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Pancreatic Neuroendocrine Neoplasms pp 175–183Cite as

Molecular Pathology of Pancreatic Neuroendocrine Neoplasms

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Abstract

Pancreatic neuroendocrine neoplasms (PanNENs) are a heterogeneous group of lesions exhibiting different genetic and epigenetic characteristics that affect the biological behavior of the tumor. Due in large part to their relative scarcity, the study of the cellular and molecular biology of PanNENs has been challenging, and it has lagged behind that of other more common cancers. However, after decades of slight improvements, the recent application of modern molecular techniques such as gene expression profiling and high-throughput DNA sequencing has shown promising potential in the identification of the molecular features of PanNENs. The current status and recent advances in the assessment of the genetic and epigenetic features of pancreatic neuroendocrine tumors (PanNETs) and of pancreatic neuroendocrine carcinomas (PanNECs) will be reviewed.

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References

  1. Jensen RT, Berna MJ, Bingham DB et al (2008) Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management, and controversies. Cancer 113:1807–1843

    Article  PubMed Central  PubMed  Google Scholar 

  2. Chandrasekharappa SC, Guru SC, Manickam P et al (1997) Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 276:404–407

    Article  CAS  PubMed  Google Scholar 

  3. Lemmens I, Van de Ven WJ, Kas K et al (1997) Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1. Hum Mol Genet 6:1177–1183

    Article  CAS  PubMed  Google Scholar 

  4. Wu X, Hua X (2008) Menin, histone h3 methyltransferase, and regulation of cell proliferation: current knowledge and perspective. Curr Mol Med 8:805–815

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Thakker RV, Newey PJ, Walls GV et al (2012) Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab 97:2990–3011

    Article  CAS  PubMed  Google Scholar 

  6. Zhang H, Li W, Wang Q et al (2012) Glucose-mediated repression of menin promotes pancreatic β-cell proliferation. Endocrinology 153:602–611

    Article  CAS  PubMed  Google Scholar 

  7. Wang Y, Ozawa A, Zaman S et al (2011) The tumor suppressor protein menin inhibits AKT activation by regulating its cellular localization. Cancer Res 71:371–382

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Bertolino P, Radovanovic I, Casse H et al (2003) Genetic ablation of the tumor suppressor menin causes lethality at mid-gestation with defects in multiple organs. Mech Dev 120:549–560

    Article  CAS  PubMed  Google Scholar 

  9. Bertolino P, Tong WM, Galendo D et al (2003) Heterozygous Men1 mutant mice develop a range of endocrine tumors mimicking multiple endocrine neoplasia type 1. Mol Endocrinol 17:1880–1892

    Article  CAS  PubMed  Google Scholar 

  10. Crabtree JS, Scacheri PC, Ward JM et al (2001) A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors. Proc Natl Acad Sci U S A 98:1118–1123

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Crabtree JS, Scacheri PC, Ward JM et al (2003) Of mice and MEN1: insulinomas in a conditional mouse knockout. Mol Cell Biol 23:6075–6085

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Agarwal SK, Guru SC, Heppner C et al (1999) Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription. Cell 96:143–152

    Article  CAS  PubMed  Google Scholar 

  13. Hughes CM, Rozenblatt-Rosen O, Milne TA et al (2004) Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus. Mol Cell 13:587–597

    Article  CAS  PubMed  Google Scholar 

  14. Karnik SK, Hughes CM, Gu X et al (2005) Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c. Proc Natl Acad Sci U S A 102:14659–14664

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Schnepp RW, Chen YX, Wang H et al (2006) Mutation of tumor suppressor gene Men1 acutely enhances proliferation of pancreatic islet cells. Cancer Res 66:5707–5715

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Scacheri PC, Davis S, Odom DT et al (2006) Genome-wide analysis of menin binding provides insights into MEN1 tumorigenesis. PLoS Genet 2(4):e51

    Article  PubMed Central  PubMed  Google Scholar 

  17. Agarwal SK, Impey S, McWeeney S et al (2007) Distribution of menin-occupied regions in chromatin specifies a broad role of menin in transcriptional regulation. Neoplasia 9:101–107

