John L. Doppman

Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma. An ultrastructural, immunohistochemical, and flow cytometric study of 35 cases.

Based on our review of 35 cases and the literature, we found the spectrum of pulmonary neuroendocrine (NE) tumors to be too broad to fit into the traditional threecategory classification scheme of typical carcinoid (TC), atypical carcinoid (AC), and small-cell lung carcinoma (SCLC). We found that a spectrum of high-and low-grade tumors exist between TC and SCLC and that in the past many of these tumors have been called AC. We chose to adhere to Arrigonis definition of AC, as his original criteria characterized a low-grade tumor. For the higher grade non-small-cell tumors (NSCLC), we propose a fourth category of large-cell neuroendocrine carcinoma (LCNEC), which is characterized by: (a) light microscopic NE appearance; (b) cells of large size, polygonal shape, low nuclear-cytoplasmic ratio (N:C), coarse nuclear chromatin, and frequent nucleoli; (c) high mitotic rate [> 10/10 high-power fields (HPF)] and frequent necrosis; and (d) NE features by immunohistochemistry (IHC) or electron microscopy (EM). Thus, after deciding that a pulmonary NE tumor is high grade, the major diagnostic issue is separation of LCNEC from SCLC. This distinction is based not only on cell size, but on a variety of morphologic features. We studied 20 TC, six AC, five LCNEC, and four SCLC and characterized the clinical, light microscopic, EM, IHC, and flow cytometric features of each type of tumor. We did not find any advantage to IHC. EM, or flow cytometry over light microscopy in the subclassification or prediction of prognosis; however, these methods were useful in characterizing these four types of pulmonary NE tumors and in demonstrating their NE properties. LCNEC must be distinguished from a fifth category pulmonary NE tumor: NSCLC with NE features in which NE differentiation is not evident by light microscopy and must be demonstrated by EM or IHC. Although the prognosis of LCNEC appears to be intermediate between AC and SCLC, larger numbers of patients will be needed to demonstrate significant differences in survival.

Petrosal Sinus Sampling with and without Corticotropin-Releasing Hormone for the Differential Diagnosis of Cushing's Syndrome

BACKGROUND Measurement of adrenocorticotropin levels in plasma from the inferior petrosal sinuses of patients with Cushings syndrome can distinguish adrenocorticotropin-secreting pituitary tumors (Cushings disease) from other causes of the syndrome, principally ectopic adrenocorticotropin secretion from an occult tumor. However, it is unknown whether such measurement consistently identifies patients with Cushings disease and whether testing with corticotropin-releasing hormone (CRH) enhances the value of the procedure. METHODS We prospectively studied 281 patients with Cushings syndrome to evaluate the diagnostic efficacy of the procedure. Bilateral sampling was successfully accomplished in 278 patients, with no major morbidity; 262 of these patients underwent sampling before and after administration of ovine CRH. The adrenocorticotropin levels in the samples were used to calculate the ratio of the concentration in plasma from the inferior petrosal sinuses to the concentration in peripheral-blood plasma (the IPS:P ratio). RESULTS The diagnosis of 246 patients was confirmed surgically as Cushings disease in 215, as ectopic adrenocorticotropin syndrome in 20, and as primary adrenal disease in 11. An IPS:P ratio greater than or equal to 2.0 in basal samples identified 205 of the 215 patients with Cushings disease (sensitivity, 95 percent), with no false positive results (specificity, 100 percent). A peak IPS:P ratio greater than or equal to 3.0 after CRH administration identified all 203 of the patients with Cushings disease who received CRH (sensitivity, 100 percent), with no false positive results (specificity, 100 percent). The sensitivity was much lower when the adrenocorticotropin concentrations in the samples from one sinus were considered alone. In patients with Cushings disease a difference of greater than or equal to 1.4-fold between the concentrations in the two sinuses (the adrenocorticotropin gradient) predicted the location of the microadenoma in 68 percent of 104 patients during basal sampling and in 71 percent of 105 patients after CRH administration. CONCLUSIONS Simultaneous bilateral sampling of plasma from the inferior petrosal sinuses, with the adjunctive use of CRH, distinguishes patients with Cushings disease from those with ectopic adrenocorticotropin secretion with high diagnostic accuracy.

Pituitary magnetic resonance imaging in normal human volunteers: occult adenomas in the general population.

