Foregut Carcinoid Tumors Research Articles

Multiple Endocrine Neoplasia Type 1 (MEN1): An Update and the Significance of Early Genetic and Clinical Diagnosis.

Multiple endocrine neoplasia type 1 (MEN1) is a rare hereditary tumor syndrome inherited in an autosomal dominant manner and characterized by a predisposition to a multitude of endocrine neoplasms primarily of parathyroid, enteropancreatic, and anterior pituitary origin, as well as nonendocrine neoplasms. Other endocrine tumors in MEN1 include foregut carcinoid tumors, adrenocortical tumors, and rarely pheochromocytoma. Nonendocrine manifestations include meningiomas and ependymomas, lipomas, angiofibromas, collagenomas, and leiomyomas. MEN1 is caused by inactivating mutations of the tumor suppressor gene MEN1 which encodes the protein menin. This syndrome can affect all age groups, with 17% of patients developing MEN1-associated tumors before 21 years of age. Despite advances in the diagnosis and treatment of MEN1-associated tumors, patients with MEN1 continue to have decreased life expectancy primarily due to malignant neuroendocrine tumors. The most recent clinical practice guidelines for MEN1, published in 2012, highlight the need for early genetic and clinical diagnosis of MEN1 and recommend an intensive surveillance approach for both patients with this syndrome and asymptomatic carriers starting at the age of 5 years with the goal of timely detection and management of MEN1-associated neoplasms and ultimately decreased disease-specific morbidity and mortality. Unfortunately, there is no clear genotype-phenotype correlation and individual mutation-dependent surveillance is not possible currently.

Primary Carcinoid Tumors of the Pancreas: Report of Eight Cases

Context Primary pancreatic carcinoid tumors (foregut) are very rare. A typical carcinoid syndrome with diarrhea and flushing may be present. The diagnosis is based on the high urinary 5-HIAA (5-hydroxyndole acetic acid) levels (or high serum serotonin levels) or the immunostaining of serotonin (5-HT) in the tumor cells. Objective We evaluated clinical presentation, endocrine tumor markers, histology, therapeutic approach and follow up. Methods From 1986 to 2011 in our department we observed 211 neuroendocrine (NE) pancreatic tumors and 8 of them (3.8%) were primary carcinoid tumors (5 males and 3 females; averaging 55.8 years, range: 38-69 years). Follow up was updated until December 2012. Results Among the eight patients enrolled, 3 were symptomatic. Seven had high serum 5-HT or high urinary 5-HIAA, and one was asymptomatic with immunostaining of 5-HT in tumor cells. Location: 6 body-tail. All were malignant tumors: 7 liver and 1 single nodal metastases. Markers: 4 high serum 5-HT (up to 176 µmol/L), 7 high urinary 5-HIAA (up to 522 µmol/L). Surgery: 1 left pancreatectomy, 7 biopsy. Histology: 7 NE tumor, 1 negative pancreatic biopsy (liver metastases). Other therapy: 3 treated with somatostatin analogues (SST-A) and chemotherapy (CT), 1 CT and radiometabolic therapy after hepatic artery embolization (HAE), 1 HAE and SST-A, 1 CT. Follow up: 6 dead for disease progression (mean survival 52 months), 2 alive (1 without disease 78 months after surgery; 1 asymptomatic with high 5-HIAA 33 months after SST-A and CT). Conclusion Most of primary pancreatic carcinoids are locally advanced tumors or have liver metastases at time of diagnosis, then patients are not amenable to surgery. Although most patients had high 5-HIAA urinary excretion, few patients had carcinoid syndrome. A long term survival may be achieved with multimodal approach, including chemotherapy, in foregut carcinoid tumors.

