Pancreatic neoplasm of the endocrine cells of the pancreas.

clinical presentation, diagnosis and treatment neoplasms of pancreas arising from different types of endocrine cells, both benign and malignant. exocrine tumours are not included in the presentation.

1. Pancreatic neoplasm Professor Dr. Arunabha Sinha

2. Broadly speaking, there are three basic types: Ductal adenocarcinoma >90% of pancreatic cancers with a 4% 5-year survival (worst of any cancer) Neuroendocrine tumors aka islet-cell tumors, rare Cystic neoplasms account for < 1% of pancreatic cancer

3. Pancreatic endocrine neoplasm Much less commonly, tumors begin in the islets of Langerhans, the endocrine component. These are known as islet cell tumors or pancreatic neuroendocrine tumors. These can be functionally inactive islet cell carcinomas or benign or malignant functioning tumors such as insulinomas, glucagonomas, and gastrinomas.

4. Tumor growths without producing hormones is called non-functioning. If the tumor produces a hormone(s), the hormone(s) may cause metabolic imbalances, such as a very low blood sugar level (such as the case with insulinomas) or a very high blood sugar level (such as with glucagonomas), or other problems like severe diarrhea (a symptom of VIPoma's, which produce a substance called vasoactive intestinal peptide).

5. Most Pancreatic Neoendocrinal tumors are sporadic but they can be associated with hereditary endocrinopathies including MEN1,VHL,NF1,sydromes.

6. Insulinoma This is an insulin-producing tumour of the pancreas. most common functional Pancreatic neoendocrinal tumours . These are rare tumors with an incidence of four (1–32) per million. Insulinomas have been diagnosed in all age groups, with the highest incidence found in the fourth to the sixth decades. Women seem to be slightly more frequently affected.

7. Clinical presentation Patients typically develop sporadic symptoms of neuroglycopenia. Classically these manifest while fasting or during exercise, but some (18%) may develop symptoms postprandially and these may be the only symptoms. Some patients develop loss of consciousness and coma. The release of catecholamines produces symptoms such as sweating, weakness, hunger, tremor, nausea, anxiety and palpitations.

8. Diagnosis (with differential) Whipple’s triad: fasting hypoglycaemia, serum glucose level <50 mg/dl Treatment is by glucose infusion. The key test is a 72-hour fast looking for documented endogenous hyperinsulinism in association with symptoms and signs of low plasma glucose (54mg/dl), elevated insulin and high C-peptide. If the test is negative and the suspicion of insulinoma is high, a prolonged oral glucose tolerance test is done.

9. 90% are benign and solitary, and only 10% are malignant. Evenly distributed throughout head, body, and tail of the pancreas. Dx. Routine laboratory studies low blood sugar, elevated Serum insulin levels & C-peptide levels usually localized Investigations are CT scanning and EUS.

10. After a positive fast test, a CT or MRI is performed. In only a small percentage (<5–10%) insulinomas are elusive on cross-sectional imaging. In such a situation endoscopic ultrasonography (EUS) is undertaken with a positive detection rate in excess of 90%. Visceral angiography with arterial stimulation venous sampling is reserved for negative EUS studies or when more than one lesion has been identified.

11. Treatment (medical and surgical) Surgery: Most insulinomas are small, sporadic and solitary. In most cases enucleation is possible. Contraindications to enucleation are close proximity to the main pancreatic duct and larger tumors. In most cases a laparoscopic approach is recommended for localized tumors and this achieves a high success rate (98–100%).

12. For patients with MEN  1, tumors may be multifocal. The classical approach was to enucleate tumors in the ‘right’ pancreas (dictated by the portal vein) and perform a distal pancreatectomy owing to the high number of non-functioning NETs associated with the mutation. Laparoscopic enucleation of localized tumors has become the procedure of choice.

13. Medical: All patients undergoing surgery should be treated with diazoxide, which suppresses insulin secretion by direct action on the β cells, and receive frequent small meals to avoid hypoglycaemia. Somatostatin analogue (SSA) therapy may also be useful. For patients with unresectable or metastatic disease, SSAs and everolimus are effective in controlling hypoglycaemia. Other options include chemotherapy, peptide receptor radionuclide therapy (PRRT) and chemoembolization.

