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Carcinoid syndrome due to a malignant somatostatinoma

Omer Ozbakir, Fahrettin Kelestimur, Figen Ozturk, Erdogan Szfier, Ali Unal, Tahir E Patirolu, Kadri Guven

Summary Metastatic spread is usually to the liver, with Somatostatinoma is one of the rarest involvement of lymph nodes and contiguous tumours of the endocrine pancreas. Car- spread also being common. It has been sug- dinal manifestations of a somatosta- gested that the expression of the classic triad of tinoma include gallstones, mild diabetes symptoms may be more common when liver mellitus, steatorrhoea, diarrhoea and metastases are present.3 Total tumour resection dyspepsia. Like any other pancreatic islet is the first line of therapy in patients with cell carcinoma, a somatostatinoma may pancreatic somatostatinoma, while chemo- http://pmj.bmj.com/ also produce several different hormones therapy is also frequently used either as the such as adrenocorticotropic hormone, primary mode of therapy in disseminated calcitonin, vasoactive intestinal polypep- disease or as adjunctive therapy after surgery.' tide, pancreatic polypeptide, gastrin, Carcinoid syndrome is a clinical entity which insulin, and glucagon. In many cases, the is usually caused by the humoral secretions of clinical picture is dominated by the effect carcinoid tumours that originate in the midgut.

of these other hormones. We present a Lesions other than carcinoid tumours some- on September 26, 2021 by guest. Protected copyright. Erciyes University patient with somatostatinoma in which times secrete serotonin and present with symp- School ofMedicine, an immunocytochemical study of the toms of the carcinoid syndrome (see box 1). In Kayseri, Turkey specimens from pancreas and liver its most complete form, the carcinoid synd- Department of showed a weak positive reaction for gas- rome involves several different organ systems Internal Medicine for such as the vasomotor, cardiopulmonary and 0 Ozbakir trin besides a strong positive reaction F Keletimur somatostatin. Interestingly, this patient gastrointestinal systems. The cardinal manifes- A tnal also showed the signs of carcinoid syn- tations of this syndrome consist of K Guven drome which was successfully treated hepatomegaly, cutaneous flushing, facial telan- Department of with octreotide. giectasia, hypotension, diarrhoea, endocardial Pathology F Ozturk syndrome, oct- TE Patirolu Keywords: somatostatinoma, carcinoid Department of reotide Surgery Carcinoid syndrome: causes E Sozuer Gut endocrine tumours have a low incidence of ofthese * carcinoid tumours about 1 in 200 000 population and 60% ofthe thyroid Correspondence to are carcinoids.' Somatostatinomas appear to be * medullary carcinomas Doq Dr Fahrettin * oat-cell carcinomas ofthe lung Kelestimur, Erciyes one of the rarest gut endocrine tumours, and * pancreatic islet cell cancers 1lniversitesi Tip Fakultesi Iq the yearly incidence is estimated to be as low as * neuroblastomas Hastaliklari Anabilim Dali, 1 in 40 million people.2 In the majority of the * other chromaffin tumours 38039 Kayseri, Turkey patients, metastatic spread is evident at the Accepted 26 April 1995 time of presentation or shortly thereafter. Box 1 696 Ozbakir, Kelegtimur, Ozturk, et al

