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ENDOCRINE PANCREATIC TUMOURS : Surgical Treatment
Peter Balaz, Helmut Friess, Markus W Buechlernder
Department of Visceral and Transplantation Surgery, University of Bern, Inselspital, Switzerland.
INTRODUCTION
Endocrine pancreatic tumours (EPTs) are composed of tumour cells whose morphofunctional profile reproduces in part that of normal gastroenteropancreatic endocrine cells. These cells belong to the diffuse endocrine system (previously described by Pearce as the Amine Precursor Uptake and Decarboxylation [APUD] system1,2 and are localized in the islets of the pancreas, within the gastroenteral tract, biliary tree, heart, hypothalamus, hypophysis, pituitary, lung, adrenal gland, sympathetic ganglia, thyroid, parathyroid, placenta, skin and urogenital tract. The pancreas and the mucosa of the gastrointestinal tract contain as many as 15 endocrine cell types characterized by production of hormonal peptides or biogenic amines (Table 1).
Generally, under EPTs we also include duodenal endocrine tumours that can occur alone or with pancreatic endocrine tumours or as a part of multiple endocrine neoplasia. EPTs could either be functioning, associated with a specific clinical syndrome due to hormone overproduction, or non-functioning (about 30% of EPTs).
The incidence of EPTs is approximately 0.4-1 per 100,000 population, and with the exception of insulinoma, more than 60% of them are malignant.3 In contrast, only about 10% of insulinomas are malignant. Basic treatment is directed against tumour growth and hormone excess. Generally, malignant EPTs are slow growing, but most of them will cause death.
Since the development of new medical treatments (proton pump inhibitors, somatostatin analogues) that can control hormonal symptoms, the most common cause of EPT-related death has become liver failure from tumour progression.4
CLINICOPATHOLOGIC CLASSIFICATION
Many tumours are composed of more than one cell type, but as a rule only one cell type normally correlates with the associated syndrome of endocrine hyperfunction. As a result, classifying EPTs by cell typing has only limited value in practice, unless correlated with clinical symptoms and hormonal measurement in blood.
EPTs are identified by a predominant peptide which they contain. The tumour itself is named after the peptides it secretes, and for its hyperfunctional syndrome (a gastrin-secreting tumour is called a gastrinoma). This classification should be avoided in nonfunctioning tumours even if hormones are detected immunohistochemically in tumour cells and serum, as long as an association with a hyperfunctional syndrome is absent.
Most of the available follow-up studies about EPTs are syndrome based, and for this reason histopathological classifications encompassing the clinical syndrome as well as tumour morphology and biology including behaviour are preferred5 (Table 2).
TABLE 1 :
Characteristics of the endocrine cells of the human gastroenteric tract (adapted after Rindi15)Cell Main product Pa Stomach Intestine CF A small Ap large D J I C R P Unknown f + + + f f f F EC 5HT f + + + + + + + + D Somatostatin + + + + f f + f + L GLI/pYY f + + + + + A Glucagon + a PP P P + a B Insulin + X Unknown + ECL Histamine + G Gastrin + + CCK CCK + + + S + Secretin + + + GIP + + f GIP + + f M + + f Motilin + + f N + + Neurotensin f + + f = presence of a few cells, a = presence of cells in foetus and newborn, EC = enterochromaffin, GIP = gastric inhibitory polypeptide, GLI = glucagon-like immunoreactants, pYY = PP-like peptide with N-terminal tyrosine amide, PP = pancreatic polypeptide, ECL = enterochromaffin-like cells, CCK = cholecystokinin, substance P, neurokinins, opioids, guanylin and other peptides. The endocrine component of the pancreas is mostly formed by four islet cell types-A cells (glucagon), B cells (insulin), D cells (somatostatin), and PP cells (pancreatic polypeptide)-with only a few enterochromaffin (EC) cells. EPTs may express each of these cell types and produce related hormones. In addition, EPTs might contain cells which are not present in the normal pancreas, producing hormones like gastrin (G cells), vasoactive intestinal peptide (VIP cells), adrenocorticotropic hormone, calcitonin, etc.
Most insulinomas (90-95%) show benign behaviour, whereas other types of functioning tumours usually fall under the category of uncertain or malignant behaviour. Well-differentiated endocrine carcinomas (WDEC) show an increased mitotic index (2 to 9 at high power fields), an increased Ki67 proliferative index (2-10%), and angio-perineural invasion.6 At the time of diagnosis their size is usually 3 cm or more. Tumour cells spread to local lymph nodes and to the liver.
Poorly differentiated endocrine carcinomas (PDEC) are highly invasive tumours with distant metastasis high mitotic index (more than 10 mitoses per high power fields) and a proliferative Ki67 index 10%.
