Gastrointestinal neuroendocrine tumors.

It has been said that with the description of the Zollinger-Ellison syndrome in 1955, the clinical era of gastrointestinal endocrinology was inaugurated. Since that time, a virtual explosion of investigations, both basic and clinical, has occurred in which as many as 19 gastroenteropancreatic neuroendocrine cells have been identified and as many as 40 of their humoral products have been discovered. The pharmacologic and physiologic functions of some of these amines and peptides have been clearly identified and account for the clinical presentations of the various clinical syndromes so far described. However, the physiologic functions of many others remain to be elucidated. The interest in gastroenteropancreatic neuroendocrine tumors arising from these cells has markedly increased in recent years as a result of the creation of precise biochemical techniques to confirm the diagnosis and the refinement of localization techniques that allow for the identification of previously occult tumors. Therefore, the recognition and treatment of gastroenteropancreatic neuroendocrine tumors has improved so that an ever-increasing number of patients are diagnosed early and surgically treated before metastases occur. There are still more identified gastroenteropancreatic neuroendocrine cells and humoral products than there are recognized neoplasms and syndromes; continued investigation is essential. Undoubtedly, newer treatment modalities will continue to be created for chemotherapy and receptor modulation, but early surgical excision remains the cornerstone of successful treatment today.

The place for curative surgical procedures in the treatment of sporadic and familial Zollinger-Ellison syndrome.

The surgical treatment of patients with the Zollinger-Ellison syndrome has undergone a dramatic evolution since the syndrome was originally described. It is now recognized that an aggressive surgical approach is mandatory because of the malignant potential of gastrinomas in both the sporadic and the familial forms of the syndrome. Although initially regarded as an incurable neoplasm, it is now known that complete surgical resection of gastrinomas can result in eugastrinemia even in the presence of lymph node metastases. It is now recognized that extrapancreatic gastrinomas are more common than pancreatic gastrinomas, and the most common location for an extrapancreatic gastrinoma is the duodenal wall. Major improvements in preoperative imaging and intraoperative localization techniques combined with an increased awareness of the anatomic distribution of gastrinomas have markedly increased the surgeon's ability to care for and cure patients with the Zollinger-Ellison syndrome.

Embryologic concepts in the APUD system.

The amalgamation of the neural and endocrine physiologic mechanisms for functional homeostasis as a neuroendocrine system is brought into focus in this chapter on the embryologic concepts in the APUD system. The neuroendocrine system, now regarded as the third division of the nervous system, is a regulatory mechanism that links the functions of the autonomic nerves and the endocrine cells throughout the body. The current realization that both neural and endocrine actions are often involved in the clinical manifestations of many syndromes is clarified by the theories on the embryologic origin of the APUD system described here. Relevant historical developments, as well as cytochemical discoveries, have been gradually integrated into the evolving theories of the embryologic origin of the APUD system. These theories have not been without controversy, but new developments stimulate new concepts and, as new investigative tools have produced a plethora of new information that continues to push investigators, basic and clinical into new horizons, earlier theories have been modified and new theories have been developed. These theories are reviewed in chronological order in this chapter.

Role of pancreatoduodenectomy in the management of primary duodenal wall gastrinomas in patients with Zollinger-Ellison syndrome.

BACKGROUND: The role of pancreatoduodenectomy in the surgical management of duodenal wall gastrinomas (DWGs) has not been well established. Recently DWGs have been recognized with increasing frequency, and several reports have emphasized that pancreatoduodenectomy can now be performed with a low operative morbidity and mortality for other conditions. The purpose of this study was to determine the indications, safety, and efficacy of pancreatoduodenectomy in the treatment of DWGs. METHODS: Forty-five patients with Zollinger-Ellison syndrome were evaluated and surgically treated between 1960 and 1991; 15 (33%) of these had primary DWGs. RESULTS: Pancreatoduodenectomy was considered necessary for curative resection in six patients. Two of these patients had multiple gastrinomas as part of multiple endocrine neoplasia type 1 syndrome and underwent tumor excisions and total gastrectomy; both died of tumor-related complications (survival, 8.5 and 12 years). A third patient did not consent to pancreatoduodenectomy, underwent total gastrectomy and tumor excision, and also died of tumor-related complications (survival, 10 years). The remaining three patients underwent pancreatoduodenectomy. After pancreatoduodenectomies were performed, these three patients became and remained eugastrinemic with normal results from secretin stimulation tests (mean follow-up, 7.5 years). CONCLUSIONS: In patients with DWGs and Zollinger-Ellison syndrome, pancreatoduodenectomy should be considered the treatment of choice whenever complete tumor excision is not possible by a lesser procedure.

