胰腺血管活性肠肽瘤

n****8

Case report 93
Diagnosis and treatment of VIPoma in a female patient
Carol Ann Remmea,b, Gerrit H. de Groota and Gideon Schrijvera
We report a case of VIPoma in an 83-year-old female
patient, who presented with frequent and excessive
diarrhoea, muscle weakness, and severe hypokalaemia.
Abdominal computed tomography (CT) revealed a 4
6cm
mass in the body of the pancreas. Laboratory **ysis
showed elevated levels of both vasoactive intestinal
polypeptide (VIP; 153 pmol/l) and pancreatic polypeptide
(161 pmol/l). In view of the patient’s age, physical
condition, and tumour size, surgical resection was not
performed. The patient was treated with a long-acting
octreotide, after which her symptoms diminished. After 24
months of follow-up, the patient remained in good physical
condition without any further serious gastrointestinal
symptoms. The VIPoma syndrome is caused by a
neuroendocrine tumour, usually located in the pancreas,
which secretes VIP, causing severe diarrhoea, dehydration
and hypokalaemia. Treatment options include resection of
the tumour, chemotherapy or the reduction of symptoms
with somatostatin **ogues. We provide an overview of
the incidence, pathophysiology, diagnosis, treatment
strategies, and prognosis of this rare syndrome. Eur J
Gastroenterol Hepatol 18:93–99
c 2006 Lippincott
Williams & Wilkins.
European Journal of Gastroenterology & Hepatology 2006, 18:93–99
Keywords: diarrhoea, hypokalaemia, octreotide, pancreatic tumour,
vasoactive intestinal polypeptide, VIPoma
aDepartment of Internal Medicine, Red Cross Hospital, Beverwijk, The
Netherlands and bDepartment of Experimental Cardiology, Academic Medical
Centre, Amsterdam, The Netherlands.
Correspondence and reprint requests to Carol Ann Remme, MD PhD,
Department of Experimental Cardiology, Academic Medical Centre,
Room M0-107, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Tel: +31 20 5663262; fax: +31 20 6975458;
e-mail: c.a.remme@amc.uva.nl
Received 17 June 2005 Accepted 22 September 2005
Background
The VIPoma syndrome, also known as the Verner–
Morrison syndrome or the watery diarrhoea, hypokalaemia,
and hypochlorhydria or achlorhydria syndrome, is
caused by a neuroendocrine tumour, usually located in
the pancreas, which secretes vasoactive intestinal polypeptide
(VIP) [1–4]. As a result, patients usually present
with severe and frequent diarrhoea, leading to dehydration
and hypokalaemia. Treatment options include
resection of the tumour, chemotherapy or the reduction
of symptoms with somatostatin **ogues [1,4,5]. We
report a case of excessive diarrhoea caused by a VIPoma in
an 83-year-old female patient, whose symptoms were
successfully diminished by octreotide treatment. In
addition, we provide an overview of the recent literature
regarding the incidence, pathophysiology, diagnosis,
treatment strategies, and prognosis of this rare syndrome.
Case report
An 83-year-old female patient was referred to our
Department of Internal Medicine with complaints of
frequent and excessive diarrhoea, abdominal discomfort
and muscle weakness. Her medical history revealed an
episode of gastritis caused by Helicobacter pylori infection.
For over one year, she had experienced multiple bouts of
watery diarrhoea, up to 3–4 l a day, without blood or
mucus. At a previous evaluation at the outpatient clinic,
she was initially diagnosed as lactose intolerant and
referred to a dietician. Laboratory **ysis revealed
hypokalaemia in the absence of diuretics, which was
substituted with oral potassium tablets. Nevertheless,
daily multiple episodes of watery diarrhoea occurred
persistently, leading to weight loss, dehydration, and
exhaustion. In the weeks before admission, the patient
experienced severe muscle cramps and progressive
weakness in both the upper and lower extremities. There
was no previous history of abdominal surgery, flushing,
thyroid disease, visits to tropical countries, or laxative
abuse.