On the basis of such evidence it is advisable to evaluate the following variables of EPTs: tumour size (larger tumours are more aggressive), invasion of nearby tissue, angioinvasion, perineural invasion, solid structure, necrosis, cell atypia, more than 2 mitoses in 10 microscopic high power fields, high proliferative Ki 67 index, loss of chromogranin A immunoreactivity, argyrophilia, hormone expression and nuclear p53 protein accumulation.6
TABLE 2
Clinicopathologic classification of endocrine tumours of the pancreas (after Capella [5] ) Well-differentiated endocrine tumour Benign behaviour: confined to the pancreas, nonangioinvasive, < 2 cm in size or < 2% Ki 67 index - Functioning
- Insulinoma
- NonfunctioningUncertain behaviour: confined to the pancreas,> 2 cm in size, < 2% Ki67% index or angioinvasive - Functioning
- Gastrinoma, insulinoma, vipoma, glucagonoma, somatostatinoma or inappropriate syndrome* tumour
- NonfunctioningWell-differentiated endocrine carcinoma Low-grade malignant: with gross local invasion and/or metastases - Functioning
- Gastrinoma, insulinoma, glucagonoma, vipoma, somatostatinoma or inappropriate syndrome* tumour
- NonfunctioningPoorly differentiated endocrine carcinoma - High-grade malignant: small to intermediate cell carcinoma
* Inappropriate hormone syndromes: Cushing (ACTH), acromegaly or gigantism (GRH), hypercalcaemia, etc. Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant disorder associated with mutations in the so-called MEN 1 tumour suppressor gene on chromosome 11q.
MEN 1 is characterized by parathyroid hyperplasia, enteropancreatic endocrine tumours and pituitary adenomas. In approximately 7% of the cases they can be combined with highly malignant bronchial and thymic carcinoid tumours.7 MEN 2a syndrome does not include pancreatic tumours; it manifests as medullary thyroid carcinoma, pheochromocytoma and hyperparathyroidism. MEN 2b includes instead hyperparathyroidism, mucosal neuromata and a marfanoid habitus.
DIAGNOSISEPTs share some common characteristics: [8] , [9] , [10]
a) inconstancy of typical clinical syndromes (functional vs. non-functional syndromes),
b) biological abnormalities that will be revealed by provocative testing,
c) integration of MEN 1, which in many cases will change the management strategy,
d) benefit from recent diagnostic strategies, including determination of chromogranin A and B plasma levels, somatostatin receptor scintigraphy and endoscopic ultrasonography of the duodenopancreatic area,
e) some effects of long-acting somatostatin analogue therapy.Functional tumours produce and secrete a large number of peptides, hormones and amines. These substances cause well-known clinical syndromes, including hypoglycaemic syndrome (insulinoma); Zollinger-Ellison syndrome (gastrinoma); glucagonoma syndrome; somatostatinoma syndrome; watery diarrhoea hypokalaemia achlorhydria (WDHA) syndrome (vasoactive intestinal peptide); and carcinoid syndrome (serotonin) (Table 2).
The most common functional EPTs are insulinomas (about 40%), followed by gastrinomas (about 25%), glucagonomas, somatostatinomas and VIPomas (about 1-2%), and non-functioning EPTs (30%). [11]
There are specific and general biochemical markers for endocrine tumours. [12]
Specific markers are urinary 5-hydroxyindoleacetic acid (5-HIAA), neuropeptide K, [13] substance P for carcinoid EPTs, or hormones such as gastrin, insulin, c-peptide, pro-insulin, vasoactive intestinal peptide, glucagon and somatostatin.
General tumour markers are chromogranins, pancreatic polypeptide, neuron-specific enolase, and choriogonadotrophin subunits. Chromogranins (A, B and C) are a family of secretory proteins exclusively present in endocrine cells in large dense-core vesicles. [14]
Chromogranin A is the first member of this family and is ubiquitous in endocrine cells. Its co-secretion with neuropeptides makes it a suitable tissue and serum marker for endocrine neoplasms. Plasma levels of chromogranin A are elevated in EPTs with the exception of prolactinomas and insulinomas, in which chromogranin B is a better marker.
False positive elevation of chromogranin A can be seen in patients with liver failure, renal impairment, atrophic gastritis and inflammatory bowel disease. Chromogranin A measurement is the best marker in follow-up treatment. Elevated levels precede radiological evidence of progression.
The expression of the proliferation marker Ki-67 has been shown to correlate with prognosis and should be assessed before initiation of treatment in all patients.
After clinical and biochemical evaluation and suspected diagnosis of EPTs, most patients undergo noninvasive and invasive preoperativelocalizing studies, as shown in Table 3. The next step when an operation is indicated is intraoperative staging and localizing.