14. Gastrinomas Zollinger–Ellison syndrome (ZES) is a condition that includes: fulminating ulcer diathesis in the stomach, duodenum or atypical site (ii) recurrent ulceration despite ‘adequate’ therapy; and (iii) non- β islet cell tumours of the pancreas (gastrinoma).

15. Zollinger-Ellison Syndrome is caused by Gastrinomas, an endocrine tumour that secretes gastrin, leading to acid hypersecretion and peptic ulceration. At the time of Diagnosis, 21% of patients have diarrhea. 70-90%,found in Passaro’s triangle Approximately 50% of gastrinomas metastasize to LN or liver and therefore considered malignant. Diagnosis by hormonal test, >1000 pg /mL Somatostatin receptor scintigraphy in combination with CT

16. Pathology In sporadic disease the tumors are mostly located in the duodenum (60–80%) and are small (<5 mm) and multiple. In MEN 1, all tumors are in the duodenum. The vast majority (approximately 90%) occur within the ‘gastrinoma triangle’, an area bounded by the junction of the neck and body of the pancreas medially, the junction of the second and third parts of the duodenum inferiorly and the junction of the cystic and common bile ducts superiorly. Tumors <2 cm in diameter without signs of invasion are considered benign.

17. Tumors are graded according to WHO NET criteria. In general, the progression of gastrinomas is relatively slow with a 5-year survival rate of 65% and a 10-year survival rate of 51%. Patients with complete tumor resection have excellent 5- and 10-year survival rates (90–100%). Patients with pancreatic tumors have a worse prognosis than those with primary tumors in the duodenum. There is no established marker to predict the biological behavior of gastrinoma.

18. Clinical presentation Over 90% of patients with gastrinomas have peptic ulcer disease, often multiple or in unusual sites. Diarrhea is another common symptom, caused by the large volume of gastric acid secretion. Abdominal pain from either peptic ulcer disease or gastro-esophageal reflux disease remains the most common symptom, occurring in more than 75% of patients. Around 60–95% have a history of high alcohol use, which may be a risk factor. The majority of tumors have metastasized by the time of presentation.

19. Diagnosis (with differential) The cornerstone of diagnosing ZES is an elevated fasting serum gastrin (FSG). If elevated, the gastric pH is measured. If the pH is <2 and the FSG is more than 10-fold elevated, the diagnosis is confirmed. If the FSG is less than 10-fold higher, a secretin provocation test should be performed. Once a diagnosis is confirmed all patients are screened for MEN 1 (biochemical and genetic).

20. Localization studies are then indicated as the tumors are often small and multiple. The majority of gastrinomas have a high density of somatotropin receptors. 68Ga-labelled SSAs with PET-CT have been found to be sensitive and specific. If not available, somatostatin scintigraphy (SRS) and EUS should be done. .

21. Treatment Surgery: All patients with sporadic gastrinoma without metastases should have a surgical operation by an experienced surgeon. At the time, the peritumoral lymph nodes should be sampled for histological assessment. In MEN 1/gastrinoma, surgery is not recommended for patients with tumors 2 cm are enucleated. Parathyroidectomy reduces gastric acid secretion.

22. Medical: PPI therapy is the management of choice. Even when patients undergo a surgical cure, most (60%) require continued medical treatment. For patients with advanced locoregional disease or metastases, PPI remains the first-line treatment supplemented with SSA therapy. In refractory cases, locoregional ablative therapy (radiofrequency ablation or chemoembolization) or PRRT may be effective.

23. The diagnosis can be elusive owing to its rarity and it is not uncommon for patients to have been investigated for epilepsy (fitting, loss of consciousness) or drug abuse (altered mental state) before the correct diagnosis is established. It is typical that patients will have put on weight prior to presentation (learning to eat to survive)

24. Glucagonoma It is a very rare tumor of the pancreatic alpha cells that results in the overproduction of the glucagon, typically associated with rash (NME), wt. loss and mild DM. Diagnosis is confirmed by serum glucagon levels, >500 pg./mL

25. Somatostatinoma It is a rare neuro endocrinal tumour arise from delta cells of pancreas. originate proximal pancreas or pancreatoduodenal groove. 60% ampulla & periampullary The most common presentations are abdominal pain 25%, jaundice 25%, cholelithiasis 19%. Diagnosis by confirming elevated serum somatostatin levels, >10 ng/ml.

