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Pancreatic Neuroendocrine Tumors
- 1. Pancreatic Neuroendocrine Tumors (Insulinoma) DR JUNISH BAGGA SR – GI SURGERY GUIDE – DR SATPAL SINGH VIRK PROF. & HEAD. GI SURGERY. DMCH
- 2. Introduction to NETs NETs arise from cells which produce and secrete hormones Most NETs are slow growing and malignant, with metastatic potential Carcinoid, APUDomas Common sites of origin are: GI tract Lungs Pancreas Burns WR, Edil BH (March 2012). "Neuroendocrine pancreatic tumors: guidelines for management and update". Current Treatment Options in Oncology. 13 (1): 24–34. PMID 22198808
- 3. Pancreatic NETs Overview PNETs are rare, slow-growing neoplasms Symptoms from excess hormone production or mechanical problems 7% of all NETs are found in pancreas 1-2% of all pancreatic tumors Historically – islet cell tumors Amin, Mahul B., ed. (2017). "30 - Neuroendocrine Tumors of the Pancreas". AJCC Cancer Staging Manual (8 ed.). Springer. pp. 415–416. ISBN 978-3-319- 40617-6.
- 4. ORIGIN Debated Arise from pluripotent stem cells in pancreatic ductal acinar system and not from pancreatic islet themselves Schimmack S, et al: The diversity and commonalities of gastroenteropancreatic neuroendocrine tumors, Langenbecks Arch Surg 396:273– 298, 2011.
- 5. Epidemiology Incidence rate of 0.4 cases per 100,000 Incidence is increasing Males = Females Age – 60 – 80 years 5% familial association – MEN1, VHL, TS, NF1 Tend to be diagnosed at a younger age Family history is the only identified risk factor Fraenkel M, et al: Epidemiology of gastroenteropancreatic neuroendocrine tumours, Best Pract Res Clin Gastroenterol 26:691–703, 2012.
- 6. Potential Reasons for Increased Incidence and Prevalence in PNET • 0.17-0.43 cases / 100,000 • Exact reasons are unknown but may include: – Potential underdiagnoses and underreporting in the past – Improved diagnostic techniques – Increased awareness of NET in the community Fraenkel M, et al: Epidemiology of gastroenteropancreatic neuroendocrine tumours, Best Pract Res Clin Gastroenterol 26:691– 703, 2012.
- 8. Well circumscribed solitary masses Majority are well differentiated Potential to grow & metastasise > malignant Likelihood of metastatic spread is very low , benign has been used as a classification variable Malignant- invades locoregionally, has metastasised distantly or to regional lymph nodes, greater than 2 cms insize, displays vascular, lymphatic or neural invasion or has proliferative tndex of greater than 2 % Klöppel G, et al: The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification, Ann N Y Acad Sci 1014:13–27, 2004.
- 9. Biologic Behaviour GRADE AND STAGE
- 10. Grading system for PNETs Good Poor
- 11. Ki-67 Antigen KI-67 also known as Ki-67 or MKI67 is a protein that in humans is encoded by the MKI67 gene Ki derived from the city of discovery – Kiel, Germany. Associated with cell replication and ribosomal RNA transcription. Present during all active phases of cell cycle Absent from resting cell – G0
- 12. Staging – TNM (AJCC 2010)
- 13. Staging
- 14. Classification Based on Functional Activity Functioning Non-functioning PNETs may or may not have secretory symptoms Secretory symptoms related to specific hormones Tumors (nonfunctional) may secrete peptides but cause no clinical symptoms
- 15. Non-functional PNETs Most PNETs ~75% Often found incidentally Symptoms relate to tumor’s mass effect – abd pain, vomiting, weight loss, jaundice, pancreatitis Tend to be larger than other PNETs Nodes involved at time of diagnosis
- 17. Pancreatic NETs Types Relative frequency: Asymptomatic >Insulinoma > Gastrinoma > Glucagonoma > VIPomas > Somatostatinoma > Others
- 18. Systematic Approach to Diagnosing NET Is Needed History and physical exam Biochemical markers (serum, tissue, urine) Specific tests Imaging Computed tomography scan (CT)/ Magnetic Resonance Imaging (MRI) Nuclear Imaging Endoscopic ultrasound
- 19. Insulinoma 1-2% of all pancreatic tumors Small <2cms Solitary Rarely malignant 5 year OS- 56%, 10 year OS - 29% Baudin E, et al: Malignant insulinoma: recommendations for characterisation and treatment, Ann Endocrinol (Paris) 74:523–533, 2013. Okabayashi T, et al: Diagnosis and management of insulinoma, World J Gastroenterol 19:829–837, 2013.
