Surgical treatment of localized gastrinoma within the liver: A prospective study

doi:10.1067/msy.1998.93110

Surgery

Volume 124, Issue 6, December 1998, Pages 1145-1152

Presented at the 19th Annual Meeting of the American Association of Endocrine Surgeons, Orlando, Fla, Apr 26-28, 1998.

https://doi.org/10.1067/msy.1998.93110 Get rights and content

Abstract

Background: Studies demonstrate that liver metastases of gastrinoma significantly reduce survival. Methods: Since 1982 we have prospectively studied 213 patients with Zollinger-Ellison syndrome. For this report the results of surgery for localized liver gastrinoma were analyzed. Results: Zollinger-Ellison syndrome was diagnosed biochemically in all patients and acid output was controlled with medications. Imaging studies demonstrated liver gastrinoma in 69 patients (32%). Fifty-two had diffuse unresectable disease, whereas 17 (10%) had localized disease. All patients with localized liver gastrinoma and 2 patients with diffuse disease who needed surgery are the subject of this report. Major hepatic lobectomy was performed in 10 patients and wedge resections in 9. Three patients had apparent liver primary gastrinomas and 16 had metastatic disease. Seventeen of 19 patients were able to have all identifiable gastrinoma resected. Extrahepatic tumor was also removed at the same procedure. Extirpation of liver gastrinoma required hepatic lobectomy in 10 patients and wedge resections in the others. Five-year survival was 85%. Five of 17 completely resected patients (29%) remained disease free. Conclusions: Resectable localized liver gastrinoma is rare. Primary liver gastrinomas can occur. Surgical resection of localized liver gastrinoma provides a cure rate similar to that of extrahepatic gastrinoma and an excellent long-term survival. (Surgery 1998;124:1145-52.)

Section snippets

Methods

Since 1982 we have prospectively studied 213 patients with ZES. The diagnosis was ascertained in all patients by measuring an elevated fasting serum level of gastrin and an elevated basal acid output. Further, a secretin stimulation test was confirmatory of the diagnosis in approximately 87%, as previously described.⁶ Each patient had gastric acid hypersecretion controlled medically with drugs to keep the basal acid output less than 10 mEq per hour (if no prior surgery to reduce acid output had

Patient demographics

Seventeen patients were identified with ZES who had imaging evidence of localized potentially resectable hepatic gastrinoma (n = 17, 25% of patients with liver gastrinoma). Two additional patients with diffuse bilobar liver tumor were included because they underwent hepatic surgery as part of an operative procedure intended not to remove all tumor, but rather to palliate another symptom related to tumor or tumor treatment. One patient had a large tumor abscess after chemoembolization and

Discussion

Patients with localized resectable liver metastases from gastrinoma are rare. In this prospective study of 213 patients with ZES, only 17 (8%) had localized liver gastrinoma and were candidates for surgical resection. Further, these patients represented only 25% of patients with liver metastases. Demographic data suggested that fasting serum levels of gastrin were markedly elevated in these patients and were higher than had been previously reported in patients with localized surgically

