Primary endocrinomas (carcinoids and variant neoplasms) of the gallbladder. A statistical evaluation of 138 reported cases.

This study was carried out to obtain extensive information on carcinoids (the carcinoid group) and related variant endocrinomas (the variant group) of the gallbladder, and to statistically analyze their characteristics from various clinicopathologic aspects. A total of 138 cases were collected from the international sources, 101 belonging to the carcinoid group and 37 to the variant group. The first group consisted of 81 cases of typical and 20 atypical carcinoids. Comparative evaluation was attempted mainly between the carcinoid and variant groups, and occasionally between the typical and atypical carcinoid series when statistical significance was suspected. The carcinoid group showed a statistically significant difference from the variant group by exhibiting a younger average age (61.7 years vs 69.7 years: P<0.01), a higher incidence of associated cholelithiasis (87.3% vs 56.0%: P<0.01), a higher incidence of small tumors 50 mm or less (85.2% vs 52.9%: P<0.01), a smaller average tumor-size (29.6 mm vs 58.7 mm: P<0.01), a lower rate of metastases (40.7% vs 70.6%: P<0.05), a higher immunoreactivity rate of chromogranin (100.0% vs 66.7%: P<0.01), a lower immunoreactivity rate of gastrin (23.8% vs 70.6%: P<0.01), and a higher five-year survival rate (60.4% vs 21.3%: P<0.0005). Significant differences in various clinicopathological aspects confirmed between the carcinoid group and the variant group suggested that endocrine carcinomas of these two groups perform a different clinical pattern, represented most clearly by postoperative outcomes. These groupings are decided on the basis of histologic patterns, namely, well to poorly differentiated endocrine carcinomas (typical to atypical carcinoids) and undifferentiated or anaplastic variants of other endocrine carcinomas. The basic criteria for such classification of these endocrine carcinomas based on international agreements are required.

Importance-satisfaction discrepancies are associated with health-related quality of life in five-year survivors of endocrine gastrointestinal tumours.

BACKGROUND: Little is known about the health-related-quality of life (HRQoL) of patients with endocrine gastrointestinal tumours. In this study, HRQoL was investigated in long-term survivors of endocrine GI tumours. PATIENTS AND METHODS: A questionnaire including the EORTC QLQ-C30 and ratings of importance of and satisfaction with a variety of HRQoL aspects was mailed to patients with carcinoid tumours (n = 64), or endocrine pancreatic tumours (EPT, n = 55). Median time since diagnosis was 120 months (range 60-360). The majority of patients (77 of 119) had ongoing treatment. RESULTS: The EORTC QLQ-C30 ratings suggest that in spite of a long disease duration and treatment, patients perceived their HRQoL as relatively good. There were no major differences in HRQoL ratings between patients with carcinoid tumours and those with EPT. Patients whose ratings of importance was higher than their ratings of satisfaction with a specific HRQoL aspect also evidenced a low HRQoL for that aspect. CONCLUSIONS: The results indicate that survivors of endocrine GI tumours enjoy a relatively good HRQoL and suggest that importance > satisfaction discrepancies identify patients with a low quality of life.

Long-term prognosis of Zollinger-Ellison syndrome in multiple endocrine neoplasia.

BACKGROUND: The long-term prognosis of Zollinger-Ellison Syndrome (ZES) is not well defined. The findings of other endocrinopathies, the need for long-term surveillance, and the role of surgical treatment are controversial. METHODS: To help provide more information about these topics the records of 76 patients with ZES were reviewed. RESULTS: Nineteen patients with gastrinoma had multiple endocrine neoplasia (MEN). Fifteen had hyperparathyroidism from 14 years before to 38 years after the diagnosis of ZES. Three patients had pituitary adenomas. The unusual findings of pheochromocytoma were also seen in three patients. Sixteen patients were followed at least 10 years and 12 were followed for more than 20 years. Surgical cure was achieved in only one patient after a 12-year follow-up. The actual 5-, 10-, 15-, and 20-year survival rates of 94%, 75%, 61%, and 58%, respectively, were compared with patients with sporadic ZES with 5-, 10-, 15-, and 20-year survival rates of 62%, 50%, 37%, and 31%, respectively. CONCLUSIONS: Multiple endocrinopathies are common but are rarely diagnosed synchronously, mandating life-long surveillance for patients with ZES. Long-term prognosis is good. Survival is longer for patients with ZES and MEN compared with patients with sporadic ZES. Surgical cure is rare. Surgical excision without a single localized lesion does not seem justified.