Upon presentation, physical examination revealed a
dehydrated woman with decreased skin turgor, and
normal blood pressure (135/65 mmHg), pulse (72 beats/
min), and temperature (36.61C). Apart from a slightly
extended and tender abdomen, no relevant abnormalities
were observed. Laboratory **ysis showed severe hypokalaemia
with moderate hypercalcaemia and hyperchloraemia
(sodium 143 mmol/l, potassium 1.7 mmol/l,
chloride 111mmol/l, calcium 2.61 mmol/l, magnesium
0.95mmol/l, urea 11.1 mmol/l, creatinine 79 mmol/l,
albumin 32 g/l, glucose 6.4 mmol/l). Capillary blood gas
**ysis showed signs of metabolic acidosis with respiratory
compensation (pH 7.34, partial pressure carbon
dioxide 35 mmHg, hydrogen carbonate 18mmol/l, base
excess – 6.0 mmol/l, partial pressure oxygen 54 mmHg,
oxygen saturation 90%). Urine **ysis showed a potassium
concentration of 14 mmol/l, and a sodium concentration
of 60mmol/l; urine measurement of
5-hydroxyindoleacetic acid was negative. Electrocardiogram
**ysis revealed QRS complex broadening and T-wave
0954-691X
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flattening concomitant with hypokalaemia. Stool specimen
**ysis revealed a measured osmolality of 309mosm/kg
with a low osmolal gap (sodium 125mmol/l, potassium
31 mmol/l, calculated osmolality 312 mosm/kg), suggestive
of secretory diarrhoea. Repetitive stool cultures were
negative for bacterial or parasite infection. Additional
laboratory **ysis showed normal values for parathyroid
hormone (0.8 pmol/l), free thyroxine (12 pmol/l), thyroidstimulating
hormone (0.5 mE/l), calcitonin (0.06 mg/l),
and gastrin (0.10 mg/l). A lactose breath hydrogen test
showed slightly raised levels of exhaled hydrogen after
105 min, suggesting a minor imbalance in lactose digestion.
On further examination, abdominal computed
tomography (CT) revealed a mass of 4 6 cm in the
body of the pancreas, with dilatation of the common bile
duct and to a minor extent of the intrahepatic bile ducts
(Fig. 1). There were no signs of hepatic (metastatic)
lesions or enlarged lymph nodes. Radiolabelled pentetreotide/
somatostatin receptor scintigraphy (octreoscan)
showed intense activity at the location of the pancreatic
tumour, without signs of metastatic activity (Fig. 2).
These findings suggested a diagnosis of secretory
diarrhoea caused by a VIP-secreting pancreatic tumour
or VIPoma. Increased values of both VIP (153 pmol/l,
normal <50 pmol/l) and pancreatic polypeptide (PP;
161 pmol/l, normal <50–100 pmol/l) were observed on
laboratory **ysis.
Upon admittance, the patient was rehydrated with
intravenous saline (0.9% sodium chloride) supplemented
with potassium chloride. In addition, with a suspected
diagnosis of VIPoma, treatment with the somatostatin
**ogue octreotide (100 mg subcutaneously three times a
day) was started, upon which the frequency of diarrhoea
decreased dramatically. During a 2-day discontinuation of
the drug, for the purpose of performing the radionucleotide
scan (octreoscan), the diarrhoea reappeared
in its original frequency and quantity and was again
suppressed upon the re-administration of octreotide. In
view of the patient’s age and physical condition, as well as
the size and location of the pancreatic tumour, surgical
resection was not feasible and therefore not performed.
For chronic treatment, the patient was started on a longacting
octreotide consisting of a once-monthly intramuscular
injection of 10 mg Sandostatin LAR. During a
follow-up period of 24 months, the patient remained
in good physical condition, although she experienced
some mild diarrhoea 18 months after starting treatment.
After increasing the monthly dose of Sandostatin
LAR to 20 mg intramuscularly, no further gastrointestinal
symptoms were observed. In addition, repeated
abdominal CT **ysis showed identical, stable tumour
size after one year of treatment (Fig. 1). After
re-administration of octreotide, an immediate decrease
in PP levels was observed, but after one year of
treatment, PP was again slightly increased (108 pmol/l)
(Fig. 3). However, VIP levels have remained consistently
low since octreotide treatment was started (12 pmol/l
after one year).
In conclusion, we described an 83-year-old female patient
with excessive secretory diarrhoea caused by a VIPsecreting
pancreatic tumour or VIPoma, whose symptoms
were successfully treated with a long-acting octreotide.
During future follow-up, repeated abdominal CT scan
Fig. 1
Abdominal computed tomography **ysis revealing a mass of 46cm
in the body of the pancreas before (top panel) and after one year of
octreotide treatment (lower panel).
