Pankreasın Nöroendokrin Tümörleri
Özet
Pankreasın nöroendokrin tümörleri (NET), pankreasın endokrin dokularında nadiren ortaya çıkan ve adacık hücre tümörleri olarak da bilinen neoplazmlardır. Tüm pankreas tümörlerinin yüzde 1 ila 2'sini oluşturan bu hastalık, çoğunlukla yaşamın dördüncü ila altıncı dekatlarında saptanır. NET’ler, Dünya Sağlık Örgütü kriterlerine göre tümörün diferansiyasyonuna ve proliferatif hızına (Ki-67 ve mitotik indeks) bağlı olarak G1, G2 ve G3 gibi farklı evrelerde sınıflandırılır. Klinik olarak fonksiyonel (insülin, gastrin, glukagon, VIP salgılayanlar) ve fonksiyonel olmayan tümörler olarak ikiye ayrılırlar. Fonksiyonel tümörler ürettikleri hormona özgü semptomlar sergilerken, büyük bir kısmı oluşturan fonksiyonel olmayan tümörler hormonal sendrom göstermez ve genellikle lokal kitle etkileri ya da karaciğer gibi uzak organ metastazları ile teşhis edilirler. Tanıda BT ve MRI gibi kesitsel görüntülemelerin yanı sıra SSTR varlığını saptayan Galyum-68 DOTATATE PET/BT gibi nükleer tıp yöntemleri ve biyobelirteç olarak Kromogranin A (CgA) testi kullanılır. Tedavide en etkili ve küratif yaklaşım cerrahi rezeksiyondur. Cerrahiye uygun olmayan ileri evre hastalarda ise somatostatin analogları, hedefe yönelik medikal tedaviler, kemoterapi, peptit reseptör radyonüklid tedavisi (PRRT) ve karaciğere yönelik lokorejyonel tedaviler uygulanır.
Pancreatic neuroendocrine tumors (NETs), also known as islet cell tumors, are rare neoplasms arising from the endocrine tissues of the pancreas. Accounting for 1 to 2 percent of all pancreatic tumors, they are mostly diagnosed in the fourth to sixth decades of life. Based on World Health Organization criteria, NETs are classified into G1, G2, and G3 grades depending on tumor differentiation and proliferative rates, such as Ki-67 and mitotic indices. Clinically, they are divided into functional (secreting insulin, gastrin, glucagon, or VIP) and non-functional tumors. While functional tumors display specific symptoms related to the hormones they secrete, non-functional tumors, which constitute the majority, lack hormonal syndromes and are often diagnosed through local mass effects or distant metastases, primarily in the liver. Diagnostic approaches leverage cross-sectional imaging like CT and MRI, nuclear medicine modalities such as Gallium-68 DOTATATE PET/CT to evaluate SSTR status, and serum biomarkers including Chromogranin A (CgA). Surgical resection remains the most effective and curative treatment strategy. For advanced or unresectable cases, medical options include somatostatin analogs, molecular targeted therapies, chemotherapy, peptide receptor radionuclide therapy (PRRT), and liver-directed locoregional interventions.
Referanslar
Rindi G, Klimstra DS, Abedi-Ardekani B, et al. 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. 2018;31(12):1770-86.
Klimstra DS. Nonductal neoplasms of the pancreas. Mod Pathol. 2007;20 Suppl 1:S94-112.
Metz DC, Jensen RT. Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. Gastroenterology. 2008;135(5):1469-92.
Hochwald SN, Zee S, Conlon KC, et al. Prognostic factors in pancreatic endocrine neoplasms: an analysis of 136 cases with a proposal for low-grade and intermediate-grade groups. J Clin Oncol. 2002;20(11):2633-42.
de Mestier L, Hentic O, Cros J, et al. Metachronous hormonal syndromes in patients with pancreatic neuroendocrine tumors: a case-series study. Ann Intern Med. 2015;162(10):682-9.
Cheema A, Weber J, Strosberg JR. Incidental detection of pancreatic neuroendocrine tumors: an analysis of incidence and outcomes. Ann Surg Oncol. 2012;19(9):2932-6.
