Pancreatic neuroendocrine tumor

Last updated

Pancreatic neuroendocrine tumor
Diagram showing the position of the pancreas CRUK 356.svg
Specialty Oncology
TreatmentRadiation, chemotherapy
Prognosis Five-year survival rate ~ 61%

Pancreatic neuroendocrine tumours (PanNETs, PETs, or PNETs), often referred to as "islet cell tumours", [1] [2] or "pancreatic endocrine tumours" [3] [4] are neuroendocrine neoplasms that arise from cells of the endocrine (hormonal) and nervous system within the pancreas.

Contents

PanNETs are a type of neuroendocrine tumor, representing about one-third of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Many PanNETs are benign, while some are malignant. Aggressive PanNET tumors have traditionally been termed "islet cell carcinoma".

PanNETs are quite distinct from the usual form of pancreatic cancer, the majority of which are adenocarcinomas, which arises in the exocrine pancreas. Only 1 or 2% of clinically significant pancreas neoplasms are PanNETs. [5]

Types

The majority of PanNETs are benign, while some are malignant. The World Health Organization (WHO) classification scheme places neuroendocrine tumors into three main categories, which emphasize the tumor grade rather than the anatomical origin. [3] In practice, those tumors termed well or intermediately differentiated PanNETs in the WHO scheme are sometimes called "islet cell tumors". The high-grade subtype termed neuroendocrine cancer (NEC) in the WHO scheme, is synonymous with "islet cell carcinoma".

Types of PNET based on hormones produced
TypeRelative incidenceTypical location of tumor [6] Biomarkers [6] Symptoms [7]
Insulinoma 35–40% [7] Head, body, tail of pancreasinsulin, proinsulin, C-peptide Hypoglycemia
Gastrinoma 16–30% [7] Gastrinoma triangle gastrin, PP
VIPoma <10% [7] Distal pancreas (body and tail) VIP
Somatostatinoma <5% [7] Pancreatoduodenal groove, ampullary, periampullary somatostatin
PPomaHead or pancreas pancreatic polypeptide
Glucagonoma 1% [8] Body and tail of pancreas glucagon, glycentin

Relative incidence is given as percentage of all functional pancreatic neuroendocrine tumors.

Signs and symptoms

Relative incidences of various pancreatic neoplasms, with pancreatic endocrine neoplasms in blue. Relative incidence of pancreatic neoplasms.png
Relative incidences of various pancreatic neoplasms, with pancreatic endocrine neoplasms in blue.

Some PanNETs do not cause any symptoms, in which case they may be discovered incidentally on a CT scan performed for a different purpose. [10] : 43–44  Symptoms such as abdominal or back pain or pressure, diarrhea, indigestion, or yellowing of the skin and whites of the eyes can arise from the effects of a larger PanNET tumor, either locally or at a metastasis. [11] [ medical citation needed ] About 40%[ medical citation needed ] of PanNETS have symptoms related to excessive secretion of hormones or active polypeptides and are accordingly labeled as "functional"; the symptoms reflect the type of hormone secreted, as discussed below. Up to 90% [12] of PanNETs are nonsecretory or nonfunctional, in which there is no secretion, or the quantity or type of products, such as pancreatic polypeptide (PPoma), chromogranin A, and neurotensin, do not cause a clinical syndrome although blood levels may be elevated. [13] In total, 85% of PanNETs have an elevated blood marker. [2]

Functional tumors are often classified by the hormone most strongly secreted, for example:

In these various types of functional tumors, the frequency of malignancy and the survival prognosis have been estimated dissimilarly, but a pertinent accessible summary is available. [17]

Diagnosis

Because symptoms are non-specific, diagnosis is often delayed. [18]

Measurement of hormones including pancreatic polypeptide, gastrin, proinsulin, insulin, glucagon, and vasoactive intestinal peptide can determine if a tumor is causing hypersecretion. [18] [19]

Multiphase CT and MRI are the primary modalities for morphologic imaging of PNETs. While MRI is superior to CT for imaging, both of the primary tumor and evaluation of metastases, CT is more readily available. Notably, while many malignant lesions are hypodense in contrast-enhanced studies, the liver metastases of PNETs are hypervascular and readily visualized in the late arterial phase of the post-contrast CT study. However, morphological imaging alone is not sufficient for a definite diagnosis [18] [20]

