/​s12022-020-09660-z
18.
Pelosi G, Bianchi F, Dama E, Simbolo M, Mafficini A, Sonzogni A, Pilotto S, Harari S, Papotti M, Volante M, Fontanini G, Mastracci L, Albini A, Bria E, Calabrese F, Scarpa A (2018) Most high-grade neuroendocrine tumours of the lung are likely to secondarily develop from pre-existing carcinoids: innovative findings skipping the current pathogenesis paradigm. Virchows Arch 472:567-577PubMedCrossRef
19.
Pelosi G, Bianchi F, Dama E, Metovic J, Barella M, Sonzogni A, Albini A, Papotti M, Gong Y, Vijayvergia N (2021) A subset of large cell neuroendocrine carcinomas in the gastroenteropancreatic tract may evolve from pre-existing well-differentiated neuroendocrine tumors. Endocr Pathol Jan 12. https://​doi.​org/​10.​1007/​s12022-020-09659-6.
20.
Elvebakken H, Perren A, Scoazec JY, Tang LH, Federspiel B, Klimstra DS, Vestermark LW, Ali AS, Zlobec I, Myklebust TÅ, Hjortland GO, Langer SW, Gronbæk H, Knigge U, Tiensuu Janson E, Sorbye H (2020) A consensus developed morphological re-evaluation of 196 high-grade gastroenteropancreatic neuroendocrine neoplasms and its clinical correlations. Neuroendocrinology Oct 1. https://​doi.​org/​10.​1159/​000511905
21.
Fazio N, Milione M (2016) Heterogeneity of grade 3 gastroenteropancreatic neuroendocrine carcinomas: New insights and treatment implications. Cancer Treat Rev 50:61-67PubMedCrossRef
22.
Sorbye H, Baudin E, Borbath I, Caplin M, Chen J, Cwikla JB, Frilling A, Grossman A, Kaltsas G, Scarpa A, Welin S, Garcia-Carbonero R; ENETS 2016 Munich Advisory Board Participants (2019) Unmet needs in high-grade gastroenteropancreatic neuroendocrine neoplasms (WHO G3). Neuroendocrinology 108:54-62CrossRef
23.
Uccella S, La Rosa S, Volante M, Papotti M (2018) Immunohistochemical biomarkers of gastrointestinal, pancreatic, pulmonary, and thymic neuroendocrine neoplasms. Endocr Pathol 29:150-168PubMedCrossRef
24.
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 44:1391-1399PubMedCrossRef
25.
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 42:1373-1384PubMedCrossRef
26.
Vanoli A, La Rosa S, Miceli E, Klersy C, Maragliano R, Capuano F, Persichella A, Martino M, Inzani F, Luinetti O, Di Sabatino A, Sessa F, Paulli M, Corazza GR, Rindi G, Bordi C, Capella C, Solcia E (2018) Prognostic evaluations tailored to specific gastric neuroendocrine neoplasms: analysis of 200 cases with extended follow-up. Neuroendocrinology 107:114-126PubMedCrossRef
27.
Tang LH, Gonen M, Hedvat C, Modlin IM, Klimstra DS (2012) Objective quantification of the Ki67 proliferative index in neuroendocrine tumors of the gastroenteropancreatic system: a comparison of digital image analysis with manual methods Am J Surg Pathol 36:1761–1770
28.
Reid MD, Bagci P, Ohike N, Saka B, Erbarut Seven I, Dursun N, Balci S, Gucer H, Jang KT, Tajiri T, Basturk O, Kong SY, Goodman M, Akkas G, Adsay V (2015) Calculation of the Ki67 index in pancreatic neuroendocrine tumors: a comparative analysis of four counting methodologies Mod Pathol 28:686–694
29.
30.
Volante M, Brizzi MP, Faggiano A, La Rosa S, Rapa I, Ferrero A, Mansueto G, Righi L, Garancini S, Capella C, De Rosa G, Dogliotti L, Colao A, Papotti M (2007) Somatostatin receptor type 2A immunohistochemistry in neuroendocrine tumors: a proposal of scoring system correlated with somatostatin receptor scintigraphy. Mod Pathol 20:1172-1182PubMedCrossRef
31.
Marchevsky AM, Hendifar A, Walts AE (2018) The use of Ki-67 labeling index to grade pulmonary well-differentiated neuroendocrine neoplasms: current best evidence. Mod Pathol 31:1523-1536PubMedCrossRef
32.
Caplin ME, Baudin E, Ferolla P, Filosso P, Garcia-Yuste M, Lim E, Oberg K, Pelosi G, Perren A, Rossi RE, Travis WD; ENETS consensus conference participants (2015) Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids. Ann Oncol 26:1604-1620.PubMedCrossRef
33.