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Francis J, Lin W, Rozenblatt-Rosen O et al (2011) The menin tumor suppressor protein is phosphorylated in response to DNA damage. PLoS One 6:e16119

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Fang M, Xia F, Mahalingam M et al (2013) MEN1 is a melanoma tumor suppressor that preserves genomic integrity by stimulating transcription of genes that promote homologous recombination-directed DNA repair. Mol Cell Biol 33:2635–2647

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Lonser RR, Glenn GM, Walther M et al (2003) von Hippel-Lindau disease. Lancet 361:2059–2067

    Article  CAS  PubMed  Google Scholar 

  21. Mukhopadhyay B, Sahdev A, Monson JP et al (2002) Pancreatic lesions in von Hippel-Lindau disease. Clin Endocrinol (Oxf) 57:603–608

    Article  CAS  Google Scholar 

  22. Corcos O, Couvelard A, Giraud S et al (2008) Endocrine pancreatic tumors in von Hippel-Lindau disease: clinical, histological, and genetic features. Pancreas 37:85–93

    Article  CAS  PubMed  Google Scholar 

  23. Latif F, Tory K, Gnarra J et al (1993) Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260:1317–1320

    Article  CAS  PubMed  Google Scholar 

  24. Hoang MP, Hruban RH, Albores-Saavedra J (2001) Clear cell endocrine pancreatic tumor mimicking renal cell carcinoma: a distinctive neoplasm of von Hippel-Lindau disease. Am J Surg Pathol 125:602–609

    Article  Google Scholar 

  25. Libutti SK, Choyke PL, Bartlett DL et al (1998) Pancreatic neuroendocrine tumors associated with von Hippel-Lindau disease: diagnostic and management recommendations. Surgery 124:1153–1159

    Article  CAS  PubMed  Google Scholar 

  26. Lee S, Chen DY, Humphrey JS et al (1996) Nuclear/cytoplasmic localization of the von Hippel-Lindau tumor suppressor gene product is determined by cell density. Proc Natl Acad Sci U S A 93:1770–1775

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Pause A, Lee S, Worrell RA et al (1997) The von Hippel-Lindau tumor-suppressor gene product forms a stable complex with human CUL-2, a member of the Cdc53 family of proteins. Proc Natl Acad Sci U S A 94:2156–2161

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Kaelin WG Jr (2002) Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer 2:673–682

    Article  CAS  PubMed  Google Scholar 

  29. Maxwell PH, Wiesener MS, Chang GW et al (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:271–275

    Article  CAS  PubMed  Google Scholar 

  30. Carmeliet P, Dor Y, Herbert JM et al (1998) Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394:485–490

    Article  CAS  PubMed  Google Scholar 

  31. Kim WY, Kaelin WG (2004) Role of VHL gene mutation in human cancer. J Clin Oncol 22:4991–5004

    Article  CAS  PubMed  Google Scholar 

  32. Crossey PA, Richards FM, Foster K et al (1994) Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype. Hum Mol Genet 3:1303–1308

    Article  CAS  PubMed  Google Scholar 

  33. Webster AR, Richards FM, MacRonald FE et al (1998) An analysis of phenotypic variation in the familial cancer syndrome von Hippel-Lindau disease: evidence for modifier effects. Am J Hum Genet 63:1025–1035

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Sgambati MT, Stolle C, Choyke PL et al (2000) Mosaicism in von Hippel-Lindau disease: lessons from kindreds with germline mutations identified in offspring with mosaic parents. Am J Hum Genet 66:84–91

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Brauch H, Kishida T, Glavac D et al (2005) Von Hippel-Lindau (VHL) disease with pheochromocytoma in the Black Forest region of Germany: evidence for a founder effect. Hum Genet 95:551–556

    Article  Google Scholar 

  36. Prowse AH, Webster AR, Richard FM et al (1997) Somatic inactivation of the VHL gene in von Hippel-Lindau disease tumors. Am J Hum Genet 60:765–771