Multiple Endocrine Neoplasia Type 1 Associated with a New Mutation in Menin Gene and a Midgut Carcinoid Tumor: Report of a Case and Review of the Literature

Purpose: Multiple endocrine neoplasia type 1 (MEN-1) is an autosomal dominant disorder that has a varied clinical presentation. Its classic features include hyperparathyroidism, pituitary adenomas and pancreatic neuroendocrine tumors. MEN-1 is typically only associated with foregut carcinoid tumors, such as those arising from the thymus, lung, stomach and duodenum. This vignette reports a rare case of a patient who had a classic presentation of MEN-1 and developed a metastatic carcinoid tumor of the ileum, a midgut tumor. This patient also was found to have an unpublished menin gene mutation. This patient had classic features of MEN-1: hyperparathyroidism, a pituitary adenoma and a pancreatic neuroendocrine tumor. He had been clinically well for three years after having a distal pancreatectomy and splenectomy for the pancreatic neuroendocrine tumor. Three years post-operatively, he experienced diarrhea, flushing and fatigue. Evaluation at our institution revealed a recurrent tumor in the remaining pancreas, a mass in the right lower quadrant and several small lesions in the liver. He underwent resection of the recurrent pancreatic tumor, ileal-mesenteric mass and liver lesions. The pathologic impression from positive immunostaining for serotonin and CDX2 in the ileal and liver tumors revealed that he had developed a primary midgut carcinoid tumor arising in the ileum with subsequent metastasis. Genetic testing revealed a new mutation of the MEN-1 gene -- S583P. This mutation involves a heterozygous cytosine to thymine point mutation in exon 10 of the menin gene. It has not been previously described in the literature. This case report describes an initial classic presentation of MEN-1, associated with a new MEN-1 mutation and a metastatic midgut carcinoid. Numerous MEN-1 gene mutations have been described, however, it is interesting to speculate whether this new mutation conferred an increased risk for developing the metastatic midgut carcinoid. Furthermore, this case report demonstrates that in a patient with MEN-1 and recurrent carcinoid symptoms, one can consider diagnosing a new tumor in an unlikely location.

NANETS Consensus Guidelines for the Diagnosis of Neuroendocrine Tumor

Neuroendocrine tumors (NETs) are rare, slow-growing neoplasms characterized by their ability to store and secrete different peptides and neuroamines. 1 Some of these substances cause specific clinical syndromes, 2 whereas other may have elevated plasma or urine levels that are not associated with specific syndromes or symptom complexes Unfortunately, there is no Bideal neuroendocrine tumor marker,[ 3 but according to the presentation, the sensitivity and specificity of each marker vary, and it is generally possible to choose those of greatest value for each clinical syndrome. The biochemical markers are those hormones or amines secreted by the neuroendocrine cells from which these tumors are derived. Some of these are not specific to any tumor, but are produced and secreted by most NETs, whereas other biochemical markers are more specific to the type of tumor and where their quantification can lead to the suspicion or confirmation of the presence of such a tumor. The annual incidence of NETs has risen to 40 to 50 cases per million, perhaps because of better diagnosis and the availability of highly specific and sensitive ways to measure these tumors’ products, improved immunohistochemistry, and enhanced techniques for tumor detection. Thus, the perceived increase in incidence may not be a real change in the incidence of the disease. There are a number of impediments to the diagnosis of these tumors. They are rare, comprising less than 2% of gastrointestinal (GI) malignancies, and are therefore not high on the list of causes of specific symptom complexes. Symptoms themselves are often nonspecific and do not lend themselves readily to identifying the specific underlying tumor. In addition, the manifestations are protean and mimic a variety of disorders. Tumors may be found incidentally on laparoscopy for abdominal pain or during the surgical removal of an appendix or even during a computerized tomographic scan of the abdomen for unexplained symptoms. Lung carcinoids may present with hemoptysis or asthma-like symptoms, and midgut carcinoids may be confused with irritable bowel syndrome (IBS). The natural history of this disease is invariably attended by a long history of vague abdominal symptoms, a series of visits to a primary care practitioner, and referral to a gastroenterologist, often with a misdiagnosis of IBS. These symptoms persist with a median latency to correct diagnosis of 9.2 years by which time the tumor has metastasized, causing symptoms such as flushing and diarrhea and progressing on its slow but relentless course until the patient dies. Clearly, a greater index of suspicion and a carcinoid tumor profile screen are warranted for all patients presenting with Btraditional IBS symptoms.[ Midgut carcinoids are associated with mesenteric fibrosis, which can compress mesenteric vessels and cause bowel ischemia and malabsorption, which may be found in the absence of an abdominal mass. The diagnosis of metastases to the liver is generally more obvious but often still takes place only after a delay of many years. Even then, an incorrect diagnosis is not uncommon. Unless biopsy material is examined for the secretory peptides chromogranin, synaptophysin, or neuron-specific enolase (NSE), tumors may be labeled erroneously as adenocarcinoma, with a negative impact on physician’s attitudes regarding management and underestimation of prospects for survival. 4 The common symptomatic manifestations of patients with carcinoid tumors are illustrated in Tables 1 and 2. Flushing

