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Washington University School of Medicine St. Louis, Missouri 63110
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Introduction |
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The hyperparathyroidism in patients with MEN 1 is characterized by four gland hyperplasia. It is treated surgically either by subtotal (31/2 gland) parathyroidectomy or by total parathyroidectomy with heterotopic autotransplantation. The recurrence rate is unacceptably high with lesser procedures. Unfortunately, there has never been a prospective randomized controlled trial comparing the two acceptable surgical procedures for parathyroid hyperplasia. In patients with MEN 1 who have both hyperparathyroidism and the Zollinger-Ellison Syndrome (ZES), parathyroidectomy should be performed as normalization of the serum calcium reduces the basal gastric acid production, the serum gastrin level, and often the symptoms of peptic ulcer disease.
The pancreatic islet cell tumors are characteristically multicentric and intermixed with islet cell microadenomas, but not necessarily islet cell hyperplasia. The management of the islet cell tumors in patients with MEN 1 depends on the clinical syndrome resulting from hormone overproduction. Generally, the operative treatment of a given islet cell tumor in patients with MEN 1 is less successful than the treatment of the same tumor that occurs in the sporadic setting. This is because sporadic islet cell tumors are solitary and unassociated with the extrapancreatic diseases characteristic of the MEN 1 syndrome.
There is little controversy about the treatment of patients with MEN 1 and insulinomas. The diagnosis is made by documenting hypoglycemia in association with inappropriately increased plasma levels of insulin and C-peptide during a prolonged fast. Insulinomas do not occur outside of the pancreas, and 85% of them are benign. Preoperative radiographic localization procedures, particularly abdominal angiography with calcium as a secretagogue, define the site of an insulinoma in 80% of patients and are also helpful in identifying metastases to the liver and other parts of the peritoneal cavity. There is no satisfactory medical therapy for insulinoma; therefore, all patients merit exploration whether or not a tumor is located in the pancreas. During the exploration the pancreas is carefully palpated, and any identified islet cell tumors are enucleated. Intraoperative ultrasound is especially helpful in the localization of insulinomas and should be employed in all patients. Some surgeons also perform a distal subtotal pancreatectomy in hopes of removing more of the diseased pancreatic tissue. Regardless of the operative method chosen, the postoperative results are excellent, with greater than 90% of patients being cured permanently (2).
The management of patients with MEN 1 and glucagonomas, VIPomas, or carcinoid tumors is similar to that of patients who have insulinomas. The VIPomas and glucagonomas are usually malignant, and octreotide is the only medical treatment for the clinical syndromes associated with hypersecretion of VIP or glucagon. No single medical center has a large experience in the management of patients with these tumors; however, resection of the evident neoplasm appears to be the treatment of choice.
The management of patients with MEN 1 and gastrinoma has changed markedly since 1955 when the Zollinger-Ellison syndrome was first described (3). At that time there was inadequate medical therapy for the severe ulcer diathesis associated with the syndrome, and the treatment of choice was total gastrectomy. Over the last three decades new drugs, such as the H-2 blocking agents and more recently the H+, K+-ATPase inhibitors, have been introduced into clinical practice and have proven highly effective in controlling gastric acid secretion. Because most are malignant, attention has been focused on the biology of the gastrinomas and how best to treat them. The operative management of patients with MEN 1 and gastrinomas has been influenced by several findings. (1) Gastrinomas occur in the pancreas of patients with MEN 1, but recently it has become evident that gastrinomas are almost always found in the duodenum, regardless of their presence in the pancreas. The duodenal gastrinomas may be solitary or multiple and are very small (4–6 mm). (2) Whether duodenal or pancreatic in origin, gastrinomas are usually malignant, and regional lymph node metastases are found in 50% of patients at the time of pancreatic surgery. The presence of lymph node metastases alone is not associated with a poor prognosis (7). (3) Perhaps because of the presence of multiple duodenal gastrinomas and the frequency of metastases to regional lymph nodes, it is very difficult to cure gastrinomas in patients with MEN 1. This is evidenced by the presence of elevated basal or stimulated plasma gastrin levels postoperatively, regardless of the operative procedure employed (8, 9). (4) The single factor that most determines a poor prognosis, regardless of the setting in which the gastrinoma develops, is the presence of liver metastases. In a study of 149 patients with gastrinoma and no liver metastases, the 10-yr survival was 90%, whereas in 36 patients with liver metastases the survival was 30% (7). In the same study, the occurrence of liver metastases in patients with MEN 1 was only 6% at the time of their initial presentation (7). This is much lower than the 15–44% incidence of hepatic metastases in patients with MEN 1 reported by other investigators (10, 11, 12). The frequency with which patients with MEN 1 develop hepatic metastases is of critical importance because surgical therapy of the primary disease should be directed toward preventing this complication. (5) Despite the frequency of lymph node metastases and the relatively incurability of the gastrinomas surgically, patients with MEN 1 and gastrinomas appear to have a long survival. The 20-yr survival of 34 patients with gastrinoma and MEN 1 studied at the National Institutes of Health was 100% compared with a 20-yr survival of 68% in 151 patients who had sporadic gastrinoma (7). Grama and associates found no difference in the survival of patients with MEN 1 and gastrinoma compared with patients with sporadic gastrinomas (13).