- 20. Diagnosis Whipple’s Triad plasma glucose- 40-50mg/dl Fasting induced Neuroglycopenic symptoms of hypoglycaemia Resolution of symptoms after meals Plasma gluose, insulin, Proinsulin and C-Peptide over 72 hour fast This panel can detect 90% Ito T, et al: Pancreatic neuroendocrine tumors: clinical features, diagnosis and medical treatment: advances, Best Pract Res Clin Gastroenterol 26:737–753, 2012.
- 21. Gastrinoma 1955, Zollinger and colleagues Sporadic- 67%, familial- 33% Mostly solitary 60% malignant- spread to regional lymph nodes by time of diagnosis ^ gastrin -> recurrent peptic ulcers, diarrhoea, reflux esophagitis. Diagnosis- Thickened mucosal folds – hallmark Demonstration of hypergastrinemia – fasting serum gastrin levels (10 times) Abnormal gasric acid secretion- gastric pH <2 Secretin or glucagon stimulation test Zollinger RM, et al: Primary peptic ulcerations of the jejunum associated with islet cell tumors of the pancreas, Ann Surg 142:709–723, 1955. Anlauf M, et al: Sporadic versus hereditary gastrinomas of the duodenum and pancreas: distinct clinico-pathological and epidemiological features, World J Gastroenterol 12:5440–5446, 2006.
- 22. Gastrinoma triangle Apex- junction of cystic duct and CBD INF- 2nd and 3rd part of duodenum MEDIAL- jn of head and body of pancreas 90% of gastrinomas lie in this anatomic location Howard TJ, et al: Anatomic distribution of pancreatic endocrine tumors. Am J Surg 159:258-264, 1990
- 23. Glucagonoma ~400 cases Large size >6cms Solitary Symptoms- glucose intolerance, migratory necrolytic erythema, weight loss Diagnosis- elevated glucagon levels + enhancing pancreatic mass on CT ~60% will have liver mets at diagnosis(Kulke et al) Case series of 23 gluganomas – 5 yr survival was 75% (regardless of treatment) Kulke MH, et al: Neuroendocrine tumors, version 1.2015: clinical practice guidelines in oncology, J Natl Compr Canc Netw 13:78–108, 2015. Kindmark H, et al: Endocrine pancreatic tumors with glucagon hypersecretion: a retrospective study of 23 cases during 20 years, Med Oncol 24:330–337, 2007
- 24. Vasoactive Intestinal Peptide secreting neuroendocrine tumor Solittary, intrapancreatic tumor >50% malignant VIP – neurotransmitter & intestinal secretagogue “pancreatic cholera” Verner-Morrison syndrome Symptoms – high volume watery diarrhoea leading to metabolic acidosis Achlorhydria Hypokalemia Diagnosis – elevated plasma VIP, pancreatic tumor on imaging Renal failure secondary to hypovolemia Verner JV, et al: Islet cell tumor and a syndrome of refractory watery diarrhea and hypokalemia, Am J Med 25:374–380, 1958. Fabian E, et al: Diarrhea caused by circulating agents, Gastroenterol Clin North Am 41:603–610, 2012.
- 25. Somatostatinoma Less defined clinical syndrome than other PNETs Symptoms – glucose intolerance, cholelithiasis, weight loss, diarrhoea, steatorrhoea, anemia Located in the pancreas (56%) or duodenum Duodenal Ssomas are associated with NF-1 in 50% of cases Less likely to be malignant Nesi G, et al: Somatostatinoma: clinico-pathological features of three cases and literature reviewed, J Gastroenterol Hepatol 23:521–526, 2008. Williamson JM, et al: Pancreatic and peripancreatic somatostatinomas, Ann R Coll Surg Engl 93:356–360, 2011.