Rapid Regression of Multiple Gastric Carcinoid Tumors with Hypergastrinemia and Atrophic Gastritis after Renal Transplantation

To the Editor Gastric carcinoid tumors are rare. Nevertheless, when they occur, they are often found in patients diagnosed as having type A gastritis [1]. In patients with type A gastritis, the development of carcinoids and the widespread hyperplasia of enterochromaffin-like cells are related to atrophic changes of fundic mucosa and the trophic action of subsequently raised serum gastrin levels. In the past gastrectomy was the treatment of choice for carcinoid tumors; however, recent reports have shown that multiple gastric carcinoid tumors associated with type A gastritis are indolent and recommend that patients should receive more conservative treatment [1, 2]. We herein present one case where multiple gastric carcinoid tumors with hypergastrinemia and type A gastritis regressed after renal transplantation. In November 2000, a 51-year-old woman presented with epigastric pain and she received upper gastrointestinal endoscopy in our hospital. Endoscopic examination revealed multiple gastric polyps in the body and funds (Fig. 1). The polyps, measuring between 1 and 15 mm, were covered by intact mucosa identical to the surrounding tissue. The intervening gastric mucosa appeared atrophic with a pale shiny lining and visible submucosal vessels. Biopsies were taken for a histopathology of the polyps. Biopsies of the polyps showed gastric carcinoid tumors (Fig. 2), cells were positive for chromogranin A, synaptophysin, and neuron-specific enolase. Serum gastrin level was over 3,000 pg/ml (normal 0–90). Serum serotonin and urine 5-HIAA levels were normal. Antiparietal cell antibody was negative. Helicobacter pylori serology was negative. The patient was diagnosed as having multiple type I gastric carcinoid tumors. The question was how to manage this case. The patient did not want to receive surgical treatment, such as a total gastrectomy or antrectomy, because she had already received hemodialysis treatment for chronic renal failure. Therefore,with agreement of the patient, we decided to do an endoscopic follow-up. We performed endoscopic examination at six-month intervals. Between 2000 and 2004, follow-up endoscopy showed that the polyps had the same size as on the initial picture, and a histological examination of biopsies specimens revealed a residual carcinoid tumor in the mucosal layer. In December 2004, she received renal transplantation. After renal transplantation, she was treated with corticosteroid ( prednisolone, 10 mg/day) and Tacrolimus (Prograf, 4 mg/day) to prevent kidney graft rejection. The endoscopic examination at three months after renal transplantation showed marked regression of the carcinoid tumors. Furthermore, the endoscopic examination at six months after renal transplantation showed complete regression of the disease, though the serum gastrin level was still high (over 3,000 pg/ml) (Fig. 3). The endoscopic examination showed no progression of tumors at the end of the follow-up. Gastric carcinoid tumors fall under the broad classification of foregut carcinoid tumors. However, it is well known that these tumors are clinically and biologically distinct from the carcinoid tumors involving the rest of the gastrointestinal tract. In 1993, Rindi et al. classified gastric carcinoid tumor into three subtypes, based on pathogenesis [3]: type I and type II gastric carcinoids develop under the trophic influence of gastrin, whereas type III carcinoids are M. Odashima (&) M. Otaka M. Jin Y. Horikawa T. Matsuhashi R. Ohba N. Mimori S. Koizumi N. Kinoshita T. Takahashi S. Watanabe Department of Gastroenterogy, Akita University School of Medicine, 1-1-1, Hondo, Akita city, Akita 010-8543, Japan e-mail: odashima@doc.med.akita-u.ac.jp

