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Reviews in Endocrine and Metabolic Disorders
Published in: Reviews in Endocrine and Metabolic Disorders 2/2018

01-06-2018

Multilayered heterogeneity as an intrinsic hallmark of neuroendocrine tumors

Authors: Sergio Pedraza-Arévalo, Manuel D. Gahete, Emilia Alors-Pérez, Raúl M. Luque, Justo P. Castaño

Published in: Reviews in Endocrine and Metabolic Disorders | Issue 2/2018

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Abstract

Neuroendocrine tumors (NETs) comprise a complex and highly heterogeneous group of neoplasms that can arise all over the body, originating from neuroendocrine cells. NETs are characterized by a general lack of symptoms until they are in advanced phase, and early biomarkers are not as available and useful as required. Heterogeneity is an intrinsic, pivotal feature of NETs that derives from diverse causes and ultimately shapes tumor fate. The different layers that conform NET heterogeneity include a wide range of distinct characteristics, from the mere location of the tumor to its clinical and functional features, and from its cellular properties, to the core signaling and (epi)genetic components defining the molecular signature of the tumor. The importance of this heterogeneity resides in that it translates into a high variability among tumors and, hence, patients, which hinders a more precise diagnosis and prognosis and more efficacious treatment of these diseases. In this review, we highlight the significance of this heterogeneity as an intrinsic hallmark of NETs, its repercussion on clinical approaches and tumor management, and some of the possible factors associated to such heterogeneity, including epigenetic and genetic elements, post-transcriptional regulation, or splicing alterations. Notwithstanding, heterogeneity can also represent a valuable and actionable feature, towards improving medical approaches based on personalized medicine. We conclude that NETs can no longer be viewed as a single disease entity and that their diagnosis, prognosis and treatment must reflect and incorporate this heterogeneity.
Literature
1.
Kloppel G, et al. Siegfried Oberndorfer: a tribute to his work and life between Munich, Kiel, Geneva, and Istanbul. Virchows Arch. 2007;451(Suppl 1):S3–7.PubMedCrossRef
2.
3.
Petersenn S, Koch CA. Neuroendocrine neoplasms - still a challenge despite major advances in clinical care with the development of specialized guidelines. Rev Endocr Metab Disord. 2017;18(4):373–8.PubMedCrossRef
4.
Fraenkel M, Faggiano A, Valk GD. Epidemiology of neuroendocrine tumors. Front Horm Res. 2015;44:1–23.PubMedCrossRef
5.
Dasari A, et al. Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncol. 2017;3(10):1335–42.PubMedPubMedCentralCrossRef
6.
7.
Hendifar AE, Marchevsky AM, Tuli R. Neuroendocrine tumors of the lung: current challenges and advances in the diagnosis and management of well-differentiated disease. J Thorac Oncol. 2016;12(3):425–36.PubMedCrossRef
8.
Wolin EM. Advances in the diagnosis and management of well-differentiated and intermediate-differentiated neuroendocrine tumors of the lung. Chest. 2016;151(5):1141–6.PubMedCrossRef
9.
Ramirez RA, et al. Management of pulmonary neuroendocrine tumors. Rev Endocr Metab Disord. 2017;18(4):433–42.PubMedCrossRef
10.
11.
Litvak A, Pietanza MC. Bronchial and thymic carcinoid tumors. Hematol Oncol Clin North Am. 2016;30(1):83–102.PubMedCrossRef
12.
Phan AT, et al. NANETS consensus guideline for the diagnosis and management of neuroendocrine tumors: well-differentiated neuroendocrine tumors of the thorax (includes lung and thymus). Pancreas. 2010;39(6):784–98.PubMedCrossRef
13.
Weissferdt A, Moran CA. Neuroendocrine differentiation in thymic carcinomas: a diagnostic pitfall: an immunohistochemical analysis of 27 cases. Am J Clin Pathol. 2016;145(3):393–400.PubMedCrossRef
14.
Oberg K, et al. Neuroendocrine bronchial and thymic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23(Suppl 7):vii120–3.PubMedCrossRef
15.