- 26. Pancreatic Polypeptide- secreting neuroendocrine tumor PNETs predominantly secreting PP- extremely rare Functional/non-functional – debated No specific syndrome Intermittent abdominal pain, pancreatitis, may develop glucose intolerance MEN-1 – multifocal and malignant Fasting PP levels > 3 times -> presence of PNET and it will likely be large enough to be detected on ct Kuo SC, et al: Sporadic pancreatic polypeptide secreting tumors (PPomas) of the pancreas, World J Surg 32:1815–1822, 2008. Mutch MG, et al: Pancreatic polypeptide is a useful plasma marker for radiographically evident pancreatic islet cell tumors in patients with multiple endocrine neoplasia type 1, Surgery 122:1012–1020, 1997
- 27. Biochemical Assessment and Monitoring for PNETS 1. Chromogranin A(CgA)- correlate with tumor burden CgA can be used as a marker in patients with both functional and non-functional pancreatic endocrine tumors Decreses post treatment – favourable outcomes Rising levels may suggest recurrent or progressive disease 2. Pancreatic polypeptide- where CgA is negative 3. Pancreastatin (PST)- post translational product of CgA. More powerful prognostic test in surgically managed PNET. Pts with elevated PST pre and post-op- 90% chance of progression and 40% risk of death within 5 years. 4. Neurokinin A & Synaptophysin more diagnostic and less prognostic.
- 29. CECT valuable for primary/regional/metastatic 80-100% sensitive for tumors > 2cms Capturing the vascular blush in the arterial phase is critical for identification and differentiation More sensitive for liver mets Both PNET and their metastasis tend to be hypervascular and best seen in arterial phase. Arterial phase of a contrast-enhanced computed tomography of the abdomen showing an early enhancing pancreatic neuroendocrine tumor in the head and uncinate process of the pancreas (white arrow), with a necrotic node medially (red arrow). Van Hoe L, Gryspeerdt S, Marchal G, et al: Helical CT for the preoperative localization of islet cell tumors of the pancreas: Value of arterial and parenchymal phase images. AJR Am J Roentgenol 165:1437–1439, 1995.
- 30. Arteriographic demonstration of an insulinoma. A, Selective injection into the specific dorsal pancreatic artery demonstrates the tumor precisely. B, Insulinoma with triphasic enhancement on CT. The mass in the pancreatic body (arrow) demonstrates early and prolonged enhancement (A from Edis AJ, McIlrath DC, Ven Heerden JA, et al: Insulinoma: Current diagnosis and surgical management. Curr Prob Surg 13:1–45, 1976; B from Ros PR, Mortelé KJ: Imaging features of pancreatic neoplasms. JBR-BTR 84:239–249, 2001.)
- 31. MRI Second line Superior delineation of hepatic metastasis is required Renal failure Hypo intense (low signal intensity) on T1 Hyper intense (high signal intensity) on T2 In one large series of insulinomas, contrast-enhanced MRI identified all lesions larger than 3 cm, 50% of lesions 1 to 2 cm, and no lesions smaller than 1 cm. Overall sensitivity for PNET 85% 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 214:483– 490, 2000. Boukhman MP, Karam JM, Shaver J, et al: Localization of insulinomas. Arch Surg 134:818–822; discussion 822– 813, 1999.
- 32. Endoscopic Ultrasound Overall sensitivity of 93% High sensitivity for small tumors less than 3cms More in head region Allows FNAC for pathologic diagnosis FNAC accuracy – 90% Muller MF, Meyenberger C, Bertschinger P, et al: Pancreatic tumors: evaluation with endoscopic US, CT, and MR imaging. Radiology 190:745–751, 1994. Proye C, Malvaux P, Pattou F, et al: Noninvasive imaging of insulinomas and gastrinomas with endoscopic ultrasonography and somatostatin receptor scintigraphy. Surgery 124:1134–1143; discussion 1143–1134, 1998.
- 33. Nuclear imaging Somatostatin receptor scintigraphy Diagnosis and Surveillance To determine if pt will benefit from PRRT SSTR 1-5 Most common SSTR2 – well deferentiated NET OctreoScan Radiotracer indium-111- DPTA-octreotide SPECT + OctreoScan 68Ga-PETCT / DOTATOC Gallium-68 DOTATOC - 68Ga-DOTA- Tyr(3)-octreotide DOTANOC DOTATATE Variation in ligand affinity for SSTR subtypes but not clinically significant Superior to conventional imaging
- 34. Comparison of CT, MRI , and SRS in a patient with Zollinger- Ellison syndrome. Neither the CT scan (top) nor MRI (middle) localized a gastrinoma. SRS , however, showed a focus in the left lobe of the liver.