Peptide receptor radionuclide therapy with 177Lu-octreotate in patients with foregut carcinoid tumours of bronchial, gastric and thymic origin.

Foregut carcinoid tumours have a different embryological origin than other gastroenteropancreatic neuroendocrine tumours (GEP NETs). In the total group of GEP NETs (n = 131), treatment with (177)Lu-octreotate resulted in tumour remission in 47% of patients, with a median time to progression (TTP) of >36 months. As patients with foregut carcinoids may respond differently, we here present the effects of this treatment in a subgroup of patients with foregut carcinoids of bronchial, gastric or thymic origin. Nine patients with bronchial, five with gastric and two with thymic carcinoids were treated. All patients had metastasised disease. The intended cumulative dose of (177)Lu-octreotate was 22.2-29.6 GBq. Southwest Oncology Group criteria were used for response evaluation. Bronchial carcinoids: Five patients had partial remission, one had minor response (MR, tumour size reduction: > or =25%, <50%), two had stable disease (SD) and one had progressive disease (PD). Median TTP was 31 months. Gastric carcinoids: One patient had complete remission, one had MR and two had SD, including one with PD at baseline. One patient developed PD. Thymic carcinoids: One patient had SD. In the other patient, disease remained progressive. All patients: Overall remission rate was 50%, including MR. (177)Lu-octreotate treatment can be effective in patients with bronchial and gastric carcinoids. Its role in thymic carcinoids cannot be determined yet because of the limited number of patients. The overall remission rate of 50% in patients with the studied foregut carcinoids is comparable to that in the total group of GEP NETs.

Multiple Endocrine Neoplasia: Spectrum of Radiologic Appearances and Discussion of a Multitechnique Imaging Approach

Multiple endocrine neoplasia (MEN) is characterized by the occurrence of two or more tumors that may be associated with hyperfunction and malignancy. MEN is caused by genetic defects, and two major types, MEN 1 and MEN 2, are recognized. Each type is characterized by the development of tumors within specific endocrine organs. A multidisciplinary approach involving cooperation between endocrinologists, surgeons, oncologists, and radiologists is pivotal for optimizing patient treatment. Imaging plays a vital role in the diagnosis and management of the disease. To contribute effectively, however, the radiologist must understand the range of anatomic and functional imaging modalities used in the assessment of endocrine disorders. In addition, knowledge of the optimal techniques for evaluating the pituitary, thyroid, parathyroid, pancreatic, adrenal, and foregut carcinoid tumors that occur in these MEN syndromes is essential. Finally, an understanding of the spectrum of disease and of the manifestations of each component is crucial for accurate detection, staging, and surveillance in this diverse patient group.

Comparative genomic hybridization analysis of thymic neuroendocrine tumors

Thymic neuroendocrine (carcinoid) tumors are a rare neoplasm of the anterior mediastinum. The tumors frequently exhibit a wide spectrum of histology and appear to follow a more aggressive behavior than their nonthymic counterparts. Given the differing clinicopathologic manifestations, thymic neuroendocrine tumors may also possess different cytogenetic abnormalities from those that occur in foregut carcinoid tumors. In this study, we employed comparative genomic hybridization to detect genomic instability in 10 sporadic thymic neuroendocrine tumors and one multiple endocrine neoplasia type 1 (MEN1)-associated case. Gross chromosomal imbalances were found in nine cases, including gains of chromosomal material on regions X, 8, 18 and 20p and losses on 3, 6, 9q, 13q and 11q. We did not observe deletion at locus 11q13 where the MEN1 gene is located. These findings were essentially dissimilar to those reported in sporadic and MEN1-associated foregut carcinoid tumors. Consequently, we consider that a distinctive cytogenetic mechanism is at work in the development of thymic neuroendocrine tumors, which is different from that of foregut carcinoid tumors.