TABLE 3 :
Noninvasive and invasive diagnostic procedures in EPTsNoninvasive - transabdominal ultrasonography
- CT
- MRI
- somatostatin receptor scintigraphy (SRS)Invasive - pancreatic angiography, or provocative secretine angiography
- selective venous sampling
- ERCP
- endoscopic ultrasound
- intraoperative ultrasound
- surgical palpation
- endoscopy with duodenal transillumination
- duodenotomy
The basic method is surgical bidigital palpation of the head, body and tail of the pancreas after an extended Kocher manoeuvre (mobilization of the right colon and duodenum through the retroperitoneum); this procedure has a sensitivity of 61% to 88% and a specificity of 86% to 95%. Intraoperative ultrasound is a very sensitive method for identification of insulinomas (86-100%), but is less sensitive for gastrinomas (20-75%) localised in the duodenum. [16-19]
MEDICAL TREATMENT
The demonstration of somatostatin receptors in 80-90% of EPTs has clarified the rationale for the therapeutic effect of somatostatin analogues. [20-22] With interferon alpha therapy, tumour stabilization occurs in 80% of patients over a median of 20 months and tumour reduction in 11%. [23] , [24] The antitumour effects of interferon alpha include antiproliferation by blocking the G1-S cell cycle, apoptosis induction, and antiangiogenetic effects. From a chemotherapeutic point of view, combination of streptozocin, 5-fluorouracil or doxorubicin can produce partial remission in 40-60% of patients over a median duration of 2 years. [3]
INSULINOMA
Insulinomas are usually solitary, benign (90-95%) neoplasms evenly distributed within the pancreas. [11] , [25] The tumour’s size is predominantly between 5 and 30 mm, and most of them are encapsulated. Malignant behaviour is usually displayed by tumours with a diameter over 3 cm and demonstrated angioinvasion. Insulinoma cells contain less insulin than normal B cells, but their storage capacity is impaired. [26] Clinical presentations are characterized by fasting hypoglycaemia and Whipple triad: hypoglycaemic symptoms, glucose concentration less than 50 mg/dl (2.8 mmol/l), and relief of symptoms with administration of glucose. The mean duration of symptoms prior to diagnosis varies from 15 months to more than 3 years. [27] Interestingly, each patient has an individual pattern of symptoms. This observation explains why some insulinoma patients are diagnosed only in psychiatric hospitals, having been admitted with a misdiagnosis. [28] The gold standard for the diagnosis is a 72h fasting test under strict supervision. [29] In healthy subjects, prolonged fasting suppresses plasma insulin and C-peptide to unmeasurable levels. In insulinoma patients, insulin and C-peptide are inadequately suppressed.
Localization procedures have varying sensitivity. Transabdominal ultrasound (US), CT, MRI(10-50%) is less sensitive, [11] , [19] whereas selective portal and hepatic sampling for insulin are more highly sensitive but are invasive. For endoscopic (EUS) and laparoscopic US sensitivity, rates between 57% and 92% have been reported.25 Intraoperative ultrasound (IOUS) sensitivity is 69-100%, and intraoperative palpation sensitivity is 33% in the pancreatic head, 88% in the body and 86% in the tail.19 These findings suggest that IOUS improves the ability to find pancreatic head insulinomas. Insulinomas express fewer somatostatin receptors, so somatostatinoma receptor scintigraphy achieves a sensitivity of only 10-50%. [11] , [19]
Differential diagnoses of hypoglycaemia havebeen reported extensively, [29] and include factitious hypoglycaemia, tumours, insulin antibodies, drugs, food stimulated, hormone deficiency, sepsis, end stage of liver failure and metabolic diseases.
Primary treatment is operative removal of the insulinoma. Medical treatment is focused on controlling symptoms of hypoglycaemia in the preoperative phase, in cases with unresectable metastatic disease and in inoperable patients with poor condition. There are combined dietary (small, frequent and slowly absorbable meals) and medical measures to treat insulinoma conservatively. Diazoxide has an efficacy of 50%; [11] , [31] it is effective only in insulinomas with typical beta granules, and not in agranular or atypical beta granule tumours. Intravenous glucose infusion is necessary to treat severe hypoglycaemia-induced neurological symptoms and in the perioperative period. Rapid glucose assays greatly facilitate intraoperative glucose monitoring. A baseline glucose level is obtained soon after induction of anaesthesia and is monitored in 15-20-minute intervals until tumour enucleation or resection. Following this, serum glucose is monitored at 5-minute intervals. Usually a rise in glucose level is obtained within 15-20 min following removal. It is also not uncommon to have a hyperglycaemic rebound of a marked degree (200-300 mg/dl) within 12-18 h postoperatively. However, this does not usually require treatment. During this period the urine should be tested to detect the presence of ketosis, a circumstance which requires therapy. Generally in the first 12-18 h postoperatively no glucose-containing fluids are administered. [11]
Because only 50% of insulinomas have type II somatostatin receptors, [30] the effect of long-acting somatostatin analogue therapy is unpredictable in individual patients. In insulinoma patients who are not responding to somatostatin analogue treatment, hypoglycaemia can be aggravated through suppression of counter-regulatory hormones such as glucagon. Therefore, the administration of somatostatin analogues can be recommended only with caution in patients with metastatic disease. [32] ,[33]
SURGICAL TREATMENT
The goals of operative intervention are: [11]
(1) to locate and excise if possible all abnormally functioning tissue,
(2) to differentiate between benign and malignant tumours by searching for the presence of metastatic disease, and
(3) to accomplish both of the above with minimal concomitant postoperative morbidity and mortality.If the insulinoma is thought to be in the head or the uncinate process of the pancreas, wide kocherization of the entire duodenum (the third and fourth portions) is imperative.
If the tumour is thought to be in the neck, body or tail of the pancreas, the best exposure is obtained by dividing the gastrocolic ligamentum widely and entering the lesser sac.