Magnetic resonance imaging (MRI) at 1.5 tesla, combined with the use of the paramagnetic contrast agent, gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA), enhances the capacity to visualize the pituitary gland and to screen patients for pituitary adenomas. However, in autopsy series of unselected humans, the prevalence of silent pituitary adenomas was estimated to be 3% to 27% [1-5]. If there is a substantial prevalence of occult pituitary adenomas detected by MRI in the general population, the usefulness of MRI as a screening test or as a method to confirm the pituitary cause of endocrinopathy is compromised. To determine the prevalence of focal pituitary lesions compatible with the diagnosis of a pituitary adenoma in humans with normal endocrine function, we did MRI scans of the pituitary gland before and after administration of Gd-DTPA in 100 volunteers. Methods Seventy women and 30 men, 18 to 60 years old, were recruited from the general population and the normal-volunteers office of the National Institutes of Health. The volunteers had normal physical examinations and were selected by age and sex to correspond to the distribution of patients with symptomatic pituitary adenomas [6, 7]. Fifty-eight of the women (83%) were between 20 and 45 years old, and 27 of the men (90%) were between 30 and 60 years old. Random basal values of serum prolactin and -subunit, plasma growth hormone, thyroid-stimulating hormone, thyroxine, triiodothyronine, free thyroxine, and thyroxine-binding globulin were measured. Young women selected for the study had normal menstrual cycles. Persons with previous or current endocrine disturbances were excluded. The protocol was approved by the Investigational Review Board of the National Institute of Neurological Disorders and Stroke, and all participants gave informed consent. Magnetic Resonance Imaging All scans were obtained with a 1.5-T scanner (Sigma, General Electric; Milwaukee, Wisconsin). T1-weighted coronal and sagittal images of the pituitary fossa were obtained with a repetition time (TR) of 600 ms and an echo time (TE) of 15 ms (TR/TE = 600/15). In the coronal plane, interleaved sections 3 mm in thickness without intersection gap were obtained with two repetitions and a 16-cm field of view. The acquisition matrix was 256 192. Gadolinium-DTPA (0.1 mmol/kg body weight) was administered intravenously over 2 minutes, and the T1-weighted coronal images were repeated immediately (Figure 1). Figure 1. Pituitary magnetic resonance scan of a normal volunteer. Left. Right. Evaluation of Pituitary Glands Magnetic resonance scans were interpreted independently by three experienced reviewers. The scans of the normal volunteers were randomly mixed with scans of 57 patients with surgically confirmed Cushing disease. The reviewers were aware that the scans of the patients had been intermingled with those of the volunteers. Identifying information for patients and volunteers was masked. Reviewers evaluated the pituitary gland before and after the administration of Gd-DTPA by appraising gland and sellar size, stalk deviation, gland convexity, and position and size of focal pituitary abnormalities. Measurements were made with hand-held calipers. The readers also provided a summary interpretation of each MRI scan. The diagnosis of a pituitary abnormality, including the presence of an adenoma, was accepted only when the same area of the gland was independently interpreted as similarly abnormal by at least two of the three reviewers. Results Pituitary Gland Magnetic Resonance Scans in Normal Volunteers Pituitary Size and Shape The mean gland height in the 100 volunteers was 6.9 0.1 mm. It was greater in women (7.1 1.3 mm; mean SD) than in men (6.6 1.2 mm; P = 0.008). On coronal scans, the superior surface of the gland was convex upward in 33 persons (29 women). Upward convexity of the superior surface of the gland was limited to one side in 21 persons (12 right, 10 left) and occurred centrally in 11. The posterior pituitary gland was identified as a small focus of high-signal intensity in the posterior sella by at least two reviewers in 92 persons (by three reviewers in 77). One participant was considered to have an enlarged sella. Fifty-nine volunteers were interpreted by all three reviewers as having a normal pituitary gland. In 3, cerebrospinal fluid filled the superior portion of the sella (partially empty sella). Focal Pituitary Abnormalities Before Gd-DTPA was administered, 22 sites of focal abnormal signal intensity in the pituitary were detected by at least one reviewer in 21 volunteers (Table 1). All three reviewers considered the same site as an adenoma (by the presence of an area of low-signal intensity) in 1 person. Seven (6 women, 1 man) had focal areas of decreased signal, which were interpreted by at least two of the three reviewers as adenomas. Fourteen sites in 13 persons were considered abnormal by a single reviewer. Table 1. Pituitary Magnetic Resonance Imaging in 100 