The role of genetics in the surgical management of familial endocrinopathy syndromes.

Our knowledge of genetics has increased dramatically in recent decades and this has led to important changes in the medical and surgical management of hereditary endocrine diseases. Genetic screening for disease-causing mutations can identify carriers at young ages, which has enabled earlier diagnosis and surgical intervention. For example prophylactic thyroidectomy is now routine in patients with multiple endocrine neoplasia type 2 (MEN2). Appropriately timed surgical intervention will minimize disease-specific morbidity and mortality, but the diagnosis and surgical treatment of disease in presymptomatic patients is much more complex than in symptomatic patients with measurable disease. Surgeons must remain conversant with the developments in genetic technology and the established role for genetic counselors in the multidisciplinary management of hereditary endocrine syndromes. In this article we briefly review the clinically relevant information and indications for genetic testing for the most common hereditary endocrine syndromes including multiple endocrine neoplasia type 1 (MEN1), MEN2, von Hippel-Lindau syndrome (VHL), and hereditary paraganglioma syndrome. We also use several case descriptions to illustrate the impact of genetic counseling on the management of familial cancer. Finally we provide several key genetic counseling resources available for the proper identification and expeditious referral of patients at risk for these familial endocrine syndromes. MULTIPLE ENDOCRINE NEOPLASIA TYPE 1 MEN1 is an autosomal dominant disease that demonstrates nearly complete penetrance in the form of various combinations of endocrine tumors involving the parathyroid glands, pancreatic islet cells and duodenum, and pituitary gland (Table 1). Hyperparathyroidism (HPT) is the most prevalent (90% to 97%) and is usually the first manifestation, typically appearing between the ages of 20 and 25 years but sometimes as late as the fifth decade of life. Anterior pituitary gland tumors in patients with MEN1 are less common (33%) and may be nonfunctioning or may secrete hormones such as prolactin. Tumors of the pancreatic islet cells and duodenum (pancreatic endocrine tumors, PETs) occur in as many as 30% to 80% of patients. Some PETs are nonfunctioning, but many secrete one or more pancreatic hormones. With earlier diagnosis and control of hormone-associated complications such as ZollingerEllison syndrome, metastatic neuroendocrine tumors of the pancreas are now the leading cause of disease-specific mortality in patients with MEN1. Because PETs in MEN1 patients are multifocal and distributed throughout the pancreas, their proper management remains poorly defined. This issue was summarized in a recent consensus statement in which it was concluded that surgical treatment for MEN1-related PETs is controversial except for patients with hypoglycemia secondary to insulinoma syndrome in whom pancreatic resection is indicated. There is currently no consensus on the timing and extent of surgical treatment for gastrinoma and nonfunctioning PETs in patients with MEN1. Less prevalent tumors associated with MEN1 include adrenocortical tumors, lipomas, and foregut carcinoid tumors. Foregut carcinoids are found in 2% to 8% of patients with MEN1, but bronchial carcinoids are more common in women and thymic carcinoids are more common in men. The malignant potential of carcinoids, particularly thymic carcinoids, has led to recent No competing interests declared.

