pancreatic neuroendocrine tumors ( pnets ) represent a relatively uncommon form of malignancy with an incidence of 0.43 cases per 100,000 in the usa . at diagnosis ,
nearly 70% of patients have metastatic disease , of which 85% will have liver metastases .
management options for pnets metastatic to the liver include surgical , ablative , cytotoxic , and radioisotope approaches .
unfortunately , due to the scarcity of these tumors there is a paucity of randomized trials to guide optimal therapy sequencing .
the north american neuro - endocrine tumor society and european neuroendocrine tumor society both support the use of radioembolization for progressive or symptomatic liver metastasis [ 3 , 4 ] . to date , yttrium-90 ( y ) therapy has appeared safe ; however , there is no randomized controlled trial assessing toxicities .
we present the case of a woman undergoing y therapy for metastatic pnet to the liver who developed liver enzyme elevation and subsequent cirrhosis following treatment .
there are only 3 other reported de novo cases of cirrhosis following y administration , with only 1 demonstrating confirmatory pathology [ 6 , 7 , 8 ] .
ultrasonography and computed tomography ( ct ) of the abdomen revealed a 9.5  8.6  10.5 cm , heterogeneous , hypervascular mass adjacent to the spleen and abutting the stomach wall and tail of the pancreas .
fine - needle aspiration guided by endoscopic ultrasound revealed cytologic evidence of a neuroendocrine tumor .
the patient proceeded to a distal pancreatectomy , splenectomy , wedge resection of the stomach , and partial resection of the left adrenal gland .
pathology demonstrated a 13-cm , well - differentiated neuroendocrine tumor of the pancreas with perineural invasion , but no vascular invasion and negative margins .
it was found to be adherent to both the spleen and the stomach , but did not invade either .
it had a mitotic rate of 2 mitoses / high - power field and a ki-67 index of < 2% .
two months postoperatively , the patient was found to have 4 subcentimeter hypervascular lesions in the liver which were in octreotide scan negative . over the following 9 months , the patient developed 8 new lesions , while the original lesions increased to a maximum size of 1.2 cm .
therapy with octreotide lar 20 mg intramuscularly once monthly was initiated but discontinued after 9 months due to progressive hepatic disease .
a ct scan of the liver performed 3 months after embolization demonstrated a mixed tumor response with the overall impression of progressive disease and development of new liver metastasis .
the patient was presented with the option of systemic therapy with everolimus , shown in phase iii trials to improve progression - free survival in patients with well - differentiated pnets . due to the absence of extrahepatic metastasis ,
liver - directed therapy with y embolization was also offered , which the patient chose to proceed with .
prior to y treatment , there was no radiologic evidence of cirrhosis and the liver enzymes were within normal ranges ( ast 24 u / l [ normal range ( n ) 1038
< 50 u / l ] , alkaline phosphatase 156 u / l [ n 50200 u / l ] , total bilirubin 5 mol / l [ n 018 mol / l ] ) .
she had a technetium-99 macroaggregate albumin planning spect ct demonstrating multiple focal regions of increased activity in the left and right lobes of the liver which corresponded to the patient 's known metastases .
radioembolization with 3.5 gbq of y theraspheres was administered to the right hepatic artery , delivering a total dose of 140 gy to the right lobe of the liver , and 1.8 gbq of y theraspheres was delivered through the left hepatic artery with a dosing of 140 gy to the left lobe of the liver on the same day . over the following 3 months ,
the patient developed abdominal pain and nausea and was found to have elevated liver enzymes , in a pattern suggesting damage to the biliary tree ( ast 52 u / l , alt 86 u / l , alkaline phosphatase 405 u / l , ggt 604 u / l , total bilirubin 5
ct scanning of the abdomen demonstrated generalized mottling of the liver , compatible with postembolization edema with a substantial decrease in tumor burden and 2 significant lesions remaining .
the patient 's liver enzymes remained elevated over the following 6 months until she developed significant right upper quadrant pain .
ct 9 months after y treatment revealed a very inhomogeneous liver texture and a large biloma traversing segments 5 and 8 of the liver , measuring 8.5  6.5  5.5 cm .
this was initially noted 10 months after y treatment and was slightly progressive on the 14-month scan ( fig .
1 ) . imaging also demonstrated multiple subcentimeter right hepatic lesions raising concern for metastatic disease , some of which had not previously been seen . due to radiographic evidence of progressive disease , everolimus
10 mg once daily was initiated , and the patient continued on this for 36 months with stabilization of the disease .
her liver enzymes remained unchanged over this time , with elevated hepatobiliary enzymes and borderline - elevated hepatocellular enzymes . at 25 months after initiation of everolimus therapy ,
progressive disease was noted in 2 solitary hepatic lesions and was treated with radiofrequency ablation .
due to disease control in the remainder of the hepatic parenchyma , everolimus was resumed after radiofrequency ablation .
thirty - five months after initiation of everolimus therapy , radiographic note was made of the advanced cirrhotic appearance of the liver ( fig . 1 ) and the increase in size of a left hepatic lesion .
there was no evidence of portal hypertension . due to the radiographic evidence of progressive disease and the cirrhotic appearance of the liver ,
everolimus therapy was interrupted and a liver biopsy to further characterize the nature of the parenchymal disease was performed .
a single 18-gauge core was obtained from the left lobe of the liver in order to avoid the biloma involving the right lobe .
the biopsy demonstrated large fibrotic bands in keeping with cirrhosis with mildly active steatohepatitis ( approx .
the patient had not been started on any other new medications , did not drink alcohol excessively , performed no high - risk activities for viral hepatitis , and had no family history of liver disease .
