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Paola
Tomassetti, Davide Campana, Lydia Piscitelli, Elena Mazzotta, Emilio
Brocchi, Raffaele Pezzilli, Roberto Corinaldesi, Department of
Internal Medicine and Gastroenterology, University of Bologna, Italy
Correspondence to: Professor Paola Tomassetti, Department of
Internal Medicine and Gastroenterology, University of Bologna,
Policlinico S.Orsola-Malpighi, Via Massarenti, 9, 40138, Bologna,
Italy. paola.tomassetti@unibo.it
Telephone: +39-51-6364186
Fax: +39-51-6364186
Received: 2005-01-31
Accepted: 2005-03-09
Abstract
In this article, we have reviewed the main therapeutic measures for
the treatment of Zollinger-Ellison syndrome (ZES). Review of the
literature was based on computer searches (Pub-Med, Index Medicus)
and personal experiences. We have evaluated all the measures now
available for treating patients with sporadic gastrinomas or
gastrinomas associated with Multiple Endocrine Neoplasia Type 1,
(MEN 1) including medical therapy such as antisecretory drugs and
somatostatin analogs (SST), chemotherapy and chemoembolization, and
surgical procedures. In ZES patients, the best therapeutic procedure
is surgery which, if radical, can be curative. Medical treatment can
be the best palliative therapy and should be used, when possible, in
association with surgery, in a multimodal therapeutic approach.
© 2005 The WJG Press and Elsevier Inc. All rights reserved.
Key words: Gastrinoma; Zollinger-Ellison Syndrome; MEN 1;
Proton pump inhibitors; Somatostatin analogs; Chemoembolization
Tomassetti P, Campana D, Piscitelli L, Mazzotta E, Brocchi E,
Pezzilli R, Corinaldesi R. Treatment of Zollinger-Ellison Syndrome. World
J Gastroenterol 2005;
11(35): 5423-5432
http://www.wjgnet.com/1007-9327/11/5423.asp
INTRODUCTION
The Zollinger-Ellison Syndrome (ZES) represents a clinical,
diagnostic and therapeutic challenge. In this paper, we have
reviewed the recent advances on this fascinating syndrome. One
MEDLINE (PubMed) search, was carried out using only MESH terms with
the following strategy: Therapy AND (gastrinoma OR Multiple
Endocrine Neoplasia Type 1 OR Zollinger-Ellison Syndrome). No limits
were set and 4 369 papers were found. Only those papers in-extenso
were considered. The authors reviewed all the papers and other
papers or chapters in the published book were also manually searched
in the references of the papers reviewed, if considered necessary
for the present review.
CAUSES
The ZES, as described in 1955, is characterized by peptic ulcers of
the upper gastrointestinal tract refractory to medical therapy,
diarrhea and severe gastric acid hypersecretion associated with
non-beta islet cell tumors of the pancreas[1].
It was later demonstrated that this pancreatic tumor, named
gastrinoma, ectopically releases gastrin, which is responsible for
the gastric hypersecretion. More than 80% of gastrinomas are
localized in the anatomic area called the triangle of the
gastrinomas. This triangle includes the convergence of the cystic
duct and the common bile duct, the junction of the second and third
portion of the duodenum, and the junction of the head and body of
the pancreas[2-5].
Most gastrinomas arise from the duodenum (about 75%), whereas they
are localized in the pancreas in 25% of cases[4].
Occasionally gastrinomas occur in the ovary, mesentery, liver, bile
duct, gastric antrum/pyloric area, renal capsule, and in the jejunum[6,7].
Furthermore, extra-abdominal primary gastrinomas in the heart[8,9]
and gastrin-releasing lung tumor causing ZES have recently been
described[10].
The structure can be glandular or trabecular, and
the cells are round with small nuclei and prominent nucleolus. The
cells which produce gastrin are generally well-differentiated and
contain the histological markers typical of neuroendocrine tumors,
i.e., chromogranin A, neurospecific enolase and synaptophysin. These
tumors are positive at immunohistochemistry not only for gastrin
but, frequently, also for other peptides, including the pancreatic
peptide (PP), somatostatin (SST), the adrenocorticotrophic hormone
(ACTH) and the vasoactive intestinal peptide (VIP).
This tumor presents itself at various ages from 7
to 90 years, but the diagnosis is usually made between the ages of
30 and 50 years. There is no clear sex prevalence even if 60% of the
patients affected are men[11-14].