Normal Women and Men After Gd-DPTA was administered, 41 different sites of abnormal signal intensity in the pituitary gland were detected in 34 volunteers. Ten of them (7 women, 3 men) had focal areas of decreased signal intensity that were interpreted as pituitary adenomas by at least two reviewers. All three reviewers considered the same site as an adenoma in 2 persons. Six of the 7 women were 25 to 45 years old (1 was 48 years old) and the men were 22, 35, and 53 years old. The lesions were 3 3 mm to 6 6 mm in diameter (coronal plane). Thirty-two sites in 23 participants were considered abnormal by a single reviewer. The scan of only 1 volunteer interpreted as having an adenoma had stalk deviation. An upward convex shape of the superior surface of the pituitary gland occurred in 8 of the 10 volunteers considered to have an adenoma. However, in only five of these studies was the elevation on the side of the lesion. Endocrine Screening Tests The endocrine studies done were normal in the 10 persons with an abnormal MRI scan. In the 90 volunteers whose MRI scans were interpreted as normal, 3 (1 woman, 41 years old; 2 men, 37 and 48 years old) had evidence of mild primary hypothyroidism. Three women (33, 34, and 44 years old) had elevated growth hormone levels (>10 g/L; single random sample). Pituitary Gland Magnetic Resonance Scans in Patients with Cushing Disease Cushing disease was confirmed by adrenocorticotropin staining of an adenoma or by remission of hypercortisolism after selective adenomectomy or hemihypophysectomy. Five macroadenomas and 45 microadenomas were identified at surgery in the 57 patients with Cushing disease. In the 50 patients with adenomas identified at surgery, 56% (all patients with macroadenomas and 51% of 45 patients with microadenomas) had areas of focal low-signal intensity after administration of Gd-DTPA that were diagnosed by at least two reviewers as adenomas. However, in 4 of the 23 patients with microadenomas and a focal pituitary MRI abnormality, the position of the adenoma in the gland was incorrect as read on the MRI scan. In two patients, the MRI scan indicated a lateral tumor, but the tumor was found in the midline at surgery. In the third patient the reverse occurred, and in the fourth the tumor was found on the opposite side of the gland. Thus, 26 of 45 (58%) of the 45 microadenomas that were large enough to be found and selectively excised at surgery were not detected by MRI. The size of the tumors that were not detected (6 2 mm) did not differ significantly from the size of those that were (5 2 mm). Discussion The configuration of the pituitary gland is influenced by age and sex, the location of the carotid arteries, the shape of the pituitary fossa, transmission of cerebrospinal fluid pulsation into the sella turcica permitted by an incompetent diaphragma sella, and the presence of an intrasellar mass [8-12]. The results of our study of the size and shape of the normal pituitary gland confirm the findings of other studies using computed tomography (CT) or MRI scanning without Gd-DPTA enhancement [11, 12]. A convex contour of the superior surface of the pituitary gland was once considered to be unusual or abnormal [3, 11, 12]. (However), recent studies using CT or MRI scanning found that convex superior contours occur in as many as 35% to 44% of women of childbearing age [9, 12, 13]. An upward convex shape of the superior surface of the pituitary gland occurred in 34% of our 70 women. Deviation of the pituitary stalk also has been suggested as an indirect sign of the presence and site of an adenoma. However, rates of stalk deviation as high as 46% have been reported in normal persons [14]. Stalk deviation occurred in 13% of our volunteers. The 4% incidence of an empty sella in our volunteers agrees with the 3% to 4% prevalence reported by others using CT [3, 12] and MRI [13]. Autopsy series estimate the prevalence of asymptomatic pituitary adenomas to be 1.5% to 27% [1-6]. Microscopic examination of the pituitary gland at autopsy is much more sensitive than contrast-enhanced MRI scanning for detecting adenomas, and immunohistochemical techniques allow direct hormonal assessment of the tissue. However, the prevalence of asymptomatic adenomas in a young adult cohort is unknown because autopsy series do not accurately reflect this population. Young women, the group in which symptomatic pituitary tumors occur most frequently, are under-represented in autopsy studies. Previous imaging techniques, such as plain roentgenography, polytomography, and pneumoencephalography, were unreliable for detecting pituitary microadenomas [1]. Shortly after its introduction, CT scanning became the diagnostic procedure of choice for examining the pituitary gland because it was noninvasive, offered improved resolution, and, for the first time, permitted direct visualization of the pituitary gland. By high-resolution, contrast-enhanced CT scanning, Wolpert and colleagues [12] identified p