Immunohistologic analysis of gastrointestinal and pulmonary carcinoid tumors

Carcinoid tumors are potentially malignant neoplasms that arise in various body sites, including the lung and gastrointestinal tract. Those that appear cytologically atypical are more likely to behave aggressively than more typical carcinoid tumors. However, in the absence of cytological atypia or large tumor size, it is difficult to predict the biology of an individual tumor, because some lesions metastasize, whereas others do not. This study had four aims: (1) To study the expression pattern of p53, Ki-67, NCAM, and S-100 in carcinoid tumors and to relate these expression patterns to classical histopathologic features and to tumor location. (2) To identify nonhistological markers that might more accurately predict the early behavior of carcinoid tumors. (3) To determine whether sustentacular cells are present in carcinoid tumors arising in tissues derived from different embryological derivatives. (4) To determine the synaptophysin and chromogranin immunoreactivity in neuroendocrine tumors arising in various locations. The immunostaining reactions were quantitatively scored by three observers. Only 3 of the 39 tumors (all histologically atypical) were strongly positive for Ki-67; two of these were also strongly p53 immunoreactive. NCAM immunostaining differed according to the site of origin: 76.5% of foregut lesions, 58% of the midgut lesions, and 20% of hindgut lesions were positive. S-100 immunostaining ranged from 41% in foregut lesions to 50% in both the hindgut- and midgut-derived tumors. S-100-positive sustentacular cells were present in 20.5% of carcinoid tumors. All tumors stained with antibodies against synaptophysin. In contrast, 100% of midgut, 60% of hindgut, and 88% of foregut tumors were chromogranin positive. Carcinoid tumors tend to have low proliferative rates. p53 immunostaining tends to be strongly positive in tumors that are histologically atypical, but it is negative in typical carcinoid tumors arising in the gastrointestinal tract and lungs. Immunostaining reactions with antibodies to NCAM, S-100, and chromogranin differ depending on the site of origin. Synaptophysin stains 100% of carcinoid tumors regardless of their site of origin. In contrast, antibodies to chromogranin fail to stain 40% of hindgut tumors and 12% of foregut carcinoid tumors. S-100-positive sustentacular cells are present in foregut and midgut tumors but not in hindgut tumors.

A patient with co-existing bronchial carcinoid tumour and bilateral phaeochromocytoma

We report a 31-year-old Chinese man with bronchial carcinoid tumour and bilateral phaeochromocytoma. His sister also gave a history of bilateral carotid body paraganglioma. This case demonstrates the importance of screening for other endocrine disorders in patients with foregut carcinoid tumours.

111In-DTPA-D-Phe1]octreotide scintigraphy in patients with carcinoid tumours: the predictive value for somatostatin analogue treatment.

This study was performed to evaluate whether the presence or absence of somatostatin receptors in malignant carcinoid tumours detected by [111In-DTPA-D-Phe1]octreotide scintigraphy can be used to predict response to somatostatin analogue treatment. Thirty patients were investigated, 28 with midgut carcinoid tumours and two with foregut carcinoid tumours. Twenty-seven patients showed pathological uptake in tumour lesions at scintigraphy; of these, 22 responded to somatostatin analogue treatment using octreotide, somatuline or octastatin, while five patients failed to respond. None of the three patients displaying negative scintigraphic investigations responded to treatment with somatostatin analogues. These results show a good correlation between the somatostatin receptor status and the patients' ability to respond to somatostatin analogue treatment (p = 0.014). We conclude that somatostatin receptor scintigraphy using [111In-DTPA-D-Phe1]octreotide can be used to select patients with malignant carcinoid tumours suitable for somatostatin analogue treatment and exclude those that will not benefit from such medication.

Histamine metabolism in patients with foregut carcinoid tumours

The urinary excretion of the histamine metabolite, tele-methylimidazoleacetic acid (MemAA), was measured in 15 patients with foregut carcinoid tumours (5 ECLomas, 4 gastric carcinoids of the mixed type and 6 bronchial carcinoids), High levels were related to tumour burden and presence of the foregut carcinoid syndrome. Control of symptoms was either achieved by octreotide in combination with blockade of histamine receptors or by hyperthermic liver perfusion chemotherapy. MemAA served as an exellent tumour marker for diagnosis and guidance of therapy.