Rindi G, Klersy C, Inzani F, Fellegara G, Ampollini L, Ardizzoni A, Campanini N, Carbognani P, De Pas TM, Galetta D, Granone PL, Righi L, Rusca M, Spaggiari L, Tiseo M, Viale G, Volante M, Papotti M, Pelosi G (2013) Grading the neuroendocrine tumors of the lung: an evidence-based proposal. Endocr Relat Cancer 21:1-16.PubMedCrossRef
34.
Dermawan JKT, Farver CF (2020) The role of histologic grading and Ki-67 index in predicting outcomes in pulmonary carcinoid tumors. Am J Surg Pathol 44:224-231PubMedCrossRef
35.
Fabbri A, Cossa M, Sonzogni A, Papotti M, Righi L, Gatti G, Maisonneuve P, Valeri B, Pastorino U, Pelosi G (2017) Ki-67 labeling index of neuroendocrine tumors of the lung has a high level of correspondence between biopsy samples and surgical specimens when strict counting guidelines are applied. Virchows Arch 470:153-164PubMedCrossRef
36.
Marchiò C, Gatti G, Massa F, Bertero L, Filosso P, Pelosi G, Cassoni P, Volante M, Papotti M (2017) Distinctive pathological and clinical features of lung carcinoids with high proliferation index. Virchows Arch 471:713-720PubMedPubMedCentralCrossRef
37.
Kasajima A, Konukiewitz B, Oka N, Suzuki H, Sakurada A, Okada Y, Kameya T, Ishikawa Y, Sasano H, Weichert W, Klöppel G (2019) Clinicopathological profiling of lung carcinoids with a Ki67 index > 20%. Neuroendocrinology 108:109-120PubMedCrossRef
38.
Rekhtman N, Desmeules P, Litvak AM, Pietanza MC, Santos-Zabala ML, Ni A, Montecalvo J, Chang JC, Beras A, Preeshagul IR, Sabari JK, Rudin CM, Ladanyi M, Klimstra DS, Travis WD, Lai WC (2019) Stage IV lung carcinoids: spectrum and evolution of proliferation rate, focusing on variants with elevated proliferation indices. Mod Pathol 32:1106-1122PubMedPubMedCentralCrossRef
39.
Volante M, Pelosi G (2021) Thoracic (lung/thymus) neuroendocrine neoplasms. In: Asa SL, La Rosa S, Mete O (eds) The spectrum of neuroendocrine neoplasia. A practical approach to diagnosis, classification and therapy. Springer Nature, New York, pp 151–206
40.
Solcia E, Klöppel G, Sobin LH (In collaboration with 9 pathologist from 9 countries) (2000) Histological typing of endocrine tumors. WHO international histological classification of tumors2nd ed. Springer-Verlag, Heidelberg
41.
La Rosa S, Sessa F, Uccella S (2016) Mixed neuroendocrine-nonneuroendocrine neoplasms (MiNENs): unifying the concept of a heterogeneous group of neoplasms. Endocr Pathol 27:284-311PubMedCrossRef
42.
Moch H, Humphrey PA, Ulbright TM, Reuter V (2016) WHO classification of tumours of the urinary system and male genital organs. IARC, Lyon
43.
El-Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PJ (2017) WHO classification of head and neck tumours. IARC, Lyon
44.
Lloyd RV, Osamura RY, Klöppel G, Rosai J (2017) WHO classification of tumours of endocrine organs. IARC, Lyon
45.
Elder D, Massi D, Scolyer RA, Willemze R (2018) WHO classification of skin tumours. IARC, Lyon
46.
Rindi G, Klimstra DS, Abedi-Ardekani B, Asa SL, Bosman FT, Brambilla E, Busam KJ, de Krijger RR, Dietel M, El-Naggar AK, Fernandez-Cuesta L, Klöppel G, McCluggage WG, Moch H, Ohgaki H, Rakha EA, Reed NS, Rous BA, Sasano H, Scarpa A, Scoazec JY, Travis WD, Tallini G, Trouillas J, van Krieken JH, Cree IA (2018) A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol 31:1770-1786PubMedPubMedCentralCrossRef
47.
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 11:1765-1775PubMedCrossRef
48.
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 36:601-611PubMedCrossRef
49.
La Rosa S, Furlan D, Franzi F, Battaglia P, Frattini M, Zanellato E, Marando A, Sahnane N, Turri-Zanoni M, Castelnuovo P, Capella C (2013) Mixed exocrine-neuroendocrine carcinoma of the nasal cavity: clinico-pathologic and molecular study of a case and review of the literature. Head Neck Pathol 7:76-84PubMedCrossRef
50.