94 European Journal of Gastroenterology & Hepatology 2006, Vol 18 No 1
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**ysis and VIP/PP level measurements will be used to
monitor tumour progression and the effectiveness of
treatment.
Vasoactive intestinal polypeptide: biology
and (patho)physiology
VIP is a 28 amino acid peptide that was first isolated from
the porcine duodenum and was found to be similar to
pituitary adenylate cyclase-activating polypeptide [6,7].
VIP is expressed in the central nervous system and
neurones of the gastrointestinal, respiratory, and urogenital
tracts. The physiological actions of VIP include
relaxation of smooth muscles, and control of motility and
secretion in the digestive tract, as well as the stimulation
of hormone release [8]. In addition, VIP is considered an
anti-inflammatory agent and modulator of the immune
system [9,10]. In the gastrointestinal tract, VIP is a
potent stimulator of adenylate cyclase and adenosine 30,
50-cyclic phosphate, leading to massive secretion of water
and electrolytes, mainly chloride and potassium [11]. In
addition, VIP abolishes water and electrolyte absorption
in the small intestine, further contributing to the
formation of secretory diarrhoea, with substantial loss of
fluid and electrolytes [12].
Clinical presentation of VIPoma
The VIPoma syndrome, which was first described in
1958 by Verner and Morrison, has a very low incidence of
0.05–0.1 per million per year [2,13,14]. The mean age
of patients at diagnosis of the syndrome is approximately
50 years, with a slightly higher incidence in women
compared with men [3,15]. VIPomas are more commonly
located in the body and tail of the pancreas, although
Fig. 2
Anterior Posterior
Radiolabelled pentetreotide/somatostatin receptor scintigraphy (octreoscan) showing intense activity after 24 h at the location of the pancreatic
tumour, without signs of metastatic activity.
Diagnosis and treatment of VIPoma in a female patient Remme et al. 95
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extrapancreatic localizations have also been reported
[4,16–18]. These neuroendocrine pancreatic tumours
typically produce high amounts of VIP, but may also
secrete PP and other peptide hormones [19]. Pancreatic
VIPomas usually occur solitarily, but may also be part of
the multiple endocrine neoplasia type I (MEN I)
syndrome [20]. At presentation, metastatic spread of
the disease has already occurred in approximately 60–80%
of patients, with hepatic metastases occurring much more
frequently than lymph node, lung or kidney metastases
[4,19,21]. As mentioned before, the major clinical
symptom of the VIPoma syndrome is excessive watery
(secretory) diarrhoea, which persists during fasting, with
large faecal losses of chloride, bicarbonate and potassium
in the small intestine. As a result, dehydration, hypokalaemia,
hypomagnesaemia, hypo or hyperchloraemia, and
metabolic acidosis occurs [2]. Hypochlorhydria (or in
some cases achlorhydria) is often present, with a
reduction in gastric acid secretion probably caused by
an inhibitory effect of VIP on the parietal cells in the
gastric mucosa [22,23]. In addition, hypercalcaemia may
be observed, which may partly be caused by the
stimulating effects of VIP on parathyroid hormone release
by interaction with 30,50-cyclic phosphate production of
the parathyroid cells [24]. Finally, the glycogenolytic
effect of VIP on the liver in addition to the inhibitory
effect of hypokalaemia on pancreatic islet beta cells may
lead to hyperglycaemia [3]. During the initial stages of
the disease, diarrhoea may be intermittent but becomes
profuse and continuous with progression of the tumour.
If inadequately treated, the resulting dehydration and
electrolyte disturbances may cause serious metabolic
disturbances and renal failure, and ultimately result in
cardiac arrest.
(Differential) diagnosis of VIPoma
As the VIPoma syndrome represents a rare clinical entity,
it is vital to exclude any other possible underlying cause
in patients presenting with profuse diarrhoea (Table 1).