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Speisky D, Duces A, Bièche I et al (2012) Molecular profiling of pancreatic neuroendocrine tumors in sporadic and Von Hippel-Lindau patients. Clin Cancer Res 18:2838–2849

    Article  CAS  PubMed  Google Scholar 

  38. McClatchey AI (2007) Neurofibromatosis. Annu Rev Pathol 2:191–216

    Article  CAS  PubMed  Google Scholar 

  39. European Chromosome 16 Tuberous Sclerosis Consortium (1993) Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 75:1305–1315

    Article  Google Scholar 

  40. van Slegtenhorst M, de Hoogt R, Hermans C et al (1997) Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 277:805–808

    Article  PubMed  Google Scholar 

  41. Arva NC, Pappas JG, Bhatla T et al (2012) Well-differentiated pancreatic neuroendocrine carcinoma in tuberous sclerosis–case report and review of the literature. Am J Surg Pathol 36:149–153

    Article  PubMed  Google Scholar 

  42. Tee AR, Fingar DC, Manning BD et al (2002) Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proc Natl Acad Sci U S A 99:13571–13576

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  43. Perren A, Anlauf M, Henopp T et al (2007) Multiple endocrine neoplasia type 1 (MEN1): loss of one MEN1 allele in tumors and monohormonal endocrine cell clusters but not in islet hyperplasia of the pancreas. J Clin Endocrinol Metab 92:1118–1128

    Article  CAS  PubMed  Google Scholar 

  44. Hessman O, Lindberg D, Einarsson A et al (1999) Genetic alterations on 3p, 11q13, and 18q in nonfamilial and MEN 1-associated pancreatic endocrine tumors. Genes Chromosomes Cancer 26:258–264

    Article  CAS  PubMed  Google Scholar 

  45. Corbo V, Dalai I, Scardoni M et al (2010) MEN1 in pancreatic endocrine tumors: analysis of gene and protein status in 169 sporadic neoplasms reveals alterations in the vast majority of cases. Endocr Relat Cancer 17:771–783

    Article  CAS  PubMed  Google Scholar 

  46. Görtz B, Roth J, Krähenmann A et al (1999) Mutations and allelic deletions of the MEN1 gene are associated with a subset of sporadic endocrine pancreatic and neuroendocrine tumors and not restricted to foregut neoplasms. Am J Pathol 154:429–436

    Article  PubMed Central  PubMed  Google Scholar 

  47. D’adda T, Pizzi S, Azzoni C et al (2002) Different patterns of 11q allelic losses in digestive endocrine tumors. Hum Pathol 33:322–329

    Article  PubMed  Google Scholar 

  48. Debelenko LV, Zhuang Z, Emmert-Buck MR et al (1997) Allelic deletions on chromosome 11q13 in multiple endocrine neoplasia type 1-associated and sporadic gastrinomas and pancreatic endocrine tumors. Cancer Res 57:2238–2243

    CAS  PubMed  Google Scholar 

  49. Pizzi S, Azzoni C, Bassi D et al (2003) Genetic alterations in poorly differentiated endocrine carcinomas of the gastrointestinal tract. Cancer 98:1273–1282

    Article  CAS  PubMed  Google Scholar 

  50. Toliat MR, Berger W, Ropers HH et al (1997) Mutations in the MEN I gene in sporadic neuroendocrine tumours of gastroenteropancreatic system. Lancet 350:1223

    CAS  PubMed  Google Scholar 

  51. Capelli P, Martignoni G, Pedica F et al (2009) Endocrine neoplasms of the pancreas: pathologic and genetic features. Arch Pathol Lab Med 133:350–364

    PubMed  Google Scholar 

  52. Zhuang Z, Vortmeyer AO, Pack S et al (1997) Somatic mutations of the MEN1 tumor suppressor gene in sporadic gastrinomas and insulinomas. Cancer Res 57:4682–4686

    CAS  PubMed  Google Scholar 

  53. Schmitt AM, Schmid S, Rudolph T et al (2009) VHL inactivation is an important pathway for the development of malignant sporadic pancreatic endocrine tumors. Endocr Relat Cancer 16:1219–1227