Kloppel G. Classification and pathology of gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer. 2011;18(Suppl 1):S1–16.PubMedCrossRef
16.
Viudez A, et al. Pancreatic neuroendocrine tumors: challenges in an underestimated disease. Crit Rev Oncol Hematol. 2016;101:193–206.PubMedCrossRef
17.
Vortmeyer AO, et al. Non-islet origin of pancreatic islet cell tumors. J Clin Endocrinol Metab. 2004;89(4):1934–8.PubMedCrossRef
18.
Anlauf M, et al. Microadenomatosis of the endocrine pancreas in patients with and without the multiple endocrine neoplasia type 1 syndrome. Am J Surg Pathol. 2006;30(5):560–74.PubMedCrossRef
19.
Morita M, et al. Conversion to neuroendocrine carcinoma from squamous cell carcinoma of the esophagus after definitive chemoradiotherapy. Anticancer Res. 2016;36(8):4045–9.PubMed
20.
21.
Scherubl H, et al. Neuroendocrine tumors of the stomach (gastric carcinoids) are on the rise: small tumors, small problems? Endoscopy. 2010;42(8):664–71.PubMedCrossRef
22.
Capelli P, Fassan M, Scarpa A. Pathology - grading and staging of GEP-NETs. Best Pract Res Clin Gastroenterol. 2012;26(6):705–17.PubMedCrossRef
23.
de Herder WW. GEP-NETS update: functional localisation and scintigraphy in neuroendocrine tumours of the gastrointestinal tract and pancreas (GEP-NETs). Eur J Endocrinol. 2014;170(5):R173–83.PubMedCrossRef
24.
Kidd M, et al. Decoding the molecular and mutational ambiguities of gastroenteropancreatic neuroendocrine neoplasm pathobiology. Cell Mol Gastroenterol Hepatol. 2015;1(2):131–53.PubMedPubMedCentralCrossRef
25.
Rindi G, Wiedenmann B. Neuroendocrine neoplasms of the gut and pancreas: new insights. Nat Rev Endocrinol. 2011;8(1):54–64.PubMedCrossRef
26.
Niederle B, et al. ENETS consensus guidelines update for neuroendocrine neoplasms of the jejunum and ileum. Neuroendocrinology. 2016;103(2):125–38.PubMedCrossRef
27.
Singer J, et al. Ectopic Cushing's syndrome caused by a well differentiated ACTH-secreting neuroendocrine carcinoma of the ileum. Exp Clin Endocrinol Diabetes. 2010;118(8):524–9.PubMedCrossRef
28.
Kojima M, et al. Neuroendocrine tumors of the large intestine: Clinicopathological features and predictive factors of lymph node metastasis. Front Oncol. 2016;6:173.PubMedPubMedCentralCrossRef
29.
Pape UF, et al. ENETS consensus guidelines for neuroendocrine neoplasms of the appendix (excluding goblet cell carcinomas). Neuroendocrinology. 2016;103(2):144–52.PubMedCrossRef
30.
Vortmeyer AO, et al. Concordance of genetic alterations in poorly differentiated colorectal neuroendocrine carcinomas and associated adenocarcinomas. J Natl Cancer Inst. 1997;89(19):1448–53.PubMedCrossRef
31.
Ramage JK, et al. ENETS consensus guidelines update for colorectal neuroendocrine neoplasms. Neuroendocrinology. 2016;103(2):139–43.PubMedCrossRef
32.
33.
Chauhan A, et al. Transition of a pancreatic neuroendocrine tumor from ghrelinoma to insulinoma: a case report. J Gastrointest Oncol. 2015;6(2):E34–6.PubMedPubMedCentral
34.
35.
Voss RK, et al. Medullary thyroid carcinoma in MEN2A: ATA moderate- or high-risk RET mutations do not predict disease aggressiveness. J Clin Endocrinol Metab. 2017;102(8):2807–13.PubMedPubMedCentralCrossRef
36.
Raue F, et al. Long-term survivorship in multiple endocrine neoplasia type 2B diagnosed before and in the new millennium. J Clin Endocrinol Metab. 2018;103(1):235–43.PubMedCrossRef
37.