Strosberg J, Gardner N, Kvols L. Survival and prognostic factor analysis in patients with metastatic pancreatic endocrine carcinomas. Pancreas. 2009;38(3):255-8.
Sadowski SM, Neychev V, Millo C, et al. Prospective Study of 68Ga-DOTATATE Positron Emission Tomography/Computed Tomography for Detecting Gastro-Entero-Pancreatic Neuroendocrine Tumors and Unknown Primary Sites. J Clin Oncol. 2016;34(6):588-96.
Nikfarjam M, Warshaw AL, Axelrod L, et al. Improved contemporary surgical management of insulinomas: a 25-year experience at the Massachusetts General Hospital. Ann Surg. 2008;247(1):165-72.
Khashab MA, Yong E, Lennon AM, et al. EUS is still superior to multidetector computerized tomography for detection of pancreatic neuroendocrine tumors. Gastrointest Endosc. 2011;73(4):691-6.
Thoeni RF, Mueller-Lisse UG, Chan R, et al. Detection of small, functional islet cell tumors in the pancreas: selection of MR imaging sequences for optimal sensitivity. Radiology. 2000;214(2):483-90.
Hellman P, Hennings J, Akerstrom G, et al. Endoscopic ultrasonography for evaluation of pancreatic tumours in multiple endocrine neoplasia type 1. Br J Surg. 2005;92(12):1508-12.
Cadiot G, Lebtahi R, Sarda L, et al. Preoperative detection of duodenal gastrinomas and peripancreatic lymph nodes by somatostatin receptor scintigraphy. Groupe D'etude Du Syndrome De Zollinger-Ellison. Gastroenterology. 1996;111(4):845-54.
King CM, Reznek RH, Dacie JE, et al. Imaging islet cell tumours. Clin Radiol. 1994;49(5):295-303.
Kulke MH, Anthony LB, Bushnell DL, et al. NANETS treatment guidelines: well-differentiated neuroendocrine tumors of the stomach and pancreas. Pancreas. 2010;39(6):735-52.
Ma ZY, Gong YF, Zhuang HK, et al. Pancreatic neuroendocrine tumors: A review of serum biomarkers, staging, and management. World J Gastroenterol. 2020;26(19):2305-22.
Korse CM, Taal BG, Vincent A, et al. Choice of tumour markers in patients with neuroendocrine tumours is dependent on the histological grade. A marker study of Chromogranin A, Neuron specific enolase, Progastrin-releasing peptide and cytokeratin fragments. Eur J Cancer. 2012;48(5):662-71.
Walter T, Chardon L, Chopin-laly X, et al. Is the combination of chromogranin A and pancreatic polypeptide serum determinations of interest in the diagnosis and follow-up of gastro-entero-pancreatic neuroendocrine tumours? Eur J Cancer. 2012;48(12):1766-73.
Dizon AM, Kowalyk S, Hoogwerf BJ. Neuroglycopenic and other symptoms in patients with insulinomas. Am J Med. 1999;106(3):307-10.
Soga J, Yakuwa Y. Glucagonomas/diabetico-dermatogenic syndrome (DDS): a statistical evaluation of 407 reported cases. J Hepatobiliary Pancreat Surg. 1998;5(3):312-9.
Bloom SR. Vasoactive intestinal peptide, the major mediator of the WDHA (pancreatic cholera) syndrome: value of measurement in diagnosis and treatment. Am J Dig Dis. 1978;23(4):373-6.
Berna MJ, Hoffmann KM, Serrano J, et al. Serum gastrin in Zollinger-Ellison syndrome: I. Prospective study of fasting serum gastrin in 309 patients from the National Institutes of Health and comparison with 2229 cases from the literature. Medicine (Baltimore). 2006;85(6):295-330.
Berna MJ, Hoffmann KM, Long SH, et al. Serum gastrin in Zollinger-Ellison syndrome: II. Prospective study of gastrin provocative testing in 293 patients from the National Institutes of Health and comparison with 537 cases from the literature. evaluation of diagnostic criteria, proposal of new criteria, and correlations with clinical and tumoral features. Medicine (Baltimore). 2006;85(6):331-64.