Gastrinomas may behave in a benign or malignant
manner, but usually, even when malignant, they can be slow growing.
Numerous studies support the conclusion that gastrinomas pursue an
aggressive growth pattern in 20-30% of cases and an indolent growth
pattern in the rest; this seems to be independent of the presence or
the absence of positive lymph nodes[3,15,16].
The most common site of metastases are the local lymph nodes,
followed by the liver; these metastatic lesions, unlike those of
adenocarcinomas, are vascular. Bone metastases are common in
advanced disease, probably occurring in the majority of patients[17].
The percentage of patients presenting a malignant form of sporadic
ZES is not clear; some data in the literature report that about 65%
of gastrinomas are malignant, but perhaps this is overestimated[18].
Furthermore, it has been suggested that a poor prognosis is
associated with the development of ectopic Cushing’s syndrome,
reported in up to 5% of patients with ZES[19].
The gastrin secreting tumor responsible for ZES
is the most common tumor in patients affected by Multiple Endocrine
Neoplasia type 1 (MEN 1).
MULTIPLE ENDOCRINE NEOPLASIA TYPE 1
MEN 1 is an autosomal dominant inherited syndrome characterized
mainly by the development of hyperplasia and/or multiple tumors in
the parathyroid, endocrine pancreas, duodenum, anterior pituitary,
foregut-derived neuroendocrine tissue, and adrenocortical glands.
This syndrome, first described by Wermer in 1954, has a prevalence
of 0.2-2/100 000 people/year, even if this is underestimated since,
generally, the endocrinopathies which constitute this disease are
not adequately classified[20,21].
MEN 1 is associated with inactivating mutations of a tumor
suppressor gene (MEN1), mapped on chromosome 11q13 in 1988[22].
The MEN 1 gene was sequenced in 1997 and was found to encode for a
transcriptional regulator, named “menin”[23].
In MEN 1 patients, one allele of the gene is inactivated by the
germline mutation, and phenotype expression occurs with inactivation
of the second allele by somatic cellular mutation. Somatic mutations
of the MEN 1 gene have also been reported in sporadic forms of
endocrine tumors with a variable incidence of 20-30% in the
parathyroid, the endocrine pancreas (33% gastrinomas, 17%
insulinomas), 25% in lung carcinoids, but less than 1% in pituitary
and adrenocortical tumors[24-27].
In clinical practice, it is important to perform
genetic analysis in order to diagnose MEN 1, but the diagnosis
cannot be excluded with certainty, when a mutation is not found[28].
Therefore, the clinical screening of patients remains a prerequisite
for genetic analysis. Screening for MEN 1 is a crucial step in the
diagnosis and the management of neuroendocrine tumors, because
prognosis and treatment may differ from the sporadic case.
Gastrinoma with ZES is found in 20-61% of
patients with MEN 1[29,30];
conversely, MEN 1 is found in 30-38% of all patients with
gastrinomas[30-32].
In MEN 1, gastrinomas are mainly localized in the duodenum, they are
small and frequently multifocal and may therefore be difficult to
detect either by traditional imaging methods or at surgery[33,34].
ZES-MEN 1 is associated with gastric carcinoids,
also called ECL-omas (type 2 carcinoids), due to chronic effect of
hypergastrinemia on ECL cells. These tumors seem to be found in
13-30% of patients with ZES-MEN 1 and in 0-0.6% of patients without
MEN 1[35,36].
ECL-cell tumors in MEN 1 are often multicentric and are generally
characterized by a low mitotic index; most of these tumors are less
than 1 cm in diameter and are limited to the mucosa and
submucosa[37].
The percentage of patients in whom these tumors are invasive is
unknown; metastases to local lymph nodes can be observed, but
patient survival is usually excellent with tumor persistence for
more than 25 years and very few related deaths[38].
CLINICAL MANIFESTATIONS
The signs and symptoms of ZES are primarily due to gastric acid
hypersecretion. The most common initial symptom is abdominal pain
and 90-95% of patients develop peptic ulcers in the upper
gastrointestinal tract. In 36% of cases, the ulcers are multiple or
in an unusual site; however, there is a percentage of patients with
ZES (from 18% to 25%) who do not have ulcers at diagnosis. The ulcer
can appear as a common duodenal ulcer, but it is usually less
responsive to therapy with respect to ulcers in patients without
gastrinomas. The most common is a single ulcer of the duodenal bulb
which can also appear in the second, third, or fourth portion of the
duodenum or in the jejunum[39].