DeLellis RA, et al. Medullary thyroid carcinoma. In: Lloyd R, Osamura RY, Kloppel G, Rosai J, editors. WHO classification of Tumours of endocrine organs. 4th ed. Lyon: IARC; 2017. p. 108–13.
38.
Eloy C, et al. Small cell tumors of the thyroid gland: a review. Int J Surg Pathol. 2014;22(3):197–201.PubMedCrossRef
39.
Starker LF, et al. Expression and somatic mutations of SDHAF2 (SDH5), a novel endocrine tumor suppressor gene in parathyroid tumors of primary hyperparathyroidism. Endocrine. 2010;38(3):397–401.PubMedCrossRef
40.
Matias-Guiu X, et al. Paraganglioma and mesenchymal/stromal tumours. In: Lloyd R, Osamura RY, Kloppel G, Rosai J, editors. WHO Classification of Tumours of Endocrine Organs, 4th ed. Lyon: IARC; 2017. p. 127.
41.
DeLellis RA, Erickson LA, Thompson LDR. Secondary, mesenchymal and other tumours. In: Lloyd R, Osamura RY, Kloppel G, Rosai J, editors. WHO Classification of Tumours of Endocrine Organs, 4th ed. Lyon: IARC; 2017. p. 159.
42.
Strosberg JR. Update on the management of unusual neuroendocrine tumors: pheochromocytoma and paraganglioma, medullary thyroid cancer and adrenocortical carcinoma. Semin Oncol. 2013;40(1):120–33.PubMedCrossRef
43.
Favier J, Amar L, Gimenez-Roqueplo AP. Paraganglioma and phaeochromocytoma: from genetics to personalized medicine. Nat Rev Endocrinol. 2015;11(2):101–11.PubMedCrossRef
44.
Pacak K, Teila SH. Pheochromocytoma and paraganglioma. In: De Groot LJ, et al., editors. Endotext. South Dartmouth: MDText.com, Inc.; 2018.
45.
Kimura N, et al. Tumours of the adrenal medulla and extraadrenal paraganglia. In: Lloyd RV, Osamura RY, Kloppel G, Rosai J, editors. WHO classification of Tumours of endocrine organs. 4th ed. Lyon: IARC; 2017. p. 179–206.
46.
Tischler AS, de Krijger RR. Phaeochromocytoma. In: Lloyd R, Osamura RY, Kloppel G, Rosai J, editors. WHO Classification of Tumors of Endocrine Organs, 4h ed. Lyon: IARC; 2017. p. 183–9.
47.
Kimura N, Capella C. Extraadrenal paraganglioma. In: Lloyd R, Osamura RY, Kloppel G, Rosai J, editors. WHO classification of Tumours of endocrine organs. 4th ed. Lyon: IARC; 2017. p. 190–5.
48.
49.
Kouba E, Cheng L. Neuroendocrine tumors of the urinary bladder according to the 2016 World Health Organization classification: molecular and clinical characteristics. Endocr Pathol. 2016;27(3):188–99.PubMedCrossRef
50.
Priemer DS, et al. Neuroendocrine tumors of the prostate: emerging insights from molecular data and updates to the 2016 World Health Organization classification. Endocr Pathol. 2016;27(2):123–35.PubMedCrossRef
51.
Kwon YS, Im KS, Choi DI. Ovarian large cell neuroendocrine carcinoma in the youngest woman. Eur J Gynaecol Oncol. 2016;37(2):244–6.PubMed
52.
53.
Ganesan R, et al. Neuroendocrine carcinoma of the cervix: review of a series of cases and correlation with outcome. Int J Surg Pathol. 2016;24(6):490–6.PubMedCrossRef
54.
Koch CA, et al. Carcinoid syndrome caused by an atypical carcinoid of the uterine cervix. J Clin Endocrinol Metab. 1999;84(11):4209–13.PubMedCrossRef
55.
Adams RW, Dyson P, Barthelmes L. Neuroendocrine breast tumours: breast cancer or neuroendocrine cancer presenting in the breast? Breast. 2014;23(2):120–7.PubMedCrossRef
56.