- 35. Intra-op usg
- 36. Localisation of insulinoma Arterial stimulation venous sampling (94-100%) calcium is injected successively into gastroduodenal, proximal splenic, superior mesenteric and proper hepaic arteries After each injection, venous blood is sampled from hepatic veins at 30, 60 and 120 seconds. Positive localisation corresponds to 2 fold increase hepatic vein insulin levels
- 37. Surgical Management RESECTION OF THE PRIMARY TUMOR : SURGICAL CONSIDERATIONS
- 38. Indications for Surgery 1. Functional, symptomatic 2. Isolated , G1 and G2 PNET greater than 2 cms 3. Patients with metastatic disease where all visible mets can be resected 4. Palliative resection and hepatic debulking may be considered for those pts with symptomatic advanced disease when liver is the only focus of distant metastasis ~80% of liver mets are resectable
- 39. Small, Non-functional PNET Serial imaging -> progression Lee and colleagues(2012), compared patients with non functional PNET Non-operatively(77) – no change in tumor size Resection(56) – 9% had positive nodes (2.4cms) Kuo and colleagues(2013) 27.3% nodal mets and 9.1% distant mets – reasonable number to offer patients curative surgery NCDB – improved OS >5 years with resection 2017 BJS – active surveillance of patients affected by sporadic, small, asymptomatic NF-PNETs may…
- 40. Enucleation Limited procedure Low complication rates Better results than radical procedures in terms of blood loss, length of surgery, less panc. Insufficiency Laparotomy/laparoscopically
- 41. Enucleation Indications- benign Small, isolated tumors < 2 cm 2-3mm away from mpd Located near surface of pancreatic parenchyma
- 42. PNETs- Body and Tail
- 44. PNETs – head
- 46. Management of metastatic disease Lymph node mets are associated with increased recurrence. Recent studies suggest that a more aggressive approach may benefit Hepatic metastasis- surgical debulking of hepatic disease is prudent, in whom 80-90% reduction of metastatic disease is made. Formal segmental resection is gold standard Other techniques – radiofrequency/microwave ablation, hepatic artery embolization (<5cm) Liver transplant – 5 yr survival – 68% Predictor of poor outcome- location of primary in pancreas or duodenum, need for upper abd exentration and hepatomegaly Tsutsumi K, et al: Analysis of lymph node metastasis in pancreatic neuroendocrine tumors (PNETs) based on the tumor size and hormonal production, J Gastroenterol 47:678–685, 2012. Hashim YM, et al: Regional lymphadenectomy is indicated in the surgical treatment of pancreatic neuroendocrine tumors (PNETs), Ann Surg 259:197–203, 2014.
- 47. Non surgical management Goal – improve quality of life, extend survival Insulinoma – diazoxide(200-600mg/day) ZES – PPI – titrated to effect Somatostatin based analogues – first line for nf met Octreotide Lanreotide Peptide receptor radionucleotide therapy- approved only in Europe Systemic chemotherapy – CAPTEM- Capecitabine temozolomide Grade 3 – cisplatin + etoposide Biologic therapies –mTOR inhibitors – EVEROLIMUS RADIANT-3 trial – tumor shrinkage - 68% Sunitinib
- 48. Thank you
Notas do Editor
- NETs arise from cells of the neuroendocrine system, which produce and secrete regulatory hormones. Most NETs are slow growing and malignant, with metastatic potential. The exception is insulinomas, which are usually benign. These cella show A- amine P- precursor (l-dopa, 5-hydroxyl tryptophan) U-uptake & D-decarboxylation To produce biogenic amines such as catecholamines ana serotonin. NETs can arise nearly anywhere in the body, although the most common sites of origin are the- Gastrointestinal (GI) tract, including the small intestine, rectum, large bowel, stomach, appendix, and liver Lungs Pancreas
- Pancreatic NETS (PNETs) are rare and usually slow-growing neoplasms, with symptoms resulting from excess hormone production or mechanical problems secondary to tumor bulk. 7% of all NETs are found in the pancreas Until the ….
- Cellular origin has been debated It is slikely that these tumors arise from pluripotent stem cells in the pancreatic ductal acinar system and not from pancreatic islet themselves
- The incidence rate of pNETs in the US is about 0.4 cases per 100,000 persons. Incidence is thought to be increasing over the past 3 decades. Von hippel-landau, tuberous sclerosis Cigarette, dm, chronic pancreatitis, obesity
- The incidence has been rising in the last three decades. This might be due to greater awareness, improved diagnostic capabilities, improved reporting to registries, or a change in nomenclature from carcinoid. With new successful treatments to control or slow the progression of the disease, the prevalence of cancer will increase.
