Pancreatic neuroendocrine tumors: gastrinoma
What is the surgical management of gastrinoma and ZES?
Once the diagnosis of a gastrinoma has been made, a referral to a surgeon expert in the management of this disease should be made. Since these are rare tumors, it is important that the surgeon have experience with their management and that the surgeon is at a medical center with expertise in gastrinoma and ZES. While some cases of gastrinoma, especially when associated with MEN-1, can be managed with medications, patients with sporadic gastrinoma not associated with MEN-1 should be evaluated for surgery.
Before embarking on surgery, a thorough assessment of the extent of disease should be made including computed tomography (CT scanning) of the chest abdomen and pelvis as well as somatostatin receptor scintigraphy (SRS). SRS is a technique that uses a radiolabled agent to visualize neuroendocrine tumors. If pre-operative imaging fails to reveal evidence of metastatic disease, surgical management should be considered.
The use of antisecretory and acid reducing medications has dramatically altered the management of ZES patients. The availability of these agents as well as their long duration of action, has greatly simplified management, because they can be taken once or twice per day. The role of surgery in the management of patients with ZES has therefore changed in its focus from managing the ulcers that are the result of acid hypersecretion, to managing the long-term outcome for patients due to the malignant potential of the primary tumor. Total gastrectomy can now be reserved for very rare and specific circumstances, such as when a patient does not have access to routine medical follow-up or cannot or will not take oral medications reliably. Parietal cell vagotomy (PCV) in ZES patients, in whom no tumor was resected, decreased basal acid output by 66%. However, most patients still needed some antisecretory medications and therefore at present, PCV is no longer performed routinely. In patients with ZES and the MEN-1 syndrome, correction of hyperparathyroidism reduces the fasting serum gastrin concentration, increases the responsiveness to a given dose of antisecretory medication, or decreases the basal acid output. Therefore, in patients with ZES and MEN-1 with hypercalcemia due to hyperparathyroidism, parathyroidectomy should be performed before any other contemplated surgical procedure to control the acid hypersecretion.
The impact of surgical resection of the primary gastrinoma on overall survival in ZES patients has been extensively studied. In a number of reports, the 5-year survival rate for all patients with ZES was 62% to 87% and the 10-year survival was 47% to 77%. A comprehensive study reported long-term outcome in 151 consecutive ZES patients who underwent operation with the intent to cure them of their gastrinoma. Among patients with sporadic gastrinoma, 34% were free of disease at 10 years compared to none with MEN-1 and ZES. The overall 10-year survival however was excellent at 94%. A normal post-operative fasting serum gastrin (FSG) test significantly predicts cure.
Patients with sporadic gastrinoma arising in the duodenum enjoy similar results following resection. In a study of 63 patients with a gastrinoma in the duodenum who underwent surgery with the intent to cure the gastrinoma, the disease-free survival at 10 years was 60% with a disease-specific survival of 100%. The most important predictor of duration of disease-free survival was lymph node status.
Since the resection of a gastrinoma results in an excellent prognosis and since there is evidence of the increased importance of the malignancy in determining survival, surgical resection of gastrinoma is offered to patients with ZES who are without other risk factors for surgery (such as severe heart disease). Surgical resection of gastrinoma may, in fact, alter the natural history of the disease. Only 3% of patients with ZES undergoing tumor resection developed liver metastases during follow-up, whereas significantly more patients treated medically developed liver metastases (26%). The percentage of patients in whom gastrinoma can be identified and removed has increased with increasing experience of the surgeon in an appreciation for the presence of small duodenal tumors.
It is important, when contemplating a surgical resection with curative intent of a sporadic gastrinoma, for the surgeon to carefully establish the biochemical diagnosis and to rule out the presence of metastatic disease. The improvement in outcome following surgical exploration and resection with curative intent in most series is due to a number of factors. Because elevated gastric acid secretion can be managed in all patients with proper medications, surgical exploration can be done electively and safely. The fact that small duodenal primary tumors are more frequent than had been appreciated previously, has resulted in their increased detection and resection.
A careful standardized surgical approach is critical to the detection and resection of a primary gastrinoma and any additional sites of metastatic disease. At the time of surgery, the surgeon will make an incision on the abdomen either under the ribs in a side to side fashion (transverse incision) or up and down from under the breast bone to above the pubic bone (midline incision). The entire pancreas as well as the duodenum will be examined. A combination of other studies such as intraoperative ultrasound (IOUS), duodenal transillumination via upper endoscopy, and routine opening and examination of the duodenum will be performed. Even small duodenal primaries can be detected with careful palpation through an opening in the duodenum. By employing this systematic approach, gastrinomas can be found in all patients undergoing operation.
At surgery, if a gastrinoma is found as a solitary lesion in the liver, it should be removed, provided the removal can be performed safely. If gastrinoma is found in the pancreatic head it should be enucleated ("scooped out") if technically possible. If an extensive gastrinoma not amenable to enucleation is found in the pancreatic head area, performing a pancreaticoduodenectomy (Whipple's operation) for potential cure can be considered. Careful patient selection with consideration of other medical problems is important.
The role of surgery in the treatment of patients with ZES in the setting of MEN-1 is still in evolution. Cure is not possible in patients with MEN-1 and ZES short of a pancreaticoduodenectomy because 30% of patients have more than 20 duodenal tumors and 86% of patients have positive lymph nodes. Relapse occurs in over 95% of individuals within 3 to 5 years of surgery. Despite this recurrence rate, there is an excellent prognosis for patients with MEN-1 and ZES with or without surgery. The acid secretion can be completely controlled with medications. Since there are multiple other pancreatic tumors seen routinely in MEN-1 patients, and since there can be morbidity associated with a Whipple resection, it is not routinely recommended. The current recommendation is to operate on patients with MEN-1 and ZES when a tumor of at least 2.5 cm is seen on imaging studies. This policy is based on the observation that metastases to the liver correlate with tumor size. If the tumor is in the pancreatic head it is enucleated if possible, and in the pancreatic tail it is resected and a duodenal exploration is performed.
The role of reoperation in ZES patients is important because most patients with sporadic ZES undergoing operation and resection will have persistent or recurrent disease. The site of recurrent disease identified at reoperation was related to the initial operative findings in most cases. In those who had lymph node disease removed initially, most patients had lesions identified in the duodenum at reoperation. By contrast, for those who had a primary duodenal or pancreatic lesion initially removed, the recurrence was commonly identified in regional lymph nodes. Due to the increase in potential risk associated with reoperation in this setting, consideration of reoperation should be made carefully and performed only by an experienced surgeon.
In summary, surgery is recommended for patients with sporadic gastrinoma in most cases, while surgery is reserved for selected cases of gastrinoma in patients with
MEN-1. Experienced surgeons can perform surgery for gastrinoma, and ZES safely. Proper evaluation prior to surgery is extremely important.