First of all, the presence of secretory diarrhoea should be
examined and may be confirmed by a measured stool
osmolality significantly exceeding the calculated value
(i.e. an osmolal gap is present). The differential diagnosis
of secretory diarrhoea includes enteritis caused by
enterotoxins (Escherichia coli, Vibrio cholerae), laxantia
abuse, bile salt malabsorption because of ileal resection,
coeliac disease, and endocrine tumours. The latter
include pancreatic endocrine tumour syndromes (gastrinomas,
VIPomas, glucagonomas, somatostatinomas, pancreatic
endocrine tumours releasing calcitonin), carcinoid
syndrome, medullary thyroid cancer, and systemic mastocytosis
[25]. Secretory watery diarrhoea in copious
amounts, hypokalaemia and a pancreatic mass on either
abdominal ultrasound or CTshould suggest the presence
of a VIPoma. For the detection of small pancreatic
tumours, endoscopic ultrasonography may be used. The
diagnosis can be confirmed by repeated elevated serum
levels of VIP in excess of 200 pg/ml [26]. To exclude the
presence of other endocrine tumours, serum levels of
calcitonin, parathyroid hormone, free thyroxine, thyroidstimulating
hormone, serotonin, and the urinary excretion
of 5-hydroxyindoleacetic acid should be measured. The
presence of metastatic disease should be evaluated by
CT **ysis, with special focus on hepatic involvement.
More recently, somatostatin receptor scintigraphy
using indium-labelled octreotide (111In-DTPA-octreotide;
octreoscan) was introduced for the accurate detection
of the primary tumour location as well as an
evaluation of the presence of metastases [27].
In our patient, profuse watery diarrhoea with severe
hypokalaemia was observed in the presence of a large
pancreatic mass on CT. Plasma VIP and PP levels were
found to be elevated, intense activity at the location of
the pancreatic tumour was observed on the octreoscan,
and symptoms disappeared upon octreotide treatment,
confirming a diagnosis of VIPoma. Although the VIP level
Fig. 3
0
50
100
150
200
0 min 10 min 30 min 45 min 60 min 90 min 1 month 1 year
Time after start octreotide treatment
PP (pmol/l)
Decrease in pancreatic polypeptide plasma levels after acute and longterm
treatment with octreotide. PP, Pancreatic polypeptide.
Table 1 Differential diagnosis of osmotic and secretory diarrhoea
Osmotic diarrhoea:
Lactose/disaccharidose intolerance
Coeliac disease
Glucose malabsorption
Secretory diarrhoea:
Enterotoxin-producing pathogens (E. coli, V. cholerae)
Laxantia abuse
Villous adenoma
Coeliac disease
Bile salt malabsorption (after ileal resection)
Hyperthyroidism
Pancreatic endocrine tumour syndromes:
Glucagonoma
Gastrinoma
VIPoma
Somatostatinoma
Calcitonin-releasing tumour
Carcinoid syndrome
Medullary thyroid cancer
Systemic mastocytosis
96 European Journal of Gastroenterology & Hepatology 2006, Vol 18 No 1
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in our patient may not be as high as levels previously
reported in the literature, it has been reported that VIP
plasma concentrations may show a large **ytical and
biological variation, possibly depending on the severity of
diarrhoea at the time of **ysis [3,5].
Treatment of VIPoma
Initial treatment in patients with VIPoma should focus on
the replacement of fluid losses, and correction of
hypokalaemia and metabolic acidosis. Usually, this
requires temporary hospital admission with intensive
intravenous therapy, although in some cases long-term
replacement of fluid and electrolytes through a subclavicular
catheter is required at home [28]. Currently,
the only curative treatment for VIPoma is complete
surgical resection, although in most advanced cases, only
palliative tumour debulking (to prevent local mechanical
symptoms) is feasible because of the presence of
metastases [4,21,29]. Preoperative treatment with a
hydrogen blocker or proton pump inhibitors in combination
with somatostatin **ogues (see below) is advised
to prevent possible rebound gastric acid hypersecretion
and intravascular volume overload, respectively [1,30]. In
all cases in which complete surgical resection is either
unsuccessful or not feasible, an important pharmacotherapeutic
approach to controlling symptoms in VIPoma
patients is the use of somatostatin, a potent inhibitor of
human exocrine pancreatic secretion, which suppresses
the effects of VIP and other peptides secreted by
endocrine tumours [12,31]. Because of the short serum
half-life of somatostatin, the derivative octreotide is used
in clinical practice by subcutaneous injection, starting at
50–100 mg three times a day, but depending on the
efficacy of symptom control, gradually increasing to a
maximum dose of 500 mg three times per day [32,33].