Gastroesophageal reflux, present in two-thirds of
patients with ZES, can vary from light to severe forms and can be
complicated by stenosis or Barrett’s mucosa[39].
Diarrhea is the second most common symptom, developing in 50-65% of
patients, and can precede, accompany or follow the ulcerous disease;
in 7-35%, it may be the only initial symptom[39].
The diarrhea is due to massive acid hypersecretion which activates
pepsinogens which are responsible for mucosal damage; in addition,
acid inactivation of the pancreatic enzyme and acid damage to
enterocytes also contribute to it. Steatorrhea is a result of
inactivation of pancreatic lipase
by intraluminal acid in the upper small intestine; the low pH
also renders some primary bile acids insoluble, reducing the
formation of micelles, which are needed for absorption of fatty acid
and monoglycerides[3].
DIAGNOSIS
The diagnosis of ZES is based on the finding of elevated fasting
serum gastrin associated with gastric acid hypersecretion. Other
conditions exist in which gastrin levels can be elevated; these are
hypochlorhydria in the course of chronic atrophic gastritis, the
prolonged use of proton pump inhibitors or the presence of Helicobacter
pylori (H pylori) infection. When the diagnosis is not
completely clear, a reliable test is the measurement of basal acid
secretion (BAO) or, alternatively, it can be useful to determine the
pH of the gastric juice which can be obtained during endoscopy or
through a nasogastric tube. If the gastric pH is >2 in the
absence of antisecretory therapy, the patient is hypochlorhydric
and, therefore, ZES can be excluded; if the pH is <2 and the
plasma gastrin is higher than 1 000 pg/mL, the diagnosis of ZES is
certain while, if the pH is <2 and the plasma gastrin
concentration is between 100 and 1 000 pg/mL, a secretin test must
be carried out[40].
The secretin test is performed by the administration of 2 IU/kg of
secretin intravenously in 2 min, after having taken a blood sample
in order to perform the basal gastrin concentration; after the
injection, blood samples are taken after 2.5, 5, 10, 15 and 30 min.
An increase of plasma gastrin >200 pg/mL is diagnostic of ZES.
The test can give a false positive result in some patients with Type
A chronic atrophic gastritis, but this is identified by measuring
the gastric pH[41].
The secretin test can also give a false negative result in 10% of
patients with ZES, and this is usually associated with a malignant
course of the disease[42].
The calcium test might be of value in those patients in whom ZES is
strongly suspected when the secretin test is negative. There is
agreement in the literature that calcium and meal tests are less
useful than secretin for detecting ZES.
Imaging techniques
To localize and stage gastrinomas, conventional non-invasive and
occasionally invasive diagnostic modalities may be required. At
present, the most important study should be somatostatin receptor
scintigraphy (SRS) using 111In-pentetreotide
with single photon emission tomography (SPECT) scanning[4].
Recent studies demonstrated that SRS allows total body localization
study simultaneously at one time, thus allowing detection of liver
and distant metastases and it is more sensitive in both localizing
the primary gastrinoma and identifying patients with liver
metastases than conventional methods such as CT, MRI, US[43].
Unfortunately, SRS detects 30-75% of gastrinomas measuring less than
1 cm, primarily duodenal gastrinomas; a negative scan in the
presence of a visible tumor suggests either a poorly-differentiated
neuroendocrine tumor or a pancreatic adenocarcinoma[44].
Ultrasonography can detect gastrinomas in 30% of
cases and the detection rates are better for lesions greater than 3
cm in diameter and are poor for lesions smaller than 1 cm[45].
Using EUS, the sensitivities as high as 79-82%
can be obtained[46,47].
A recent prospective study found a sensitivity of 93% and a
specificity of 95% in the localization of intrapancreatic lesions[48].
EUS, in combination with SRS up to 69%, although it may still miss
up to 50% of duodenal gastrinomas[49].
Therefore, when a gastrinoma is suspected, endoscopy or EUS should
also be performed to identify duodenal as well as pancreatic
gastrinomas, especially when multiple lesions are suspected as in
MEN 1[33,34].
Regarding CT and MRI, the most recently published
series showed that CT with bolus of contrast administration can
achieve sensitivities ranging from 82% to 92%[50,51]
and MRI, using T1-weighed fat suppression images, has a 91%
sensitivity[52,53].