26. Non-functioning pancreatic neuroendocrine tumours These P-NETs are clinically classified as non-functioning (NF-PNET) when they do not cause a clinical syndrome. Incidence of NF-P-NETs accounts for 60–90% of all P-NETS.

27. Pathology NF-P-NETs cannot be distinguished from functional tumors by immunocytochemistry because they may also express hormones such as gastrin and insulin. They usually stain positively for chromogranin A and synaptophysin. The tumours are usually large (>5 cm).

28. Clinical presentation They are generally diagnosed at a more advanced stage owing to their indolent nature, slow growth and lack of functional secretion causing a delay in the onset of symptoms. Therefore, in contrast to functioning PETs, patients with NF-PETs present with various non- specifc symptoms, including jaundice, abdominal pain, weight loss and pancreatitis. In some cases liver metastases are the frst presentation.

29. Diagnosis Increased levels of chromogranin A and PP are usual. The majority of these tumors are large and are easily identified by transabdominal ultrasonography or CT scanning. Recognition of NF-PNETs is imperative because of their respectability and excellent long-term survival compared with their exocrine counterparts.

30. Treatment (medical and surgical) For grade 1 and 2 unresectable tumors, SSAs may be effective because of their antiproliferative properties. Alternatively novel targeted drugs (everolimus and sunitinib) could be considered. Platinum-based chemotherapy is the treatment of choice for grade 3 and NEC tumors.

31. CONGENITAL ABNORMALITIES CYSTIC FIBROSIS This is inherited as an autosomal recessive condition. It occurs most frequently among Caucasians, in whom it is the most common inherited disorder (incidence of 1:2000 live births in the UK). Cystic fibrosis (CF) develops when there is a mutation in the CFTR (cystic fibrosis transmembrane conductance regulator) gene on chromosome 7. This gene creates a cell membrane protein that helps to control the movement of chloride across the cell membrane. CF is a multisystem disorder of exocrine glands that affects the lungs, intestines, pancreas and liver, and is characterised by elevated sodium and chloride ion concentrations in sweat. The mother may notice that the child is salty when kissed.

32. Most of the organ damage is due to blockage of narrow passages by thickened secretions. Chronic pulmonary disease arises from plugging of bronchi and bronchioles. CF is the most common cause of chronic lung disease among children in resource-rich countries. Cor pulmonale may develop later.

33. At birth, the meconium may set in a sticky mass and produce intestinal obstruction (meconium ileus) Secretions precipitate in the lumen of the pancreatic duct causing blockage, which results in duct ectasia and fatty replacement of exocrine acinar tissue. Pancreatic exocrine insufficiency leads to fat malabsorption. Steatorrhea is usually present from birth, resulting in stools that are bulky, oily and offensive.

34. The islets of Langerhans usually appear normal, but diabetes mellitus can occur in older patients. The liver may become cirrhotic as a result of bile duct plugging, and signs of portal hypertension may appear. Infertility is common, due to the absence of the vas deferens in men and thick cervical mucus in women.

35. Outside the newborn period, the earliest clinical signs of CF are poor growth, poor appetite, rancid greasy stools, abdominal distension, chronic respiratory disease and finger clubbing. The appearance of secondary sexual characteristics may be delayed. The diagnosis can be made by genetic testing (which may be part of prenatal or newborn screening) and by the sweat test. Levels of sodium and chloride ions in the sweat above 90 mmol/L confirm the diagnosis.

36. Treatment is aimed at control of the secondary consequences of the disease. Pulmonary function is preserved with aggressive physiotherapy and antibiotics. Malabsorption is treated by administration of oral pancreatic enzyme preparations. The diet should be low in fat but contain added salt to replace the high losses in the sweat.