Zollinger-Ellison syndrome. A new look at regression of gastrinomas.

Of 44 patients with the Zollinger-Ellison syndrome treated at our institution, nine appeared to have undergone "regression" of their gastrinomas. Six of the nine patients had sporadic gastrinomas and became permanently eugastrinemic following excision of nodal metastases and total gastrectomy (n = 4), antrectomy (n = 1), or pancreatoduodenectomy (n = 1) (mean survival, 13 years). The other three patients had Zollinger-Ellison syndrome as part of the multiple endocrine adenopathy type 1 syndrome and became temporarily eugastrinemic after total gastrectomy (mean survival, 11 years). Occult submucosal duodenal-wall microgastrinomas (mean size, 3.0 mm) were found to have been serendipitously excised in four patients. Long-term follow-up of these nine patients, as well as of six other patients described in the literature, demonstrates that excision of occult duodenal-wall gastrinomas provides a plausible explanation for the phenomenon of apparent regression of primary gastrinomas and the eugastrinemia that may follow total gastrectomy.

Characteristics of duodenal wall gastrinomas.

Fifteen patients with duodenal wall gastrinomas (DWGs) and the Zollinger-Ellison syndrome have been treated since 1960. In 6 of 11 patients, DWGs were recognized at operation and totally excised. In four patients, the tumor was subsequently found in the proximal duodenum of the surgical specimens. In 12 patients, DWGs were single and lymph node metastases were present in 8. In three patients, DWGs were multiple and lymph node metastases were present in two. All DWGs were submucosal and all were located in the first or second portions of the duodenum except one found in the fourth portion. Tumor size ranged from 1 to 15 mm, and nine were less than 5 mm. Of 12 patients with single DWGs, 9 have remained eugastrinemic after resection (mean follow-up: 5.5 years). None of the patients with multiple DWGs became eugastrinemic after surgery. DWGs are characteristically single, small or microscopic, submucosal, located in the proximal duodenum, rarely metastasize to the liver, and are usually curable by surgical resection.

Significance of tumor spread in adenocarcinoma of the ampulla of Vater.

Twenty-eight patients with ampullary carcinoma were treated between 1965 and 1988: 22 underwent pancreaticoduodenectomy with 1 operative death (5 percent), 1 had local excision, 3 had bypass, and 2 were not explored. Of the 21 patients who survived pancreaticoduodenectomy, 4 had tumor confined to the ampulla, 7 had tumor extending into the duodenum, and 10 had tumor invasion beyond the duodenum. Nine of these patients had positive lymph nodes and 12 had negative lymph nodes. The patient who had local excision was disease-free at last follow-up 104 months postoperatively. Each of the three bypassed patients died of tumor progression within 15 months. The estimated 5-year survival rate for resected patients was 60 percent and was independently related to lymph node metastases (p = 0.031) and to tumor size (p = 0.039). This experience suggests that long-term survival is possible in patients with lymph node metastases or invasive tumors extending beyond the duodenal wall and that curative pancreaticoduodenectomy can be performed with a low operative mortality; therefore, aggressive surgical resection is recommended for all patients with ampullary carcinoma.

Selective surgical management of correctable hypergastrinemia.