A comparative study demonstrated that MRI is equivalent to dynamic
CT. Furthermore, MRI is considered the most sensitive technique for
demonstrating liver and bone metastases in patients with
neuroendocrine tumors and is recommended for monitoring the response
to therapy. However, CT and MRI are both very sensitive and specific
methods for demonstrating hepatic metastases and pancreatic tumors,
and they show specific advantages in routine tumor staging and
monitoring of therapy[54,55].
Functional studies, measuring hormonal gradients
by transhepatic portal venous sampling, seem to be more sensitive;
however, this method is invasive, and does not lead to the exact
location and requires considerable expertise. A modification of the
hormonal gradient during angiography has been developed; in brief,
secretin is injected intra-arterially selectively into different
vessels and hepatic venous samplings are collected and assayed for
hormonal gradients. Selective angiography can identify the site of
the tumor in up to 75% of cases, but has largely been supplanted by
the combination of Octreoscan, EUS and CT[56,57].
In about 20% of patients, a gastrinoma cannot be
identified by conventional imaging techniques and SRS[58].
In these cases, during laparotomy, operative techniques such as
duodenal transillumination and intraoperative ultrasound can be used[4].
A suggested algorithm for the diagnosis of ZES is
reported in Figure 1.
Figure 1
(PDF) Diagnostic
algorithm for Zollinger-Ellison Syndrome. SRS: somatostatin receptor
scintigraphy; CT: computed tomography; MRI: magnetic resonance
imaging; US: ultrasonography; EUS: endoscopic ultrasonography.
TREATMENT
In patients with ZES, the two main principal therapeutic objectives
are to control the gastric acid hypersecretion which causes the most
debilitating symptoms (ulcers, diarrhea and dehydration) and to
control the growth of the tumor which, even if slow-growing, is able
to produce early and diffuse hepatic metastases.
Until the end of the 1970s, the only effective
therapy for controlling acid hypersecretion was total gastrectomy.
Currently, after the introduction of potent antisecretory drugs,
such as H2
antagonists and proton pump inhibitors, the most important aspect
for these patients is the growth of the neoplasm. In fact, half of
the patients die from causes related to the tumoral mass and not
from the effects of the massive gastric acid hypersecretion[59].
Thus, at present, a large number of treatment options are available
for the therapy of patients with ZES: control of the gastric acid
hypersecretion; control of the gastrin hypersecretion; surgical
resection or cytoreduction of the tumor; control of the tumor size
by using chemotherapy or interferon alfa; control of the hepatic
metastases with chemoembolization and/or embolization.
Control of gastric acid hypersecretion
If ZES is suspected, it is important, while waiting for the
conclusive results of the diagnostic tests, to prevent the
complications which could arise. For this reason, it is advised to
rapidly start an antisecretory therapy which is usually
well-tolerated and without particular contraindications.
Histamine H2
receptor antagonists
Since proton pump inhibitors have been available commercially, H2
receptor antagonists are no longer the drugs of choice for patients
with ZES, even if they have actually been proven effective in
alleviating the symptoms and healing ulcers in gastrinomas.
Ranitidine is the drug of choice among the H2
antagonists, due to its low side effects and its limited interaction
with other drugs. However, despite the first excellent results,
long-term studies have shown that the use of these drugs is limited
by many factors such as poor control of the gastric acid
hypersecretion and sometimes the need for high and frequent doses of
the drug[60]. The
pharmacological basis of these observations is unknown, even if
various possibilities have been suggested, such as a diminished
bioavailability due to reduced absorption, an altered metabolism of
the drug with increased excretion, the development of tachyphlaxis
and the hypersecretory state itself[61].
The poor effectiveness of H2
antagonists is usually evident in ZES associated with severe
gastroesophageal reflux, MEN 1 with hyperparathyroidism and partial
gastric resection[62].
Proton pump inhibitors
Omeprazole, the first proton pump inhibitor available, belongs to a
new class of drugs which has proven to be safe and effective in
controlling gastric hypersecretion in patients with ZES and has
completely substituted the use of H2
antagonists. The PPIs commonly used are omeprazole, lansoprazole,
pantoprazole, rabeprazole and esomeprazole[63].
These drugs show differences in pharmokinetics and pharmodynamics,
but it is not always clear, if these fine variations have clinical
importance[64].