- Mostly Well circumscribed solitary masses that can occur anywhere in the pancreas. All pnets have potential to grow and eventually metastasise, because of this these tumors are considered malignant. Because the Likelihood of metastatic spread is so very low in subsets of patients with pnets, benign has been used as a classification variable
- Grading is determined by ki-67 and mitotic index. Mitotic index is expressed as number of mitotic figures per 10 hpf and it is recommended that atleast 40-50 hpf must be examined.
- Antigen KI-67 is a nuclear protein that is associated with and may be necessary for cellular proliferation. Furthermore, it is associated with ribosomal RNA transcription. Inactivation of antigen KI-67 leads to inhibition of ribosomal RNA synthesis. During interphase, the Ki-67 antigen can be exclusively detected within the cell nucleus, whereas in mitosis most of the protein is relocated to the surface of the chromosomes. Ki-67 protein is present during all active phases of the cell cycle (G1, S, G2, and mitosis), but is absent from resting cells (G0).[8] Cellular content of Ki-67 protein markedly increases during cell progression through S phase of the cell cycle.[9]
- T3- without involving celiac axis or sma
- PNETs may or may not have secretory symptoms. Secretory symptoms are related to the specific hormone released. Tumors without secretory symptoms (nonfunctional) may still secrete peptides; however, they cause no specific clinical symptom. Presence of symptoms is due to the tumor bulk.
- Tumors without secretory symptoms are not associated with a hormonal syndrome. Because of this, they may be present as an incidental finding at surgery or be detected radiographically when investigating for nonspecific abdominal pain. Patients usually present late in the disease course with large primary malignancies or advanced disease. Symptoms are due to tumor growth or spread. Abdominal pain Jaundice Diarrhea Indigestion Weight loss
- There are several subtypes of pNETs. These are dependent on which islet cell type gets differentiated from the pleuripotent cells and consequently, which hormone is over-produced.
- A good history and physical examinations is important to the diagnosis of NET. Characteristic symptoms are present in 8% to 35% of metastatic NET and include dry flushing, cramps, nocturnal diarrhea, erythematous to purplish skin, telangiectasias, hepatomegaly, cardiac murmurs, edema, hypoglycemia, confusion, dyspepsia, and GI bleeding. Lab tests for biochemical markers should include: Serum CgA and other biomarkers as appropriate for symptoms (eg, if glucagonoma is suspected, glucagon levels should be tested) Tissue Once a biopsy is performed, the specimen should be stained for Ki-67, CgA, synaptophisin, and neuron specific enolase Urine 5-HIAA if patient has symptoms consistent with carcinoid syndrome Imaging Should include CT scan with contrast or MRI Nuclear imaging with Octreoscan and PET scan Endoscopic ultrasound is useful for diagnosing pNET
- Most common pnet Multiple in MEN1. Intra-pancreatic and cause hypoglycaemia.
- Critical part of diagnosis includes establishment of whipple triad Symptoms of hypoglycaemia - diaphoresis, shaking, mental confusion, obtundation, and seizures Whipple’s triad can be emulated by other entities, including surreptitious administration of insulin or sulfonylurea compounds 72 hour fast- two reasons; the first is to prevent life-threatening hypoglycemia and the second is to rule out the possibility of factitious hypoglycemia as a result of exogenous insulin administration
- First published case series dealing with clinical course of 2 patients The syndrome would be named after these authors and the tumors would eventually be known as gastrinomas In familial MEN1 – small multiple and mostly found in duodeum
- Migratory rash is often the first manifestation, tends to start in perineum and extends to trunk and extrimities
- Blood tests Patients with normalised PST post-operatively have low risk of death
- Usg has no role Once the diagnosis of functional pnet is made Cect as cross sectional imaging – first line imaging tool for localisation less sensitive than Endoscopic ultrasound in detection smaller lesions These lesions will washout in venous and delayed phases.
- Another note
- Eus should be performed if unable to localize on ct/mri
- Not yet been approved in us Peptide receptor radionucleotide therapy
- High frequency probe – 7.5 – 10 mhz
- Nonfunctional >2 cms should be resected Smaller non functional tumors resection is debatable
- Ncdb – national cancer database
- There are no guidelines on number of lymph nodes that should be sampled or requirement that formal lymphadenectomy be performed in pnet pts. Because most patients presenting with liver mets have large and multiple lesions – hepatic artery embolic therapy remains more rational approach
- High grade disease that are not candidates for surgical resection Studies have shown stable disease/progression free survival with somatostatin based analogues 60% PRRT –combines sstn analogues to radioactive elements – beta particles Suniti – vegf inhibitor