The avascular peritoneum along the inferior border of the pancreas can be incised, which allows mobilization of the pancreas to the splenic hilus. This also allows gentle and systematic bidigital or bimanual palpation.
Once the tumour is localized, the decision is made either to enucleate it or to perform pancreatic resection. This crucial decision has been facilitated by the routine use of intraoperative ultrasonography. The relative indications for pancreatic resection-either duodenopancreatectomy or distal resection-are: [34]
(1) infiltrating lesion without a well-defined pseudocapsule,
(2) large lesions (4 cm),
(3) multifocal lesions and
(4) lesions for which enucleation results in injury to the main panreatic duct and high risk of high-output pancreatic fistula. The size of the lesion alone should not be a contraindication for an enucleation even the risk is high for main pancreatic duct injury. Secretin injection (maximum 1 U/kg body weight i.v.) is very effective in determining whether a duct has been injured (an injured duct can be repaired with a very fine suture) or whether pancreatic resection is indicated at that time. Enucleation can be performed using electrocautery in combination with small haemoclips, and can be facilitated by the use of a cavitron ultrasonic aspirator (CUSA). The enucleation site may be gently approximated with interrupted nonabsorbable sutures over an omental plug. Surgeons also successfully used fibrin glue in these cases. [35], [36] To minimize pancreatic fistulas in patients undergoing enucleation, the administration of octreotide is strongly recommended.[37] An extremely rare occurence is the failure of all localizing studies with a nonpalpable tumour. In these cases a so-called "blind" distal pancreatectomy cannot be recommended, as the overall failure rate is about 50%.Laparoscopic surgery to resect the insulinoma is solely dependent on laparoscopic ultrasonography and is a safe technique with low morbidity. [25] It can be recommended for tumours located in the corpus or tail of the pancreas when they are not localized near the pancreatic duct or portal venous confluence. In the latter circumstances and when localization procedures fail, conversion to laparotomy is required, followed by IOUS, palpation and sometimes venous sampling.
The overall morbidity in insulinoma surgery is between 13% and 33% (caused by pancreatic fistulas, subphrenic abscess, empyema, etc.), and mortality for enucleation should be near 0%. [11] , [38] , [39] All successfully operated insulinoma patients should be normoglycaemic postoperatively. The surgical difficulties inherent in reoperating insulinoma patients, as in almost all reoperative situations, emphasize the importance of a successful primary operation, and in these cases the experience of the surgical team and intraoperative ultrasonography are of paramount importance. [40] , [41]
GASTRINOMA
Benign ulceration of the distal duodenum and upper jejunum associated with extreme gastric acid hypersecretion and a pancreatic islet cell tumour were the triad of clinical findings described in two patients by Zollinger and Ellison in 195542 (Zollinger-Ellison syndrome, ZES). These patients had recurrent peptic ulcers following standard ulcer surgery and eventually required total gastrectomy to stop acid hypersecretion and control symptoms. All this was caused by gastrin-secreting tumours (gastrinomas) of the gastrointestinal tract.
Gastrinomas are malignant in 60-90% of cases, and approximately 20% of patients with ZES will also have a MEN 1 syndrome. [43] , [44] Gastrinomas are localized in the pancreas (24%), duodenum (49%), peripancreatic lymph nodes (11%), and rarely in another location. [44]
Epigastric pain is the most common symptom of ZES. Less common is diarrhoea. The duration of symptoms prior to diagnosis of ZES ranges from 2 months to over 20 years.[45] ZES should be suspected if a patient has one or more of the symptoms listed in Table 4.
The best single screening test for ZES is the fasting serum concentration of gastrin. Only 1% of ZES patients will have a normal fasting serum gastrin concentration.43,46 If only slight elevation occurs, antisecretory medication must be stopped for 3 days and the test has to be repeated. Basal acid output (BAO) greater than 15 meq/h in patients without and 5 meq/h in patients with a previous acid-reducing operation have a sensitivity of 70% and 55%, respectively.11 Maximal acid output (MAO) is not useful in ZES diagnosis, and a ratio of 0.6 or greater of BAO to MAO is present only in 15-50% of ZES patients. [11]
Differential diagnosis of hypergastrinaemia and gastric acid hypersecretion has to be performed with these tests, as well as provocation tests. The secretin stimulation test has an 85% sensitivity,47 whereas the calcium infusion test is less sensitive.[11]
TABLE 4
Conditions that should prompt an evaluation for Zollinger-Ellison syndrome [11]Multiple ulcers Peptic ulceration of the distal duodenum or jejunum Recurrent or persistent ulcers resistant to standard medicaltherapy (H2 blockers or proton pump inhibitors) Peptic ulceration associated with severe oesophagitis Peptic ulceration associated with diarrhoea Unexplained diarrhoea or steatorrhoea Postoperative ulcer recurrence Family history of peptic ulceration Patients undergoing elective surgery for complicatedpeptic ulcer disease Peptic ulceration associated with hypercalcaemia ornephrolithiasis Gastric rugal hypertrophy or prominent duodenal folds MEDICAL MANAGEMENT