Somatostatin Receptor Scintigraphy: Its Sensitivity Compared with That of Other Imaging Methods in Detecting Primary and Metastatic Gastrinomas: A Prospective Study

Studies have shown that many tumors, such as gastroenteropancreatic tumors (pancreatic endocrine tumors, carcinoid tumors), various lymphomas, and central nervous system tumors (meningiomas, astrocytomas), have a high density of somatostatin receptors and can be imaged in vivo by using somatostatin receptor scintigraphy with either [123I-Tyr3]octreotide or [111In-DTPA-DPhe1]octreotide [1-6]. Recently, [111In-DTPA-DPhe1]octreotide was approved for use in the United States for the imaging of primary and metastatic neuroendocrine tumors [6]. Many conventional imaging methods, including ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), selective arteriography, and selective intra-arterial secretin stimulation with venous sampling, already exist for the localization of gastroenteropancreatic tumors [7-10]. Although numerous studies have shown somatostatin receptor scintigraphy to be sensitive for the detection of neuroendocrine tumors, information on its sensitivity compared with that of other imaging techniques is limited; thus, it is difficult for the practitioner to define the potential role of somatostatin receptor scintigraphy in the evaluation of a patient with a gastroenteropancreatic syndrome. This is important because somatostatin receptor scintigraphy and the other imaging studies are expensive [1] and because accurate localization of the primary tumor is particularly important for the management of neuroendocrine tumors, which are often small and difficult to find [11-13]. Furthermore, accurate assessment of the extent of the tumor is essential for making decisions about resectability, tumoricidal therapy, disease progression, and liver transplantation [8, 14, 15]. Because neuroendocrine tumors are uncommon [8], many studies do not provide the data needed to define the role of somatostatin receptor scintigraphy in the management of these tumors. Several studies have compared the sensitivity of somatostatin receptor scintigraphy with that of ultrasonography or CT by assessing tumor detection on a lesion-by-lesion basis. However, few studies have compared somatostatin receptor scintigraphy with the most sensitive conventional imaging studies, particularly selective arteriography and MRI using STIR (short-time inversion-inversion recovery sequences) [8, 16, 17]. Thus, it is difficult to know the sensitivity and the role of somatostatin receptor scintigraphy in relation to these methods. Furthermore, only one study [18] has evaluated the possibility of conventional imaging combined with somatostatin receptor scintigraphy; therefore, it remains unclear whether additional localization studies are helpful when somatostatin receptor scintigraphy results are negative. Finally, most studies have not assessed the sensitivity of somatostatin receptor scintigraphy relative to other methods in different clinical situations. Patients with gastroenteropancreatic tumors are assessed for location of the primary tumor (to assist in possible tumor resection [7, 11-13]), for metastasis to the liver (for possible resectability [8, 14, 19, 20]), for the need for tumoricidal therapy [21], and for distant metastases (for possible specific tumoricidal therapies, such as local radiation to bone metastases [22]). Different localization methods are better for certain clinical situations [8, 9, 17], and somatostatin receptor scintigraphy needs to be compared with other methods in each of these clinical circumstances. Sixty percent to 90% of patients with the Zollinger-Ellison syndrome have malignant tumors, and their tumors thus resemble all pancreatic endocrine tumors with the exception of insulinomas [8, 23, 24]. The Zollinger-Ellison syndrome occurs more frequently than other malignant pancreatic endocrine tumors. Therefore, several groups, including ours, have a sufficient number of patients with this syndrome to be able to systematically address questions about localization in different clinical situations [8, 25, 26]. Gastrinomas resemble other, less common pancreatic endocrine tumors in that they are composed of amine precursor uptake and decarboxylation (APUD) cells and have similar growth patterns, locations, imaging properties, metastatic rates, immunohistochemistry, and rates of occurrence of somatostatin receptors [24, 27]. Gastrinomas are therefore an excellent model from which to obtain information that is also pertinent to the less common pancreatic endocrine tumors [25]. We prospectively compared the ability of somatostatin receptor scintigraphy with that of other conventional localization methodsultrasonography, CT, MRI, bone scanning, and selective angiographyin the localization of primary and metastatic gastrinoma in patients with the Zollinger-Ellison syndrome. Methods We prospectively studied 80 consecutive patients with the Zollinger-Ellison syndrome who were admitted to the National Institutes of Health (NIH) between June 1994 and May 1995. Our study is part of a prospective study of patients with the Zollinger-Ellison syndrome that has been ongoing at the NIH since 1974, as approved by the clinical research committee of the National Institute of Diabetes and Digestive and Kidney Diseases. Thirty-one of the patients had no previous gastrinoma resection, and 49 had had noncurative resections of gastrinomas 0.25 years to 13 years before the study. The Zollinger-Ellison syndrome was diagnosed as described elsewhere [28]. Serum gastrin levels were determined by Bioscience Laboratories (New York, New York). The diagnostic criteria for the presence of multiple endocrine neoplasia type I in a patient with the Zollinger-Ellison syndrome have been described elsewhere [29]. Basal acid output and maximal acid output were determined for each patient by using methods described previously [30]. Doses of oral antisecretory drug were determined by establishing the dose required to reduce gastric acid output to less than 10 mEq per hour before the next dose of medication and to less than 5 mEq per hour for patients who had had gastric acid-reducing surgery or who had advanced esophageal disease [31]. Specific Protocol The localization and the extent of gastrinomas were evaluated in all patients as described elsewhere [17, 32] by using upper gastrointestinal endoscopy, CT, MRI, transabdominal ultrasonography [33], and bone scanning. With MRI, T1-weighted spin-echo sequences and STIR sequences were obtained with a repetition time of 400 to 600 ms and an echo time of 10 ms as described [16]. We did CT as described [16, 17] at 10-mm thickness with an oral contrast agent (diatrizoate sodium, Winthrop-Breon, Rensselaer, New York) with and without the rapid (2 mL/s) intravenous injection of the contrast agent iopamidol 300 (Winthrop-Breon). If surgical exploration was being considered or the extent of disease remained unclear, selective abdominal angiography was done with injection of the splenic, superior mesenteric, gastroduodenal, and hepatic arteries as described elsewhere [17, 34]. One radiologist evaluated the results of all conventional imaging studies. For somatostatin receptor scintigraphy studies, patients were hydrated before and after the intravenous injection of [111In-DTPA-DPhe1]octreotide and were given a laxative on the night of administration to avoid artifacts from radioactive accumulation in the intestines. Each patient received 6 mCi of [111In-DTPA-DPhe1]octreotide intravenously as recommended by the manufacturer for single-photon emission computed tomographic (SPECT) imaging (Mallinckrodt Diagnostic Imaging Service Radiopharmacy, Beltsville, Maryland). Images were obtained 4 and 24 hours after injection using a TRIONIX (Twinburg, Ohio) or ADAC (Milipitas, California) dual-headed camera with 20% windows at 173 and 247 keV. At 4 hours, a 30-minute whole-body scan was obtained; 10-minute planer spot views of the abdomen and other regions were obtained as needed. At 35 minutes and at 24 hours, SPECT images of the abdomen were obtained. Forty-second, 128 128 matrix SPECT images were acquired at 4-degree intervals over 360 degrees. The images were reconstructed with the manufacturers software using a standard filter back projection algorithm. A Hamming filter was used. Images were displayed as orthogonal (transverse, coronal, sagittal) sections and as reprojected views. Results of somatostatin receptor scintigraphy were obtained while the investigator was blinded to the results of the conventional imaging studies. Surgical exploration was done in all new patients and all patients who had a positive extrahepatic gastrinoma localized, had no liver metastases, had multiple endocrine neoplasia type I or a recent exploration (< 2 years), and had had exploratory laparotomy for possible gastrinoma resection (n = 15). All patients with possible liver metastases had percutaneous CT- or ultrasonography-guided biopsies (n = 24). Statistical Analysis The Fisher exact test was used to compare independent percentages, and the McNemar test was used to compare sensitivities in the same patients. Two-tailed P values and 95% CIs from the StatXact statistical package (Version 3.0, Cytel Software Corp., Cambridge, Massachusetts) are reported. P values less than 0.05 were considered statistically significant. Results The clinical and laboratory characteristics of the 80 study patients are shown in Table 1. These patients resemble patients in other large series [8, 35] with regard to sex, age, multiple endocrine neoplasia type I, basal acid output, maximal acid output, fasting serum gastrin concentration, and disease duration. Table 1. Clinical and Laboratory Characteristics of Patients with the Zollinger-Ellison Syndrome* Somatostatin receptor scintigraphy detected tumors either inside or outside of the liver in 56 of the 80 patients (70%); conventional imaging studies were significantly less sensitive (P < 0.001) (Figure 1). Angiography, CT, and MRI each detected tumors in 38% to 45% of patients; ultrasonograph