37. With early diagnosis and optimal treatment, patients in resource-rich countries can now expect to survive to their mid-thirties. Those with endstage lung disease may be considered for lung transplantation. Heterozygous carriers of the various gene mutations are asymptomatic but can be identified by DNA analysis. There is a suggestion that such patients may develop pancreatitis later in life.

38. PANCREAS DIVISUM Pancreas divisum occurs when the embryological ventral and dorsal parts of the pancreas fail to fuse . The dorsal pancreatic duct becomes the main pancreatic duct and drains most of the pancreas through the minor or accessory papilla. The incidence of pancreas divisum ranges from 5% in autopsy series to 10% in some ERCP and MRCP series.

39. Pancreas divisum found incidentally in an asymptomatic person does not warrant any intervention. But the incidence of pancreas divisum ranges from 25–50% in patients with recurrent acute pancreatitis, chronic pancreatitis and pancreatic pain. The minor papilla is substantially smaller than the major papilla (and many of these patients probably have papillary stenosis).

40. A large volume of secretions flowing through a narrow papilla probably leads to incomplete drainage, which may then cause obstructive pain or pancreatitis. Certainly in patients with idiopathic recurrent pancreatitis, pancreas divisum should be excluded. The diagnosis can be arrived at by MRCP, EUS or ERCP, augmented by injection of secretin if necessary. There may be changes indicative of obstruction or chronic inflammation in the dorsal duct system. Endoscopic sphincterotomy and stenting of the minor papilla may relieve the symptoms. Surgical intervention can take the form of sphincteroplasty, pancreatojejunostomy or even resection of the pancreatic head.

41. ANNULAR PANCREAS This is the result of failure of complete rotation of the ventral pancreatic bud during development, so that a ring of pancreatic tissue surrounds the second or third part of the duodenum. It is most often seen in association with congenital duodenal stenosis or atresia and is therefore more prevalent in children with Down syndrome. Duodenal obstruction typically causes vomiting in the neonate . The usual treatment is bypass (duodenoduodenostomy). The disease may occur in later life as one of the causes of pancreatitis, in which case resection of the head of the pancreas is preferable to lesser procedures

42. ECTOPIC PANCREAS Islands of ectopic pancreatic tissue can be found in the submucosa in parts of the stomach, duodenum or small intestine (including Meckel’s diverticulum), the gall bladder, adjoining the pancreas, in the hilum of the spleen and within the liver. Ectopic pancreas may also be found in the wall of an alimentary tract duplication cyst

43. Congenital cystic disease of the pancreas Von Hippel–Lindau syndrome. An autosomal dominant disease characterised by central nervous system and retinal haemangiomas (60–80%), renal cysts (50–70%), clear cell renal cell carcinoma (30%), pancreatic neuroendocrine tumours (P-NETs) (8–17%), PPGL (20%), endolymphatic sac tumours (6–15%) and epididymal/broad ligament cyst adenoma (50%). This sometimes accompanies congenital disease of the kidneys and liver and nervous system and occurs as part of the von Hippel–Lindau syndrome.

44. INJURIES TO THE PANCREAS EXTERNAL INJURY PRESENTATION AND MANAGEMENT The pancreas, is somewhat protected location in the retroperitoneum, is not frequently damaged in blunt abdominal trauma. If there is damage to the pancreas, it is often concomitant with injuries to other viscera, especially the liver, the spleen and the duodenum. Occasionally, a forceful blow to the epigastrium (such as a kick from a human or a horse, or pressure from the steering wheel in a car accident) may crush the body of the pancreas against the vertebral column. Penetrating trauma to the upper abdomen or the back carries a higher chance of pancreatic injury. .

45. Blunt pancreatic trauma usually presents with epigastric pain, which may be minor at first, with the progressive development of more severe pain due to the sequelae of leakage of pancreatic fluid into the surrounding tissues. The clinical presentation can be quite deceptive; careful serial assessments and a high index of suspicion are required. A rise in serum amylase occurs in most cases. A CT scan of the pancreas will delineate the damage that has occurred to the pancreas . If there is doubt about duct disruption, an urgent ERCP should be sought. MRCP may also provide the answer, but the images can be difficult to interpret. Support with intravenous fluids and a ‘nil by mouth’ regimen should be instituted while these investigations are performed.