The hypersecretion of acid can be controlled by ZES involved total gastrectomy, as this was the only means of controlling gastric acid hypersecretion. Long-term follow-up of patients treated by total gastrectomy has shown that progression of the tumour was a major factor in long-term mortality, accounting for up to 57% of the deaths. [50] Thus the malignant potential of the gastrinoma is an important factor in the prognosis of these patients. It is currently recommended that patients with sporadic gastrinoma and no serious contraindications to surgery undergo careful localization studies and be considered for explorative laparotomy for potential curative resection. [11] These patients should undergo exploration in surgical centres under the care of experienced surgeons as long as unresectable metastatic disease, such as bilobar liver metastases, is not present on the imaging studies. Exploration should be performed even if preoperative localization studies fail to identify the tumour, because gastrinomas may be still found and resected at the time of laparotomy. At the operation a complete exploration of the entire abdomen is performed because 30-50% of gastrinomas are not evident on preoperative imaging studies. [51] There have been reported ectopic gastrinomas in ovarium, stomach, jejunum, kidney, lymph nodes, greater omentum and mesenterium. [52] Gastrinomas usually appear as reddish blue: occasionally they may be white. [43] The liver should be carefully inspected and palpated, with excisional biopsy of any superficial lesion. Pancreas inspection and exploration have already been described above (see insulinomas). The duodenum should also be explored, as a primary tumour may have been missed. Approximately 80% of duodenal gastrinomas are smaller than 0.6 cm, and their prevalence decreases distally. [53] Operative endoscopic transillumination has increased sensitivity (83%) over IOUS and palpation in identifying duodenal gastrinomas. [54] In this procedure the endoscope is passed orally into the duodenum, and the lights in the operating room are dimmed. The duodenum is examined from the pylorus distally to the ligamentum of Treitz, with transillumination performed by the surgeon from the serosal side and by the endoscopist from the luminal side. The purpose is to identify focal areas which do not transilluminate on the serosal side. Operative endoscopic transillumination detects about 75% of gastrinomas as small as 1 cm and 100% of gastrinomas greater than 1.5 cm in size. [54] After transillumination, 3-6 cm anterior longitudinal duodenotomy is performed. If no submucosal tumour is palpable, the mucosa is everted and carefully palpated. The distal third and fourth parts of the duodenum are examined by everting them into the incision. Duodenotomy is important to identify tumors on the medial wall of the duodenum, as these lesions cannot be transilluminated. Tumours as small as 1-2 mm may be associated with lymph node metastases, but excision of all tumour can result in normal gastrin serum levels. These microgastrinomas are frequently not palpable through the duodenal wall and can only be detected by duodenotomy and evaluation of the mucosa by eversion and direct palpation.
TABLE 5 :
Other rare EPTs, adapted after Mignon [10]EPT type Predominant hormone Dominant symptomatology Prognosis Pancreatic serotoninoma serotonin a typical carcinoid
(carcinoid) syndrome5 year survival 70%
70% malignantAmpullary carcinoid serotonin jaundice, rare carcinoid syndrome 5 year survival 90% Pancreatic calcitoninoma calcitonin VIP/PP WDHA improved since chemo/biotherapy Pancreatic cholecystokininoma CCK ZES, negative secretin test ? Pancreatic GIPoma GIP WDHA poor Pancreatic bombesinoma (GRPoma) GRP like immunoreactivity Diabetes, flush haemorrhagic gastritis liver metastases With these combined methods of surgical exploration, gastrinomas may be found in 92-100% of cases. A metastatic lymph node may be helpful in determining the most appropriate location for a duodenotomy when no tumour is palpable. Tumours smaller than 4 mm in diameter can be locally excised with a partial thickness of mucosa and submucosa. Tumours greater than 5 mm are usually locally invasive in the submucosa and should be removed by excision of a full wall thickness with a margin around the tumour.56 Systematic sampling of anterior and posterior lymph nodes around the head of the pancreas, the coeliac axis and common bile duct must also be performed, so all lymph nodes in the drainage area of the tumour should be removed regardless of their size. Gastrinomas in the body and tail of the pancreas usually require distal or subtotal pancreatectomy and splenectomy when enucleation is not possible. Gastrinomas in the head of the pancreas may be enucleated, if possible, although some centres perform duodenopancreatectomy in the majority of these patients.58 It is currently not established whether the morbidity and mortality of a duodenopancreatectomy outweigh the adverse consequences of an unresected solitary gastrinoma. A blind distal pancreatectomy should not be performed if the gastrinoma is not found at the exploration, as greater than 80% of gastrinomas are found in a triangle defined superiorly by the junction of cystic and common bile duct, inferiorly by the junction of the second and third portions of the duodenum and medially by the junction of the neck and body of the pancreas. [59]
Total gastrectomy can be advocated for the small subset of patients who cannot afford H2 blocker or proton pump inhibitor medication or who cannot comply with prescriptions. Because of the efficacy of antisecretory drugs, vagotomy is not recommended as a routine procedure. [59] If no tumour is found at laparotomy, or if the gastrinoma is unresectable or metastatic to the liver and the patient has a high antisecretory drug requirement, a highly selective vagotomy may be considered. [59]
The 5-year survival when the gastrinoma is completely resected is 69% to 100%; if the tumor is incompletely resected or unresectable or there is recurrent tumour disease, the 5-year survival is about 43%. [44] , [55] , [60]
VASOACTIVE PEPTIDE-SECRETING TUMOURS (VIPOMAS)
Vipomas represent a rare subtype of EPTs. The association between islet cell tumours and a syndrome of refractory watery diarrhoea and hypokalaemia was first described by Verner and Morrison in 1958. [61] In 1973 Bloom made the association between vasoactive intestinal polypeptide (VIP) and the Verner Morrison syndrome. [62] The clinical syndrome associated with VIP-secreting EPTs has been referred to by multiple names, including the watery diarrhoea hypokalaemia, achlorhydria (WDHA) syndrome; watery diarrhoea syndrome (WDS); pancreatic cholera syndrome; endocrine cholera; Verner-Morrison syndrome and VIPoma syndrome.
