Journal of the Pancreas Open Access

Keywords

Case Report; Digestive System Neoplasms; Neoplasms; Neoplasms by Histologic Type; Neoplasms, Germ Cell and Embryonal; Neuroendocrine Tumors; Pancreatic Neoplasms; Pancreatitis; Pancreatitis, Acute Necrotizing

Abbreviations

EUS: endoscopic ultrasonography; FNA: fine needle aspiration; MRCP: magnetic resonance cholangiopancreatography; PNT: pancreatic neuroendocrine tumours

INTRODUCTION

Pancreatic neuroendocrine tumours (PNT) represent less than 10% of all pancreatic tumours [1]. They usually manifest few symptoms, except when there is a hormone syndrome associated with them; therefore, they are diagnosed at an advanced stage [2]. Furthermore, pancreatic tumours are a known but uncommon cause of acute pancreatitis [3]. We report on three patients having acute pancreatitis secondary to PNT. One of them (Case 1) was previously reported [4].

CASE REPORT

Case 1

A 73 year old woman was admitted to our hospital complaining of intense epigastric pain. On admission, she had hyperamylasemia (820 U/L) and hyperlipasemia (447 U/L). Abdominal ultrasonography showed the presence of perihepatic fluid, but the pancreas could not be seen. There were no gallstones. On abdominal CT scan, the pancreas was seen to be enlarged, particularly the tail. There were large peripancreatic collections of fluid at this level, but no signs of necrosis. The main pancreatic duct was not enlarged on either ultrasonography or CT. The outcome was poor, with progressive worsening, fever, anaemia and finally organ failure. Surgical treatment was therefore indicated four weeks after hospital admission. At surgery, fluid was drained, and a previously undetected mass seen in the tail of the pancreas, surrounded by extensive areas of tissue, was excised. The patient died of multi-organ failure a few days post-operatively. Histological study of the tissue removed showed a neoplasm with neuro-endocrine features which stained positively with an immuno-histochemical technique for synaptophysin and enolase but was negative for hormones.

Case 2

A 43 year old man was admitted to our hospital with epigastric pain of sudden onset. Two years previously, he had had a cholecystectomy for biliary colic. On admission, he was found to have elevated serum amylase and lipase levels (1,017 U/L and 2,137 U/L, respectively). Abdominal ultrasonography was normal. Subsequently, a helical CT scan of the abdomen showed a hyperdense mass, 2 cm in diameter, at the level of the pancreatic uncinate process (Figure 1). The main pancreatic duct was not dilated. Therefore, percutaneous fine needle aspiration (FNA) was done, which led to the diagnosis of a tumour having neuro-endocrine characteristics. The peripheral blood levels of insulin, parathyroid hormone (PTH), gastrin, vasoactive intestinal peptide (VIP) and somatostatin were normal, while the level of glucagon was slightly elevated (238 pg/mL). Magnetic resonance (MR) confirmed the presence of a tumour located in the head of the pancreas and a 1cm nodule in the liver in the fourth hepatic segment, which had not been previously detected (Figure 2). Somatostatin receptor scintigraphy was normal. Subsequently, it was decided to perform surgical resection in two stages. Initially, a cephalic duodenopancreatectomy was done and then, some months later, the liver metastasis was resected. Histological examination of the two resected specimens confirmed the preoperative diagnosis: neoplastic proliferation, with cells which tended to be grouped together in solid nests or in an alveolar or trabeculated manner. An immunohistochemical study showed that the tumour cells stained positive for cytokeratins and synaptophysins but negative for gastrin, VIP, ACTH and insulin, weakly positive for glucagons and over 20% of the cells positive for somatostatin. All this was compatible with a neuro-endocrine tumour. One year later, a single liver metastasis was detected on MR in hepatic segment six. This was surgically resected. Subsequently, three new metastases developed and a liver transplant was indicated. However, the patient died immediately post-operatively due to technical complications.

Case 3

A 44 year old man was admitted complaining of intense abdominal pain. On admission, he had hyperamylasemia (1,591 U/L). The abdominal ultrasonography was normal. A helical CT scan showed a hyperdense mass of 2.2 cm in the head of the pancreas. The main pancreatic duct was not enlarged. The FNA of the pancreatic mass showed the presence of neuroendocrine cells. A study of the peripheral blood hormones showed the levels of insulin, gastrin, VIP, glucagon, PTH and somatostatin to be normal. Somatostatin receptor scintigraphy showed a pancreatic neoplasm, with no evidence of local or distant spread (Figure 3). A cephalic duodenopancreatectomy was done. Histological study of the surgical specimen confirmed the presence of a tumour whose architecture was mainly trabecular, with cells of uniform size and morphology similar to that of the islet cells, occasional mitoses and the absence of vascular infiltration and necrosis. An immunohistochemical study was positive for neuro-endocrine markers (synaptophysin and enolase) but no hormones were shown. The patient died after acute necrotizing pancreatitis occurred post-operatively.