serology was nonreactive for hbsag , hbcab , and hepatitis c virus , and the patient had immunity to hepatitis b virus .
her antinuclear antibody was equivocal , and her anti - smooth muscle antibody and antimitochondrial antibody were negative . given the chronologic association of y administration with liver enzyme elevation , with the exclusion of other causes of cirrhosis , the diagnosis of y - induced cirrhosis was made .
she has not suffered any cirrhosis - associated complications and is currently child - turcotte - pugh class a.
to date , y - related cirrhosis has only been reported in 3 cases [ 6 , 7 , 8 ] . a prior systematic review assessing outcomes following y radioembolization identified grade 3 and higher adverse events in 012.9% of patients . in their review ,
the authors were able to identify 1 episode of cirrhosis and 3 episodes of hepatic failure .
the 1 cirrhotic patient identified was seen by saxena et al . , who described a patient with cirrhosis and ascites 6 months after treatment with grade 3 elevation of serum alkaline phosphatase and grade 2 elevations of alt and bilirubin .
other reported cases of cirrhosis come from case reports by brock et al .   and ayav et al .
brock et al .   described a patient with metastatic breast cancer with bone and liver metastases who received y. the patient had a good response to treatment at 4 weeks , but 3 months later developed ct imaging findings consistent with cirrhosis and portal hypertension .
described a 39-year - old man who received y for colon carcinoma metastatic to the liver .
four months after administration , the patient was found to have signs of portal hypertension and had a biopsy consistent with cirrhosis .
the timeline of initial hepatic changes seen with our patient closely resembles these previous reports , with a subacute onset of irregular echotexture and cirrhosis occurring several months following treatment with y [ 6 , 7 , 8 ] .
y microspheres deliver focused radiotherapy to metastases in the liver while sparing viable hepatic tissue , due to the predominant arterial supply of hepatic metastases as compared to the predominantly portal venous blood supply of normal liver parenchyma .
an assessment of explanted livers following y treatment showed no fibrosis > 1 cm from tumor borders .
the case of our patient adds to 3 previously reported cases that demonstrate cirrhosis as a potential long - term complication of y treatment .
an increasingly long median life expectancy is observed with pnets , with a 5-year overall survival of patients with low - grade tumors of 75% .
therapies with a significant rate of long - term toxicities should therefore be avoided early in the course of therapy among patients with advanced disease .
the notion that y therapy may lead to cirrhosis is supported by radiographic studies assessing volume changes and signs of portal hypertension following y treatment . in a series of 17 patients treated with y , a mean decrease in liver volume of 11.8% and a mean increase in splenic volume of 27.9%
were noted , accompanied by increases in portal vein diameter . in another series of 45 patients ,
liver volumes were shown to decrease in lobes treated with radioembolization by up to 45% at 12 months after treatment .
the difficulty with utilizing volume changes and liver texture to define outcomes following y administration lies in differentiating normal radiographic changes following radioembolization from true cirrhosis . in the current case report ,
imaging was reported as being consistent with prior radioembolization throughout many of the reports , with a progressive worsening noted over time . while differentiating this from cirrhosis is very difficult , the differential for these radiographic changes needs to include cirrhosis . the only other agent that could be chronologically associated with cirrhosis in our patient is everolimus ; however , this was started after radiographic changes had already been seen in the liver . in addition
, early preclinical work suggests that inhibition of the mtor pathway with mtor inhibitors may be antifibrotic .
there is , however , 1 case report of steatohepatitis following administration of everolimus . while our patient did not have steatosis severe enough to be considered solely responsible for the observed cirrhosis , it is possible that she suffered an initial insult from y administration and had impaired hepatic regeneration subsequently due to everolimus - induced steatosis , thus causing accelerated progression to cirrhosis
she developed a large biloma 10 months following y treatment . in a 327-patient retrospective review by atassi et al .
in contrast to normal hepatocytes , intrahepatic bile ducts lack a dual blood supply and are fed by intrahepatic arteries .
biloma development is thought to develop following peripheral bile duct necrosis , resulting in biliary drainage into surrounding tissue .
this case report adds to a growing body of evidence that y treatment may cause serious damage to the biliary tree , and it is clinically important because it demonstrates pathology confirming that a long - term outcome of y administration may be cirrhosis .
this long - term risk needs to be considered when sequencing therapy for patients who have a high rate of 5-year survival and who have other systemic and ablative treatment options .
 backgroundmanagement options for pancreatic neuroendocrine tumors ( pnets ) metastatic to the liver include surgical , ablative , cytotoxic , and radioisotope approaches . 
 one potential local treatment option includes selective internal radiotherapy utilizing yttrium-90 ( 90y ) microspheres . 
 90y has also been used in the treatment of hepatocellular carcinoma and tumors metastatic to the liver . 
 it appears to be well tolerated ; however , there is no randomized controlled trial reporting long - term toxicities . 
 previous retrospective reports have described biliary damage as a potential complication of therapy with 90y and chemoembolization ; however , the long - term sequelae of 90y treatment are poorly understood.case presentationwe present the case of a 65-year - old caucasian woman who suffered biliary damage following 90y administration for metastatic pnets and subsequently developed cirrhosis . given the timeline of her various treatments and the lack of any other identifiable etiology for her cirrhosis 
 , we believe this to be a potential long - term complication of 90y therapy.conclusionthis case provides pathologic confirmation of cirrhosis as a potential long - term sequela of 90y treatment . 
 this long - term risk needs to be considered when sequencing therapy for patients with neuroendocrine tumors who have a good prognosis . 
 there are now several other systemic and ablative treatment options available to these patients , and long - term complications must be considered during treatment . 
Introduction
Case Report
Discussion
Conclusions
Statement of Ethics
Disclosure Statement