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.

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.

Pancreatic polypeptide update: its roles in detection of the trait for multiple endocrine adenopathy syndrome, type I and pancreatic polypeptide-secreting tumors.

Circulating human pancreatic polypeptide (hPP) concentrations in the plasma of 61 patients were determined by radioimmunoassay and compared with concentrations in normal age-matched subjects to assess the role of plasma hPP in diagnosis and detection of pathologic dysplasias in endocrinopathies. Basal fasting plasma hPP concentrations greater than 3.0 times normal values were found in six of six patients with multiple endocrine adenopathy syndrome, type I (MEA I) who had islet cell tumors that contained hPP and in only three of 15 nonfamilial patients with sporadic islet cell tumors. An exaggerated plasma hPP response to meal stimulation that exceeded greater than 4.5 times the basal value was found in 15 of 18 patients with MEA I, which indicated the presence of endocrine cell hyperplasia as the underlying genetic trait. The abnormal plasma hPP response to meal stimulation correlated most strongly with islet cell hyperplasia in both the genetic and sporadic endocrinopathies and to some extent with antral G cell hyperplasia. In patients with primary hyperparathyroidism, an exaggerated plasma hPP response to meal stimulation is highly indicative of genetic parathyroid hyperplasia in MEA I and not of sporadic parathyroid adenoma. Informed consent was obtained from all patients who were subjects of these investigations.

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.

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.

Effective streptozocin therapy for metastatic pancreatic polypeptide apudoma.

An apparently complete remission of metastases in the liver from a resected pure pancreatic polypeptide apudoma occurred following intra-arterial and intravenous administration of streptozocin to a patient in a family with multiple endocrine adenopathy, type 1. Plasma concentrations of human pancreatic polypeptide constitute an excellent marker system for the detection and assessment of tumor status before and after surgical and streptozocin therapy.

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.

Treatment of the Zollinger-Ellison syndrome. A 25 year assessment.

An assessment of treatment methods for the Zollinger-Ellison syndrome over 25 years suggests that the dual surgical approach of excision of resectable tumor and total gastrectomy provides the greatest possibility of attaining tumor and serum gastrin control. Normal serum gastrin levels and reduction of tumor status, not observed with nonoperative management, were attained by surgical treatment, particularly when the tumor (or hyperplasia) was limited to the pancreas, stomach, duodenum and regional lymph nodes. Eleven of 16 such operations resulted in tumor control, and 10 of these patients developed normal serum gastrin concentrations. In elective clinical situations combined medical and surgical therapy is a rational approach allowing confirmation of diagnosis and safe, definitive surgical control of the syndrome before metastases occur.

Pancreatic polypeptide as screening marker for pancreatic polypeptide apudomas in multiple endocrinopathies.

Prospective screening was carried out in 12 members of three families with multiple endocrine adenopathies, type I (MEA,I) and in 14 patients with no multiple endocrine adenopathies with and without other endorcinopathies. Elevated basal and responsive (after a meal) plasma concentrations of a relatively new candidate-hormone, human pancreatic polypeptide (hPP), were associated with pancreatic apudoma tumors in three asymptomatic patients with multiple endocrine adenopathies, type I. Two of these patients had excision of the tumors that resulted in normal plasma hPP concentrations postoperatively. Both tumors contained hPP predominantly by immunocytochemistry; one, a pure pancreatic polypeptide apudoma, was studied extensively demonstrating also by radioimmunoassay a high content of hPP and negligible amounts of insulin, glucagon, somatostatin, vasoactive intestinal polypeptide and gastrin. In this patient plasma concentrations of other polypeptides including insulin, glucagon, somatostatin, vasoactive intestinal polypeptide, gastrin, parathyrin, thyrocalcitonin, prolactin, corticotropin, growth hormone, thyrtropin and amine, serotonin, were within normal limits. The other patient, after excision of an hPP-detected pancreatic mixed hPP-gastrinoma, also became eugastrinemic postoperatively. Normal basal plasma hPP concentrations, but with exaggerated hPP responses to a meal in 11 patients, were associated with various combinations of islet cell hyperplasia, antral G cell hyperplasia with moderate hypergastrinemia and parathyroid hyperplasia. The patients with multiple endocrine adenopathies who have demonstrated this type of increased hPP response to a meal have not been operated on but are at risk for islet hyperplasia. Four of the 12 patients with multiple endocrine adenopathies, type I, with both normal basal and normally responsive hPP concentrations have no evidence as yet of pancreatic involvement.

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.

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.

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.

Current dimensions of the endocrine system.

The basic and clinical sciences have become fused in the investigation of relatively new syndromes and their pathogenesis. The measurement of hormone content in serum and tissues and the elucidation of its biologic effect via the membrane and cytoplasmic receptors leads to diagnostic and prognostic accuracy. New breakthrough advances in clinical and cellular phenomena will portend new horizons for more specific diagnoses and modern treatment of present and new endocrinopathies. The dimensions of the neuroendocrine system are expanding; the future perimeters are beyond sight today.