About 50% of VIPoma are malignant, three-quarters of which have metastasized at the time of initial exploration.63,64 The main clinical findings of VIP-secreting tumours have been recognized as watery diarrhea (89%), weight loss (72%), hypokalaemia (67%), and hypercalcaemia, dehydration and abdominal pain (about 50% each). [65] Flushing occurs in about 20% and achlorhydria only in 6% of patients. [64] The flushing is characterized by a patchy erythematous rash involving the face and upper trunk, and is associated with urticaria. [66]The aetiology is unknown and the VIPoma flushing can be confused with carcinoid syndrome, in which flushing is caused by serotonin hypersecretion. The predominant syndrome is profuse watery diarrhoea, often of many years’ duration prior to diagnosis. Because the diarrhoea is secretory in nature, fasting does not alter its severity and faecal volume often exceeds 6 to 8 liters per day. [65] Hypermotility is not a feature, and crampy abdominal pain is unusual.
The diagnosis of VIPoma is established by demonstrating an increased concentration of VIP in a patient with secretory diarrhoea despite 48-72 h fasting. [11] A single normal value need not exclude the diagnosis, because as with all endocrine tumours, secretion of VIP (and patients’ diarrhoea) may be episodic. VIPomas also can produce additional neuropeptides, including glucagon, human pancreatic polypeptide, insulin, gastrin, etc. A single hormone is usually responsible for the clinical syndrome, and polyfunctioning islet cell tumours are classified by their dominant clinical syndrome.
In differential diagnosis it is important to distinguish other endocrine tumours which present with diarrhoea. ZES are associated with increased gastric acid output and metabolic alkalosis; hypoglycaemia and hypocalcaemia are more typical as well. Carcinoid-associated diarrhoea is secondary to intestinal hypermotility and shortened transit time.67 These patients also have malabsorption and steatorrhoea, and exhibit bronchospasm, increased serum concentration of serotonin and increased urinary excretion of 5-HIAA.68
The sensitivity of radiologic localization studies is similar to those in other EPTs. Somatostatin receptor scintigraphy can also be used because VIPomas have high-affinity somatostatin receptors.32 Primary tumour localization is most common in the tail and body of the pancreas, and the size of tumours has been reported between 2.7 and 7.0 cm (mean 4.4 cm).65 Metastatic disease is present in 56% to 89% of patients, with metastases mostly localized to the liver and regional lymph nodes.63-65,69 As many as 10% of VIPoma may be ectopic. They occur along the ganglia of the autonomic nervous system and in the adrenal medulla, retroperitoneum, oesophagus, jejunum, and bronchus. Multicentric VIPomas are rare and account for less than 2% of patients.69-70
The first line of therapy in VIPomas is correction of electrolytic abnormalities. The advent of somatostatin analogues facilitated the preoperative preparation of VIPoma patients. Some patients may develop increasing tolerance to somatostatin analogue therapy, requiring increasing doses.65 Somatostatin analogues act by inhibition of hormone release from tumours and by direct inhibition of water and electrolyte secretion from the intestine.68 Recommended doses are 50-200 g octreotide acetate s.c. three times a day, 30 mg lanreotide SR i.m. every 14 days and 10-30 mg octreotide LAR i.m. every 28 days.65 If the neoplasm is localized, complete resection is curative. Operative exploration has been described above. It is necessary in VIPomas to emphasize also the mobilization of the spleen to evaluate the tail of the pancreas. Candidates for curative resection include those with unifocal or multifocal pancreatic tumours, with resectable metastases, and even those with evidence of local or metastatic recurrences. Procedures range from distal pancreatectomy with or without splenectomy to duodenopancreatectomy, with regional lymph node dissection and resection of hepatic metastases if identified. Most investigators advise no treatment for asymptomatic patients with advanced metastatic disease, unless the tumour demonstrates aggressive biological behaviour, i.e., rapid growth.71 In symptomatic patients, an aggressive approach with debulking should be considered if technically feasible. The 5-year survival rate for curatively resected VIPoma patients is 60% to 68.5%; the rates for patients with surgically palliated or unresectable tumours are 33% and 40%, respectively.65,69
GLUCAGONOMA
Glucagonomas are the third or fourth most common EPTs and have an incidence of 1 in 20-30 million people.72,73
The glucagonoma syndrome is characterized by necrolytic migratory erythema (NME), glucose intolerance, stomatitis, glossitis, and weight loss. Less common are anaemia, thromboembolic disease and mental depression. Hyperglucagonaemia upsets the delicate balance between insulin and glucagon and causes a mild diabetes mellitus, which rarely requires insulin for control and probably does not lead to diabetes-related sequelae. Typically the diagnosis of the glucagonoma syndrome is not considered until the characteristic (NME) develops, in conjunction with glucose intolerance.74,75 NME is found in most glucagonoma patients and ranges from mild to severe. This desquamating pruritic rash may be found anywhere on the body, but usually occurs in areas of friction or local trauma, such as the feet, lower legs, hands, buttocks, groin, perineum, perioral area, and intertriginous areas. The individual lesions involve a characteristic cycle, which lasts 7-14 days.76