On biopsy, immunohistochemistry is generally positive for chromogranin and synaptophysin. [21] Genetic testing thereof typically shows altered MEN1 and DAXX/ATRX. [21]

Staging, classification and grading

The new 2019 WHO classification and grading criteria for neuroendocrine tumors of the digestive system grades all the neuroendocrine tumors into three grades, based on their degree of cellular differentiation (from well-differentiated NET grade (G)1 to G3, and poorly-differentiated neuroendokrina cancer, NEC G3), morphology, mitotic rate and Ki-67 index. [22] The NCCN recommends the use of the same AJCC-UICC staging system as pancreatic adenocarcinoma. [10] : 52  Using this scheme, the stage by stage outcomes for PanNETs are dissimilar to pancreatic exocrine cancers. [23] A different TNM system for PanNETs has been proposed by The European Neuroendocrine Tumor Society. [24]

Treatment

In general, treatment for PanNET encompasses the same array of options as other neuroendocrine tumors, as discussed in that main article. However, there are some specific differences, which are discussed here. [10]

In functioning PanNETs, octreotide is usually recommended prior to biopsy [10] : 21  or surgery [10] : 45  but is generally avoided in insulinomas to avoid profound hypoglycemia. [10] : 69 

PanNETs in Multiple endocrine neoplasia type 1 are often multiple, and thus require different treatment and surveillance strategies. [10]

Some PanNETs are more responsive to chemotherapy than are gastroenteric carcinoid tumors. Several agents have shown activity. [16] In well differentiated PanNETs, chemotherapy is generally reserved for when there are no other treatment options. Combinations of several medicines have been used, such as doxorubicin with streptozocin and fluorouracil (5-FU) [16] and capecitabine with temozolomide.[ citation needed ] Although marginally effective in well-differentiated PETs, cisplatin with etoposide has some activity in poorly differentiated neuroendocrine cancers (PDNECs), [16] particularly if the PDNEC has an extremely high Ki-67 score of over 50%. [10] : 30 

Several targeted therapy agents have been approved in PanNETs by the FDA based on improved progression-free survival (PFS):

Genetics

Pancreatic neuroendocrine tumors may arise in the context of multiple endocrine neoplasia type 1, Von Hippel–Lindau disease, neurofibromatosis type 1 (NF-1) or tuberose sclerosis (TSC) [31] [32]

Analysis of somatic DNA mutations in well-differentiated pancreatic neuroendocrine tumors identified four important findings: [33] [7]

Related Research Articles

<span class="mw-page-title-main">Pancreas</span> Organ of the digestive system and endocrine system of vertebrates

The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e., it has both an endocrine and a digestive exocrine function. 99% of the pancreas is exocrine and 1% is endocrine. As an endocrine gland, it functions mostly to regulate blood sugar levels, secreting the hormones insulin, glucagon, somatostatin and pancreatic polypeptide. As a part of the digestive system, it functions as an exocrine gland secreting pancreatic juice into the duodenum through the pancreatic duct. This juice contains bicarbonate, which neutralizes acid entering the duodenum from the stomach; and digestive enzymes, which break down carbohydrates, proteins and fats in food entering the duodenum from the stomach.

<span class="mw-page-title-main">Pancreatic islets</span> Regions of the pancreas

The pancreatic islets or islets of Langerhans are the regions of the pancreas that contain its endocrine (hormone-producing) cells, discovered in 1869 by German pathological anatomist Paul Langerhans. The pancreatic islets constitute 1–2% of the pancreas volume and receive 10–15% of its blood flow. The pancreatic islets are arranged in density routes throughout the human pancreas, and are important in the metabolism of glucose.

<span class="mw-page-title-main">Multiple endocrine neoplasia</span> Group of genetic conditions

Multiple endocrine neoplasia is a condition which encompasses several distinct syndromes featuring tumors of endocrine glands, each with its own characteristic pattern. In some cases, the tumors are malignant, in others, benign. Benign or malignant tumors of nonendocrine tissues occur as components of some of these tumor syndromes.

<span class="mw-page-title-main">Zollinger–Ellison syndrome</span> Condition in which tumours stimulate excessive gastric acid production

Zollinger–Ellison syndrome is rare disease in which tumors cause the stomach to produce too much acid, resulting in peptic ulcers. Symptoms include abdominal pain and diarrhea.