Cause of death in multiple endocrine neoplasia type 1.

OBJECTIVE: Little data are available on the natural history of untreated multiple endocrine neoplasia type 1 (MEN-1). These data are essential in deciding treatment that may carry significant morbidity. We determined the causes of death in a large MEN-1 kindred with data available over a period of 130 years. Most cases were unrecognized as MEN-1 at the time of patient's death. DESIGN: Retrospective study of recorded medical data from 1861 to 1991. PATIENTS: One hundred fifty-nine deaths occurred, of which 46 were in individuals classified as "highly probable" of having MEN-1. RESULTS: Of 46 deaths in those classified as "highly probable" of having MEN-1, 20 (43.5%) died of a recognized complication of MEN-1 (12 of malignant neoplasms, six of renal calculi, and two of peptic ulcer). If accidental deaths are excluded, 50% of the deaths in patients with MEN-1 were the result of MEN-1, and the mean age of death (50.9 years)was significantly younger than that of other family members. CONCLUSIONS: It is concluded that MEN-1 leads to premature death, and that neoplasia rather than peptic ulcer disease is the main cause of death. Deaths from pituitary tumor or malignant endocrine tumors within the thorax were just as common or more common than deaths from pancreatic malignant neoplasms.

Clinical, anatomical, and evolutive features of patients with the Zollinger-Ellison syndrome combined with type I multiple endocrine neoplasia.

The clinical evolution of type I multiple endocrine neoplasia (MEN I) was studied in 45 patients among a consecutive series of 172 with Zollinger-Ellison syndrome (ZES). These 172 patients were seen in our hospital between 1959 and 1989. Diarrhea was half as frequent in ZES-MEN I as in sporadic ZES cases. At diagnosis, mean basal acid output and serum gastrin levels in MEN I patients (28.8 +/- 6.6 mmol/h and 587 +/- 487 pg/ml, respectively) were not different from those observed in the others with sporadic ZES. Laparotomy was performed in all 36 patients with no diffuse liver involvement to attempt the removal of gastrinomas. Twenty-nine patients had adenomas, located in the pancreas in 21, in the duodenal wall in 3, and in both in 5. Adenomas were multiple in 23 cases (78%). No tumor was found in seven patients. Twenty-nine of the 36 operated patients were tumor-free after surgery; 7 died in the postoperative period between 1959 and 1970. Median follow-up of the 38 other patients was 95 months (range 17-278 months). Among the 24 patients without residual tumor at discharge (group I), biological and/or morphological evidence of a persistent or recurrent source of gastrin was obtained in 22. Among the 14 patients with residual tumor (group II), an increase in tumor size was seen in 5 after a median of 27 months (range 9-36 months), while no change occurred in 9 after 54 months (3-100 months). Actuarial survival curves were not different, either in group I versus group II patients (67 and 72% at 5-year follow-up, respectively) or in MEN I versus sporadic ZES patients. Apparently, complete resection of primary tumor did not reduce the incidence of subsequent liver metastases. In all, 21 of the 45 patients had malignant gastrinomas (47%), consisting of liver metastases in 14 (31%), metastatic lymph nodes in 11 (24%), and lung metastases in 2 (4%). Monitoring of fundic argyrophil cells disclosed hyperplasia in 13 of the 14 MEN I patients (92%), and 5 had invasive carcinoid tumors. Taken together, these results prompt us to recommend that in ZES-MEN I patients, surgery should be avoided and oxyntic mucosa regularly monitored.

