Cell Carcinoid Tumors Research Articles

Biokinetics of 111In-DTPA-D-Phe1-octreotide in nude mice transplanted with the human carcinoid tumour cell line GOT1

s: Abstracts of an International Conference on Peptide Radiopharmaceuticals in Diagnosis and Therapy Rome, Italy, 25-28 May 2000: Poster Presentations

The interferon-α regulation of interferon regulatory factor 1 (IRF-1) and IRF-2 has therapeutic implications in carcinoid tumors

Interferon regulatory factor 1 (IRF-1) has been demonstrated to possess antiproliferative and tumor suppressor functions, on the contrary. IRF-2 has been suggested to induce oncogenetic effect in some cell lines, but not evaluated in tumor patients. In 35 carcinoid tumor patients, expressions of IRF-1 and IRF-2 were investigated by immunohistochemistry and their values were analyzed with clinical treatment response. In carcinoid tumor cell line, Bonl, effects of IFN-alpha on the expression of both IRF-1 and IRF-2 mRNAs and proteins were determined by Northern blot, RNase protection assays and Western blot analysis. IFN-alpha up-regulated the expression of IRF-1 and IRF-2 both in vivo and in vitro. In carcinoid tumors, IFN-alpha treatment led to a significant increase in the expression of IRF-1 (P < 0.001) and IRF-2 (P < 0.001). Moreover, the IRFs induction was correlated with the clinical response of IFN-alpha treatment, although their baseline values were not predictive. In addition, expressions of IRF-1 and IRF-2 were significantly correlated with the p68 kinase expression (P = 0.032 and P = 0.0176, respectively) and the expression of IRF-1 protein was positively correlated with that of IRF-2 (r = 0.671, P = 0.0001) tested in the same specimens. IRF-1 as well as IRF-2 have therapeutic implications in carcinoid tumors during treatment with interferon-alpha and IRFs induction might be used as indicators of response to treatment with interferon-alpha.

Selective Hepatic Arterial Chemoembolization for Liver Metastases in Patients with Carcinoid Tumor or Islet Cell Carcinoma

In many patients with liver metastases from islet cell or carcinoid tumor, vascular occlusion therapy results in prolonged control of symptoms, biochemical response, and also tumor regression. Chemotherapy agents were added to evaluate safety and efficacy. Thirty patients with liver metastases from either carcinoid tumor or islet cell carcinoma underwent sequential vascular occlusion therapy combined with che-motherapeutic agents. In patients with carcinoid tumor, a combination of cisplatin (150 mg) and doxorubicin (50 mg) was used. In patients with islet cell carcinoma, a combination of 5-fluorouracil (350 mg) and streptozotocin (1000–2000 mg) was used. Sixteen patients had carcinoid tumor and 14 had islet cell carcinoma. Biochemical response was observed in 12 of 16 (75%) carcinoid patients and 9 of 10 (90%) islet cell patients. The overall partial response rate was 37% (11/30 patients). Partial response occurred in 4 of 16 (25%) patients with carcinoid tumor and 7 of 14 (50%) with islet cell carcinoma. The median duration of partial responses was 24 months (range, 6–63+ months). The median survival of all patients was 15 months (range, 2–67+ months). No treatment-related deaths occurred. Our data suggest that the addition of these chemotherapeutic agents to vascular occlusion, although safe, has no additional benefit.

Expression of p68 protein kinase and its prognostic significance during IFN-α therapy in patients with carcinoid tumours

The aim of this study was to evaluate the antiproliferative effects of interferon alpha (IFN-α) on neuroendocrine differentiated cell lines and, retrospectively, to assess the prognostic significance of p68 protein kinase (PKR) induction in neuroendocrine gut and pancreatic tumour patients. Archive specimens from 56 patients were studied, 43 before IFN-α and 56 during therapy. The tissues were immunostained for p68 protein kinase (PKR) using the monoclonal antibody (MAb) TJ4C4. A significant increase in immunostaining after treatment with IFN-α compared with before treatment (3.47±0.12 versus 2.72±0.15, P<0.001) was noted. The p68 score was significantly increased after treatment only in patients with stable disease before=2.71±0.19, after=3.40±0.14 ( P<0.001) or an objective response before 3.13±0.22, after=4.00±0.24 ( P<0.05) but not in those with progressive disease (before=2.32±0.24, after 2.86±0.26, NS). A low p68 score (<3.0) during treatment was a predictor of shorter duration of response and overall survival ( P=0.0062 and P<0.0001, respectively). Furthermore, IFN-α showed a significant antiproliferative effect (by [ 3H]thymidine incorporation) on two carcinoid tumour cell lines in a dose-dependent manner which correlated with a dose-dependent induction of p68 mRNA and protein expression (by Northern and Western blot analysis). We conclude that IFN-α can effectively inhibit the in vitro growth of carcinoid tumor cell lines and upregulates the expression of p68 at both mRNA and protein levels in carcinoid tumours. The induction of p68 could be a prognostic indicator of response in patients with carcinoid tumours during IFN-α treatment.