<span class="mw-page-title-main">Pancreatic cancer</span> Type of endocrine gland cancer

Pancreatic cancer arises when cells in the pancreas, a glandular organ behind the stomach, begin to multiply out of control and form a mass. These cancerous cells have the ability to invade other parts of the body. A number of types of pancreatic cancer are known.

<span class="mw-page-title-main">Everolimus</span> Chemical compound

Everolimus, sold under the brand name Afinitor among others, is a medication used as an immunosuppressant to prevent rejection of organ transplants and as a targeted therapy in the treatment of renal cell cancer and other tumours.

Glucagonoma is a very rare tumor of the alpha cells of the pancreas that results in the overproduction of the hormone glucagon. Typically associated with a rash called necrolytic migratory erythema, weight loss, and mild diabetes mellitus, most people with glucagonoma contract it spontaneously. However, about 10% of cases are associated with multiple endocrine neoplasia type 1 (MEN-1) syndrome.

<span class="mw-page-title-main">Insulinoma</span> Tumor of the pancreas which secretes insulin

An insulinoma is a tumour of the pancreas that is derived from beta cells and secretes insulin. It is a rare form of a neuroendocrine tumour. Most insulinomas are benign in that they grow exclusively at their origin within the pancreas, but a minority metastasize. Insulinomas are one of the functional pancreatic neuroendocrine tumour (PNET) group. In the Medical Subject Headings classification, insulinoma is the only subtype of "islet cell adenoma".

<span class="mw-page-title-main">Pancreatectomy</span> Surgical removal of the pancreas

In medicine, a pancreatectomy is the surgical removal of all or part of the pancreas. Several types of pancreatectomy exist, including pancreaticoduodenectomy, distal pancreatectomy, segmental pancreatectomy, and total pancreatectomy. In total pancreatectomy, the gallbladder, distal stomach, a portion of the small intestine, associated lymph nodes and in certain cases the spleen are removed in addition to the entire pancreas. In recent years, the TP-IAT has also gained respectable traction within the medical community. These procedures are used in the management of several conditions involving the pancreas, such as benign pancreatic tumors, pancreatic cancer, and pancreatitis.

<span class="mw-page-title-main">Carcinoid</span> Slow-growing type of neuroendocrine tumor

A carcinoid is a slow-growing type of neuroendocrine tumor originating in the cells of the neuroendocrine system. In some cases, metastasis may occur. Carcinoid tumors of the midgut are associated with carcinoid syndrome.

<span class="mw-page-title-main">Multiple endocrine neoplasia type 1</span> Medical condition

Multiple endocrine neoplasia type 1 (MEN-1) is one of a group of disorders, the multiple endocrine neoplasias, that affect the endocrine system through development of neoplastic lesions in pituitary, parathyroid gland and pancreas. Individuals suffering from this disorder are prone to developing multiple endocrine and nonendocrine tumors. It was first described by Paul Wermer in 1954.

<span class="mw-page-title-main">Gastrinoma</span> Medical condition

Gastrinomas are neuroendocrine tumors (NETs), usually located in the duodenum or pancreas, that secrete gastrin and cause a clinical syndrome known as Zollinger–Ellison syndrome (ZES). A large number of gastrinomas develop in the pancreas or duodenum, with near-equal frequency, and approximately 10% arise as primary neoplasms in lymph nodes of the pancreaticoduodenal region.

<span class="mw-page-title-main">Sunitinib</span> Cancer medication

Sunitinib, sold under the brand name Sutent, is an anti-cancer medication. It is a small-molecule, multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST) in January 2006. Sunitinib was the first cancer drug simultaneously approved for two different indications.

<span class="mw-page-title-main">Neuroendocrine tumor</span> Tumors of the endocrine and nervous systems

Neuroendocrine tumors (NETs) are neoplasms that arise from cells of the endocrine (hormonal) and nervous systems. They most commonly occur in the intestine, where they are often called carcinoid tumors, but they are also found in the pancreas, lung, and the rest of the body.