Stelmachowska-Banas M, Glogowski M, Vasiljevic A, et al. Ectopic acromegaly due to growth hormone-releasing hormone secretion from bronchial carcinoid causing somatotroph hyperplasia and partial pituitary insufficiency. Pol Arch Intern Med. 2019;129(3):208-10.
Khan MS, Kirkwood A, Tsigani T, et al. Circulating tumor cells as prognostic markers in neuroendocrine tumors. J Clin Oncol. 2013;31(3):365-72.
Pavel M, Jann H, Prasad V, et al. NET Blood Transcript Analysis Defines the Crossing of the Clinical Rubicon: When Stable Disease Becomes Progressive. Neuroendocrinology. 2017;104(2):170-82.
Thorns C, Schurmann C, Gebauer N, et al. Global microRNA profiling of pancreatic neuroendocrine neoplasias. Anticancer Res. 2014;34(5):2249-54.
Zurita AJ, Khajavi M, Wu HK, et al. Circulating cytokines and monocyte subpopulations as biomarkers of outcome and biological activity in sunitinib-treated patients with advanced neuroendocrine tumours. Br J Cancer. 2015;112(7):1199-205.
Hussain F, Wang J, Ahmed R, et al. The expression of IL-8 and IL-8 receptors in pancreatic adenocarcinomas and pancreatic neuroendocrine tumours. Cytokine. 2010;49(2):134-40.
Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17(6):1471-4.
You Y, Jang JY, Kim SC, et al. Validation of the 8th AJCC Cancer Staging System for Pancreas Neuroendocrine Tumors Using Korean Nationwide Surgery Database. Cancer Res Treat. 2019;51(4):1639-52.
Akirov A, Larouche V, Alshehri S, et al. Treatment Options for Pancreatic Neuroendocrine Tumors. Cancers (Basel). 2019;11(6).
Shah MH, Goldner WS, Halfdanarson TR, et al. NCCN Guidelines Insights: Neuroendocrine and Adrenal Tumors, Version 2.2018. J Natl Compr Canc Netw. 2018;16(6):693-702.
Souche R, Hobeika C, Hain E, et al. Surgical Management of Neuroendocrine Tumours of the Pancreas. J Clin Med. 2020;9(9).
Sabater L, Ausania F, Bakker OJ, et al. Evidence-based Guidelines for the Management of Exocrine Pancreatic Insufficiency After Pancreatic Surgery. Ann Surg. 2016;264(6):949-58.
Falconi M, Eriksson B, Kaltsas G, 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.
van der Pas MH, Haglind E, Cuesta MA, et al. Laparoscopic versus open surgery for rectal cancer (COLOR II): short-term outcomes of a randomised, phase 3 trial. Lancet Oncol. 2013;14(3):210-8.
Nickel F, Haney CM, Kowalewski KF, et al. Laparoscopic Versus Open Pancreaticoduodenectomy: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Ann Surg. 2020;271(1):54-66.
Butturini G, Damoli I, Crepaz L, et al. A prospective non-randomised single-center study comparing laparoscopic and robotic distal pancreatectomy. Surg Endosc. 2015;29(11):3163-70.
Brown KM, Shoup M, Abodeely A, et al. Central pancreatectomy for benign pancreatic lesions. HPB (Oxford). 2006;8(2):142-7.
Pitt SC, Pitt HA, Baker MS, et al. Small pancreatic and periampullary neuroendocrine tumors: resect or enucleate? J Gastrointest Surg. 2009;13(9):1692-8.
Sciuto A, Abete R, Reggio S, et al. Laparoscopic spleen-preserving distal pancreatectomy for insulinoma: experience of a single center. Int J Surg. 2014;12 Suppl 1:S152-5.
Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 Trial of (177)Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med. 2017;376(2):125-35.
Costa R, Costa R, Bacchi CE, et al. Metastatic insulinoma managed with radiolabeled somatostatin analog. Case Rep Endocrinol. 2013;2013:252159.
Kennedy A, Bester L, Salem R, et al. Role of hepatic intra-arterial therapies in metastatic neuroendocrine tumours (NET): guidelines from the NET-Liver-Metastases Consensus Conference. HPB (Oxford). 2015;17(1):29-37.