[Image analysis DNA cytometry in medullary thyroid gland cancer. Comparison with histomorphologic parameters and prognostic effect]. / Bildanalytische DNS-Cytometrie beim medullären Schilddrüsencarcinom. Vergleich mit histomorphologischen Parametern und prognostischem Einfluss.

In 24 patients with a medullary thyroid cancer a histopathological reexamination was performed. In 16 patients the DNA content was measured. Patients with a diploid or hypotriploid tumor had a 5-year survival rate of 100% in contrast to 48% of patients with a triploid or hypertriploid aneuploid tumor. Aneuploid tumors were more often found in patients with a high pre- or postoperative calcitonin level and lymph node metastasis. No correlation was found between the DNA content and the patients age, sex, preoperative CEA value, tumor size, pT4 stage, invasion of vessels calcitonin immunoreactivity, silver or amyloid staining, and distant metastasis.

Prognostic factors in medullary thyroid carcinoma: evaluation of 741 patients from the German Medullary Thyroid Carcinoma Register.

A retrospective study of 741 patients with medullary thyroid carcinoma diagnosed between 1967 and 1991 was carried out by members of the German Medullary Thyroid Carcinoma Study Group to evaluate prognostic factors. A total of 559 patients (75%) were considered to have sporadic disease, and 182 (25%) had the familial type. The sex ratio (male to female) was 1:1.4 in sporadic disease patients, and the mean age at diagnosis was 45.9 years (range 5-81 years). For familial disease patients the sex ratio was 1:1.1, and the mean age at diagnosis was 33.4 (range 5-77 years). The follow-up time for 630 patients ranged from 1 month to 20.8 years (mean 13.0 years). The overall adjusted survival rate was 86.7% at 5 years and 64.2% at 10 years. In a univariate analysis the stage of disease at diagnosis, age, sex, and type of disease (sporadic, familial) were relevant prognostic factors, with a better prognosis for young female patients with familial disease and diagnosed at an early stage. In a multivariate proportional hazards analysis, the difference in the survival rate of patients with familial disease versus those with the sporadic form disappeared, while prognostic information provided by age and sex was still significant. The poorer prognosis of patients with sporadic medullary thyroid carcinoma may be related to the patients' older age at detection and more advanced tumor stage at diagnosis. There seems to be no difference in biological behavior between tumors of the sporadic and those of the familial type.

Biologic behavior of sporadic gastrinoma located to the right and left of the superior mesenteric artery.

Among a series of 107 closely followed patients with gastrinoma, 60 patients with sporadic type tumors were identified and evaluated. There were 44 patients (73%) with tumors to the right of the superior mesenteric artery (SMA). Of these, 16 (36%) had extrapancreatic tumors, 28 (64%) had tumor within lymph nodes, and 9 (20%) had multiple tumors. In this group of patients, there were 19 (43%) cures, and only 9 (20%) patients had hepatic metastases. In contrast, in 16 patients (27%) with tumors to the left of the SMA, there were no extrapancreatic tumors, only 3 patients (19%) had tumor within lymph nodes, and 7 (44%) had multiple tumors. In this group, there was only one cure (6%), and nine (56%) patients had hepatic metastases. These findings suggest two distinct populations of sporadic gastrinoma, one to the right (gastrinoma triangle) and the other to the left (outside triangle) of the SMA, which appear to have different biologic behaviors. These differences may reflect divergent etiologies for these two groups of tumors.

Pancreatic tumors in multiple endocrine neoplasia type 1: clinical presentation and surgical treatment.