More recently, long-acting octreotide preparations such as
Sandostatin LAR have become available, allowing for once
monthly administration of the drug, starting with 10–20mg
a month with a maximum of 60mg [32,34,35]. Octreotide
treatment decreases VIP plasma levels and may completely
abolish or greatly improve the severity of secretory diarrhoea
[34,36,37]. Apart from their obvious effectiveness in the
symptomatic management of endocrine tumours, there is
debate as to whether somatostatin **ogues also reduce
tumour size [38,39]. The long-term application of
octreotide may result in the development of resistance
to this compound, sometimes necessitating extremely
high doses of octreotide for continuous beneficial effects
[28,40]. In patients with disease progression or persistent
symptoms despite octreotide treatment, the antineoplastic
agent IFN-a in combination with somatostatin
**ogues may result in clinical improvement and limited
tumour regression [18,41,42].
In patients with metastatic disease, surgical resection of
at least 90% of liver metastases is effective in reducing
symptoms caused predominantly by hormonal oversecretion,
and may increase the survival rate [43,44]. In cases
of unresectable liver metastases, repetitive hepatic
arterial embolization or transcatheter arterial chemoembolization
of the hepatic artery using doxorubicin or
cisplatin may provide long-term palliation [45,46]. When
these approaches for metastatic disease control prove
ineffective or unfeasible, local ablative therapy using
percutaneous or intraoperative radiofrequency interstitial
tumour ablation of liver metastases may be considered
[47]. Although this technique is not ideal for larger-sized
metastases, it can successfully be used in combination
with surgical resection, for the palliation of symptoms,
and as treatment of recurrent disease after previous
unsuccessful resection or ablation [33,48].
With neuroendocrine tumours in general, systemic
chemotherapy with streptozotocin, doxorubicin or fluorouracil
may provide some benefit, although small study
populations make reliable interpretation difficult
[28,29,49]. Although platinum derivatives are considered
the best option in the case of high-grade neuroendocrine
tumours [50], this therapeutic approach requires further
research [33]. Finally, a relatively new application is the
use of somatostatin receptor-mediated radiotherapy with
radiolabelled octreotide [51]. Therapeutic effects, mostly
the stabilization of previously progressive tumours, have
been observed in half of the patients studied, with
generally only mild bone marrow toxicity unless high
doses were used [52]. This approach appears to be
effective in patients with inoperable or disseminated
neuroendocrine tumours, but randomized trials are
required to determine which radiolabelled somatostatin
**ogue (or combinations of **ogues) is optimal [53].
Table 2 summarizes the therapeutic options described
above. In general, most of the available data discussed in
this section refer primarily to neuroendocrine tumours in
general, and specific data on VIPomas are scarce. The
survival rate in patients with VIPoma is highly dependent
on the stage of the disease at the time of diagnosis, and
may be high in non-metastatic tumours (5-year survival of
up to 95%), but moderate in patients with advanced
Table 2 Acute and long-term treatment of VIPoma
Acute treatment:
Replacement of fluid losses
Correction of electrolyte disturbances
Chronic treatment:
Surgery: tumour resection/debulking
Pharmacological treatment of symptoms:
Subcutaneous octreotide (somatostatin derivative)
Long-acting octreotide
Interferon-alfa
Treatment of liver metastases:
Surgical resection of metastases
Hepatic artery embolization
Transcatheter arterial chemoembolization
Radiofrequency interstitial tumour ablation
Systemic chemotherapy
Radiotherapy (labelled somatostatin **ogues)
Diagnosis and treatment of VIPoma in a female patient Remme et al. 97
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disease (5-year survival approximately 60%) [21]. For the
latter group of patients, large clinical trials comparing
various chemotherapy and radiotherapy strategies are
required for the development of optimal treatment
strategies in the future.
Conclusion
We have presented an 83-year-old female patient with
excessive secretory diarrhoea caused by a VIP-secreting
pancreatic tumour or VIPoma, whose symptoms were
successfully treated with a long-acting octreotide. This
syndrome may be diagnosed in patients with secretory
diarrhoea in the presence of elevated plasma VIP levels
and a pancreatic mass observed on ultrasound, CT or
octreoscan. The complete cure of VIPoma is possible only
by resection of the tumour, but additional (palliative)
treatment options include chemotherapy, hepatic artery
embolization, and radiotherapy. Furthermore, symptom
reduction and clinical improvement is often achieved
with the use of the somatostatin **ogue octreotide.