The characteristics of the three patients are summarized in Table 1.

DISCUSSION

In Spain, as in most western countries, gallstones and alcohol intake are the most common causes of acute pancreatitis [5]. Pancreatic neoplasms are a known but uncommon cause of acute pancreatitis. The exact mechanism whereby a tumour may cause acute pancreatitis is not clear. It may be due to obstruction of the duct, ischaemia secondary to vascular occlusion due to the malignant cells or to the activation of pancreatic enzymes due to tumour cells [3]. PNTs account for a small proportion of such tumours. There are neoplasms which may cause chronic pancreatitis, either due to associated hormone activity (such as the Zollinger-Ellison syndrome) [6] or directly due to an obstructive mechanism [7, 8]. However, the association between acute pancreatitis and PNT is uncommon. Considering only patients with abdominal pain and increased pancreatic enzymes and/or acute signs on imaging techniques (without evidence of chronic pancreatitis in histological studies), up to now, only twenty cases of acute pancreatitis induced by PNT have been described [4, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21]. We present two new cases together with one previously reported (Case 1) [4]. The pathophysiology of acute pancreatitis in PNTs is attributed to several mechanisms. Some tumours release hormones which may be responsible for acute pancreatitis (i.e., hypercalcaemia secondary to parathyroid hormone). However, most PNTs produce mechanical obstruction of the pancreatic ducts, regardless of whether the tumour is functioning or non-functioning [9]. All our patients had non-functioning PNTs. Although there was no evidence of main pancreatic duct obstruction on imaging methods (ultrasonography, CT scan, MR), pancreatography was not possible using either MRCP or ERCP. Therefore, mechanical obstruction could not be ruled out. Table 2 shows the characteristics of the previously reported patients with acute pancreatitis secondary to PNT. Sex distribution is homogeneous (8 males, 7 females, 4 nonspecified). Most patients were young when the tumour was diagnosed, although one of our patients is the oldest in the series (73 years old).

In all cases but one (gastrinoma) [13] the tumours were considered to be nonfunctioning. The tumour, which was previously unsuspected, probably appeared as a result of it causing acute pancreatitis. In this regard, at least nine patients had distant or regional metastases when the tumour was diagnosed, suggesting a delayed diagnosis due to this silent evolution.

The course of the acute pancreatitis associated with these tumours tends to be mild, without the development of complications. Two patients suffered severe acute pancreatitis, one of them developed a pseudocyst [16] and the other, one of our cases, developed severe acute pancreatitis with multi-organ failure and died. However, the course of the illness due to the tumour itself tends to be more varied, as is shown in Table 2. In four patients, death occurred as a direct result of the tumour or its treatment. In our cases, death was a direct consequence of the tumour due to severe acute pancreatitis and, in the others, death was secondary to surgery (post-surgical severe acute pancreatitis and technical complications of liver transplant).

In one third of the cases, tumours were found in the head of the pancreas. In no case, however, did the tumour cause obstructive jaundice, as opposed to what may be expected in cases of adenocarcinoma of the head of the pancreas. The relatively slow growth of these tumours could be an explanation. Tumours were also common in the tail of the pancreas and only two patients had involvement at distant sites.

Diagnosis of the site of these tumours is made using imaging techniques. Classically, ultrasonography, CT and ERCP have been used. However, the results are not really satisfactory since there may be up to 60% of false negatives [22, 23]. In our cases, no tumour was detected on ultrasonography. CT only showed neoplasms in two cases, namely, in those in which helicoidal CT, which gives better resolution in pancreatic tumours, was used. In the other case, apart from conventional CT being used, the presence of a considerable amount of peritumoural inflammatory tissue may have made it impossible to detect the tumour using this technique. MR may improve the diagnosis of pancreatic tumours, regarding both their site and extension [24]. In one of our patients, MR was the technique which permitted the detection of liver metastases which had not been diagnosed on either ultrasonography or helicoidal CT scan. At present, endoscopic ultrasonography (EUS) and somatostatin receptor scintigraphy are the techniques of choice for evaluation of the size and extent of these tumours, with good results and great sensitivity [25, 26]. The existence of somatostatin receptors, a common event in neuroendocrine tumours, enhances the diagnostic accuracy of scintigraphy [27]. However, although somatostatin receptor scintigraphy was used on two patients, findings were positive in only one.