Among 33 patients with endocrine pancreatic tumors due to multiple endocrine neoplasia type 1 (MEN-1), 19 (58%) patients had hypergastrinemia, 7 (21%) patients had hyperinsulinism, and 7 (21%) patients had clinically non-functioning lesions. At least one gross tumor was found in all patients undergoing pancreatic surgery, including those with negative localization studies prior to operation. The patients also had additional macroscopic tumors as well as numerous microadenomas, and the lesions frequently were positive for immunostaining with multiple hormones, mainly pancreatic polypeptide, insulin, glucagon, and somatostatin. Duodenal endocrine lesions were found in 4 of 5 investigated patients and stained with gastrin and somatostatin antibodies. Distal, mainly subtotal pancreatic resection, was performed in 18 patients, eventually combined with caput tumor enucleation or duodenotomy, while a few patients underwent only tumor enucleation or a Whipple procedure. The long-term outcome of operation was most favorable in patients with hyperinsulinism; only 1 patient had clinical recurrence. Patients with hypergastrinemia experienced only transitory lowering of serum gastrin values after pancreatic surgery and 47% of them had or developed metastases. Such tumor spread was seen in 57% of the patients with non-functioning lesions. Nine patients died from progressive tumor disease during follow-up. Consistent with previous studies, we found that surgery is indicated in MEN-1 patients with hyperinsulinism even if a lesion is not visualized by radiology. In addition, these indications should be extended to also include patients with only biochemical markers of disease, including elevations of gastrin, as these indicate the presence of gross tumors.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical characteristics, treatment and survival in patients with pancreatic tumors causing hormonal syndromes.

Eighty-five patients with endocrine pancreatic tumors associated with clinical syndromes of hormone excess were retrospectively analyzed regarding symptomatology, means of diagnosis, and results of surgical and medical treatment during follow-up of 3-18 years (median 8 years). The combination of angiography and computed tomography was most successful in pre-operative localization of both primary tumors and metastases. Surgery provided long term cure in 39 of 44 patients with benign islet cell lesions, the majority having insulinomas. Forty-one patients had malignant tumors, which at the time of diagnosis or operation were associated with liver and/or regional lymph gland metastases in 56% and 24%, respectively. Sixteen patients with metastatic disease and/or very large tumors were considered inoperable, 5 patients underwent palliative resection of their malignant tumors, while grossly radical tumor removal was accomplished in 20 patients. Long-term cure was achieved in 5 patients by excision of primary tumors and localized liver or lymph gland metastases. Half of the patients, particularly those with insulinoma, gastrinoma, or vipoma, showed response to streptozotocin, in combination with other cytostatics, for a median of 24 months or a response to interferon for a median of 10 months. The overall 5-year and 10-year survival among the patients with malignant islet cells tumors was 54% and 28%, respectively. Absence of liver metastases at time of operation/diagnosis, smaller size of the primary tumor, grossly radical tumor resection as well as response to medical therapy predicted the more favorable survival.

[Therapy and prognosis of medullary thyroid cancer]. / Therapie und Prognose des medullären Schilddrüsenkarzinoms.

Medullary thyroid cancers have different morphological, endocrine and biological qualities than all the other tumors of the thyroid. Therapy is the thyroidectomy with modified, radical neck dissection. The ten year survival rate was 65% in our own patient material. The prognosis depended on tumor size, invasion of vessels by the tumor, grade of differentiation, tumor stage, metastasis and radicality of the operation.

The natural history of multiple endocrine neoplasia type 2A--a clinical analysis.

The records of 18 patients with multiple endocrine neoplasia (MEN) type 2A in a family consisting of 87 members in 5 generations, were reviewed with respect to age at onset and length of survival in a study of the natural history of this syndrome. Of these 18 patients, 8 were alive following surgical treatment, while 10 had died without treatment. The clinical onset of medullary thyroid carcinoma was noticed as a nodule in the neck at between 17 and 34 years of age (mean 24 years); the onset of pheochromocytoma was characterized by palpitation, hypertensive attacks or recurrent headache at between 17 and 42 years of age (mean 27 years); and death occurred in 10 patients at between 23 and 67 years of age (mean 40.6 years). This information on the age at onset of individual clinical manifestations, and on the length of survival of gene carriers, may be useful for clinicians who are asked to assess the risk of the development of this syndrome in a genetically predisposed asymptomatic individual, because screening tests are often refused by members of Japanese families with MEN type 2A.