Acknowledgements
VIP and PP measurements were courtesy of Professor Dr
C.B. Lamers and Dr I. Biemond, Leiden University
Medical Centre, the Netherlands. The authors would like
to thank Professor Dr C.B. Lamers for critical reading of
the manusc**t.
Conflict of interest
None declared.
Authors’ contributions
C.A. Remme: patient care, literature review and writing of the paper; G.H. de
Groot: patient care and review of the paper; G. Schrijver: patient care, treatment
and follow-up and review of the paper.
References
1 Grier JF. WDHA (watery diarrhea, hypokalaemia, achlorhydria) syndrome:
clinical features, diagnosis, and treatment. South Med J 1995; 88:22–24.
2 Krejs GJ. VIPoma syndrome. Am J Med 1987; 82:37–48.
3 Park SK, O’Dorisio MS, O’Dorisio TM. Vasoactive intestinal polypeptidesecreting
tumours: biology and therapy. Baillieres Clin Gastroenterol 1996;
10:673–696.
4 Smith SL, Branton SA, Avino AJ, Martin JK, Klingler PJ, Thompson GB, et al.
Vasoactive intestinal polypeptide secreting islet cell tumours: a 15-year
experience and review of the literature. Surgery 1998; 124:1050–1055.
5 O’Dorisio TM, Mekhjian HS, Gaginella TS. Medical therapy of VIPomas.
Endocrinol Metabol Clin North Am 1989; 18:545–556.
6 Said SI, Mutt V. Polypeptide with broad biological activity: isolation from
small intestine. Science 1970; 169:1217–1218.
7 Klimaschewski L. VIP: a ‘very important peptide’ in the sympathetic nervous
system? Anat Embryol 1997; 196:269–277.
8 Fahrenkrug J. Transmitter role of vasoactive intestinal peptide. Pharmacol
Toxicol 1993; 72:354–363.
9 Pozo D, Delgado M, Martinez C, Guerrero JM, Leceta J, Gomariz RP, et al.
Immunobiology of vasoactive intestinal peptide (VIP). Trends Immunol Today
2000; 21:7–11.
10 Gomariz RP, Martinez C, Abad C, Leceta J, Delgado M. Immunology of VIP:
a review and therapeutical perspectives. Curr Pharm Des 2001; 7:89–111.
11 Laburthe M, Couvineau A, Amiranoff B, Voisin T. Receptors for gut regulatory
peptides. Baillieres Clin Endocrinol Metab 1994; 8:77–110.
12 Krejs GJ. Effect of somatostatin infusion on VIP-induced transport changes
in the human jejunum. Peptides 1984; 5:271–276.
13 Verner JV, Morrison AB. Islet cell tumour and a syndrome of refractory watery
diarrhea and hypokalaemia. Am J Med 1958; 9:374–380.
14 Modlin IM, Lewis JJ, Ahlmann H, Bilchik AJ, Kumar RR. Management of
unresectable malignant endocrine tumours of the pancreas. Surg Gynecol
Obstet 1993; 176:507–518.
15 Phan GQ, Yeo CJ, Hruban RH, Lillemoe KD, Pitt HA, Cameron JL. Surgical
experience with pancreatic and pe**ancreatic neuroendocrine tumours:
review of 125 patients. J Gastrointest Surg 1998; 2:472–482.
16 Mozell E, Stenzel P, Woltering EA, Rosch J, O’Dorisio TM. Functional
endocrine tumours of the pancreas: clinical presentation, diagnosis, and
treatment. Curr Problems Surg 1990; 27:303–386.
17 Ayub A, Zafar M, Abdulkareem A, Ali MA, Lingawi T, Harbi A. Primary hepatic
VIPoma. Am J Gastroenterol 1993; 88:958–961.
18 Cellier C, Yaghi C, Cuillerier E, Siauve N, Berger A, Carnot F, et al.
Metastatic jejunal VIPoma: beneficial effect of combination therapy with
interferon-a and 5-fluorouracil. Am J Gastroenterol 2000; 95:289–293.
19 Capella C, Polak JM, Buffa R, Tapia FJ, Heitz P, Usellini L, et al. Morphologic
patterns and diagnostic criteria of VIP-producing endocrine tumours.
A histologic, histochemical, ultrastructural, and biochemical study of 32
cases. Cancer 1983; 52:1860–1874.