Asioli S, et al. Working formulation of neuroendocrine tumors of the skin and breast. Endocr Pathol. 2014;25(2):141–50.PubMedCrossRef
57.
Lubana SS, et al. Primary neuroendocrine tumor (carcinoid tumor) of the testis: a case report with review of literature. Am J Case Rep. 2015;16:328–32.PubMedPubMedCentralCrossRef
58.
Aung PP, et al. Primary neuroendocrine tumors of the kidney: morphological and molecular alterations of an uncommon malignancy. Hum Pathol. 2013;44(5):873–80.PubMedCrossRef
59.
Yamagata K, et al. A rare primary neuroendocrine tumor (typical carcinoid) of the sublingual gland. Case Rep Dent. 2016;7462690:2016.
60.
Iype S, et al. Neuroendocrine tumours of the gallbladder: three cases and a review of the literature. Postgrad Med J. 2009;85(1002):213–8.PubMedCrossRef
61.
Thar YY, et al. An extremely rare case of advanced metastatic small cell neuroendocrine carcinoma of sinonasal tract. Case Rep Oncol Med. 2016;1496916:2016.
62.
Coriat R, et al. Gastroenteropancreatic well-differentiated grade 3 neuroendocrine tumors: review and position statement. Oncologist. 2016;21(10):1191–9.PubMedPubMedCentralCrossRef
63.
de Mestier L, et al. Digestive system mixed neuroendocrine-non-neuroendocrine neoplasms. Neuroendocrinology. 2017;105(4):412–25.PubMedCrossRef
64.
Scoazec JY, Couvelard A. Classification of pancreatic neuroendocrine tumours: changes made in the 2017 WHO classification of tumours of endocrine organs and perspectives for the future. Ann Pathol. 2017;37(6):444–56.PubMedCrossRef
65.
Travis WD, et al. The 2015 World Health Organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol. 2015;10(9):1243–60.CrossRefPubMed
66.
Caplin ME, et al. Pulmonary neuroendocrine (carcinoid) tumors: European neuroendocrine tumor society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids. Ann Oncol. 2015;26(8):1604–20.PubMedCrossRef
67.
Inzani F, et al. Cyto-histology in NET: what is necessary today and what is the future? Rev Endocr Metab Disord. 2017;18(4):381–91.PubMedCrossRef
68.
Nunez-Valdovinos B, et al. Neuroendocrine tumor heterogeneity adds uncertainty to the World Health Organization 2010 classification: real-world data from the Spanish tumor registry (R-GETNE). Oncologist. 2018;23(4):422–32.PubMedCrossRefPubMedCentral
69.
Trantakis C, et al. Acromegaly caused by a thoracic neuroendocrine tumor. Exp Clin Endocrinol Diabetes. 2005:113–58.
70.
Koch CA. Cushing's syndrome and glucocorticoid excess. In: Berbari AE, Mancia G, editors. Disorders of blood pressure regulation. New York: Springer; 2018. p. 481–512.CrossRef
71.
Falconi M, et al. ENETS consensus guidelines update for the management of patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic neuroendocrine tumors. Neuroendocrinology. 2016;103(2):153–71.PubMedCrossRef
72.
Vinik A. Diffuse hormonal systems. In: De Groot LJ, et al., editors. Endotext. South Dartmouth: MDText.com, Inc.; 2017.
73.
Vinik A, et al. Carcinoid tumors. In: De Groot LJ, et al., editors. Endotext. South Dartmouth: MDText.com, Inc.; 2018.
74.
Amin S, Kim MK. Islet cell tumors of the pancreas. Gastroenterol Clin N Am. 2016;45(1):83–100.CrossRef
75.
Cloyd JM, Poultsides GA. Non-functional neuroendocrine tumors of the pancreas: advances in diagnosis and management. World J Gastroenterol. 2015;21(32):9512–25.PubMedPubMedCentralCrossRef
76.
Boutzios G, Kaltsas G. Clinical syndromes related to gastrointestinal neuroendocrine neoplasms. Front Horm Res. 2015;44:40–57.PubMedCrossRef
77.