Initial therapy
The goal of ZES therapy is to obtain improvement of the symptoms and
healing of the ulcers by controlling the gastric hypersecretion.
Various studies have shown that a reliable criterion for the control
of the hypersecretion is the reduction of the BAO below 10 mEq/h in
the hour preceding the next administration of the drug in cases of
uncomplicated ZES and below 5 mEq/h in cases of ZES associated with
MEN 1, gastro-esophageal reflux disease or in patients undergoing a
partial gastrectomy[2,65].
Using the acute upward dose titration method,
widely accepted for establishing the initial dosage of omeprazole,
some studies have demonstrated that the average dosage of omeprazole
capable of controlling gastric hypersecretion in the majority of
patients is between 60 and 100 mg of the drug per day[66].
The only reliable parameter able to demonstrate the absence of
damage to the mucosa is the level of acid inhibition when the
“steady state” has been reached; therefore, the BAO must be
measured every 3-4 wk and the patient should be evaluated by
endoscopy and acid secretion analysis at intervals from 3 to 6 mo
and, successively, from 6 to 12 mo. The objective of the therapy is
not achlorhydria, but a BAO between 1 and 10 mmol/h; if complete
inhibition of the acid hypersecretion is seen, the dosage of
omeprazole should be reduced by 50% and the patient should be
re-evaluated. If the BAO is greater than 10 mmol/h, the dosage of
the PPI should be increased gradually and, for doses of omeprazole
over 60 mg (or equivalent doses of another PPI), it would be
advisable to administer the drug in two divided doses. The lack of
control of gastric acid secretion could be a high risk for patients
affected by ZES[66,67]
and some data in the literature have demonstrated that an initial
dose of 20 mg is not able to control the acid secretion and the
symptoms linked to the disease[68].
PPI long-term treatment
Many data have been reported on the effectiveness and safety of the
PPIs, when these drugs are administered on a long-term basis in
patients with ZES. After having established the initial dosage and
having monitored the gastric secretion, the long-term maintenance
dosages can be reduced significantly in the majority of patients,
when control of the gastric secretion is stabilized[69,70].
This can be easily explained by the fact that the effectiveness of
omeprazole increases with time[70-72].
In fact, Metz et al., have shown that the maintenance dosages
of omeprazole can be partially or completely reduced in all patients
with ZES, above all in those who are not affected by MEN 1, serious
gastro-esophageal reflux or those who have undergone a partial
gastrectomy[70].
Some studies have shown that, in the long-term, it is not necessary
to increase the dosage of omeprazole; if, however, during the first
year, repeated increments in therapy are necessary, it means that
the initial dose was inappropriate and there was no progressive
development of pharmaceutical resistance[73].
While the H2
antagonists have demonstrated the phenomenon of
tachyphylaxis with prolonged use, only in 10% of patients is
it necessary to increase the dose of the PPIs[74].
PPIs have been proven to be safe and effective in the maintenance
therapy of patients with ZES for more than 10 years, without any
effect of related toxicity[65].
It does not seem that treatment with PPIs in ZES has induced any
significant increase in the concentration of plasma gastrin or
alterations in the percentage of argyrophil cells[75].
Intravenous PPIs
Patients affected by ZES who are not able to take PPIs orally and
who need a therapy which primarily suppresses gastric acid
secretion; patients with active peptic ulcer, recent hemorrhage and
endoscopic stigmata that puts them at high risk of rebleeding, are
candidates to receive PPIs intravenously. Another possible means of
administration of solutions prepared with oral PPIs is intragastric,
which can be utilized as an alternative to the intravenous route in
critically ill patients or in whom esophageal stenosis is present.
Vitamin B12 levels during prolonged treatment with PPIs
During prolonged treatment with proton pump inhibitors, reduced
serum levels of vitamin B12, but not of folate, have occasionally
been documented[76].
This phenomenon seems to be related to the achlorhydria induced by
the drug which, moreover, is not common during therapy with PPIs.
Helicobacter pylori and ZES
Some studies have considered the interactions between ZES, H
pylori and PPIs, pointing out how the Helicobacter
infection does not constitute a risk factor for the onset of peptic
ulcers in these patients. In fact, the prevalence of H pylori
infection in these subjects is lower than in the overall population
and is much lower than in patients with common peptic ulcer disease.