20 Lee CH, Ching KN, Lui WY, P’eng FK, Franklin WA, Kaplan EL. Carcinoid
tumour of the pancreas causing the diarrheogenic syndrome: report of a
case combined with multiple endocrine neoplasia, type I. Surgery 1986;
99:123–129.
21 Soga J, Yakuwa Y. VIPoma/diarrheogenic syndrome: a statistical evaluation
of 241 reported cases. J Exp Clin Cancer Res 1998; 17:389–400.
22 Escourrou J, Ebeid AM, Fischer JE. Vasoactive intestinal peptide-associated
inhibition of stimulated gastric secretion. II. Inhibition of pentagastrinstimulated
gastric secretion. Am J Surg 1980; 139:824–828.
23 Nassar CF, Abdallah LE, Barada KA, Atweh SF, Saade NE. Effects of
intravenous vasoactive intestinal peptide injection on jejunal alanine
absorption and gastric acid secretion in rats. Regul Pept 1995; 55:
261–267.
24 Joborn H, Larsson R, Rastad J, Nygren P, Akerstrom G, Ljunghall S.
Vasoactive intestinal polypeptide stimulates parathyroid hormone release by
interaction with cyclic adenosine monophosphate production of bovine
parathyroid cells. Acta Endocrinol 1991; 124:54–59.
25 Jensen RT. Overview of chronic diarrhea caused by functional
neuroendocrine neoplasms. Semin Gastrointest Dis 1999; 10:156–172.
26 Delcore R, Friesen SR. Gastrointestinal neuroendocrine tumours. J Am Coll
Surg 1994; 178:187–211.
27 Thomason JW, Martin RS, Fincher ME. Somatostatin receptor scintigraphy:
the definitive technique for characterizing vasoactive intestinal peptidesecreting
tumors. Clin Nucl Med 2000; 25:661–664.
28 Nguyen HN, Backes B, Lammert F, Wildberger J, Winograd R, Busch N,
et al. Long-term survival after diagnosis of hepatic metastatic VIPoma.
Report of two cases with disparate courses and review of therapeutic
options. Dig Dis Sci 1999; 44:1148–1155.
29 Brentjens R, Saltz L. Islet cell tumours of the pancreas: the medical
oncologist’s perspective. Surg Clin North Am 2001; 81:527–542.
30 Jaffe BM. Surgery for gut hormone-producing tumours. Am J Med 1987;
82:68–76.
31 Dueno MI, Bai JC, Santangelo WC, Krejs GJ. Effect of somatostatin
**ogue on water and electrolyte transport and transit time in human small
bowel. Dig Dis Sci 1987; 32:1092–1096.
32 Santangelo WC, O’Dorisio TM, Kim JG, Severino G, Krejs GJ. Pancreatic
cholera syndrome: effect of a synthetic somatostatin **ogue on intestinal
water and ion transport. Ann Intern Med 1985; 103:363–367.
33 Ramage JK, Davies AHG, Ardill J, Bax N, Caplin M, Grossman A, et al.
Guidelines for the management of gastroenteropancreatic neuroendocrine
(including carcinoid) tumours. Gut 2005; 54 (suppl IV):iv1–iv16.
34 Dogliotti L, Tampellini M, Stivanello M, Gorzegno G, Fabiani L. The clinical
management of neuroendocrine tumours with long-acting repeatable (LAR)
octreotide: comparison with standard subcutaneous octreotide therapy.
Ann Oncol 2001; 12 (suppl 2):S105–S109.
35 Wymenga AN, Eriksson B, Salmela PI, Jacobsen MB, Van Cutsem EJ, Fiasse
RH, et al. Efficacy and safety of prolonged-release lanreotide in patients with
gastrointestinal neuroendocrine tumours and hormone-related symptoms.
J Clin Oncol 1999; 17:1111–1117.
36 Debas HT, Gittes G. Somatostatin **ogue therapy in functioning
neuroendocrine gut tumours. Digestion 1993; 54 (suppl 1):68–71.
37 Harris AG, O’Dorisio TM,Woltering EA, Anthony LB, Burton FR, Geller RB,
et al. Consensus statement: octreotide dose titration in secretory diarrhea.
Diarrhea Management Consensus Development Panel. Dig Dis Sci 1995;
40:1464–1473.