Prospective Study of the Clinical Course, Prognostic Factors, Causes of Death, and Survival in Patients With Long-Standing Zollinger-Ellison Syndrome

PURPOSE The long-term clinical course of unselected patients with gastrinomas as well as other functional pancreatic endocrine tumors (PETs) in whom the excess-hormone state is controlled is largely unknown. To address this issue, patients with gastrinomas were assessed. PATIENTS AND METHODS Two hundred twelve patients with Zollinger-Ellison syndrome (ZES) were prospectively studied. All had controlled acid hypersecretion and were assessed yearly, with a mean follow-up period of 13.8+/-0.6 years (range, 0.1 to 31 years). Annual assessments of possible factors that might affect prognosis or treatment approaches were performed, such as those for tumor size and location; the presence, location, and extent of metastases; and the occurrence of ectopic Cushings syndrome or another PET syndrome. Deaths were categorized as ZES-related or non-ZES-related and classified into different causes. RESULTS Thirty-one percent of patients died, all of non-acid-related causes. One half died of a ZES-related cause; they differed from those who died of non-ZES deaths by having a large primary tumor, more frequently a pancreatic tumor; lymph node, liver, or bone metastases; ectopic Cushings syndrome; or higher gastrin levels. The extent of liver metastases correlated with survival rate. The presence of liver metastases alone only moderately decreased survival time; however, the additional development of bone metastases or ectopic Cushings syndrome markedly decreased survival rate. CONCLUSIONS In ZES, gastrinoma growth is now the main single determinant of long-term survival, with one half of patients dying a gastrinoma-related death and none an acid-related death. Large primary tumors that are pancreatic in location, the development of liver metastases, (especially if associated with bone metastases or Cushings syndrome), and the extent of liver metastases are all important prognostic factors. The identification of these factors allows the recognition of subgroups that can be used to tailor antitumor treatment approaches.

Zollinger-Ellison syndrome. Clinical presentation in 261 patients.

We prospectively evaluated the initial presenting symptoms in 261 patients with Zollinger-Ellison syndrome (ZES) over a 25-year period. Twenty-two percent of the patients had multiple endocrine neoplasia-type 1 (MEN-1) with ZES. Mean age at onset was 41.1 +/- 0.7 years, with MEN-1 patients presenting at a younger age than those with sporadic ZES (p < 0.0001). Three percent of the patients had onset of the disease < age 20 years, and 7% > 60 years. A mean delay to diagnosis of 5.2 +/- 0.4 years occurred in all patients. A shorter duration of symptoms was noted in female patients and in patients with liver metastases. Abdominal pain and diarrhea were the most common symptoms, present in 75% and 73% of patients, respectively. Heartburn and weight loss, which were uncommonly reported in early series, were present in 44% and 17% of patients, respectively. Gastrointestinal bleeding was the initial presentation in a quarter of the patients. Patients rarely presented with only 1 symptom (11%); pain and diarrhea was the most frequent combination, occurring in 55% of patients. An important presenting sign that should suggest ZES is prominent gastric body folds, which were noted on endoscopy in 94% of patients; however, esophageal stricture and duodenal or pyloric scarring, reported in numerous case reports, were noted in only 4%-10%. Patients with MEN-1 presented less frequently with pain and bleeding and more frequently with nephrolithiasis. Comparing the clinical presentation before the introduction of histamine H2-receptor antagonists (pre-1980, n = 36), after the introduction of histamine H2-receptor antagonists (1981-1989, n = 118), and after the introduction of proton pump inhibitors (PPIs) (> 1990, n = 106) demonstrates no change in age of onset; delay in diagnosis; frequency of pain, diarrhea, weight loss; or frequency of complications of severe peptic disease (bleeding, perforations, esophageal strictures, pyloric scarring). Since the introduction of histamine H2-receptor antagonists, fewer patients had a previous history of gastric acid-reducing surgery or total gastrectomy. Only 1 patient evaluated after 1980 had a total gastrectomy, and this was done in 1977. The location of the primary tumor in general had a minimal effect on the clinical presentation, causing no effect on the age at presentation, delay in diagnosis, frequency of nephrolithiasis, or severity of disease (strictures, perforations, peptic ulcers, pyloric scarring). Disease extent had a minimal effect on symptoms, with only bleeding being more frequent in patients with localized disease. Patients with advanced disease presented at a later age and with a shorter disease history (p = 0.001), were less likely to have MEN-1 (p = 0.0087), and tended to have diarrhea more frequently (p = 0.079). A correct diagnosis of ZES was made by the referring physician initially in only 3% of the patients. The most common misdiagnosis made were idiopathic peptic ulcer disease (71%), idiopathic gastroesophageal reflux disease (GERD) (7%), and chronic idiopathic diarrhea (7%). Other less common misdiagnosis were Crohn disease (2%) and various diarrhea diseases (celiac sprue [3%], irritable bowel syndrome [3%], infectious diarrhea [2%], and lactose intolerance [1%]). Other medical disorders were present in 55% of all patients; patients with sporadic disease had fewer other medical disorders than patients with MEN-1 (45% versus 90%, p < 0.00001). Hyperparathyroidism and a previous history of kidney stones were significantly more frequent in patients with MEN-1 than in those with sporadic ZES. Pulmonary disorders and other malignancies were also more common in patients with MEN-1. These results demonstrate that abdominal pain, diarrhea, and heartburn are the most common presenting symptoms in ZES and that heartburn and diarrhea are more common than previously reported. The presence of weight loss especially with abdominal pain, diarrhea, or heartburn is an important clue suggesting the presence of gastrinoma. The presence of prominent gastric body folds, a clinical sign that has not been appreciated, is another important clue to the diagnosis of ZES. Patients with MEN-1 presented at an earlier age; however, in general, the initial symptoms were similar to patients without MEN-1. Gastrinoma extent and location have minimal effects on the clinical presentation. Overall, neither the introduction of successful antisecretory therapy nor widespread publication about ZES, attempting to increase awareness, has shortened the delay in diagnosis or reduced the incidence of patients presenting with peptic complications. The introduction of successful antisecretory therapy, however, has dramatically decreased the rate of surgery in controlling the acid secretion and likely led to patients presenting with less severe symptoms and fewer complications. (ABSTRACT TRUNCATED)