Indeed long term PPIs therapy in HP-positive patients with ZES may
lead to the reduction of parietal cell mass[77].
Control of the hormonal secretion
Somatostatin analogs It is well-known that somatostatin and
its analogs are able to reduce gastric acid and serum gastrin levels
in patients with ZES, with both short-term and long-term
administration[78].
In addition to immediate-release subcutaneous octreotide, other
long-acting somatostatin analogs such as lanreotide, which can be
administered every 10-14 d, and octreotide LAR, which can be
administered every 28 d, are currently available on the market[79,80].
In 1993, Rusniewsky noted an average decrease in serum gastrin
of 87% in patients with ZES treated with octreotide subcutaneously
for a period of 9–12 mo. It was also seen that octreotide was
capable of controlling gastric hypersecretion without an “escape
phenomenon” and was able to reduce, and sometimes eliminate, the
hyperplasia of the ECL cells when this was present before treatment[81].
In the same period, Bordi reported that prolonged treatment with
octreotide is able to significantly decrease the fundic argyrophil
cells in patients with a gastric pathology[82].
Thereafter, several studies have shown that
treatment with somatostatin analogs has an inhibiting effect on
tumoral growth in patients with malignant gastrointestinal
neuroen-docrine neoplasias, such as pancreatic tumors or carcinoids,
and is able to stabilize the tumoral growth in 37-80% of patients;
in only a few patients (0-17%), a reduction of the tumor dimensions
has been observed[83,84].
Moreover, up to now, only one study on the
effectiveness of octreotide in controlling tumoral growth in
patients with metastatic gastrinomas has been carried out. In this
study, performed on 15 patients, it was shown that, in 53% of these
patients with malignant gastrinomas, the tumoral growth progressed,
47% of patients presented stabilization and 6% had a reduction of
the tumor size[85].
In patients who responded to treatment, stabilization of the tumor
was long lasting and the incidence of side-effects was lower in
comparison to the group treated with chemotherapy. In this study, it
was concluded that, in gastrinomas, somatostatin analogs are not the
drugs of first choice in controlling gastric acid hypersecretion,
but are very useful in controlling tumoral growth.
The most common side-effects of somatostatin
analogs are gallstones, abdominal pain, diarrhea and pain in the
injection site.
Receptor-mediated radiotherapy with 90Y-DOTA-D-Phe1-Try3-octreotide
for neuroendocrine tumors has recently been proposed as a palliative
treatment; this modality of treatment can, however, cause
myelotoxicity and nephrotoxicity[86].
In the past 3 years, several studies have been published on the use
of this therapy in neuroendocrine tumors associated with syndromes,
using not only ytrium but also lutetium which seems to be less toxic
for the kidneys[87].
As regards the therapy for gastrinomas, a regression of metastases
in 25% of the patients has been described[88].
As previously reported, long lasting somatostatin
analogs have been shown to be capable of reducing the mass of
gastric endocrine cells[89];
furthermore, it has been demonstrated that these drugs can inhibit
growth in hypergastrinemic experimental models which develop gastric
carcinoids[90,91].
This evidence supporting the use of octreotide can be utilized in
patients with gastric carcinoids. These data have been confirmed in
a recent study of our group which showed the regression of gastric
carcinoids associated with ZES-MEN 1 after 1 year of treatment with
long acting somatostatin analogs[92].
Control of neoplasia growth
Surgery The role of surgery in the treatment of ZES has
evolved considerably from 1955 to now[1].
Initially, the surgical therapy proposed was total gastrectomy with
the aim of removing the high levels of gastrin from the target organ[93];
in the past 20 years, improved pharmacological control of gastric
acid hypersecretion has eliminated the role of surgery in containing
the hypersecretion itself. The availability of PPIs allows us to
adequately control the symptoms in all patients with ZES, making the
natural history of gastrinomas, the only determining factor in
long-term survival[94].
Since adequate medical therapy is able to
eliminate the symptoms in all patients and, although it is hard to
treat the neoplastic disease with chemotherapeutic drugs, some
authors claim that the risks and complications of exeresis of the
gastrinoma exceed the actual benefits of this procedure[58].
More recently, however, some others have reported that surgical
excision of a gastrinoma has proven highly effective in order to
prevent hepatic metastases[93,95].
At present, surgical exploration plays a key role in identifying and
removing the primary tumor, and in preventing the onset of liver
metastases.