Quality of life after bilateral adrenalectomy in MEN 2.

Pheochromocytoma is a major cause of morbidity and mortality in the multiple endocrine neoplasia type 2 (MEN 2) syndrome. For the physician, surgical treatment seems well justified even though bilateral adrenalectomy will induce iatrogenically complete loss of adrenocortical function. For the patient this treatment may be a cause of medical problems as well as worry. We have evaluated quality of life after bilateral adrenalectomy in 27 MEN 2 patients through a combined oral and written approach. Mortality was low (one of 27), as was serious morbidity. Most patients had adapted well to the postadrenalectomy state. However, fatigue, worry, and noncompliance with daily medication often caused problems.

Multiple endocrine neoplasia type 1 (MEN-1). Clinical, biochemical and genetical investigations.

The syndrome of multiple endocrine neoplasia type 1 is an autosomal dominantly inherited disease affecting several endocrine organs. The affected organs include the pituitary, the parathyroids and endocrine pancreas, where different types of lesions can be found, such as hyperplasia or frank carcinomas. The most life threatening lesions are the endocrine pancreatic tumors, which cause about 80% of all deaths among the MEN-1 members. In our own series of 108 members from 16 families with multiple endocrine neoplasia, 55 members had the MEN-1 trait. Among these members, pituitary lesions were found in 42%, parathyroid involvement in 89% and endocrine pancreatic tumors in 58%. Hyperparathyroidism was the presenting lesion of the MEN-1 trait. By using a specific meal stimulation test we have been able to unveil pancreatic lesions up to a median of five years previous to radiological detection. Very recently we have been able to detect a specific genetic lesion in MEN-1 members by studying DNA rearrangements with recombinant DNA technique, using the method of polymorphic restriction enzyme recognition in three large kindreds. The MEN-1 locus maps to chromosome 11q and the MEN-1 predisposition would be a constitutional mutation in heterozygous form, inherited as an autosomal dominant trait. Tumor development involves a second mutational event which involves the chromosome 11, carrying the remaining 'wild' type allele at the MEN-1 locus by means of chromosome loss event. Survival analysis demonstrates that patients with the MEN-1 syndrome had a significantly better survival from diagnosis than patients with sporadic endocrine pancreatic tumors (median 15.1 years and 5.8 years respectively, p = 0.0068). Earlier diagnosis and start of treatment might account for a longer survival in the MEN-1 group, but a possibility of differences in tumor biology between familial and sporadic endocrine pancreatic tumors cannot be ruled out. The surgical treatment of patients with MEN-1 include resection of the parathyroids with transplantation of a piece of the gland to the forearm, resection of endocrine pancreatic tumors in the tail and local enucleation of tumors in the pancreatic head and body. Total pancreatectomy should be avoided in most instances. The causative medical treatment of patients with malignant endocrine pancreatic tumors and the MEN-1 trait include chemotherapy (streptozotocin plus 5-fluorouracil), interferons and the somatostatin analogue SMS 201-995.

Medullary thyroid carcinoma: prognosis of familial versus sporadic disease and the role of radiotherapy.

A retrospective study of 202 patients with medullary thyroid carcinoma (MTC) diagnosed between 1943 and 1987 was done to compare the prognosis of patients with sporadic disease and those with the familial form of multiple endocrine neoplasia type II and to study the effect of radiotherapy. Patients with multiple endocrine neoplasia type II had a significantly higher survival rate than did patients with the sporadic variety (P less than 0.005), but most patients with sporadic tumors were older and had more advanced disease. No differences in survival rates were found when patients from these 2 groups were matched for age and involvement of the thyroid gland only (P greater than 0.3), involvement of the thyroid gland plus cervical nodes (P greater than 0.3), and involvement of the thyroid gland, cervical nodes, and soft tissue (P greater than 0.7). When patients with MTC who received radiotherapy were matched for age, extent of disease, and surgery with patients who had had no radiotherapy, the latter group was found to live significantly longer (P less than 0.05). We conclude that 1) the apparently poor prognosis of patients with the sporadic variety of MTC may be related to the patients' older age at detection rather than to inherent differences in the two forms of disease, and 2) radiotherapy has little effect on MTC.