The debate about the management of patients with MEN 1 and gastrinomas centers around the treatment of the malignant disease and specifically how to prevent the development of liver metastases without causing inordinate operative morbidity and mortality. Therapeutic considerations have ranged from medical therapy alone for prevention of the peptic ulcer disease to performance of a pancreaticoduodenectomy. The approach that has been adopted by investigators at the National Institutes of Health has been to manage patients with medical therapy alone when the primary tumor is no larger than 3 centimeters in diameter (7). Surgical resection is employed when the primary gastrinoma is 3 cm or larger. This approach is recommended because the incidence of metastases to the liver is related to the size of the gastrinoma primary, being 4% with tumors less than 1 cm in diameter, 28% with tumors from 1 to 3 cms in diameter, and 61% with tumors greater than 3 cm in diameter (7). Because individual duodenal gastrinomas are generally much smaller (96% are less than 3 cm in diameter and 77% are less than 1 cm in diameter) than pancreatic gastrinomas (74% are larger than 3 cm in diameter, and 94% are larger than 1 cm in diameter) (7), one would expect that liver metastases would be much more common in patients with pancreatic tumors, and such is the case. Of 42 patients with primary pancreatic gastrinomas, 52% had metastases to the liver, whereas in 41 patients whose primary gastrinoma was in the duodenum only 5% had metastases to the liver (7).
If one only operates on patients whose tumors are larger than 3 cms then very few patients with MEN 1 and gastrinoma will be candidates for operative intervention. One must question whether these guidelines are too liberal, since delay of an operation until the primary is 3 cm means that in the majority of patients the gastrinoma will have to spread to the liver, and they will have a significantly shortened survival. One could argue that the time to operate on these patients would be when the tumors are less than 3 cms in size. The large majority of patients with gastrinomas this size would have no metastases to the liver but perhaps early operation and resection of the small pancreatic and duodenal tumors would prevent this lethal complication. There are some data to support this approach. Fraker and associates at the NIH evaluated 124 patients with the biochemical diagnosis of ZES and no evidence of hepatic metastases. Ninety-eight patients (15 with MEN 1) had pancreatic resection, and 26 patients (9 with MEN 1) were managed medically. After treatment was instituted, the patients were followed for 9.4 years and 7.7 years respectively. Hepatic metastases developed in 6 (23%) of the 26 patients who were managed medically and in 3 (3%) of the 98 patients who had surgery for cure. The eight-fold difference in the incidence of hepatic metastases is statistically significant (P < 0.003). Furthermore, there were two deaths from metastatic gastrinoma (neither with MEN 1) in the nonoperative group but none in the group having surgery for cure (14).
The operative approach to patients with MEN 1 and gastrinoma is open to question. There are no data that demonstrate that primary tumor size is the most important determinant. Is there a way to select patients who are likely to benefit from an operation? Once the predisposition gene for MEN 1 is identified there is a possibility that a relationship between genotype and disease phenotype will be found. Such an observation, and perhaps the identification of other biological markers of tumor aggressiveness, may be helpful in developing rational therapeutic strategies for individual patients with this rare malignancy.
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