    Article  CAS  PubMed  Google Scholar 

  54. Chung DC, Smith AP, Louis DN et al (1997) A novel pancreatic endocrine tumor suppressor gene locus on chromosome 3p with clinical prognostic implications. J Clin Invest 100:404–410

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  55. Barghorn A, Komminoth P, Bachmann D et al (2001) Deletion at 3p25.3-p23 is frequently encountered in endocrine pancreatic tumors and is associated with metastatic progression. J Pathol 194:451–458

    Article  CAS  PubMed  Google Scholar 

  56. Missiaglia E, Dalai I, Barbi S et al (2010) Pancreatic endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway. J Clin Oncol 28:245–255

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Jiao Y, Shi C, Edil BH et al (2011) DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 331:1199–1203

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  58. Goldberg AD, Banaszynski LA, Noh KM et al (2010) Distinct factors control histone variant H3.3 localization at specific genomic regions. Cell 140:678–691

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  59. Lewis PW, Elsaesser SJ, Noh KM et al (2010) Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres. Proc Natl Acad Sci U S A 107:14075–14080

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  60. Heaphy CM, de Wilde RF, Jiao Y et al (2011) Altered telomeres in tumors with ATRX and DAXX mutations. Science 333(6041):425

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. Heaphy CM, Subhawong AP, Hong SM et al (2011) Prevalence of the alternative lengthening of telomeres telomere maintenance mechanism in human cancer subtypes. Am J Pathol 179:1608–1615

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Shay JW, Reddel RR, Wright WE (2012) Cancer. Cancer and telomeres-an ALTernative to telomerase. Science 336:1388–1390

    Article  CAS  PubMed  Google Scholar 

  63. de Wilde RF, Heaphy CM, Maitra A et al (2012) Loss of ATRX or DAXX expression and concomitant acquisition of the alternative lengthening of telomeres phenotype are late events in a small subset of MEN-1 syndrome pancreatic neuroendocrine tumors. Mod Pathol 25:1033–1039

    Article  PubMed Central  PubMed  Google Scholar 

  64. Beghelli S, Pelosi G, Zamboni G et al (1998) Pancreatic endocrine tumours: evidence for a tumour suppressor pathogenesis and for a tumour suppressor gene on chromosome 17p. J Pathol 186:41–50

    Article  CAS  PubMed  Google Scholar 

  65. Speel EJ, Richter J, Moch H et al (1999) Genetic differences in endocrine pancreatic tumor subtypes detected by comparative genomic hybridization. Am J Pathol 155:1787–1794

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Speel EJ, Scheidweiler AF, Zhao J et al (2001) Genetic evidence for early divergence of small functioning and nonfunctioning endocrine pancreatic tumors: gain of 9Q34 is an early event in insulinomas. Cancer Res 61:5186–5192

    CAS  PubMed  Google Scholar 

  67. Zhao J, Moch H, Scheidweiler AF et al (2001) Genomic imbalances in the progression of endocrine pancreatic tumors. Genes Chromosomes Cancer 32:364–372

    Article  CAS  PubMed  Google Scholar 

  68. Rigaud G, Missiaglia E, Moore PS et al (2001) High resolution allelotype of nonfunctional pancreatic endocrine tumors: identification of two molecular subgroups with clinical implications. Cancer Res 61:285–292

    CAS  PubMed  Google Scholar 

  69. Jonkers YM, Claessen SM, Perren A et al (2005) Chromosomal instability predicts metastatic disease in patients with insulinomas. Endocr Relat Cancer 12:435–447

    Article  CAS  PubMed  Google Scholar 

  70. Nagano Y, Kim do H, Zhang L et al (2007) Allelic alterations in pancreatic endocrine tumors identified by genome-wide single nucleotide polymorphism analysis. Endocr Relat Cancer 14:483–492

    Article  CAS  PubMed  Google Scholar 

  71. Kim do H, Nagano Y, Choi IS et al (2008) Allelic alterations in well-differentiated neuroendocrine tumors (carcinoid tumors) identified by genome-wide single nucleotide polymorphism analysis and comparison with pancreatic endocrine tumors. Genes Chromosomes Cancer 47:84–92