46. There is no need to rush to a laparotomy if the patient is haemodynamically stable, without peritonitis. It is preferable to manage conservatively at first, investigate and, once the extent of the damage has been ascertained, undertake appropriate action. Operation is indicated if there is disruption of the main pancreatic duct; in almost all other cases, the patient will recover with conservative management.

47. In penetrating injuries, especially if other organs are injured and the patient’s condition is unstable, there is a greater need to perform an urgent surgical exploration. Assessment of pancreatic damage and duct disruption at the time of surgery can be difficult, because the bruising associated with the retroperitoneal damage prevents clear visualization of the pancreas.

48. A patient and thorough examination of the gland should be carried out. Haemostasis and closed drainage is adequate for minor parenchymal injuries. If the gland is transacted in the body or tail, a distal pancreatectomy should be performed, with or without splenectomy. If damage is purely confined to the head of the pancreas, haemostasis and external drainage is normally effective.

49. In the emergency setting, in an unstable patient with concomitant injuries, a surgeon unaccustomed to pancreatic surgery should refrain from trying to ascertain whether the duct in the pancreatic head is intact or embarking on a major resection. However, if there is severe injury to the pancreatic head and duodenum, then a pancreatoduodenectomy may be necessary.

50. PROGNOSIS The most common cause of death in the immediate period is bleeding, usually from associated injuries. Once the acute phase has passed, the mortality and morbidity related to the pancreatic injury itself are treatable, with a complete return to normal activity the usual outcome. Persistent drain output occurs in up to a third of patients Sometimes, in the aftermath of trauma that has been treated conservatively, duct stricturing develops, leading to recurrent episodes of pancreatitis. The appropriate treatment in such cases is resection of the tail of the pancreas distal to the site of duct disruption.

51. A pancreatic pseudocyst may develop. If the main duct is intact, the cyst can be aspirated percutaneously in the first instance; it may not be necessary to undertake a cyst gastrostomy. If the cyst develops in the presence of complete disruption of the pancreas, there is no alternative but to undertake a distal resection or, occasionally, a pancreatojejunostomy with a Roux-en-Y loop. In a patient who presents with a peripancreatic cyst and a history of previous blunt abdominal trauma, do not assume that it is a post-traumatic pseudocyst. The possibility of a cystic neoplasm should be considered and excluded.

52. IATROGENIC INJURY This can occur in several ways: Injury to the tail of the pancreas during splenectomy, resulting in a pancreatic fistula. Injury to the pancreatic head and the accessory pancreatic duct (Santorini), which is the main duct in 7% of patients, during Billroth II gastrectomy. A pancreatogram performed by cannulating the duct at the time of discovery of such an injury will demonstrate whether it is safe to ligate and divide the duct.

53. If no alternative drainage duct can be demonstrated, then the duct should be anastomosed to the duodenum or alternatively resection of the pancreatic head should be considered. Enucleation of islet cell tumors of the pancreas can result in fistulae. Duodenal or ampullary bleeding following sphincterotomy. This injury may require duodenotomy to control the bleeding.

54. PANCREATIC FISTULA Pancreatic fistula usually follows operative trauma to the gland or occurs as a complication of acute or chronic pancreatitis. It is important to define the site of the fistula and the epithelial structure with which it communicates (e.g. externally to skin, or internally to bowel). If there is uncertainty about whether the fluid issuing from a drain site or a wound is pancreatic juice, measurement of the amylase content will be diagnostic. Management includes correction of metabolic and electrolyte disturbances and adequate drainage of the fistula into a stoma bag with protection of the skin.

55. Investigation of the cause of the fistula is required as the underlying cause must be treated before the fistula will close. Frequently, the cause is related to obstruction within the pancreatic duct, which can be overcome by the insertion of a stent or catheter endoscopically into the pancreatic duct. While waiting for closure of the fistula, the patient should be given parenteral or nasojejunal nutritional support (as opposed to nasogastric or oral feeding; the rationale is that parenteral or nasojejunal feeding reduces the volume of pancreatic secretion). The use of octreotide will also suppress pancreatic secretion.

56. MANAGEMENT OF PANCREATIC FISTULAE

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