gastrinomas are neuroendocrine tumors ( net ) , primarily located in the duodenum or pancreas .
gastrin overproduction causes the zollinger - ellison syndrome , which includes ulceration of the gastrointestinal tract , mainly the jejunum , resulting in abdominal pain and diarrhea .
the incidence of gastrinomas is 0.52 per million per year and therefore very rare [ 2 , 3 ] .
gastrinomas are classified according to a grading system , similar to other pancreatic neuroendocrine tumors ( pnets ) .
this grading is based on histopathology and subdivided into immunostaining for tumor markers and proliferation markers ( table 1 ) .
using the current who criteria , grades 1 and 2 are well - differentiated pnets with increased expression of the tumor markers , chromogranin a , and synaptophysin .
grade 3 tumors are poorly differentiated with areas of necrosis and decreased expression of chromogranin a [ 3 , 5 ] . up to 25% of the gastrinomas
liver metastases are the most important prognostic factor for survival [ 2 , 6 ] .
ten - year survival of patients with diffuse liver metastases is 16% compared to 90% 10-year survival in patients who underwent a curative gastrinoma resection . for patients with unresectable liver metastases ,
patients with liver metastases may experience symptoms such as weight loss , pain , and anorexia , particularly caused by tumor load .
liver metastases derive the majority of their blood supply from the hepatic artery , compared with normal liver parenchyma , which derive the majority of the blood supply from the portal venous circulation .
postembolization syndrome is the most important complication after embolization , characterized by symptoms of fever , unremitting nausea , general malaise , loss of appetite , and abdominal pain .
the exact cause is not yet entirely clarified ; however , it may be a result of tumor ischemia and inflammation of the liver tissue [ 8 , 9 ] .
only a small series describes the effect of hepatic embolization of liver metastases from gastrinomas .
the aim of this study is to present our single - centre experience of the effect of selective arterial embolization for gastrinomas in symptoms reduction , complications , and response rate .
these results are compared to the literature results , and a protocol for patients care during embolization is presented .
all patients with liver metastatic gastrinomas , treated by selective hepatic artery embolization , were selected from a prospective database starting in january 1992 up till december 2012 .  
diagnostic strategy for gastrinoma patients includes serum chromogranin a and gastrin levels , preferably after a 10-day cessation of the proton pump inhibitors ( ppis ) .
our treatment protocol for gastrinoma patients consists of a resection in patients with a solitary resectable primary lesion or a resectable primary lesion with resectable liver metastases .
patients with a gastrinoma and irresectable liver metastases do not undergo resection of the primary gastrinoma .  
patients with irresectable liver metastases are treated with ppi 's sometimes combined with somatostatin analogues .
the indication for embolization is an insufficient response to medical treatment for relief of symptoms or progressive disease confined to the liver . if embolization is not possible or patients have progressive disease after embolization therapy , further chemotherapeutical options or peptide receptor radionuclide therapy options
embolization response is evaluated according the response evaluation criteria in solid tumors ( recist ) .
patients were considered in complete response ( cr ) if gastrin or chromogranin levels were normal and target lesions disappeared . a partial response ( pr ) was considered if at least 30% reduction was achieved of the tumor markers or target lesions .
the progression of disease ( pd ) is described as 20% increase of tumor makers or if new lesions were noticed .
the literature search was performed in pubmed and embase using the following headings : gastrinoma , liver metastases , neuroendocrine tumors , carcinoid , zollinger - ellison syndrome , and embolization . in the included studies ,
all abstracts in english which evaluate hepatic artery embolization for liver metastases in patients with net were included .
studies were excluded if patients were treated with hepatic arterial chemoembolization ( tace ) alone instead of hepatic artery embolization and if treated patients had no gastrinoma or pnet , such as midgut carcinoid or lung net .
three patients were identified ( table 2 ) from a total of 109 pnet patients in the database including 13 gastrinomas .
of the 13 gastrinoma patients , 1 patient had lymph nodes metastases and will not be further discussed ; 11 patients were previously described .
after an episode of undesirable weight loss of 15  kg , an ultrasound showed single liver metastases .
patient 2 is a 43-year - old male without other morbidities . at presentation , there was a disease - free survival of 76 months after resection of a pancreatic gastrinoma
. then symptoms of the zollinger - ellison syndrome recurred caused by resectable liver metastases .
after a 6/7 liver segment resection , symptoms returned 16 months later because of new liver metastases .  