    Article  PubMed  Google Scholar 

  72. Floridia G, Grilli G, Salvatore M et al (2005) Chromosomal alterations detected by comparative genomic hybridization in nonfunctioning endocrine pancreatic tumors. Cancer Genet Cytogenet 156:23–30

    Article  CAS  PubMed  Google Scholar 

  73. Guo SS, Arora C, Shimoide AT et al (2002) Frequent deletion of chromosome 3 in malignant sporadic pancreatic endocrine tumors. Mol Cell Endocrinol 190:109–114

    Article  CAS  PubMed  Google Scholar 

  74. Ebrahimi SA, Wang EH, Wu A et al (1999) Deletion of chromosome 1 predicts prognosis in pancreatic endocrine tumors. Cancer Res 59:311–315

    CAS  PubMed  Google Scholar 

  75. Chung DC, Brown SB, Graeme-Cook F et al (1998) Localization of putative tumor suppressor loci by genome-wide allelotyping in human pancreatic endocrine tumors. Cancer Res 58:3706–3711

    CAS  PubMed  Google Scholar 

  76. Chen YJ, Vortmeyer A, Zhuang Z et al (2003) Loss of heterozygosity of chromosome 1q in gastrinomas: occurrence and prognostic significance. Cancer Res 63:817–823

    CAS  PubMed  Google Scholar 

  77. Barghorn A, Speel EJ, Farspour B et al (2001) Putative tumor suppressor loci at 6q22 and 6q23-q24 are involved in the malignant progression of sporadic endocrine pancreatic tumors. Am J Pathol 158:1903–1911

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  78. Yang YM, Liu TH, Chen YJ et al (2005) Chromosome 1q loss of heterozygosity frequently occurs in sporadic insulinomas and is associated with tumor malignancy. Int J Cancer 117:234–240

    Article  CAS  PubMed  Google Scholar 

  79. Jonkers YM, Claessen SM, Veltman JA et al (2006) Molecular parameters associated with insulinoma progression: chromosomal instability versus p53 and CK19 status. Cytogenet Genome Res 115:289–297

    Article  CAS  PubMed  Google Scholar 

  80. Stricker I, Tzivras D, Nambiar S et al (2012) Site- and grade-specific diversity of LINE1 methylation pattern in gastroenteropancreatic neuroendocrine tumours. Anticancer Res 32:3699–3706

    PubMed  Google Scholar 

  81. Choi IS, Estecio MR, Nagano Y et al (2007) Hypomethylation of LINE-1 and Alu in well-differentiated neuroendocrine tumors (pancreatic endocrine tumors and carcinoid tumors). Mod Pathol 20:802–810

    Article  CAS  PubMed  Google Scholar 

  82. Stefanoli M, La Rosa S, Sahnane N et al (2014) Prognostic relevance of aberrant DNA methylation in G1 and G2 pancreatic neuroendocrine tumors. Neuroendocrinology 100:26–34

    Article  CAS  PubMed  Google Scholar 

  83. Pizzi S, Azzoni C, Bottarelli L et al (2005) RASSF1A promoter methylation and 3p21.3 loss of heterozygosity are features of foregut, but not midgut and hindgut, malignant endocrine tumours. J Pathol 206:409–416

    Article  CAS  PubMed  Google Scholar 

  84. Arnold CN, Nagasaka T, Goel A et al (2008) Molecular characteristics and predictors of survival in patients with malignant neuroendocrine tumors. Int J Cancer 123:1556–1564

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  85. Malpeli G, Amato E, Dandrea M et al (2011) Methylation-associated down-regulation of RASSF1A and up-regulation of RASSF1C in pancreatic endocrine tumors. BMC Cancer 11:351

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  86. House MG, Herman JG, Guo MZ et al (2003) Aberrant hypermethylation of tumor suppressor genes in pancreatic endocrine neoplasms. Ann Surg 238:423–431

    PubMed Central  PubMed  Google Scholar 

  87. Liu L, Broaddus RR, Yao JC et al (2005) Epigenetic alterations in neuroendocrine tumors: methylation of RAS-association domain family 1, isoform A and p16 genes are associated with metastasis. Mod Pathol 18:1632–1640