Finzi G, Cerati M, Marando A, Zoia C, Ferreli F, Tomei G, Castelnuovo P, La Rosa S, Capella C (2014) Mixed pituitary adenoma/craniopharyngioma: clinical, morphological, immunohistochemical and ultrastructural study of a case, review of the literature, and pathogenetic and nosological considerations. Pituitary 17:53-59PubMedCrossRef
51.
Sahnane N, Furlan D, Monti M, Romualdi C, Vanoli A, Vicari E, Solcia E, Capella C, Sessa F, La Rosa S (2015) Microsatellite unstable gastrointestinal neuroendocrine carcinomas: a new clinicopathologic entity. Endocr Relat Cancer 22:35-45PubMedCrossRef
52.
Woischke C, Schaaf CW, Yang HM, Vieth M, Veits L, Geddert H, Märkl B, Stömmer P, Schaeffer DF, Frölich M, Blum H, Vosberg S, Greif PA, Jung A, Kirchner T, Horst D (2017) In-depth mutational analyses of colorectal neuroendocrine carcinomas with adenoma or adenocarcinoma components. Mod Pathol 30:95-103PubMedCrossRef
53.
Jesinghaus M, Konukiewitz B, Keller G, Kloor M, Steiger K, Reiche M, Penzel R, Endris V, Arsenic R, Hermann G, Stenzinger A, Weichert W, Pfarr N, Klöppel G (2017) Colorectal mixed adenoneuroendocrine carcinomas and neuroendocrine carcinomas are genetically closely related to colorectal adenocarcinomas. Mod Pathol 30:610-619PubMedCrossRef
54.
La Rosa S, Simbolo M, Luchini C et al (2020) MiNENs composed of adenocarcinoma and well differentiated neuroendocrine tumor have a monoclonal origin. Abstracts from USCAP 2020: Endocrine Pathology (565-611). Mod Pathol 33:720–763CrossRef
55.
Schiavo Lena M, Cangi MG, Pecciarini L, Francaviglia I, Grassini G, Maire R, Partelli S, Falconi M, Perren A, Doglioni C (2020) Evidence of a common cell origin in a case of pancreatic mixed intraductal papillary mucinous neoplasm-neuroendocrine tumor. Virchows Arch Oct 1. https://​doi.​org/​10.​1007/​s00428-020-02942-1.
56.
Lewin K (1987) Carcinoid tumors and the mixed (composite) glandular-endocrine cell carcinomas. Am J Surg Pathol 11(suppl 1):71-86PubMedCrossRef
57.
Uccella S, La Rosa S (2020) Looking into digestive mixed neuroendocrine - nonneuroendocrine neoplasms: subtypes, prognosis, and predictive factors. Histopathology 77:700-717PubMedCrossRef
58.
Huang D, Ren F, Ni S, Tan C, Weng W, Zhang M, Xu M, Wang L, Xu Q, Sheng W (2019) Amphicrine carcinoma of the stomach and intestine: a clinicopathologic and pan-cancer transcriptome analysis of a distinct entity. Cancer Cell Int 19:310PubMedPubMedCentralCrossRef
59.
Misdraji J, Carr NJ, Pai RK (2019) Appendiceal goblet cell adenocarcinoma. In: WHO Classification of Tumours Editorial Board (eds) WHO classification of tumours, 5th edn. Digestive system tumours. IARC, Lyon, pp 149–151
60.
La Rosa S, Uccella S, Molinari F, Savio A, Mete O, Vanoli A, Maragliano R, Frattini M, Mazzucchelli L, Sessa F, Bongiovanni M (2018) Mixed adenoma well-differentiated neuroendocrine tumor (MANET) of the digestive system: an indolent subtype of mixed neuroendocrine-nonneuroendocrine neoplasm (MiNEN). Am J Surg Pathol 42:1503-1512PubMedCrossRef
61.
La Rosa S, Simbolo M, Franzi F, Uccella S, Imperatori A, Nardecchia E, Rotolo N, Dominioni L, Scarpa A, Sessa F (20189 Combined adenocarcinoma-atypical carcinoid of the lung. Targeted Next-Generation Sequencing (NGS) suggests a monoclonal origin of the two components. Diagn Histopathol 24:120–123
62.
Weissferdt A (2018) Pulmonary carcinomas with mucinous and neuroendocrine differentiation: expanding the spectrum of amphicrine carcinomas. Am J Surg Pathol 42:1246-1252PubMedCrossRef
Metadata
Title
Challenges in High-grade Neuroendocrine Neoplasms and Mixed Neuroendocrine/Non-neuroendocrine Neoplasms
Author
Stefano La Rosa
Publication date
01-06-2021
Publisher
Springer US
Published in
Endocrine Pathology / Issue 2/2021
Print ISSN: 1046-3976
Electronic ISSN: 1559-0097
DOI
https://doi.org/10.1007/s12022-021-09676-z

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