The main objectives of surgery are to stage the tumor, improve
survival by removing the malignant tumor and control the acid
hypersecretion syndrome. Since the majority of patients with ZES
present either with occult disease or with localized disease, the
surgeon has to search for and remove the non-localized lesion
laparotomically using imaging techniques. Furthermore,
intra-operative techniques such as palpation, ultrasonography and
transillumination of the duodenal wall can contribute to the
identification of pancreatic and duodenal gastrinomas, including
lymph nodes and hepatic metastases. It is important to consider that
a large percentage of primary occult tumors are found inside the
duodenum. Gastrinomas commonly metastasize in the lymph nodes and
sometimes arise in this site; hence, the resection of all the lymph
nodes in the peripancreatic region is important, even if they do not
appear swollen. Exploration of the liver and the rest of the abdomen
is also recommended in order to identify possible metastatic disease[96].
It has also been reported that more than 50% of
patients are free from disease after surgery and the majority of
them remain so for the following 5-10 years[93,95].
Gastric acid hypersecretion caused by hypertrophy
of parietal cells can persist, after surgery, despite biochemical
evidence of cure; for this reason it is very important for all
patients to continue maintenance, antisecretory therapy until the
BAO determination is less than 10 mEq/h[97].
In those patients in whom there is a persistence of neoplastic
tissue or post-operative relapse, debulking the tumor often leads to
a proven benefit[95].
Liver transplant is characterized by a remarkable
morbidity and, for the most part, post-operative immunosuppressive
therapy stimulates the relapse of growth of the tumor[98].
A careful evaluation of the data found in the literature shows that
a non-carcinoid histotype is present among the exclusion criteria
for liver transplants in patients with hepatic metastases and
neuroendocrine tumors. In this regard, French authors, in a
retrospective study, have pointed out an unfavorable prognosis in
patients with non-carcinoid endocrine tumors undergoing a liver
transplant[99].
Surgery in ZES associated with MEN 1 The indications for
surgery in patients with ZES-MEN 1 are controversial, since previous
experience has shown that surgery rarely cures these patients[100,101].
Some authors have carried out an exploratory laparotomy on patients
with ZES-MEN 1 in which the tumor, studied using imaging techniques,
had a diameter greater than 2.5 cm. A direct relationship between
the size of the tumor and the onset of hepatic metastases has been
hypothesized and, as in other malignant solid tumors, the
effectiveness of the cure is expected to be greater, if the tumors
are resected, when they are still small[36,102].
In a recent study, a group of Swedish researchers
established that the best surgical procedures include enucleation of
the tumor in the head of the pancreas, excision of duodenal
gastrinomas together with the removal of the metastasized lymph
nodes and, as prophylaxis of tumoral relapse, the combination of
these procedures with an 80% subtotal resection of the distal
pancreas. It is thought that a more extensive resection of the tumor
reduces the risk of the malignant evolution of pancreatic and
duodenal tumors[101].
In patients with ZES-MEN 1, hyperparathyroidism
is usually present at the moment of diagnosis[103];
therefore, in patients with hypercalcemia, a parathyroidectomy
should be performed before any other surgical procedure in order to
better control the pathological effects of hypercalcemia. It has
been demonstrated that a parathyroidectomy is capable of reducing
the fasting serum levels of gastrin and the BAO, and this,
therefore, improves the response to the antisecretory therapy[32].
Control of tumor size
Systemic chemotherapy Therapeutic strategies for the
management of patients with metastatic gastroenteropancreatic
endocrine tumors have to take into consideration the fact that
controlling the hormone-mediated symptoms often improves the quality
of life, to the point that the patients feel well despite the
extensive metastatic disease[104].
At best, chemotherapy has furnished only unclear results utilizing
the classical anti-tumoral agents, such as 5-fluorouracil, in
controlling metastatic endocrine tumors. Systemic chemotherapy
reached a new therapeutic dimension immediately after the
introduction of streptozotocin (STZ) into clinical use[105];
there have been several studies on the effects of this drug on
metastatic islet-cell tumors which have confirmed the effectiveness
of streptozotocin. Despite this, there are a number of acute and
chronic side effects, such as serious renal or hematologic toxicity[106].
Various studies have standardized the dosage and administration
schedule of streptozotocin and have suggested its combination with
other cytotoxic drugs such as 5 fluorouracil (5-FU) and doxorubicin
(adriamycin); the combination of STZ and doxorubicin has been
superior to other regimens, mainly STZ and 5-FU, and seems to be
associated with a 69% objective response lasting for 18 mo and
overall median survival of 2.2 years[107].