The majority of glucagonomas are solitary and located in the body or tail of the pancreas (75%).73 Most clinically apparent glucagonomas are large tumours (5 cm) at the time of diagnosis, when their size is enough to cause plasma glucagon levels to increase to a supraphysiological concentration. Approximately 60-80% of glucagonomas are malignant and over half are metastatic at the time of diagnosis. [77] Peripancreatic lymphatic involvement and hepatic metastasis are the most common patterns of spread. The diagnosis of glucagonoma rests on clinical suspicion and the finding of an increased fasting serum glucagon concentration. Transabdominal US sensitivity is about 65%. CT is quite accurate and sensitive (83%), as are EUS (89%) and somatostatin receptor scintigraphy. [73] A complete evaluation of the liver is necessary to determine the presence of metastatic disease. Preoperative intravenous hyperalimentation may be indicated in patients with severe catabolism and weight loss. The somatostatin analogue (octreotid acetate) may be of considerable value in the preoperative management of these patients. [78]
Operation is recommended in essentially all patients. If the tumour is small and presumably benign, enucleation may be appropriate. Most tumours, however, are large, involve the body and/or tail of the pancreas, and require formal distal pancreatic resection. Unresectable cancers require debulking procedures. These patients may show dramatic improvement in many of the symptoms in the weeks following operation. The 10-year survival rate for patients without metastasis is almost 100%; for the group with metastasis the rate is approximately 52%; and for the total series the rate is 64%. [73]
SOMATOSTATINOMA
Somatostatin inhibits the release and/or action of almost all gut hormones and influences exocrine secretory function of the stomach, pancreas, and small intestine. [79] In addition, somatostatin has direct inhibitory effects on several target organs, including the stomach, the pancreas, the small intestine, and the gallbladder. The first well-documented case of pancreatic somatostatinoma was reported in 1977. [80]
Excessive release of somatostatin into the circulation is associated with a clinical syndrome characterized by diabetes mellitus, gallbladder disease, steatorrhoea, hypochlorhydria, and weight loss. [79] Somatostatin inhibits gallbladder emptying, thereby leading to chronic gallbladder stasis, dilatation, and gallstone formation. [81] Somatostatinomas of the pancreas arise predominantly in the head of the pancreas, followed by the tail and body regions. The majority of extrapancreatic tumours originate in the upper intestinal tract and occur primarily in the duodenum or periampullary region. In general, somatostatinomas of the pancreas tend to be large and bulky (86% are over 20 mm in diameter, whereas somatostatinomas arising from the intestine tend to be smaller (only 41% are over 20 mm). [82] The diagnosis of somatostatinoma can be established on the basis of clinical features, by demonstration of increased plasma levels of somatostatin. Also the calcium-pentagastrin and tolbutamide infusion test may be useful in patients with somatostatinoma, but both appear to be positive in patients with metastatic somatostatinomas and therefore may not be useful as a screening tool to identify patients with more limited disease to be cured by operative resection. CT and angiography successfully localize large tumours, but EUS or IOUS may be necessary to identify small tumours.
Surgical Treatment
Small tumours arising in the duodenum may be adequately treated with local excision or wedge resection. Large tumours arising in the periampullary region of the duodenum or within the head of the pancreas should be managed by duodenopancreatectomy. Coexisting focal liver metastases should be resected, whenever feasible. Tumours confined to the body and tail regions of the pancreas should be resected whenever possible, even in the presence of unresectable distant disease, when preoperative symptoms warrant debulking. Tumor bulk reduction may help to palliate troublesome symptoms related to glucose intolerance or malabsorption. In general, radical resection should not be undertaken in the presence of widespread extrapancreatic nodal disease or liver metastases. The average postoperative 5-year survival rate is 75%: 60% with metastases and 100% without metastases. [82]
Pancreatic Polypeptide-Producing EPTs
Pancreatic polypeptide (PP) has been shown to inhibit pancreatic exocrine secretion, decrease gastric and small bowel motility, and inhibit gallbladder contraction. [83] The physiological importance of PP is unclear, because removal of the pancreas (and a loss of PP) does not result in a recognizable clinical syndrome. Most PP cells containing islets are located in the distal pancreas.