Dimitriadis GK, et al. Medical management of secretory syndromes related to gastroenteropancreatic neuroendocrine tumours. Endocr Relat Cancer. 2016;23(9):R423–36.PubMedCrossRef
78.
Verbeek WH, Korse CM, Tesselaar ME. GEP-NETs UPDATE: Secreting gastro-enteropancreatic neuroendocrine tumours and biomarkers. Eur J Endocrinol. 2016;174(1):R1–7.PubMedCrossRef
79.
Luis SA, Pellikka PA. Carcinoid heart disease: diagnosis and management. Best Pract Res Clin Endocrinol Metab. 2016;30(1):149–58.PubMedCrossRef
80.
81.
Granberg D. Biochemical testing in patients with neuroendocrine tumors. Front Horm Res. 2015;44:24–39.PubMedCrossRef
82.
83.
84.
Chan J, Kulke M. Targeting the mTOR signaling pathway in neuroendocrine tumors. Curr Treat Options in Oncol. 2014;15(3):365–79.CrossRef
85.
Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011;12(1):21–35.PubMedCrossRef
86.
Starker LF, Carling T. Molecular genetics of gastroenteropancreatic neuroendocrine tumors. Curr Opin Oncol. 2009;21(1):29–33.PubMedCrossRef
87.
Perren A, et al. Mutation and expression analyses reveal differential subcellular compartmentalization of PTEN in endocrine pancreatic tumors compared to normal islet cells. Am J Pathol. 2000;157(4):1097–103.PubMedPubMedCentralCrossRef
88.
89.
Sunaga N, et al. Knockdown of oncogenic KRAS in non-small cell lung cancers suppresses tumor growth and sensitizes tumor cells to targeted therapy. Mol Cancer Ther. 2011;10(2):336–46.PubMedPubMedCentralCrossRef
90.
Lea IA, et al. Genetic pathways and mutation profiles of human cancers: site- and exposure-specific patterns. Carcinogenesis. 2007;28(9):1851–8.PubMedCrossRef
91.
92.
93.
Dorantes-Heredia R, Ruiz-Morales JM, Cano-Garcia F. Histopathological transformation to small-cell lung carcinoma in non-small cell lung carcinoma tumors. Transl Lung Cancer Res. 2016;5(4):401–12.PubMedPubMedCentralCrossRef
94.
Crona J, Skogseid B. GEP- NETS UPDATE: genetics of neuroendocrine tumors. Eur J Endocrinol. 2016;174(6):R275–90.PubMedCrossRef
95.
Yates CJ, Newey PJ, Thakker RV. Challenges and controversies in management of pancreatic neuroendocrine tumours in patients with MEN1. Lancet Diabetes Endocrinol. 2015;3(11):895–905.PubMedCrossRef
96.
Wells SA Jr, et al. Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update. J Clin Endocrinol Metab. 2013;98(8):3149–64.PubMedPubMedCentralCrossRef
97.
Brauer VF, et al. RET germline mutation in codon 791 in a family representing 3 generations from age 5 to age 70 years: should thyroidectomy be performed? Endocr Pract. 2004;10(1):5–9.PubMedCrossRef
98.
99.
Uccella S, et al. Immunohistochemical biomarkers of gastrointestinal, pancreatic, pulmonary, and thymic neuroendocrine neoplasms. Endocr Pathol. 2018;29(2):150–68.PubMedCrossRef
100.
Delle Fave G, et al. ENETS consensus guidelines update for gastroduodenal neuroendocrine neoplasms. Neuroendocrinology. 2016;103(2):119–24.PubMedCrossRef
101.
Garcia-Carbonero R, et al. ENETS consensus guidelines for high-grade gastroenteropancreatic neuroendocrine tumors and neuroendocrine carcinomas. Neuroendocrinology. 2016;103(2):186–94.PubMedCrossRef
102.
Chan DL, et al. Prognostic and predictive biomarkers in neuroendocrine tumours. Crit Rev Oncol Hematol. 2017;113:268–82.PubMedCrossRef
103.
Moreira RK, Washington K. Pathology of gastrointestinal neuroendocrine tumors: an update. Surg Pathol Clin. 2010;3(2):327–47.PubMedCrossRef
104.