lesions, bronchoconstriction and oedema. A total gastrectomy + splenectomy + distal Since the liver metabolises most of the pancreatectomy + roux-en-Y oesophagoje- liver serotonin to which it is exposed, the carcinoid junostomy procedure was performed. A Postgrad Med J: first published as 10.1136/pgmj.71.841.695 on 1 November 1995. Downloaded from syndrome does not often occur from a gast- biopsy from one of the nodules was also rointestinal primary lesion until massive liver obtained. Histopathological examination replacement by the tumour has occurred.4 revealed a malignant islet cell carcinoma of We have been unable to find a report in the pancreas with liver metastases. An literature of a patient with pancreatic somato- immunocytochemical study of specimens from statinoma leading to a well-documented car- both the pancreas and liver was performed cinoid syndrome, although some patients with which showed a strong positive reaction for flushing have been reported5'6 and somato- somatostatin (figures 1 and 2), a weak positive statinoma is known to secrete a variety of reaction for gastrin (figures 3 and 4) and hormones and peptides which may affect the negative reactions for insulin, glucagon, clinical presentation. adrenocorticotropic hormone and pancreatic polypeptide. Two weeks after surgery plasma Case report and serum levels of the following hormones were within the normal range: gastrin 64 ng/l, A 50-year-old woman was first admitted to the cortisol 358 nmol/l, insulin 21 pmol/l, C- department of surgery in December 1993 peptide 0.93 nmol/l, growth hormone 0.61 jig/l because of severe upper gastrointestinal and prolactin 21.44 jtg/l. Though the level of bleeding with the signs ofhypovolaemic shock. gastrin was within normal limits, this finding In her past medical history, there was nothing supported the existence of a gastrin-secreting but an appendectomy, 21 years earlier. A tumour as the entire stomach had been significant site of bleeding could not be removed. She was put on a once a week detected though an upper gastrointestinal 5-fluorouracil regimen and discharged. endoscopy was performed. An abdominal ult- The patient was re-admitted to the Depart- rasonogram showed multiple metastatic ment of Internal Medicine in September 1994 nodules in the liver with splenomegaly. Her with recurrent watery diarrhoea, cutaneous gastrointestinal bleeding could not be cont- flushing of the head and neck, nausea, and rolled by medical measures, and she underwent vomiting. Physical examination revealed a surgery. During the surgical procedure, a cutaneous flushing of the head and neck and tumoural enlargement at the tail ofthe pancreas increased bowel movements. The serum and multiple metastatic nodules in the liver biochemical values were: fasting blood sugar were observed, along with splenomegaly. 7.33 mmol/l, sodium 136 mmol/l, potassium http://pmj.bmj.com/

) on September 26, 2021 by guest. Protected copyright.

Figure 1 Pancreatic islets and tumour cells giving a Figure 3 Pancreatic islets and tumour cells giving a positive reaction for somatostatin (immunoperoxidase, weak positive reaction for gastrin (immunoperoxidase, x 100) x 100)

Figure 2 Metastatic tumour cells in the liver giving a Figure 4 Metastatic tumour cells in the liver giving a positive reaction for somatostatin (immunoperoxidase, weak positive reaction for gastrin (immunoperoxidase, x 200) x 200) Carcinoid syndrome 697

3.4 mmol/l, chloride 99 mmol/l, total proteins 68 g/l, albumin 35 g/l, calcium 2.45 mmol/l Somatostatinoma: clinical features

and phosphorus 0.65 mmol/l. Liver and kidney Postgrad Med J: first published as 10.1136/pgmj.71.841.695 on 1 November 1995. Downloaded from * gallstones function tests were normal. The 24-hour urine * mild diabetes mellitus 5-hydroxyindoleacetic acid (5-HIAA) level * steatorrhoea was 272 pmol, which was elevated. A chest * diarrhoea X-ray and an electrocardiogram were normal. * dyspepsia An abdominal ultrasonogram showed biliary sludge and multiple metastatic nodules in the Box 2 liver. Computed tomography of the abdomen confirmed multiple metastases in the liver. An echocardiogram showed a normal appearance of the heart. After admittance, she showed Learning points episodic attacks of hypotension along with * a patient with pancreatic islet cell carcinoma flushing and diarrhoea. To control the signs of should be evaluated carefully for the existence carcinoid syndrome, subcutaneous octreotide ofa somatostatinoma treatment, 100 pg tid was initiated. During this * as is common with other types ofpancreatic the attacks but endocrine tumour, a somatostatinoma may therapy, hypotensive decreased, produce several different hormones such as did not disappear. The 24-hour urine 5-HIAA adrenocorticotropic hormone, calcitonin, level regressed to 39 limol, which was within gastrin, insulin, and glucagon, as well as normal range. Octreotide treatment was con- vasoactive intestinal polypeptide, pancreatic tinued until the 32nd day ofhospitalisation, on polypeptide, prostaglandin E2, gastrin-like which a persistent severe hypotension resistant substance and x-endorphin to The * a somatostatinoma may also cause carcinoid dopamine infusion appeared. patient syndrome died 24 hours later due to untreatable shock. * this situation may require exogenous Her family refused our request for an autopsy. administration of somatostatin or its analogue to control the signs ofcarcinoid syndrome Discussion * the prognosis ofpancreatic somatostatinoma with metastases is poor In 1977, two cases of pancreatic somato- statinoma were reported,6'7 on the basis of Box 3 which, and the known pharmacologic effects of somatostatin, a tentative description of the somatostatinoma syndrome was proposed.8 statinoma. However, as previously mentioned, Knowledge of the pharmacologic actions of the presence of concomitantly secreted hor- somatostatin allowed prediction of the clinical mones can drastically alter the clinical presen- syndrome ofexcess somatostatin (see box 2). Of tation. Several investigators have stressed the the 20 patients with a pancreatic somato- fact that the presence of the triad should not be statinoma reported up to 1994, the head of the considered necessary (or sufficient) for the pancreas was the location of the primary diagnosis of somatostatinoma. The diabetes tumour in nine, the tail in five, one each in the usually takes the form of a mild endogenous