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Today, 60% to 90% of gastrinomas are found in the gastrinoma triangle.65,67 In 2% to 24% of patients, gastrinomas are found at other locations, including the ovary, heart, liver and biliary tract, jejunum, renal capsule, omentum, and pylorus.68-71 Lymph node primary gastrinomas are reported in up to 11% of sporadic cases of ZES.63,69
Pancreatic endocrine tumors have been steadily growing in incidence and prevalence during the last two decades, showing an incidence of 4–5/1,000,000 population. They represent a heterogeneous group with very varying tumor biology and prognosis. About half of the patients present clinical symptoms and syndromes related to substances released from the tumors (Zollinger-Ellison syndrome, insulinoma, glucagonoma, etc) and the other half are so-called nonfunctioning tumors mainly presenting with symptoms such as obstruction, jaundice, bleeding, and abdominal mass. Ten percent to 15% of the pancreatic endocrine tumors are part of an inherited syndrome such as multiple endocrine neoplasia type 1 (MEN-1), von Hippel-Lindau (VHL), neurofibromatosis, or tuberousclerosis. The diagnosis is based on histopathology demonstrating neuroendocrine features such as positive staining for chromogranin A and specific hormones such as gastrin, proinsulin, and glucagon. Moreover, the biochemical diagnosis includes measurement of chromogranins A and B or specific hormones such as gastrin, insulin, glucagon, and vasoactive intestinal polypeptide (VIP) in the circulation. In addition to standard localization procedures, radiology (computed tomography [CT] scan, magnetic resonance imaging [MRI], ultrasound [US]), somatostatin receptor scintigraphy, and most recently positron emission tomography with specific isotopes such as ¹¹C-5 hydroxytryptamin (¹¹C-5-HTP), fluorodopa and ⁶⁸Ga-1,4,7,10-tetra-azacyclododecane-N,N′,N″,N‴-tetra-acetic acid (DOTA)-octreotate are performed. Surgery is still one of the cornerstones in the management of pancreatic endocrine tumors, but curative surgery is rarely obtained in most cases because of metastatic disease. Debulking and other cytoreductive procedures might facilitate systemic treatment. Cytotoxic drugs, biological agents, such as somatostatin analogs, alpha interferons, mammalian target of rapamycin (mTOR) inhibitors and tyrosine kinase inhibitors are routinely used. Tumor-targeted radioactive treatment is available in many centres in Europe and is effective in patients with tumors that express high content of somatostatin receptors type 2 and 5. In the future, treatment will be based on tumor biology and molecular genetics with the aim of so-called personalized medicine.
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There is evidence that resection of liver metastases improves survival, although it is difficult to conclude for certain that the demonstrated differences in survival are dependent on surgical treatment, and not the extent of disease itself.36,55 A significant percentage of patients with metastatic gastrinoma can undergo liver resections that result in removal of all known disease with 5-year survival up to 85%.56 In addition to possible survival benefit and surgical cure of metastatic disease, there may be benefit of cytoreductive surgery in ameliorating the functional endocrine tumor syndrome.57
A case of intrahepatic gastrinoma
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The Zollinger-Ellison syndrome is due to an endocrine gastrin-secreting tumor, the gastrinoma. This tumor is often malignant and patients develop metastases in 25% of cases. The usual localizations of gastrinomas are at the head of the pancreas, the duodenal wall and the peripancreatic lymph nodes. Ectopic localizations, such as stomach, small bowel, gallbladder, liver or ovaries, are rare. We report the case of an intrahepatic gastrinoma, surgically treated by left hepatectomy. Upon review of scientific literature, we found 19 cases of intrahepatic gastrinoma. This diagnosis is always difficult to establish, even after a complete preoperative imaging and an extensive operative search for a possible primary tumor. The best evidence for diagnosis is the gastrinemia decreasing to a normal range after liver resection, and the absence of recurrence in long-term follow-up.
Le syndrome de Zollinger-Ellison est lié à une hypersécrétion de gastrine par une tumeur endocrine à cellules G, le gastrinome. Cette tumeur est souvent maligne et les patients développent des métastases dans 25 % des cas. Les localisations habituelles du gastrinome sont le pancréas céphalique, la paroi duodénale et les ganglions lymphatiques péripancréatiques. Les localisations ectopiques, sur l’estomac, l’intestin grêle, la vésicule biliaire, le foie ou l’ovaire sont plus rares. Nous rapportons un cas de gastrinome intrahépatique traité par lobectomie gauche. La revue de la littérature permet de retrouver 19 cas de gastrinomes intrahépatiques primitifs. Le diagnostic est toujours délicat, rarement faisable d’emblée, même après un bilan préopératoire complet et une exploration peropératoire optimale à la recherche d’un éventuel primitif. L’obtention de l’eugastrinémie après résection hépatique et l’absence de récidive restent les meilleurs critères diagnostiques a posteriori.
Gastrointestinal Neuroendocrine Tumors: Pancreatic Endocrine Tumors
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In advance of surgery patients should be vaccinated against encapsulated microorganisms (pneumococcus, H influenza, meningococcus) in anticipation of a possible splenectomy and they should receive a bowel preparation in anticipation of an expected enterotomy (mandatory in the case of gastrinomas and other hormonal syndromes with a predilection for duodenal primaries).198,216–219 In general, all PETs (except imaged insulinomas) should be approached by laparotomy to permit an extensive exploration of the entire abdomen.113,203,219–221 An exception to this rule is surgery for insulinoma in non-MEN1 individuals because at least 85% of these tumors are benign, there usually is a single primary, and, if they can be localized preoperatively, laparoscopic resection is successful in 70%–100% of cases and its use hastens postoperative recovery.121,222–224
Pancreatic endocrine tumors (PETs) have long fascinated clinicians and investigators despite their relative rarity. Their clinical presentation varies depending on whether the tumor is functional or not, and also according to the specific hormonal syndrome produced. Tumors may be sporadic or inherited, but little is known about their molecular pathology, especially the sporadic forms. Chromogranin A appears to be the most useful serum marker for diagnosis, staging, and monitoring. Initially, therapy should be directed at the hormonal syndrome because this has the major initial impact on the patient's health. Most PETs are relatively indolent but ultimately malignant, except for insulinomas, which predominantly are benign. Surgery is the only modality that offers the possibility of cure, although it generally is noncurative in patients with Zollinger–Ellison syndrome or nonfunctional PETs with multiple endocrine neoplasia-type 1. Preoperative staging of disease extent is necessary to determine the likelihood of complete resection although debulking surgery often is believed to be useful in patients with unresectable tumors. Once metastatic, biotherapy is usually the first modality used because it generally is well tolerated. Systemic or regional therapies generally are reserved until symptoms occur or tumor growth is rapid. Recently, a number of newer agents, as well as receptor-directed radiotherapy, are being evaluated for patients with advanced disease. This review addresses a number of recent advances regarding the molecular pathology, diagnosis, localization, and management of PETs including discussion of peptide-receptor radionuclide therapy and other novel antitumor approaches. We conclude with a discussion of future directions and unsettled problems in the field.
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^☆: Reprint requests: Jeffrey A. Norton, MD, San Francisco Veterans Affairs Medical Center, 4150 Clement St, San Francisco, CA 94121-1598.

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American Association of Endocrine SurgeonsSurgical treatment of localized gastrinoma within the liver: A prospective study☆

Abstract

Section snippets

Methods

Patient demographics

Discussion

Gastroenterology

Gastroenterology

Med Clin North Am

Gastroenterology

Endocrine tumors of the pancreas

Curr Opin Gen Surg

Neuroendocrine tumors of the pancreas and duodenum

Curr Probl Surg

Results of a prospective strategy to diagnose, localize and resect insulinoma

Surgery

Hypergastrinaemia [editorial]

Br J Surg

Curative resection in Zollinger-Ellison syndrome: results of a 10-year prospective study

Ann Surg

Surgery in Zollinger-Ellison syndrome alters the natural history of gastrinoma

Ann Surg

Vascular occlusive therapy of pancreatic endocrine tumors metastatic to the liver

Front Gastrointest Res

Chemo-embolization of patients with liver metastases from carcinoid and islet cell tumors [abstract]

Proc Annu Meet Am Soc Clin Oncol

American Association of Endocrine Surgeons
Surgical treatment of localized gastrinoma within the liver: A prospective study☆