Somatostatinomas are a tumor of the delta cells of the endocrine pancreas that produces somatostatin. Increased levels of somatostatin inhibit pancreatic hormones and gastrointestinal hormones. Thus, somatostatinomas are associated with mild diabetes mellitus, steatorrhoea and gallstones, and achlorhydria. Somatostatinomas are commonly found in the head of pancreas. Only ten percent of somatostatinomas are functional tumours [9], and 60–70% of tumours are malignant. Nearly two-thirds of patients with malignant somatostatinomas will present with metastatic disease.

<span class="mw-page-title-main">MEN1</span> Protein

Menin is a protein that in humans is encoded by the MEN1 gene. Menin is a putative tumor suppressor associated with multiple endocrine neoplasia type 1 and has autosomal dominant inheritance. Variations in the MEN1 gene can cause pituitary adenomas, hyperparathyroidism, pancreatic neuroendocrine tumors, gastrinoma, and adrenocortical cancers.

<span class="mw-page-title-main">Somatostatin receptor 2</span> Protein-coding gene in the species Homo sapiens

Somatostatin receptor type 2 is a protein that in humans is encoded by the SSTR2 gene.

The Ewing family of tumors (EFTs) is a group of small cell sarcomas including Ewing sarcoma of the bone, extra osseous Ewing tumors, and primitive neuroectodermal tumors. They are rare cancers, usually diagnosed in peoples' twenties. The sarcoma of bone is the most common of the variants. All forms are predisposed to metastasis and have had historically high rates of mortality. The family of tumors shares a common translocation mutation of the EWS gene on chromosome 22 to an ETS-type gene, most commonly the FLI1 gene. EFTs are highly malignant, with 5-year survival for patients with metastatic disease at 20%. The current standard of care includes resection, radiation, and chemotherapy.

<span class="mw-page-title-main">Pancreatic tumor</span> Medical condition

A pancreatic tumor is an abnormal growth in the pancreas. In adults, almost 90% are pancreatic cancer and a few are benign. Pancreatic tumors are rare in children.

<span class="mw-page-title-main">Mahvash disease</span> Medical condition

Mahvash disease is an autosomal recessive, hereditary pancreatic neuroendocrine tumor syndrome. The genetic defect that causes Mahvash disease is biallelic inactivating mutations of the glucagon receptor gene (GCGR). Mahvash disease was discovered by American physician Run Yu and his colleagues in 2008. Mahvash disease is very rare. There have been approximately 15 cases of Mahvash disease described in detail by the end of 2023. Mahvash disease occurs in both females and males. Mahvash disease is also called “glucagon cell hyperplasia and neoplasia” or “glucagon cell adenomatosis” by some authors but Mahvash disease is a distinct disease entity while the two alternative terms are mostly histological descriptions. Some patients with “glucagon cell hyperplasia and neoplasia” do not have glucagon receptor mutations.