In general, treatment of these neoplasms is based on control of the hormone syndrome associated with it (if present) and resection of the tumour when it is localized [28, 29], as was done in our three cases. Unfortunately, two of them died as a consequence of surgery. The other patient developed hepatic metastases. The liver is the main target organ for metastases. Several therapies have been described regarding hepatic metastases. They include resective surgery [30], ablative methods such as thermal ablation [31, 32, 33] or liver transplant [34, 35]. In our patient, initially the metastasis located in hepatic segment 6 was resected, but later new hepatic metastases appeared; therefore, a hepatic transplant was attempted taking into account the absence of any extra-hepatic tumour.

Tables at a glance

Table 1 Table 2

Figures at a glance

Figure 1 Figure 2 Figure 3

References

1. Jensen RT, Norton JA. Endocrine tumors of the pancreas. In: Feldman M, Scharschmidt BF, Sleisenger MH, eds. Gastrointestinal and Liver Diseases. Philadelphia: W.B. Saunders Company, 1998:871-94.
2. Mignon M. Natural history of neuroendocrine enteropancreatic tumors. Digestion 2000; 62(Suppl 1):51-8. [PMID 10940688]
3. Mujica VR, Barkin JS, Go VL. Acute pancreatitis secondary to pancreatic carcinoma. Study Group Participants. Pancreas 2000; 21:329-32. [PMID 11075985]
4. Mart?nez J, Carnicer F, Mart?nez N, Garc?a MF, Palaz?n JM, G?mez A. Neuroendocrine tumor associated with acute pancreatitis. Rev EspEnferm Dig 1994; 85:221-2. [PMID 8204389]
5. Minguez M, Garcia A, Boix V. Acute pancreatitis. A prospective epidemiological study in the province of Alicante. A Hospital Group for Study of Digestive Diseases in Alicante. Rev EspEnferm Dig 1995; 87:869-73. [PMID 8562193]
6. Baffy G, Boyle JM. Association of Zollinger- Ellison syndrome with pancreatitis: report of five cases. Dig Dis Sci 2000; 45:1531-4. [PMID 11007101]
7. Sarles H, Cambon P, Choux R, Payan MJ, Odaira S, Laugier R, et al. Chronic obstructive pancreatitis due to tiny (0.6 to 8 mm) benign tumors obstructing pancreatic ducts: report of three cases. Pancreas 1988; 3:232-7. [PMID 2836852]
8. Hanson JS, Cohen AR, Van Moore A, Cloud WG, Bianchi RF. Gastrinoma presenting as chronic pancreatitis. Am J Gastroenterol 1990; 85:178-80. [PMID 2301340]
9. Shrikhande S, Kleeff J, Zimmermann A, Friess H, B?chler MW. Co-existent chronic pancreatitis and pancreatic neuroendocrine tumor. Case report and review of the literature. Pancreatology 2001; 1:117-22. [PMID 12120189]
10. Patchefsky AS, Solit R, Phillips LD, Craddock M, Harrer MV, Cohn HE, Kowlessar OD. Hydroxyndoleproducingtumores of the pancreas. Carcinoid-islet cell tumor and oat cell carcinoma. Ann Intern Med 1972; 77:53-61. [PMID 4340726]
11. Pellegrini CA, Paloyan D, Acosta JM, Skinner DB. Acute pancreatitis of rare causation. SurgGynecolObstet 1977; 144:899-902. [PMID 860190]
12. Mitchenere P, Scott J, George P. Islet cell adenoma and retention cyst: a rare cause of acute pancreatitis. Br J Surg 1981; 68:443-4. [PMID 6263394]
13. Danne PD, Buls JG, Connell J, Bennett RC. A case of pancreatitis associated with gastrinoma. Aust N Z J Surg 1985; 55:213-5. [PMID 3862397]
14. Broughan TA, Leslie JD, Soto JM, Hermann RE. Pancreatic islet cell tumores. Surgery 1986; 99:671-8. [PMID 2424108]
15. Simpson WF, Adams DB, Metcalf JS, Anderson MC. Nonfunctioning pancreatic neuroendocrine tumors presenting as pancreatitis: report of four cases. Pancreas 1988; 3:223-31. [PMID 3375232]
16. Kaufmann AR, Sivak MV Jr, Ferguson DR. Endoscopic retrograde cholangiopancreatography in pancreatic islet cell tumores. GastrointestEndosc 1988; 34:47-52. [PMID 2832244]
17. Cheslyn-Curtis S, Sitaram V, Williamson RC. Management of non-functioning neuroendocrine tumours of the pancreas. Br J Surg 1993; 80:625-27. [PMID 7686077]