Sixty patients with surgically correctable hypergastrinemia were treated between 1960 and 1988. Provocative testing was used when available to select appropriate operations. Sources of hypergastrinemia included antral G cell hyperplasia (AGCH) (17), pancreatic gastrinomas (14), duodenal gastrinomas (11), multiple gastrinomas in patients with type I multiple endocrine neoplasia (MEN I) (five), lymph node gastrinomas (four), and the source not found in nine patients. Eugastrinemia was achieved by resection in 17 of 17 patients with AGCH, nine of 11 patients with duodenal gastrinomas, three of four patients with lymph node gastrinomas, zero of 14 patients with pancreatic gastrinomas, zero of five patients with MEN I, and zero of nine patients in whom the source was not found. Hepatic metastases developed in 11 patients with pancreatic gastrinomas, two patients with MEN I, one patient with duodenal gastrinomas, and one patient with lymph node gastrinomas. One patient in whom the source of the hypergastrinemia was not found developed hepatic metastases, and seven required total gastrectomy. This experience suggests the following: (1) that patients with AGCH, duodenal gastrinomas, or lymph node gastrinomas can usually be rendered eugastrinemic by resection; (2) that patients with pancreatic gastrinomas, whether sporadic or familial (MEN I), are rarely cured by resection and frequently develop hepatic metastases; and (3) that patients in whom the source of the hypergastrinemia is not identified and removed frequently require total gastrectomy, but antroduodenectomy should be considered because it may uncover an occult duodenal microneurogastrinoma or may correct AGCH.

Outcome of lymph node involvement in patients with the Zollinger-Ellison syndrome.

Prognosis of gastrinoma patients with metastases to lymph nodes only is uncertain, and the true nature of isolated nodal gastrinomas remains controversial. The purpose of this study was to determine the outcome of such patients and whether nodal gastrinomas may occur as primary lesions. Eleven patients with nodal involvement but without hepatic metastases are reported (mean follow-up of 129 months). Primary gastrinomas were located in the duodenum in seven (Group 1) and not identified in four (Group 2). In Group 1, five patients remained eugastrinemic after excision of all gross tumors and gastrectomy (n = 4) or pancreaticoduodenectomy (n = 1), one patient had residual disease and died of other causes (survival of 88 months), and one patient had MEA-I syndrome with multiple gastrinomas (follow-up of 126 months). In Group 2, three patients became eugastrinemic after nodal excision and total gastrectomy (mean follow-up of 212 months) and may represent primary nodal gastrinomas, and in one patient, liver metastases developed and the patient died. Four deaths occurred in a 27-year period, but only one was tumor-related. There was no significant difference in 20-year survival rates between the two groups (85% vs. 75%). It is concluded that 1) lymph node gastrinomas are usually metastatic from primary duodenal lesions, 2) although rare, nodal gastrinomas may occur as primary lesions, and 3) in the absence of hepatic metastases, lymph node gastrinomas, whether primary or metastatic, have a good prognosis and should not deter aggressive surgical treatment.

Update on the diagnosis and treatment of rare neuroendocrine tumors.

A growing knowledge and awareness of bizarre clinical presentations, the physiology of new peptides, and the more frequent use of radioimmunoassay techniques has led to the identification of more patients with glucagonomas, somatostatinomas, vipomas, and ectopic tumors. Definite clinical syndromes, though sometimes seemingly "silent," occur as a result of hypersecretion of newly identified hormones and neurotransmitters that act in endocrine, neurocrine, or paracrine fashion to alter normal metabolism of carbohydrates and electrolytes. Metabolically and clinically, glucagonomas are catabolic, somatostatinomas are inhibitory, and vipomas are diarrheogenic. The clinical syndromes can be differentiated from other, more common, endocrinopathies; the measurement of the plasma concentrations of the specific peptides is not only diagnostic, but prognostic. Specific pathologic confirmation of the functional potential of these tumors by immunocytochemical techniques is now possible. The goal of diagnosis is detection and tumor localization before metastases occur so that surgical excision may be curative. Objective clinical and humoral responses to chemotherapy for nonresectable or metastatic lesions can be expected in about 50 per cent of patients; specifically, dacarbazine (DTIC) is the agent of choice for glucagonomas, streptozotocin for somatostatinomas, and leukocyte interferon for vipomas.

Post-thyroidectomy hypocalcemia. Incidence and risk factors.