The clinical syndrome of PP-producing tumours may be associated with watery diarrhoea, hypokalaemia, achlorhydria, diabetes mellitus, skin eruption, and weight loss.84 There is no reproducible clinical syndrome attributed to excess circulating levels of the hormone. The most common clinical presentation of patients with PP-producing tumours are local symptoms from the primary tumour or from liver metastases. PP-producing tumours are localized predominantly (75%) on the right side of the superior mesenteric artery. [85] The diagnosis can be established by measuring fasting circulating levels of PP83 and with imaging procedures.Surgical treatment
Tumours in the pancreatic body and tail rarely cause symptoms and therefore are often metastatic at the time of diagnosis. Surgical resection is the treatment of choice, and because of their large size, these tumours require wide resection. Duodenopancreatectomy or distal pancreatectomy is usually required. Systemic therapy is reserved forpatients with a good clinical performance status who have locally advanced primary tumours or progressive metastatic disease.11 The prognosis is similar to that of nonfunctioning tumours.
Non-functioning EPTs
Nonfunctioning tumours are relatively frequent (15-40% of endocrine pancreatic tumours). About 90% of nonfunctioning tumours are malignant.86 Their clinical symptoms are similar to those of ductal carcinomas of the pancreas (abdominal pain, weight loss, jaundice), and tumours are often revealed later by non-specific symptoms due to local expansion of the primary tumours or by liver metastases. Nonfunctional tumours do not have a predominant localization; they occur equally in the head, body and tail of the pancreas, but they tend to be multiple and small. The primary therapy is surgical resection. Tumour debulking is recommended because it can prolong survival. The prognosis is better than in ductal pancreas carcinomas. The 5-year survival rate after curative resection is about 72%, with distant metastases with or without resection in about 40%. [86]
Interventional treatment of liver metastases
The surgical/interventional treatment for liver metastases can be divided into four modalities: liver resection, vascular interventions, other peroperative procedures and liver transplantation.
Liver resection
For curative resection a good clearance margin is required, but for EPTs resected for palliative reasons this margin can be narrowed and local tumour deposits can be removed by atypical resection.89 One evident problem with an active liver surgery programme is that many resections are considered curative at the time of surgery but later prove not to be. With access to sensitive diagnostic tools (specific tumour markers, octreotide scintigraphy, spiral CT and MRI) and careful follow-up, subclinical disease can be discovered and limited lesions can re-resected.90
Vascular intervention
The rationale for ischaemic treatment of endocrine tumours of the liver is their main blood supply from the hepatic artery of the tumour, with maintained portal perfusion of the normal liver parenchyma. Ischaemia can be achieved by several techniques directed at the hepatic artery: ligation, selective embolization, chemoembolization or temporary occlusion. No prospective randomized studies on liver metastases of EPTs have been reported. The results of ischaemic treatment of liver metastases are dependent on the stage of the disease. The patients can be divided into two large groups: responders, with more than 50% tumour reduction and pronounced reduction of 5-HIAA excretion, and nonresponders, with less than 50% tumour reduction and a moderate 5-HIAA reduction; there is a clear survival advantage in the former group. [89]
Peroperative procedures
Promising results have been reported with techniques using a hand-held scintillation detector after preoperative injection of radiolabelled somatostatin analogues for radioguided surgical treatment. [92] However, scintillation detectors are not sensitive enough to detect microscopic tumour growth or microadenomas. In individual patients, regional hyperthermic liver perfusion with cytotoxic drugs (melphalan, cisplatinum) has been used. [93] In elderly patients or patients with progressive disease after previous treatment, percutaneous alcohol injection into isolated liver lesions under pharmacological blockade can be performed. [94] Alternatively, the tumour can be destroyed by cryosurgical techniques, [95] interstitial laser [96] or radiofrequency therapy [97] causing selective thermo coagulation. These techniques can be used intraoperatively or percutaneously.
Liver transplantation
The following indications for liver transplantation in patients with EPTs may be considered: [89]
(1)Metastatic disease limited to the liver, not accessible for curative liver surgery, including recurrent tumours in patients subjected earlier to curative liver resection and patients with severe hormonal symptoms due to liver tumours not possible to treat with other interventions, e.g., histamine-producing carcinoids.
(2)Tumour progression after embolization and medical therapy in patients with no proven disease outside the liver.
Multivariate analysis identified age greater than 50 years and transplantation combined with upper abdominal exenteration or Whipple’s operation as adverse prognostic factors. [98] Available studies indicate that patients with metastatic endocrine tumours confined to the liver can be offered long periods of symptom palliation through liver transplantation. [99-102]
SUMMARY
Endocrine pancreatic tumours are a rare group of pancreatic neoplasms with a much better prognosis than pancreatic adenocarcinomas. They can cause typical clinical syndromes through active hormone overproduction. Most of them are malignant and require sophisticated diagnostic and localization techniques in order to identify their presence. Improvements in diagnostic techniques and therapeutic strategies have had an impact on cure rates. Increasing numbers of patients can be identified and can now undergo more effective treatments for refractory and recurrent tumour disease.
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