18. Heller SJ, Ferrari AP, Carr-Locke DL, Lichtenstein DR, Van Dam J, Banks PA. Pancreatic duct stricture caused by islet cell tumors. Am JGastroenterol 1996; 91:147-9. [PMID 8561117]
19. Mao C, Howard JM. Pancreatitis associated with neuroendocrine (islet cell) tumors of the pancreas. Am J Surg 1996; 171:562-4. [PMID 8678200]
20. Sheppard BC. Pancreatitis associated with pancreatic islet cell tumors. Am J Surg 1999; 177:526- 7. [PMID 10414710]
21. Jamieson A, Connell JM. Neuroendocrine pancreatic cancer: an unusual case of pancreatitis. Scott Med J 2000; 45:55-6. [PMID 10862441]
22. Zimmer T, Ziegler K, Bader M, Fett U, Hamm B, Riecken EO, Wiedenmann B. Localisation of neuroendocrine tumours of the upper gastrointestinal tract. Gut 1994; 35:471-5. [PMID 8174983]
23. Galiber AK, Reading CC, Charboneau JW, Sheedy PF, James EM, Gorman B, et al. Localization of pancreatic insulinoma: comparison of pre- and intraoperative US with CT and angiography. Radiology 1988; 166:405-8. [PMID 2827232]
24. Owen NJ, Sohaib SA, Peppercorn PD, Monson JP, Grossman AB, Besser GM, Reznek RH. MRI of pancreatic neuroendocrine tumours. Br J Radiol 2001; 74:968-73. [PMID 11675319]
25. Anderson MA, Carpenter S, Thompson NW, Nostrant TT, Elta GH, Scheiman JM. Endoscopic ultrasound is highly accurate and directs management in patients with neuroendocrine tumors of the pancreas. Am J Gastroenterol 2000; 95:2271-7. [PMID 11007228]
26. Frilling A, Malago M, Martin H, Broelsch CE. Use of somatostatin receptor scintigraphy to image extrahepatic metastases of neuroendocrine tumors. Surgery 1998; 124:1000-4. [PMID 9854575]
27. Slooter GD, Mearadji A, Breeman WA, Marquet RL, de Jong M, Krenning EP, van Eijck CH. Somatostatin receptor imaging, therapy and new strategies in patients with neuroendocrine tumours. Br J Surg 2001; 88:31-40. [PMID 11136306]
28. Wiedenmann B, Jensen RT, Mignon M, Modlin CI, Skogseid B, Doherty G, Oberg K. Preoperative diagnosis and surgical management of neuroendocrine gastroenteropancreatic tumors: general recommendations by a consensus workshop. World J Surg 1998; 22:309-18. [PMID 9494425]
29. Bartsch DK, Schilling T, Ramaswamy A, Gerdes B, Celik I, Wagner HJ, et al. Management of nonfunctioning islet cell carcinomas. World J Surg 2000; 24:1418-24. [PMID 11038216]
30. Jaeck D, Oussoultzoglou E, Bachellier P, Lemarque P, Weber JC, Nakano H, Wolf P. Hepatic metastases of gastroenteropancreatic neuroendocrine tumores: safe hepatic surgery. World J Surg 2001;25:689-92. [PMID 11376398]
31. Hellman P, Ladjevardi S, Skogseid B, Akerstrom G, Elvin A. Radiofrequency tissue ablation using cooled tip for liver metastases of endocrinatumores. World J Surg 2002; 26:1052-6. [PMID 12016482]
32. Yao KA, Talamonti MS, Nemcek A, AngelosP,Chrisman H, Skarda J, et al. Indications and results of liver resection and hepatic chemoembolization for metastasic gastrointestinal neuroendocrine tumores. Surgery 2001; 130:677-82. [PMID 11602899]
33. Proye C. Natural history of liver metastaseis of gastroenteropancreatic neuroendocrine tumores: place for chemoembolization. World J Surg 2001; 25:685-8. [PMID 11376397]
34. Olausson M, Friman S, Cahlin C, Nilsson O, Jansson S, Wangberg B, Ahlman H. Indications and results of liver transplantation in patients with neuroendocrine tumores. World J Surg 2002; 26:998- 1004. [PMID 12016481]
35. Lehnert T. Liver transplantation for metastatic neuroendocrine carcinoma: an analysis of 103 patients. Transplantation 1998; 66:1307-12. [PMID 9846513]
36. Bajetta E, Ferrari L, Procopio G, Catena L, Ferrario E, Martinetti A, et al. Efficacy of a chemotherapy combination for the treatment of metastasic neuroendocrine tumours. Ann Oncol 2002; 13: 614-21. [PMID 12056713]