Two hundred twenty-one patients undergoing thyroidectomy were analyzed for factors increasing the risk of postoperative hypocalcemia. Eighty-three percent of all patients experienced hypocalcemia postoperatively, with 13 percent requiring some treatment for symptoms. Patients with advanced thyroid cancer, Graves' disease, or other manifestations of preoperative hyperthyroidism had significantly increased rates of hypocalcemia compared with patients with small cancers or benign euthyroid disease. Total thyroidectomy, repeat thyroidectomy, and thyroidectomy plus neck dissection all significantly increased the incidence of permanent hypocalcemia, whereas lobectomy or subtotal thyroidectomy for benign euthyroid disease were low risk operations. Inadvertent excision of more than one parathyroid gland during thyroidectomy also significantly increased the rate of permanent hypocalcemia.

Pancreatic polypeptide-secreting islet cell tumor. A follow-up report.

A case of documented pancreatic polypeptide (PP)-secreting islet cell tumor was followed for 3 years and 8 months until death due to multiple metastases. The patient initially presented with extremely high serum PP levels without clinical symptoms. After resection of the PP-secreting islet cell tumor, serum PP levels gradually decreased to normal levels. Serum PP levels started to elevate 10 months after the surgery, when liver metastases were verified by open biopsy. The patient was treated with streptozotocin (STZ), and normal serum PP levels returned. However, multiple liver and bone metastases were detected 32 months after resection of the tumor, which led to death. The recurrent tumor obtained at autopsy contained very little immunoreactive PP. The effect of STZ on PP secretion by the islet cell tumor is discussed.

Pancreatic polypeptide in islet cell tumors. Morphologic and functional correlations.

Twelve islet cell tumors and one islet cell hyperplasia were studied with immunocytochemical and radioimmunoassay methods. With immunocytochemical staining, all six insulinomas, one mixed insulinoma-glucagonoma, and four gastrinomas were positive for insulin, insulin and glucagon, and gastrin, respectively. Pancreatic polypeptide (PP) was positive in three insulinomas and one mixed insulinoma-glucagonoma. All of the tumors were positive for neuron-specific enolase (NSE). Radioimmunoassays of tissue extracts further disclosed that all functioning tumors contained more than one pancreatic hormone. PP concentrations of two insulinomas and one mixed insulinoma-glucagonoma were higher than that of normal control pancreases. A study of protein meal-stimulated PP secretion revealed that three of the insulinoma cases and two gastrinoma cases exhibited higher plasma PP levels than the age-matched controls. The findings suggest that: both functioning and nonfunctioning islet cell tumors derive from neuroendocrine cells positive for NSE; all functioning islet cell tumors appear to contain PP in the tumor tissue as a minor component; as many as 70% of the patients with islet cell tumors present with abnormally higher plasma PP levels after protein meals; and a study of meal-stimulated PP secretion may well be used as a marker for the presence of functional islet cell tumors.

Subtotal parathyroidectomy for secondary hyperparathyroidism.

Controversy exists regarding the relative merits of subtotal parathyroidectomy (SPTX) versus total parathyroidectomy with autotransplantation in the treatment of secondary hyperparathyroidism (HPT). Fourteen patients who underwent SPTX for secondary HPT were evaluated to determine the efficacy of this treatment in view of modern dialysis, diet, and drug treatment. Indications for operation included intractable symptoms (two patients), progressive renal osteodystrophy (eight patients), or both (four patients). Duration of renal failure ranged from 3 to 15 years (mean 7.8 years) before SPTX. The operative serum calcium level was normal in 10 patients, elevated in three patients, and low in one patient. Preoperative parathyroid hormone (PTH) levels ranged from 3.9 to 144 ng/ml (average 41 ng/ml) and decreased after operation to an average of 3.6 ng/ml (normal PTH less than 1 ng/ml). There were no deaths or major postoperative complications. Clinical or radiographic improvement occurred in 80% of patients but did not correlate with absolute reductions in PTH levels. Our results reveal that SPTX is a simple and effective treatment in the initial surgical management of uremic, secondary HPT and appears to be comparable to those obtained with more complicated surgical approaches such as total parathyroidectomy and autotransplantation.