Auernhammer CJ, et al. Advanced neuroendocrine tumours of the small intestine and pancreas: clinical developments, controversies, and future strategies. Lancet Diabetes Endocrinol. 2018;6(5):404–15.PubMedCrossRef
105.
Oberg K, et al. ENETS consensus guidelines for standard of care in neuroendocrine tumours: biochemical markers. Neuroendocrinology. 2017;105(3):201–11.PubMedCrossRef
106.
Mafficini A, Scarpa A. Genomic landscape of pancreatic neuroendocrine tumours: the international cancer genome consortium. J Endocrinol. 2018;236(3):R161–7.PubMedPubMedCentralCrossRef
107.
108.
109.
Scarpa A, et al. Whole-genome landscape of pancreatic neuroendocrine tumours. Nature. 2017;543(7643):65–71.PubMedCrossRef
110.
Fishbein L, et al. Whole-exome sequencing identifies somatic ATRX mutations in pheochromocytomas and paragangliomas. Nat Commun. 2015;6:6140.PubMedCrossRef
111.
Dreijerink KMA, Timmers HTM, Brown M. Twenty years of menin: emerging opportunities for restoration of transcriptional regulation in MEN1. Endocr Relat Cancer. 2017;24(10):T135–45.PubMedPubMedCentralCrossRef
112.
Capdevila J, et al. Translational research in neuroendocrine tumors: pitfalls and opportunities. Oncogene. 2016;36(14):1899–907.PubMedCrossRef
113.
114.
Else T. 15 YEARS OF PARAGANGLIOMA: Pheochromocytoma, paraganglioma and genetic syndromes: a historical perspective. Endocr Relat Cancer. 2015;22(4):T147–59.PubMedCrossRef
115.
Comino-Mendez I, et al. ATRX driver mutation in a composite malignant pheochromocytoma. Cancer Genet. 2016;209(6):272–7.PubMedCrossRef
116.
Ladd-Acosta C, Fallin MD. The role of epigenetics in genetic and environmental epidemiology. Epigenomics. 2016;8(2):271–83.PubMedCrossRef
117.
Karpathakis A, Dibra H, Thirlwell C. Neuroendocrine tumours: cracking the epigenetic code. Endocr Relat Cancer. 2013;20(3):R65–82.PubMedCrossRef
118.
House MG, et al. Aberrant hypermethylation of tumor suppressor genes in pancreatic endocrine neoplasms. Ann Surg. 2003;238(3):423–31 discussion 431-2.PubMedPubMedCentralCrossRef
119.
Pizzi S, et al. RASSF1A promoter methylation and 3p21.3 loss of heterozygosity are features of foregut, but not midgut and hindgut, malignant endocrine tumours. J Pathol. 2005;206(4):409–16.PubMedCrossRef
120.
Liu L, et al. Epigenetic alterations in neuroendocrine tumors: methylation of RAS-association domain family 1, isoform a and p16 genes are associated with metastasis. Mod Pathol. 2005;18(12):1632–40.PubMedCrossRef
121.
Dejeux E, et al. Hypermethylation of the IGF2 differentially methylated region 2 is a specific event in insulinomas leading to loss-of-imprinting and overexpression. Endocr Relat Cancer. 2009;16(3):939–52.PubMedCrossRef
122.
Chan AO, et al. CpG island methylation in carcinoid and pancreatic endocrine tumors. Oncogene. 2003;22(6):924–34.PubMedCrossRef
123.
Mapelli P, et al. Epigenetic changes in gastroenteropancreatic neuroendocrine tumours. Oncogene. 2015;34(34):4439–47.PubMedCrossRef
124.
Pelosi G, et al. Dual role of RASSF1 as a tumor suppressor and an oncogene in neuroendocrine tumors of the lung. Anticancer Res. 2010;30(10):4269–81.PubMed
125.
How-Kit A, et al. DNA methylation profiles distinguish different subtypes of gastroenteropancreatic neuroendocrine tumors. Epigenomics. 2015;7(8):1245–58.PubMedCrossRef
126.