References

  1. ↑ Burns WR, Edil BH (March 2012). "Neuroendocrine pancreatic tumors: guidelines for management and update". Current Treatment Options in Oncology. 13 (1): 24–34. doi:10.1007/s11864-011-0172-2. PMID   22198808. S2CID   7329783.
  2. 1 2 Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Treatment (PDQ) Health Professional Version. National Cancer Institute. March 7, 2014.
  3. 1 2 The PanNET denomination is in line with current WHO guidelines. Historically, PanNETs have also been referred to by a variety of terms, and are still often called "islet cell tumors" or "pancreatic endocrine tumors". See: Klimstra DS, Modlin IR, Coppola D, Lloyd RV, Suster S (August 2010). "The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems" (PDF). Pancreas. 39 (6): 707–12. doi:10.1097/MPA.0b013e3181ec124e. PMID   20664470. S2CID   3735444.
  4. ↑ Oberg K (December 2010). "Pancreatic endocrine tumours". Seminars in Oncology. 37 (6): 594–618. doi:10.1053/j.seminoncol.2010.10.014. PMID   21167379.
  5. ↑ Kelgiorgi, Dionysia; Dervenis, Christos (2017-05-10). "Pancreatic neuroendocrine tumors: the basics, the gray zone, and the target". F1000Research. 6: 663. doi: 10.12688/f1000research.10188.1 . ISSN   2046-1402. PMC   5428491 . PMID   28529726.
  6. 1 2 Unless otherwise specified in boxes, reference is: Vinik A, Casellini C, Perry RR, Feliberti E, Vingan H (2015). "Pathophysiology and Treatment of Pancreatic Neuroendocrine Tumors (PNETs): New Developments". In De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R (eds.). Endotext. South Dartmouth (MA): MDText.com, Inc. PMID   25905300.
  7. 1 2 3 4 5 6 McKenna LR, Edil BH (November 2014). "Update on pancreatic neuroendocrine tumors". Gland Surgery. 3 (4): 258–75. doi:10.3978/j.issn.2227-684X.2014.06.03. PMC   4244504 . PMID   25493258.
  8. ↑ "Glucagonoma: Practice Essentials, Pathophysiology, Epidemiology". Medscape. 2019-02-01.
  9. ↑ Wang Y, Miller FH, Chen ZE, Merrick L, Mortele KJ, Hoff FL; et al. (2011). "Diffusion-weighted MR imaging of solid and cystic lesions of the pancreas". Radiographics. 31 (3): E47-64. doi:10.1148/rg.313105174. PMID   21721197.{{cite journal}}: CS1 maint: multiple names: authors list (link)
    Diagram by Mikael Häggström, M.D.
  10. 1 2 3 4 5 6 7 8 "Neuroendocrine tumors, NCCN Guidelines Version 1.2015" (PDF). NCCN Guidelines. National Comprehensive Cancer Network, Inc. November 11, 2014. Retrieved December 25, 2014.
  11. ↑ Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Treatment (PDQ®) National Cancer Institute
  12. ↑ Lewis, A; Li, D; Williams, J; Singh, G (15 October 2017). "Pancreatic Neuroendocrine Tumors: State-of-the-Art Diagnosis and Management". Oncology (Williston Park, N.Y.). 31 (10): e1–e12. PMID   29083468 . Retrieved 8 July 2024.
  13. ↑ Jensen RT, Berna MJ, Bingham DB, Norton JA (October 2008). "Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management, and controversies". Cancer. 113 (7 Suppl): 1807–43. doi:10.1002/cncr.23648. PMC   2574000 . PMID   18798544.
  14. ↑ "Gastrinoma". The Lecturio Medical Concept Library. Retrieved 22 July 2021.
  15. ↑ Grant CS (October 2005). "Insulinoma". Best Practice & Research. Clinical Gastroenterology. 19 (5): 783–98. doi:10.1016/j.bpg.2005.05.008. PMID   16253900.
  16. 1 2 3 4 5 6 7 Benson AB, Myerson RJ, and Sasson AR. Pancreatic, neuroendocrine GI, and adrenal cancers. Cancer Management: A Multidisciplinary Approach 13th edition 2010. ISBN   978-0-615-41824-7 Text is available electronically (but may require free registration) at http://www.cancernetwork.com/cancer-management/pancreatic/article/10165/1802606
  17. ↑ Ramage JK, Davies AH, Ardill J, Bax N, Caplin M, Grossman A, et al. (June 2005). "Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours". Gut. 54. 54 Suppl 4 (suppl_4): iv1–iv16. doi:10.1136/gut.2004.053314. PMC   1867801 . PMID   15888809.
  18. 1 2 3 Ro C, Chai W, Yu VE, Yu R (June 2013). "Pancreatic neuroendocrine tumors: biology, diagnosis, and treatment". Chinese Journal of Cancer. 32 (6): 312–24. doi:10.5732/cjc.012.10295. PMC   3845620 . PMID   23237225.