Localization of Insulinomas to Regions of the Pancreas by Intra-arterial Stimulation with Calcium

Despite the introduction of sophisticated cross-sectional imaging techniquescomputed tomography, magnetic resonance imaging, and ultrasonographythe localization of insulinomas smaller than 2 cm remains a problem. In our previous experience [1], these noninvasive methods of localization had sensitivities of 17% (computed tomography), 25% (magnetic resonance imaging), and 26% (ultrasonography). Our results may have been biased because most patients have negative results on noninvasive imaging studies before referral to the National Institutes of Health. Of the invasive localization techniques, pancreatic arteriography visualized 35% of small (<2 cm) insulinomas. The success of portal venous sampling does not depend on tumor size, and this method localized insulinomas in 77% of patients. However, percutaneous portal venous sampling requires special skills and experience and is associated with slight but significant morbidity [2]. We have developed a technique with which one can localize insulinomas before surgery by stimulating the release of insulin using selective intra-arterial injections of calcium gluconate as a secretagogue and then measuring insulin levels in the right hepatic vein. The results in our first 9 patients were promising [3, 4], and we have since studied an additional 16 patients with surgically proven insulinomas. We present the results of arterial stimulation and venous sampling in these 25 patients studied over the past 4 years. Methods Diagnosis of insulin-secreting islet cell tumor was based on the development of symptomatic hypoglycemia (blood glucose level, <40 mg/100 mL) with inappropriate plasma insulin levels during prolonged fasting. Ten of the patients were men and 15 were women; their average age was 43 years (range, 24 to 72 years). Five patients had had previous unsuccessful explorations of the pancreas, and 3 had had distal pancreatectomy during these explorations. Two patients had multiple endocrine neoplasia type I.1;0 Most of the 25 patients had had computed tomography (n = 23), magnetic resonance imaging (n = 21), and ultrasonography (n = 22) before having arteriography with calcium stimulation. The first 9 patients had portal venous sampling, but this procedure was not done in the other 16 patients because analysis showed that calcium stimulation provided similar information with less morbidity. This decision was supported by the similar sensitivities of portal venous sampling and intra-arterial secretin stimulation in our patients with the Zollinger-Ellison syndrome [5, 6]. Computed tomography (done using a 9800 HiLite, General Electric, Milwaukee, Wisconsin) was done with 5-mm contiguous sections through the pancreas during the bolus injection of 130 mL of iodinated contrast material (iopamidol [Isovue 300, Bristol-Myers Squibb, Princeton, New Jersey]) at 2 mL per second. Magnetic resonance imaging was done using a 0.5-Tesla scanner (Picker, Highland Heights, Ohio) with 10-mm thick axial T1-weighted (repetition time [TR]/echo time [TE] = 300/10) and short inversion time inversion recovery (STIR) (TR/TI [inversion time]/TE = 1800-2200/100/30) sequences. Gadopentetate dimeglumine (Magnevist, Berlex Lab, Wayne, New Jersey) was not given. Ultrasonography was done using a 3.5- or 5-MHz phased-array sector transducer (Acuson, Mountain View, California). Pancreatic arteriography was done by selectively injecting nonionic contrast agent (Isovue 300) into the gastroduodenal, splenic, and superior mesenteric arteries. Care was taken to position the catheter at the origin of these vessels so that major pancreatic arteries originating proximally from these vessels, such as the dorsal pancreatic and pancreatic magna arteries, would be perfused. Selective arteriography of the dorsal pancreatic and pancreatic magna arteries was occasionally done, but we did not infuse calcium into these small pancreatic branches because we feared that doing so might increase the risk for pancreatitis. After each selective arteriogram, calcium gluconate 10% (Lyphomed, Rosemont, Illinois), diluted with saline to a volume of 5 mL, was injected into the selectively catheterized artery at a dose of 0.025 mEq Ca++/kg body weight. Blood samples (5 mL) for insulin determination were obtained from the right (n = 25) and left (n = 17) hepatic veins before and 30, 60, and 120 seconds after calcium infusion. Specimens from the hepatic veins were placed on ice, and plasma was separated in a refrigerated centrifuge and stored at 20C until insulin levels were measured by radioimmunoassay. Samples were obtained from the left as well as the right hepatic vein in the first 17 patients because of concern that an insulinoma in the body or tail of the pancreas might be overlooked if splenic venous effluent streamed into the left hepatic lobe. However, it is more difficult to place and maintain a catheter in the left than in the right hepatic vein. To determine whether diagnostic elevations of insulin levels were ever seen only in the left hepatic vein, we compared insulin levels in the right and left hepatic veins in a subset of 10 patients whose insulinomas were in the pancreatic body and tail. The insulinomas ranged in size from 6 to 25 mm (average, 15 mm). Twelve were located to the right of the superior mesenteric artery (pancreatic head and neck), and 13 were located to the left (pancreatic body and tail). All tumors of the head and neck were enucleated. Tumors of the body and tail were removed by enucleation (n = 5) or distal pancreatectomy (n = 8). Intraoperative ultrasonography (10-MHz transducer, Diasonics, Santa Clara, California) was done in each patient to visualize the tumor, to identify major pancreatic and biliary ducts adjacent to the tumor, and to direct the pancreatic incision for enucleation. All patients were cured. Data Analysis The results of sampling from the right (n = 25) and left (n = 17) hepatic veins were plotted for each patient. Graphs were analyzed by selecting the greatest insulin response in a given vessel in the 30- or 60-second sample after injection. Each patient was coded so that, at the time of analysis, the observers were unaware of the results of any other localizing studies or of the location of the tumor at surgery. A response after calcium infusion into the gastroduodenal or superior mesenteric artery localized the adenoma to the head and neck of the pancreas; a response after splenic artery injection localized the adenoma to the body and tail of the pancreas. A response to calcium stimulation usually involved a single artery (Figure 1). When both the gastroduodenal and superior mesenteric arteries showed a response to calcium stimulation, the insulinoma was presumed to be located to the right of the superior mesenteric artery (pancreatic head and neck) (Figure 2). When no vessel was clearly dominant, the response was considered nonlocalizing (Figure 3). Figure 1. Typical sampling results from a patient with an insulinoma in the pancreatic tail. top bottom Figure 2. In a patient with an insulinoma of the pancreatic head, greater than twofold gradients were seen after calcium injection into both the gastroduodenal and superior mesenteric arteries, with higher elevations in the gastroduodenal artery (top). bottom Figure 3. The only nondiagnostic study in the last 20 cases shows elevated insulin levels in the splenic and gastroduodenal arteries. The sensitivity of calcium stimulation in all 25 patients was calculated and compared with the sensitivity of the noninvasive imaging studies (computed tomography, magnetic resonance imaging, and ultrasonography) and arteriography. Specificity was irrelevant because all patients in the series had proven insulinomas. In the 9 patients who had portal venous sampling, the sensitivity of calcium stimulation was compared with the sensitivity of portal venous sampling. To determine whether it was necessary to sample the left hepatic vein, we compared the maximum insulin levels in the right and the left hepatic veins and the ratio of insulin levels in the hepatic vein with those in the peripheral vein in a subset of 10 patients with insulinomas of the body and tail. Results The results of all localization studies are summarized in Table 1. A response to calcium stimulationthat is, a greater than twofold elevation of insulin levels in the right or left hepatic vein on the 30- or 60-second samplesoccurred in all 25 patients. Calcium stimulation with venous sampling correctly predicted the site of the insulinoma in 22 of 25 patients (sensitivity, 88% [95% CI, 68% to 97%]). In 2 of the 3 patients with false localizations, responses to gastroduodenal and splenic artery injections occurred in the presence of a tumor in the proximal body of the pancreas (Figure 3); in the third patient, a response to a superior mesenteric artery injection occurred in the presence of a tumor in the proximal body. All patients who had a positive response to splenic artery injection only had insulinomas of the body or tail. Two of the three false localizations occurred in our first 5 patients; only one false localization occurred among our last 20 patients. Table 1. Results of Localization Studies in 25 Patients with Surgically Proven Insulinomas In the nine patients who had both portal venous sampling and calcium stimulation, portal venous sampling correctly localized six insulinomas (sensitivity, 67%), and calcium stimulation correctly localized seven insulinomas (sensitivity, 78%). Among 10 patients with surgically proven insulinomas of the body and tail of the pancreas, the maximum insulin levels in response to calcium stimulation were higher in the right than in the left hepatic vein in 8 patients and were equal in the right and left hepatic veins in 1 patient (103 U/mL compared with 107 U/mL [739 pmol/L compared with 768 pmol/L]). Only 1 patient with an insulinoma of the pancreatic body had a higher insulin level in the left than in the right hepatic vein (148 U/L compa