Modlin IM, Bodei L, Kidd M. Neuroendocrine tumor biomarkers: from monoanalytes to transcripts and algorithms. Best Pract Res Clin Endocrinol Metab. 2016;30(1):59–77.PubMedCrossRef
127.
128.
Roldo C, et al. MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors are associated with distinctive pathologic features and clinical behavior. J Clin Oncol. 2006;24(29):4677–84.PubMedCrossRef
129.
Ruebel K, et al. MicroRNA expression in ileal carcinoid tumors: downregulation of microRNA-133a with tumor progression. Mod Pathol. 2010;23(3):367–75.PubMedCrossRef
130.
Amaral T, Leiter U, Garbe C. Merkel cell carcinoma: epidemiology, pathogenesis, diagnosis and therapy. Rev Endocr Metab Disord. 2017;18(4):517–32.PubMedCrossRef
131.
132.
Mairinger FD, et al. Different micro-RNA expression profiles distinguish subtypes of neuroendocrine tumors of the lung: results of a profiling study. Mod Pathol. 2014;27(12):1632–40.PubMedCrossRef
133.
Modali SD, et al. Epigenetic regulation of the lncRNA MEG3 and its target c-MET in pancreatic neuroendocrine tumors. Mol Endocrinol. 2015;29(2):224–37.PubMedPubMedCentralCrossRef
134.
135.
136.
137.
Zhou HL, et al. Regulation of alternative splicing by local histone modifications: potential roles for RNA-guided mechanisms. Nucleic Acids Res. 2014;42(2):701–13.PubMedCrossRef
138.
Bechara EG, et al. RBM5, 6, and 10 differentially regulate NUMB alternative splicing to control cancer cell proliferation. Mol Cell. 2013;52(5):720–33.PubMedCrossRef
139.
Babic I, et al. EGFR mutation-induced alternative splicing of max contributes to growth of glycolytic tumors in brain cancer. Cell Metab. 2013;17(6):1000–8.PubMedPubMedCentralCrossRef
140.
141.
Luque RM, et al. In1-ghrelin, a splice variant of ghrelin gene, is associated with the evolution and aggressiveness of human neuroendocrine tumors: evidence from clinical, cellular and molecular parameters. Oncotarget. 2015;6(23):19619–33.PubMedPubMedCentralCrossRef
142.
Sampedro-Nunez M, et al. Presence of sst5TMD4, a truncated splice variant of the somatostatin receptor subtype 5, is associated to features of increased aggressiveness in pancreatic neuroendocrine tumors. Oncotarget. 2016;7(6):6593–608.PubMedCrossRef
143.
Chaudhry A, et al. Different splice variants of CD44 are expressed in gastrinomas but not in other subtypes of endocrine pancreatic tumors. Cancer Res. 1994;54(4):981–6.PubMed
144.
Terris B, et al. Increased expression of CD44v6 in endocrine pancreatic tumours but not in midgut carcinoid tumours. Clin Mol Pathol. 1996;49(4):M203–8.PubMedPubMedCentralCrossRef
145.
Miyanaga A, et al. Diagnostic and prognostic significance of the alternatively spliced ACTN4 variant in high-grade neuroendocrine pulmonary tumours. Ann Oncol. 2013;24(1):84–90.PubMedCrossRef
146.
Edmond V, et al. A new function of the splicing factor SRSF2 in the control of E2F1-mediated cell cycle progression in neuroendocrine lung tumors. Cell Cycle. 2013;12(8):1267–78.PubMedPubMedCentralCrossRef
147.
Cives M, Soares HP, Strosberg J. Will clinical heterogeneity of neuroendocrine tumors impact their management in the future? Lessons from recent trials. Curr Opin Oncol. 2016;28(4):359–66.PubMedCrossRef
148.
Rickman DS, et al. Biology and evolution of poorly differentiated neuroendocrine tumors. Nat Med. 2017;23(6):1–10.PubMedCrossRef
149.
Cwikla JB, et al. Circulating transcript analysis (NETest) in GEP-NETs treated with somatostatin analogs defines therapy. J Clin Endocrinol Metab. 2015;100(11):E1437–45.PubMedCrossRef
150.