In a detailed study conducted on 10 patients with
metastatic gastrinomas and treated with streptozotocin,
5-fluorouracil and doxorubicin, 4 patients showed a partial response
to the treatment, but the survival rate was the same both in the 4
responders and in the 6 non-responders[108].
Another type of chemotherapy proposed is monotherapy with
chlorozotocin, a nitrosourea having a composition similar to
streptozotocin characterized by less gastrointestinal toxicity but
increased myelosuppression or monotherapy with dacarbazine[109].
In conclusion, chemotherapy is not the treatment
of first choice in patients with gastrin secreting tumors, but seems
to be indicated in rapidly evolving tumors in which the mass of the
primary tumor increases more than 25% in a period of follow-up of 12
mo or in which the tumoral symptoms cannot be treated by other means[110].
Interferon In recent years, the validity of interferon has
been sustained in neuroendocrine tumors, especially in the carcinoid
syndrome. The data in the literature demonstrate that therapy with
interferon-alpha leads to the stabilization of the tumor in 20-40%
of patients with different gastrointestinal neuroendocrine tumors,
including those with metastatic gastrinomas, but it did not result
in an increase in the survival rate of these patients[111].
It has been proposed, therefore, that gastrinomas can be treated
with chemotherapy and/or interferon when they grow and metastasize[111].
Role of chemoembolization or embolization Selective
embolization of the hepatic arteries causes transient and complete
ischemia with an objective, symptomatic and hormonal response of 65%
and 81%, respectively; this treatment has been demonstrated to be
useful in patients with liver metastases from neuroendocrine
pancreatic tumors. Unfortunately, only a small number of gastrinomas
have been treated with chemoembolization and there are no sufficient
data on long-term survival after this procedure. Chemoembolization,
which uses a combination of gelfoam and chemotherapeutic agents (streptozotocin
or doxorubicin), may determine a notable improvement in the quality
of life of the patient and is usually accompanied by a reduction in
circulating peptide serum levels and the size of the tumor. However,
it has not been clearly demonstrated that the inhibition of tumoral
growth improves the survival rate[112-115].
Chemoembolization is an alternative to
chemotherapy for progressive liver metastases in patients with
gastrinomas.
A suggested algorithm for medical and surgical treatment of ZES is
reported in Figure 2.
Figure 2
(PDF) Therapeutic
algorithm of Zollinger-Ellison Syndrome. PPI: proton pump
inhibitors; SST: somatostatin analogs; IFN: interferon.
CONCLUSIONS
Proton pump inhibitors have been used to more drastically inhibit
gastrin action on the parietal cells, thus allowing the patient to
rapidly return to a normal clinical condition without the need for
surgery. If it is possible to eliminate the morbidity and mortality
caused by acid hypersecretion, the majority of patients affected by
ZES should be able to be maintained in good clinical condition,
without symptoms. In ZES, antisecretory drugs have been proven to be
safe and effective, without particular side effects over a long
period of time, even 15 years or more.
Recent developments in surgical techniques, and
pre-and intra-operatory imaging investigation, have permitted the
identification and successive resection of more than 95% of
gastrinomas. Therefore all localized gastrinomas should be excised,
if possible. If hepatic metastases are also present, their
enucleation may improve the symptoms and the survival rate as well
as facilitate medical treatment. Another possibility is to carry out
surgery, only when the tumor is greater than 2 cm in diameter,
because these dimensions are associated with a greater risk of
metastases in the liver. However, there is some controversy about
the surgical approach to gastrinomas associated with MEN 1.
Somatostatin analogs can be useful in reducing
gastric acid hypersecretion, serum gastrin and gastric ECL-cells,
thus contributing to curing the disease more effectively.
Furthermore, thanks to their antiproliferative effects, these drugs
are used in treating patients with hepatic metastases and in those
affected by ZES-MEN 1 with gastric carcinoids.
Chemotherapy may be particularly indicated in the
malignant evolving form, but not in slow-growing tumors or as first
choice therapy in gastrinomas.
Embolization and/or chemoembolization may be a
palliative procedure for patients with hepatic metastases.
Finally, we would like to emphasize that the
choice of treatment must involve a multidisciplinary approach.
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