  19. ↑ Vinik A, Casellini C, Perry RR, Feliberti E, Vingan H (2015). "Pathophysiology and Treatment of Pancreatic Neuroendocrine Neoplasms (PNENS): New Developments". Pathophysiology and Treatment of Pancreatic Neuroendocrine Tumors (PNETs): New Developments. MDText.com, Inc. PMID   25905300.{{cite book}}: |journal= ignored (help)
  20. ↑ Sundin, Anders; Arnold, Rudolf; Baudin, Eric; Cwikla, Jaroslaw B.; Eriksson, Barbro; Fanti, Stefano; Fazio, Nicola; Giammarile, Francesco; Hicks, Rodney J.; Kjaer, Andreas; Krenning, Eric (2017). "ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Radiological, Nuclear Medicine and Hybrid Imaging". Neuroendocrinology. 105 (3): 212–44. doi:10.1159/000471879. ISSN   0028-3835. PMID   28355596. S2CID   41115928.
  21. 1 2 Unless otherwise specified in boxes, reference is: Pishvaian MJ, Brody JR (2017). "Therapeutic Implications of Molecular Subtyping for Pancreatic Cancer". Oncology (Williston Park). 31 (3): 159–66, 168. PMID   28299752.
  22. ↑ Nagtegaal, Iris D; Odze, Robert D; Klimstra, David; Paradis, Valerie; Rugge, Massimo; Schirmacher, Peter; Washington, Kay M; Carneiro, Fatima; Cree, Ian A; the WHO Classification of Tumours Editorial Board (January 2020). "The 2019 WHO classification of tumours of the digestive system". Histopathology. 76 (2): 182–188. doi:10.1111/his.13975. ISSN   0309-0167. PMC   7003895 . PMID   31433515.
  23. ↑ National Cancer Institute. Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) Treatment (PDQ®) Incidence and Mortality
  24. ↑ Öberg K, Knigge U, Kwekkeboom D, Perren A (October 2012). "Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up". Annals of Oncology. 23 (Suppl 7): vii, 124–30. doi: 10.1093/annonc/mds295 . PMID   22997445. (Table 5 outlines the proposed TNM staging system for PanNETs.)
  25. 1 2 Everolimus Approved for Pancreatic Neuroendocrine Tumors. The ASCO Post. May 15, 2011, Volume 2, Issue 8 "The ASCO Post". Archived from the original on 2013-01-17. Retrieved 2014-12-25.
  26. 1 2 "Highlights of prescribing information" (PDF). novartis.com. Retrieved 27 September 2023.
  27. ↑ National Cancer Institute. Cancer Drug Information. FDA Approval for Sunitinib Malate. Pancreatic Neuroendocrine Tumors http://www.cancer.gov/cancertopics/druginfo/fda-sunitinib-malate
  28. ↑ "Highlights of prescribing information". pfizer.com. Retrieved 27 September 2023.
  29. ↑ "Pfizer Scores New Approval for Sutent in Europe". 2 Dec 2010.
  30. ↑ Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, et al. (February 2011). "Sunitinib malate for the treatment of pancreatic neuroendocrine tumors". The New England Journal of Medicine. 364 (6): 501–13. doi: 10.1056/NEJMoa1003825 . PMID   21306237.
  31. ↑ Ro C, Chai W, Yu VE, Yu R (June 2013). "Pancreatic neuroendocrine tumors: biology, diagnosis, and treatment". Chinese Journal of Cancer. 32 (6): 312–24. doi:10.5732/cjc.012.10295. PMC   3845620 . PMID   23237225.
  32. ↑ Backman S, Björklund P (2017). "Molecular Genetics of Gastroenteropancreatic Neuroendocrine Tumours". Diagnostic and Therapeutic Nuclear Medicine for Neuroendocrine Tumors. Contemporary Endocrinology. Humana Press, Cham. pp. 127–40. doi:10.1007/978-3-319-46038-3_6. ISBN   9783319460369.
  33. 1 2 3 4 5 Jiao Y, Shi C, Edil BH, de Wilde RF, Klimstra DS, Maitra A, et al. (March 2011). "DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors". Science. 331 (6021): 1199–203. Bibcode:2011Sci...331.1199J. doi:10.1126/science.1200609. PMC   3144496 . PMID   21252315.
  34. ↑ Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, et al. (September 2008). "Core signaling pathways in human pancreatic cancers revealed by global genomic analyses". Science. 321 (5897): 1801–06. Bibcode:2008Sci...321.1801J. doi:10.1126/science.1164368. PMC   2848990 . PMID   18772397.
  35. ↑ Harada T, Chelala C, Crnogorac-Jurcevic T, Lemoine NR (2009). "Genome-wide analysis of pancreatic cancer using microarray-based techniques". Pancreatology. 9 (1–2): 13–24. doi:10.1159/000178871. PMID   19077451. S2CID   32857283.
  36. 1 2 Heaphy CM, de Wilde RF, Jiao Y, Klein AP, Edil BH, Shi C, et al. (July 2011). "Altered telomeres in tumors with ATRX and DAXX mutations". Science. 333 (6041): 425. Bibcode:2011Sci...333..425H. doi:10.1126/science.1207313. PMC   3174141 . PMID   21719641.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.