patient 3 is a 58-year - old man with a previous history of diverticulitis which was treated with a sigmoid resection .
he presented with a duodenal perforation and underwent a damage control laparotomy and primary closure of the defect with a prolonged hospital stay including multiple drainage procedures and intensive care episodes .
imaging during this episode also showed multiple right - sided liver metastases and a gastrinoma of the pancreas .
symptoms were treated with a ppi ( 40  mg twice a day ) , and patients had increased symptoms when these ppis were discontinued , for example , for blood tests for chromogranin a and gastrin measurements .
all patients had elevated levels of chromogranin a and/or gastrin ( table 3 ) before embolization .  
indications for embolization were patients ' choice of treatment for embolization instead of liver resection in patient 1 and multiple liver metastases in left and right liver in patient 2 .
the third patient had major complications after duodenal perforation combined with zollinger - ellison syndrome , and embolization was performed to reduce symptoms while recovering before the curative gastrinoma and right liver resection could be performed .  
selective embolization was performed with polyvinyl alcohol ( pva ) particles of the selective left or right hepatic artery ( figure 2 ) . in these three patients ,
embolization was performed as a one - stage procedure , regardless if the lesions were diffusely spread in the left and right liver . in patient 1 ,
extreme selective embolization of the right hepatic artery occurred , in patient 2 , both arteries , and in patient 3 , only the right hepatic artery .
patient 1 started selective embolization treatment in 2010 , patient 2 in 2007 , and patient 3 in 2010 .  
patient 2 developed symptoms of fever , general malaise , and abdominal pain 4 days after embolization .
patient 3 experienced symptoms of general malaise , chest pain , nausea , and sweating without a cardiac or pulmonary cause .
the patient was observed for one day extra without any further complications or reinterventions .  
all patients experienced a clinical response ; in patients 2 and 3 , the ppis dose was reduced by 50% without worsening of symptoms . in all patients , symptoms of diarrhea or
chromogranin a and gastrin levels declined after embolization in two patients ( table 3 ) .
patient 2 had diffuse disease progression of other new liver lesions , including rise of gastrin level .
all patients had a complete radiological response ( table 3 ) after 6 months of the treated liver lesions .
patient 2 , with diffuse liver metastasis , had tumor progression of new liver metastases .
after embolization , he also underwent radiofrequency ablation ( rfa ) therapy , surgical metastasectomy , and finally peptide receptor radionuclide therapy ( prrnt ) .
he died 162 months after the initial pancreatic resection and 41 months after embolization therapy due to progressive disease including pancytopenia and aplastic anemia after recent pprnt .
patient 3 , with diffuse liver metastasis in the right liver lobe , was eligible for surgical resection of pancreatic gastrinoma and liver metastases after embolization which successfully took place , one year after embolization .  
progression - free survival ( pfs ) of patient 1 is 20 months after embolization . because of recurrent increase in gastrin and chromogranin a
2-no progression - free survival can be related to embolization because of the diffuse progression of new liver metastases .
patient 3 has a pfs of 26 months after embolization and is currently still tumor free but also underwent a right hemihepatectomy 12 months after embolization .
less is known about the effect of liver embolization for liver metastases in patients with pnet , given the amount of publications .
therefore , all studies regarding pnet and liver metastases treated with liver embolization are listed in table 4 .
of all the studies , 8 studies only described the results of pnet without specifying the presence of gastrinomas [ 1320 ] .
some of the studies mentioned the number of gastrinoma patients but not the specific individual response .
it is not described if the presented results apply for the included gastrinoma patients .  
two studies have included patients treated with tae or tace [ 15 , 21 ] without differentiation by types of treatment .
five studies have included gastrinomas [ 2125 ] all presented an objective response after embolization for the total group of included patients . a clinical response
is seen , from symptom relief up to a complete response in 59% of the patients , [ 2224 ] and a biochemical response is described with a reduction of hormone levels in 50% [ 2325 ] .
the radiological response is not uniformly described , from the presence of tumor regression to a partial response of 67% [ 21 , 24 , 25 ] .
all patients with liver metastatic gastrinoma in the present study treated with selective hepatic artery embolization showed a clinical , biochemical , and radiological response .