Early surgical treatment of gastrinoma.

Medical treatment of the Zollinger-Ellison syndrome has been generally accepted because of the proven efficacy of the histamine (H2)-receptor antagonists in achieving symptomatic relief, and because of early reports indicating that few, if any, gastrinomas were resectable for cure. Gastrin radioimmunoassay (RIA) has made earlier and more certain diagnosis possible, and therefore reevaluation of the surgical management of gastrinomas is necessary. Experience with 60 gastrinoma patients is reported. Comparison between the pregastrin RIA years (before 1970) and post-gastrin RIA years was made to determine whether there was evidence to support the continuation of medical treatment without attempts to resect the gastrinoma. Twenty-five cases were diagnosed in the pre-RIA years. Age at diagnosis ranged from 17 to 68 years (median, 45 years). All patients were operated on. Metastases were found in 56 percent. No tumor was identified in 8 percent. Tumor was resected for "cure" (normal fasting gastrin levels for two years postoperatively) in one patient. Seventeen patients have died, and tumor was the cause of death in 70 percent. The five-year survival rate was 44 percent; the 10-year survival rate was 40 percent. Thirty-five cases were diagnosed after 1970. Age at diagnosis ranged from 39 to 61 years (median, 46 years). Thirty patients were operated on. Metastases were identified in 23 percent and no tumor was found in 17 percent. Tumor was resected for "cure" in 30 percent of patients. Seven patients have died and tumor caused death in 42 percent. The five-year survival rate was 82 percent; the 10-year rate was 64 percent. Advances in diagnosis and surgical technique since 1970 have made early operative treatment applicable in patients with gastrinoma. Because death in most cases is caused by progression of the tumor, an aggressive surgical approach to resect the tumor is advised soon after the diagnosis of Zollinger-Ellison syndrome is established.

Management of the Zollinger-Ellison syndrome in patients with multiple endocrine neoplasia type I.

Treatment of the Zollinger-Ellison syndrome (ZES) in patients with multiple endocrine neoplasia type I (MEN I) is controversial. Unlike other patients with ZES who have a single tumor and in whom curative surgical resection is possible and desirable, patients with ZES and MEN I tend to have multiple pancreatic islet cell tumors. Therefore the chances for surgical cure are usually different. A retrospective review of 25 patients with ZES as a manifestation of MEN I seen at our institution between 1960 and 1984, an interval during which histamine type 2 (H2) receptor antagonists were introduced, provided an opportunity to study this problem. Follow-up averaged 6 1/2 years. All patients diagnosed before 1979 (14 patients) underwent surgical exploration. Ten patients (71%) had pancreatic procedures (five enucleation, four partial pancreatectomy, and one enucleation of multiple nodules with subsequent total pancreatectomy). None of these procedures was curative, and all patients required further medical and/or surgical therapy for peptic ulceration. Eighteen patients (72%) underwent gastric surgery. Seven patients had subtotal gastrectomy, five of whom required subsequent total gastrectomy. Thirteen patients ultimately had total gastrectomy. There were no immediate postoperative deaths. All patients with diagnoses since 1979 (11 patients) had H2-antagonist therapy as primary treatment. No significant complications were associated with this approach during a mean treatment period of 26 months. Only one of these patients subsequently has required gastric surgery. The proved efficacy of H2 antagonists, coupled with the recognition of the diffuse nature of the pancreatic disease in these patients, has led to a change in the therapeutic approach over the period reviewed. H2-antagonist therapy should be the initial treatment of choice in patients with MEN I who have ZES.