In situ hybridization study of chromogranin A and B mRNA in carcinoid tumors

The distribution of the mRNAs for chromogranin A and B was analyzed by in situ hybridization with 35S-labeled oligonucleotide probes in formalin-fixed paraffin-embedded carcinoid tumor tissues. All the 15 mid-gut carcinoid tumors examined contained both mRNAs for chromogranin A and B at high level in tumor cells. Sixteen of 18 bronchial carcinoid tumors but only 2 of 5 rectal carcinoid tumors expressed one or both species of chromogranin mRNAs. The same tendency was seen with the argyrophil reaction according to Grimelius where most of the mid-gut tumor cells were uniformly stained, while considerable variation in reactivity was seen in some of the bronchial and rectal carcinoid tumor cells. The sequential sections were stained with a monoclonal antibody against chromogranin A and a polyclonal antiserum which reacts with both chromogranins. The expression of the mRNA for chromogranin A on the carcinoid tumors was almost concordant with that of chromogranin B as well as with the chromogranin A protein, whereas almost all tumors stained positively with the polyclonal antibodies. Analyses of mRNA expression of chromogranin A before and after interferon therapy on 4 patients with mid-gut carcinoids indicated an inhibition at pre-translational level. In conclusion, the mRNAs for chromogranin A and B are good markers for the carcinoid tumors, especially of mid-gut origin. Fore-gut, mid-gut and rectal carcinoid tumors are different in their endocrine properties regarding the expression of the chromogranins.

Monoamine and diamine oxidase activity in the diagnosis of carcinoid tumors.

This study determines if one could distinguish foregut from midgut carcinoid tumors by quantitative measurement of the monoamine oxidase (MAO) and diamine oxidase (DAO) activities in homogenates of tumors. The MAO activity of 16 foregut carcinoid tumors (1850 +/- 342 pmol/mg/minute) was significantly higher than the MAO activity of 11 midgut carcinoid tumors (407 +/- 43 pmol/mg/minute, P less than 0.01) with no overlap between the groups. Although all ten of the midgut carcinoids had measurable DAO activity (720 +/- 190 pmol/mg/minute), with the exception of one duodenal carcinoid tumor (33 pmol/mg/minute) the nine foregut carcinoid tumors evaluated did not have detectable DAO activity. The MAO activity of all of the foregut carcinoids was higher than that of 6 islet cell tumors, 28 paragangliomas, and 12 medullary carcinomas of the thyroid. Quantitative MAO and DAO activity may be useful in distinguishing foregut carcinoid tumors from other related tumors.

Serotonin in fore-gut carcinoids. A survey of 60 cases with regard to silver stains, formalin-induced fluorescence and serotonin immunocytochemistry.

A series of 60 fore-gut carcinoid tumours was examined with regard to serotonin content after application of three different techniques, namely: the argentaffin reaction, formalin-induced fluorescence according to Falck-Hillarp and immunocytochemistry with monoclonal antibodies to serotonin. To evaluate the staining-fluorescence of individual tumour cells, the methods were applied to identical tumour sections. Twelve tumours demonstrated serotonin-immunoreactive cells, six of which were also argentaffin. Four tumours contained argentaffin cells but no serotonin-immunoreactivity. With the use of all three techniques, three types of tumour cells occurred, namely: serotonin-immunoreactive, non-argentaffin and non-fluorescence cells, serotonin-immunoreactive, argentaffin and fluorescent cells, and non-serotonin immunoreactive, argentaffin and non-fluorescent cells. The first (serotonin-immunoreactive) cell type was most frequently found in the tumours. One gastric carcinoid in which the argentaffin cells exceeded the serotonin-immunoreactive cells, a positive reaction was found with the modified Warthin-Starry reaction for demonstrating melanin. Since none of the techniques used for visualization of serotonin in endocrine tumours is unquestionably specific and since they do not give identical results, it is indicated that for a more accurate identification of serotonin in fore-gut carcinoid tumours, a positive reaction with at least two of the applied techniques is desirable.