, patients suffer from the typical zollinger - ellison syndrome , which impaired their daily life due to symptoms of the zollinger - ellison syndrome .
after selective embolization , besides heartburn , treated with only half doses of ppi , there were no symptoms left .
a complete radiological response was seen in all patients in the treated lesions after 6 months .
therefore , selective embolization of gastrinoma liver metastasis seems to be an effective treatment for the reduction of symptoms .
this is also shown in other studies including different pnet and carcinoid patients .   in general ,
liver embolization is only effective on treated lesions , other metastases remain untreated . in patients with tumors that demonstrate aggressive growth , an additional treatment is recommended . in metastatic gastrinomas ,
surgical resection remains the best option for extended survival . in patients with diffuse liver metastases ,
different kinds of treatment options , including rfa , radioembolization , and prrt , are available .
the toxic effects after rfa treatment may lead to liver abscesses , cholangitis , hepatic infarction , subcutaneous abscesses , and pleural effusion .
radioembolization may lead to pancytopenia caused by bone marrow suppression , pulmonary insufficiency secondary to radiation pneumonitis , gastric and duodenal ulceration , and ascites .
compared to these treatments , toxicity of tae is relatively mild   as was also shown in our patients .  
patients were treated according to our own institute embolization protocol to prevent the postembolization syndrome which is described in 82% of patients . nevertheless , two out of three patients suffered from mild symptoms of postembolization syndrome resulting in extended hospital stay of one day and readmission of 2 days . since liver abscess is very infrequent in patients without previous bile duct involving operations and described to be only 0,4% , no standard antibiotic prophylaxes or treatment are added to the protocol .
however , the patient with previous pancreatic and liver resections was treated with antibiotics during the hepatic artery embolization to prevent infectious complications .
this net embolization protocol does include treatment with corticosteroids , as described in patients with hcc .
the rationale for corticosteroids is not only edema prevention for decreased liver capsular pressure and subsequent pain reduction but also to reduce the immune response [ 31 , 32 ] .  
only five studies describe detailed results of hepatic artery embolization in gastrinoma patients ( table 4 ) .
most studies show results of embolization in pnet and carcinoid patients without differentiation for tumor type or tumor grade / stage .
overall results of hepatic artery embolization of patients with pnet liver metastases show a 17100% effect on either clinical , biochemical , or radiological measurements .
complications and postembolization syndrome were not well described in these studies and could not be compared to our results .
this is the first study describing the exact response rate of tae in liver metastatic gastrinomas .
gastrinoma with liver metastases is a rare condition with a broad spectrum of treatment strategies [ 2 , 3 ] .
selective hepatic artery embolization leads to symptom control of the zollinger - ellison syndrome in liver metastatic gastrinomas .
post embolization syndrome is the most important complication after hepatic artery embolization ; therefore , careful treatment protocols must be available for prevention of tumor necrosis syndrome after posthepatic artery embolization .
our advice is to discuss every patient in a multidisciplinary meeting with endocrinologists , oncologists , pathologists , hpb surgeons , and ( intervention ) radiologists .
treatment should be based on their tumor classification , tumor burden , complaints , and quality of life considerations .
 
 background . gastrinomas are rare functional neuroendocrine tumors causing the zollinger - ellison syndrome ( zes ) . at presentation , up to 25% of gastrinomas are metastasized , predominantly to the liver . 
 embolization of liver metastases might reduce symptoms of zes although a postembolization syndrome can occur . in this study , 
 the results of embolization are presented , and the literature results are described . methods . from a prospective database of pancreatic neuroendocrine tumors , 
 all patients with liver metastatic gastrinomas were selected if treated with arterial embolization . 
 primary outcome parameters were symptom reduction , complications , and response rate . 
 the literature search was performed with these items 
 . results . 
 three patients were identified ; two presented with synchronous liver metastases . 
 all the three patients had symptoms of zes before embolization . 
 postembolization syndrome occurred in two patients . 
 six months after embolization , all the 3 patients had a clinical and complete radiological response ; a biochemical response was seen in 2/3 patients . from the literature , 
 only a small number of gastrinoma patients treated with liver embolization for liver metastases were found , and similar results were described . 
 conclusion . 
 selective liver embolization is an effective and safe therapy for the treatment of liver metastatic gastrinomas in the reduction of zes . 
 individual treatment strategies must be made for the optimal success rate . 
1. Introduction
2. Patients and Methods
3. The Literature Search
4. Results of the Patient Study
5. Results of the Literature Research
6. Discussion
7. Conclusion 