Intraoperative Ultrasonographic Localization of Islet Cell Tumors: A Prospective Comparison to Palpation

The purpose of the present study was to evaluate prospectively the value of intraoperative ultrasound scanning (IOUS) in localizing islet cell tumors by comparing results of IOUS to those of palpation during 44 consecutive laparotomies for gastrinoma (36) or insulinoma (8). All patients had preoperative radiographic imaging studies and selective venous sampling for hormones, which guided the subsequent laparotomy. Any suspicious finding by palpation and/or IOUS was resected. Pathologic evidence of islet cell neoplasm served as the reference standard. Five patients were excluded from analysis because neither palpation nor IOUS had suspicious findings and no islet cell tumor was found. Seven pancreatic insulinomas were found in seven patients. IOUS was as sensitive as palpation at localizing insulinomas. Twenty-three pancreatic gastrinomas were found in 19 patients. IOUS was equal to palpation in the ability to localize gastrinomas. Gastrinomas that were successfully imaged by IOUS were significantly larger than gastrinomas that were not imaged. Twelve extrapancreatic gastrinomas were found in nine patients, and palpation was more sensitive than IOUS at localizing these small duodenal wall tumors. Five patients (11%) had their surgical management changed by IOUS. Two patients had pancreatic tumors (one gastrinoma and insulinoma) enucleated that would not have been found without IOUS, and three patients had resections of pathologically proven malignant islet cell tumors based on sonographic findings. All five patients were cured with short follow-up. The present results demonstrate that palpation and IOUS are complementary because IOUS can image tumors that are not palpable and IOUS can provide additional information concerning malignant potential not detected by palpation.

A prospective trial evaluating a standard approach to reoperation for missed parathyroid adenoma.

OBJECTIVES The authors evaluate the results of preoperative imaging protocols and surgical re-exploration in a series of patients with missed parathyroid adenomas after failed procedures for primary hyperparathyroidism. BACKGROUND The success rate is lower and the complication rate is increased in patients undergoing reoperation for primary hyperparathyroidism compared with initial procedures. Scarring and distortion of tissue planes plus the potential for ectopic gland location leads to this worsened outcome. METHODS Two hundred eighty-eight consecutive patients with persistent/recurrent hyperparathyroidism were treated at a single institution after a failed procedure or procedures at outside institutions. Two hundred twenty-two of these patients (77%) were believed to have a missed single adenoma, and these patients underwent 228 operations and 227 preoperative work-ups. Preoperative evaluation consisted of a combination of four noninvasive imaging studies--neck ultrasound, nuclear medicine scan, neck and mediastinal computed tomography scan, and neck and mediastinal magnetic resonance imaging. Based on the noninvasive testing alone, 27% patients underwent surgery whereas the other patients underwent invasive studies, including selective angiography (58%), selective venous sampling for parathyroid hormone (43%), or percutaneous aspiration of suspicious lesions (15%). RESULTS Abnormal parathyroid adenomas were found in 209 of 222 initial procedures and 6 of 6 second procedures, with an overall success rate in terms of resolution of hypercalcemia in 97% (215/222) of patients. The single most common site of missed adenoma glands was in the tracheal-esophageal groove in the posterior superior mediastinum (27%). The most common ectopic sites for parathyroid adenomas are thymus (17%), intrathyroidal (10%), undescended glands (8.6%), carotid sheath (3.6%), and the retroesophageal space (3.2%). The most sensitive and specific noninvasive imaging test is the sestamibi subtraction scan, with 67% true-positive and no false-positive results. The rate of true-positive and false-positive results for ultrasound, computed tomography, magnetic resonance imaging, and technetium thallium scans were 48%/21%, 52%/16%, 48%/14% and 42%/8%, respectively. The incidence of injury to the recurrent laryngeal nerve was 1.3%. CONCLUSIONS A single missed parathyroid adenoma is the most common cause for a failed initial parathyroid operation. Appropriate use of preoperative imaging tests and knowledge of the potential location or parathyroid adenomas can lead to very high cure rates with minimal morbidity.

Zollinger-Ellison Syndrome: Current Concepts and Management

Over the last few years the approach to managing patients with the Zollinger-Ellison syndrome has changed dramatically. The establishment of gastrin hypersecretion by a non-beta islet cell tumor as responsible for the gastric acid hypersecretion, and the subsequent development and widespread availability of gastrin radioimmunoassays have changed the criteria generally used for diagnosis and have led to an increased understanding of syndromes that can mimic Zollinger-Ellison syndrome. With the availability of histamine H2-receptor antagonists, gastric acid hypersecretion can be controlled medically in almost all patients with Zollinger-Ellison syndrome, obviating routine total gastrectomy. With the reduced mortality from gastric acid hypersecretion, increased attention is being focused on the natural history of the gastrinoma. Newer methods of localizing tumors are being investigated with a view to surgical removal of the gastrinoma, and the importance of developing an affective chemotherapeutic regimen is becoming increasingly apparent.