Bowden M, et al. Profiling of metastatic small intestine neuroendocrine tumors reveals characteristic miRNAs detectable in plasma. Oncotarget. 2017;8(33):54331–44.PubMedPubMedCentralCrossRef
151.
Kim ST, et al. Genomic profiling of metastatic gastroenteropancreatic neuroendocrine tumor (GEP-NET) patients in the personalized-medicine era. J Cancer. 2016;7(9):1044–8.PubMedPubMedCentralCrossRef
152.
153.
154.
Pavel M, de Herder WW. ENETS consensus guidelines for the standard of care in neuroendocrine tumors. Neuroendocrinology. 2017;105(3):193–5.PubMedCrossRef
155.
Kulke MH, et al. Neuroendocrine tumors. J Natl Compr Cancer Netw. 2012;10(6):724–64.CrossRef
156.
Pavel ME, Sers C. Women in cancer thematic review: Systemic therapies in neuroendocrine tumors and novel approaches toward personalized medicine. Endocr Relat Cancer. 2016;23(11):T135–54.PubMedCrossRef
157.
Pavel M, et al. ENETS consensus guidelines update for the management of distant metastatic disease of intestinal, pancreatic, bronchial neuroendocrine neoplasms (NEN) and NEN of unknown primary site. Neuroendocrinology. 2016;103(2):172–85.PubMedCrossRef
158.
Modlin IM, et al. Review article: somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours. Aliment Pharmacol Ther. 2010;31(2):169–88.PubMed
159.
Berardi R, et al. Gastrointestinal neuroendocrine tumors: searching the optimal treatment strategy--a literature review. Crit Rev Oncol Hematol. 2016;98:264–74.PubMedCrossRef
160.
Kim SJ, et al. The efficacy of (177)Lu-labelled peptide receptor radionuclide therapy in patients with neuroendocrine tumours: a meta-analysis. Eur J Nucl Med Mol Imaging. 2015;42(13):1964–70.PubMedCrossRef
161.
Parghane RV, et al. Clinical response profile of metastatic/advanced pulmonary neuroendocrine tumors to peptide receptor radionuclide therapy with 177Lu-DOTATATE. Clin Nucl Med. 2017;42(6):428–35.PubMedCrossRef
162.
Castaño JP, et al. Gastrointestinal neuroendocrine tumors (NETs): new diagnostic and therapeutic challenges. Cancer Metastasis Rev. 2014;33(1):353–9.PubMedCrossRef
163.
Reubi JC, Schonbrunn A. Illuminating somatostatin analog action at neuroendocrine tumor receptors. Trends Pharmacol Sci. 2013;34(12):676–88.PubMedCrossRef
164.
Herrera-Martinez AD, et al. The components of somatostatin and ghrelin systems are altered in neuroendocrine lung carcinoids and associated to clinical-histological features. Lung Cancer. 2017;109:128–36.PubMedCrossRef
165.
Herrera-Martinez AD, et al. Clinical and functional implication of the components of somatostatin system in gastroenteropancreatic neuroendocrine tumors. Endocrine. 2018;59(2):426–37.PubMedCrossRef
166.
Mangano A, et al. New horizons for targeted treatment of neuroendocrine tumors. Future Oncol. 2016;12(8):1059–65.PubMedCrossRef
167.
Oberg K, et al. Molecular pathogenesis of neuroendocrine tumors: implications for current and future therapeutic approaches. Clin Cancer Res. 2013;19(11):2842–9.PubMedCrossRef
168.
169.
Metadata
Title
Multilayered heterogeneity as an intrinsic hallmark of neuroendocrine tumors
Authors
Sergio Pedraza-Arévalo
Manuel D. Gahete
Emilia Alors-Pérez
Raúl M. Luque
Justo P. Castaño
Publication date
01-06-2018
Publisher
Springer US
Published in
Reviews in Endocrine and Metabolic Disorders / Issue 2/2018
Print ISSN: 1389-9155
Electronic ISSN: 1573-2606
DOI
https://doi.org/10.1007/s11154-018-9465-0

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