38 Arnold R, Frank M, Kajdan U. Management of gastroenteropancreatic
endocrine tumours: the place of somatostatin **ogues. Digestion 1994;
55 (suppl 3):107–113.
98 European Journal of Gastroenterology & Hepatology 2006, Vol 18 No 1
Copyright &copy; Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
39 Hejna M, Schmidinger M, Raderer M. The clinical role of somatostatin
**ogues as antineoplastic agents: much ado about nothing? Ann Oncol
2002; 13:653–668.
40 Lamberts SW, Pieters GW, Metselaar HJ, Ong GL, Tan HS, Reubi JC.
Development of resistance to a long-acting somatostatin **ogue during
treatment of two patients with metastatic endocrine pancreatic tumours.
Acta Endocrinol 1988; 119:561–566.
41 O ¨ berg K. Interferon-alpha versus somatostatin or the combination of
both in gastro-enteropancreatic tumours. Digestion 1996; 57 (suppl 1):
81–83.
42 Faiss S, Pape UF, Bo¨ hmig M, Do¨ rffel Y, Mansmann U, Golder W, et al.
Prospective, randomized, multicenter trial on the antiproliferative effect of
lanreotide, interferon alpha, and their combination for therapy of metastatic
neuroendocrine gastroenteropancreatic tumors – the International
Lanreotide and Interferon Alfa Study Group. J Clin Oncol 2003; 21:
2689–2696.
43 Que FG, Sarmiento JM, Nagorney DM. Hepatic surgery for metastatic
gastrointestinal neuroendocrine tumors. Cancer Control 2002; 9:67–79.
44 Sarmiento JM, Heywood G, Rubin J, Ilstrup DM, Nagorney DM,
Que GQ. Surgical treatment of neuroendocrine metastases to the
liver: a plea for resection to increase survival. J Am Coll Surg 2003;
197:29–37.
45 Case CC,Wirfel K, Vassilopoulou-Sellin R. Vasoactive intestinal polypeptidesecreting
tumour (VIPoma) with liver metastases: dramatic and durable
symptomatic benefit from hepatic artery embolization, a case report. Med
Oncol 2002; 19:181–187.
46 Roche A, Girish BV, de Bae` re T, Baudin E, Boige V, Elias D, et al.
Trans-catheter arterial chemoembolization as first-line treatment for hepatic
metastases from endocrine tumors. Eur Radiol 2003; 13:136–140.
47 Hellman P, Ladjevardi S, Skogseid B, A ° kerstro¨m G, Elvin A. Radiofrequency
tissue ablation using cooled tip for liver metastases of endocrine tumors.
World J Surg 2002; 26:1052–1056.
48 Atwell TD, Charboneau JW, Que FG, Rubin J, Lewis BD, Nagorney DM,
et al. Treatment of neuroendocrine cancer metastatic to the liver: the role
of ablative techniques. Cardiovasc Intervent Radiol 2005; 28:409–421.
49 Moertel CG, Lefkopoulo M, Lipsitz S, Hahn RG, Klaassen D. Streptozocin–
doxorubicin, streptozocin–fluorouracil or chlorozotocin in the treatment of
advanced islet-cell carcinoma. N Engl J Med 1992; 326:519–523.
50 Bajetta E, Procopio G, Ferrari L, Catena L, Del Vecchio M, Bombardieri E.
Update on the treatment of neuroendocrine tumors. Expert Rev Anticancer
Ther 2003; 3:631–642.
51 Breeman WA, de Jong M, Kwekkeboom DJ, Valkema R, Bakker WH,
Kooij PP, et al. Somatostatin receptor-mediated imaging and therapy:
basic science, current knowledge, limitations and future perspectives.
Eur J Nucl Med 2001; 28:1421–1429.
52 De Jong M, Valkema R, Jamar F, Kvols LK, Kwekkeboom DJ, Breeman WA,
et al. Somatostatin receptor-targeted radionuclide therapy of tumours:
preclinical and clinical findings. Semin Nucl Med 2002; 32:133–140.
53 Kwekkeboom DJ, Mueller-Brand J, Paganelli G, Anthony LB, Pauwels S,
Kvols LK, et al. Overview of results of peptide receptor radionuclide therapy
with 3 radiolabeled somatostatin **ogs. J Nucl Med 2005; 46 (suppl 1):
62S–66S.
Diagnosis and treatment of VIPoma in a female patient Remme et al. 99
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