    CAS  PubMed  Google Scholar 

  88. Arnold CN, Sosnowski A, Schmitt-Gräff A et al (2007) Analysis of molecular pathways in sporadic neuroendocrine tumors of the gastro-entero-pancreatic system. Int J Cancer 120:2157–2164

    Article  CAS  PubMed  Google Scholar 

  89. Strosberg JR, Cheema A, Kvols LK (2011) A review of systemic and liver-directed therapies for metastatic neuroendocrine tumors of the gastroenteropancreatic tract. Cancer Control 18:127–137

    PubMed  Google Scholar 

  90. Kulke MH, Hornick JL, Frauenhoffer C et al (2009) O6-methylguanine DNA methyltransferase deficiency and response to temozolomide-based therapy in patients with neuroendocrine tumors. Clin Cancer Res 15:338–345

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  91. Schmitt AM, Pavel M, Rudolph T et al (2014) Prognostic and predictive roles of MGMT protein expression and promoter methylation in sporadic pancreatic neuroendocrine neoplasms. Neuroendocrinology 100:35–44

    Article  CAS  PubMed  Google Scholar 

  92. Furlan D, Sahnane N, Bernasconi B et al (2014) APC alterations are frequently involved in the pathogenesis of acinar cell carcinoma of the pancreas, mainly through gene loss and promoter hypermethylation. Virchows Arch 464:553–564

    Article  CAS  PubMed  Google Scholar 

  93. Muscarella P, Melvin WS, Fisher WE et al (1998) Genetic alterations in gastrinomas and nonfunctioning pancreatic neuroendocrine tumors: an analysis of p16/MTS1 tumor suppressor gene inactivation. Cancer Res 58:237–240

    CAS  PubMed  Google Scholar 

  94. Lubomierski N, Kersting M, Bert T et al (2001) Tumor suppressor genes in the 9p21 gene cluster are selective targets of inactivation in neuroendocrine gastroenteropancreatic tumors. Cancer Res 61:5905–5910

    CAS  PubMed  Google Scholar 

  95. Welborn J, Jenks H, Taplett J et al (2004) High-grade neuroendocrine carcinomas display unique cytogenetic aberrations. Cancer Genet Cytogenet 155:33–41

    Article  CAS  PubMed  Google Scholar 

  96. 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

    Article  PubMed Central  PubMed  Google Scholar 

  97. Iacobuzio-Donahue CA, Fu B, Yachida S et al (2009) DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol 27:1806–1813

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  98. Scardoni M, Vittoria E, Volante M et al (2014) Mixed Adenoneuroendocrine Carcinomas (MANECs) of the gastrointestinal tract: targeted next generation sequencing suggests a monoclonal origin of the two components. Neuroendocrinology 100:310–316

    Article  CAS  PubMed  Google Scholar 

  99. Hruban RH, Fukushima N (2007) Pancreatic adenocarcinoma: update on the surgical pathology of carcinomas of ductal origin and PanINs. Mod Pathol Suppl 1:S61–S70

    Article  Google Scholar 

  100. Furlan D, Cerutti R, Genasetti A et al (2003) Microallelotyping defines the monoclonal or the polyclonal origin of mixed and collision endocrine-exocrine tumors of the gut. Lab Invest 83:963–971

    Article  PubMed  Google Scholar 

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  1. Department of Surgical and Morphological Sciences, Section of Anatomic Pathology, University of Insubria, O. Rossi 9, Varese, Varese, 21100, Italy

    Daniela Furlan

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  1. Department of Pathology, Ospedale di Circolo, Varese, Italy

    Stefano La Rosa

  2. Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy

    Fausto Sessa

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Furlan, D. (2015). Molecular Pathology of Pancreatic Neuroendocrine Neoplasms. In: La Rosa, S., Sessa, F. (eds) Pancreatic Neuroendocrine Neoplasms. Springer, Cham. https://doi.org/10.1007/978-3-319-17235-4_20

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