ampullary region and the body and was hyperglycaemia with significant postprandial http://pmj.bmj.com/ unspecified or unknown in four cases. In most rises in serum glucose level. The gall bladder cases the presence of a somatostatinoma was disease takes the form of a dilated gall bladder documented by a combination of an increased with or without stones. Steatorrhoea is plasma somatostatin level, immunocytochemi- presumed to be due to pancreatic insufficiency cal or hormonal content analysis demonstrating induced by hypersomatostatinaemia. Pan- somatostatin as the major tumour secretory creatic function has been shown to improve

product, a clinical syndrome, and basal and after resection of a pancreatic somatostatinoma on September 26, 2021 by guest. Protected copyright. stimulated endocrinologic studies compatible in at least one patient.' Survival of a patient with somatostatin excess. In the majority of with somatostatinoma depends on the coex- these patients, metastatic spread was evident at istence of distant metastases as well as whether the time of presentation or shortly thereafter.' or not the primary tumour is resectable. It has been suggested that the expression of the In the patient presented here, the main classic triad of symptoms may be more com- complaint was* severe upper gastrointestinal mon when liver metastases are present.3 As is bleeding which might have been a consequence common with other types of pancreatic endo- of hypergastrinaemia (or Zollinger-Ellison crine tumour, many of these tumours secreted syndrome) on first admission. Though the several different hormones such as adrenocor- serum gastrin level was not detected pre- ticotropic hormone, calcitonin, gastrin, insulin operatively, it was found to be normal during and glucagon; as well as vasoactive intestinal the postoperative period. This finding sup- polypeptide, pancreatic polypeptide, prosta- ported the existence of a gastrin-secreting glandin E2, gastrin-like substance and a- endocrine tumour which had metastasised to endorphin."3'5 In many cases, the clinical pic- the liver, as the entire G-cell population had ture was dominated by the effect of the other been removed by total gastrectomy. To our hormones. knowledge, this is the fourth case of pancreatic The classic triad of diabetes, gall bladder somatostatinoma secreting gastrin or gastrin- disease and steatorrhoea that comprises the like substance, to appear in the literature." 5'9 somatostatinoma syndrome is frequently seen Our patient was re-admitted to the hospital in the patient with a pancreatic somato- nine months after surgery, with signs of car- 698 Ozbakir, Keletimur, (zturk, et al

cinoid syndrome. Diagnosis was confirmed by tumour and probably excess somatostatin in the high level of 5-HIAA in 24 hour urine. serum (which was demonstrated immunocyto-

Although the carcinoid syndrome is known to chemically but not biochemically), our patient Postgrad Med J: first published as 10.1136/pgmj.71.841.695 on 1 November 1995. Downloaded from occur in patients with pancreatic islet cell required exogenous administration of a som- carcinoma, there has not to our knowledge been atostatin analogue. This is difficult to explain a report in the literature indicating its occur- but it may be that the somatostatin produced by rence in a patient with somatostatinoma. the tumour itself is defective or inadequate to Somatostatin is known to inhibit hormone overcome excess serotonin production by the secretion from many endocrine tumours. As a tumour cells. peptide, it requires intravenous admission, but In conclusion, one must keep in mind that octreotide, a long-acting somatostatin analogue somatostatinoma, as well as other endocrine can be given subcutaneously. When given to pancreatic tumours, may cause carcinoid syn- patients with carcinoid syndrome, flushing and drome, and this situation may require diarrhoea were promptly relieved in 88°o while exogenous administration ofsomatostatin or its 720o had a decrease of 500o or more in urinary analogue to control the signs of carcinoid 5-HIAA levels.'0 It is interesting to notice that, syndrome. although there was a somatostatin-secreting

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