Neuroendocrine differentiation is a common feature of thymic carcinoma.

Immunohistochemical evidence of neuroendocrine differentiation in the form of reactivity for synaptophysin, neuron-specific enolase, and/or chromogranin was found in 11 of 19 (58%) thymic carcinomas having the typical morphologic features of that tumor type. Four of these 19 cases were studied ultrastructurally, and neuroendocrine-type cytoplasmic dense-core granules were found in two. In contrast, 84 thymomas were negative for these markers, except for a focal immunoreactivity for neuron-specific enolase in areas of medullary differentiation in half of the lymphocyte-rich tumors. The results of this study show that in the thymus, similar to most other organs, neuroendocrine differentiation is not limited to tumors with an identifiable neuroendocrine appearance in hematoxylin-eosin-stained slides, such as carcinoid tumor and small cell carcinoma, but rather that it represents a common event shared by the major types of malignant epithelial tumors of that organ.

Horseshoe Kidney is Associated With an Increased Relative Risk of Primary Renal Carcinoid Tumor

Purpose Carcinoid tumor is a rare neoplasm of the kidney with an unknown histogenesis. Of only 31 cases previously reported in the literature 4 arose within horseshoe kidneys. We report a case of primary carcinoid tumor arising within a horseshoe kidney and discuss the unique insight it provided into the pathogenesis of this tumor. Materials and Methods We reviewed in detail all 31 reported cases of renal carcinoid tumor and, using reported incidence rates of horseshoe kidney, we calculated the relative risk of renal carcinoid tumor arising within a horseshoe kidney. Immunohistochemical staining for neuroendocrine related markers was performed on tissue sections from the present carcinoid tumor, the adjacent kidney and 5 control samples of normal renal parenchyma. Results Of the reported tumors 15.6% occurred in horseshoe kidneys, yielding a calculated relative risk of 62. The present tumor was multifocal, arising from the wall of a cystic lesion and possibly representing a dilated calix within the isthmus. Intestinal epithelium lining the cyst cavity exhibited multifocal neuroendocrine cell hyperplasia with an immunohistochemical profile identical to that of the carcinoid tumor cells. Conclusions The relative risk of renal carcinoid tumor developing in a horseshoe kidney is markedly greater than that for Wilms tumor or transitional cell carcinoma. The clinical course of renal carcinoid tumor arising within a horseshoe kidney appears to be more benign than that of the nonhorseshoe variant. Our observations support the hypothesis that renal carcinoid tumors may arise from neuroendocrine cells within foci of metaplastic or teratomatous epithelium within the kidney.

Secretory patterns of tryptophan metabolites in midgut carcinoid tumor cells.

Hormonal overproduction is a significant problem in patients with disseminated midgut carcinoid tumors. Serotonin (5-HT) is one major product secreted from such tumors and the urinary excretion of its metabolite (5-hydroxyindoleacetic acid, 5-HIAA) serves as an important tumor marker. The present study aimed at elucidating mechanisms of tryptophan metabolite secretion to facilitate the treatment of the carcinoid syndrome. When midgut carcinoid tumors were studied in primary cell cultures, several similarities with adrenergic neurons could be demonstrated. A marked dose-dependent depletion of intracellular 5-HT could be induced by reserpine, and monoamine oxidase-activity was revealed both in functional studies and by immunocytochemistry. Differences between tumors in the ratios of tryptophan metabolites released indicated that enzymes for synthesis and degradation of 5-HT were individually expressed. Treatment with the somatostatin analogue octreotide or with dexamethasone decreased the extracellular levels of tryptophan metabolites, but the mechanisms were partly different. In some tumors octreotide also decreased the synthesis of 5-HT, while dexamethasone markedly increased the intracellular 5-HIAA levels. It is of clinical interest to further elucidate these mechanisms, since the two drugs may have complementary actions in carotid crisis reactions.

Expression of somatostatin receptor subtypes in breast carcinoma, carcinoid tumor, and renal cell carcinoma

Expression of somatostatin receptor subtypes in breast carcinoma, carcinoid tumor, and renal cell carcinoma

Expression of somatostatin receptor subtypes in breast carcinoma, carcinoid tumor, and renal cell carcinoma.

The presence of transcripts for somatostatin receptor (SSTR) subtypes 1, 2, 3, and 4 was probed by reverse transcription and polymerase chain reaction in ribonucleic acid isolated from 46 malignant and 9 nonmalignant breast tissues, 15 carcinoid tumor tissues, and 13 renal cell carcinoma tissues. The transcripts for SSTR2 were amplified in all but 2 tissue samples, whereas transcripts for SSTR1, SSTR3, and SSTR4 were detected sporadically. In renal cell tumors, SSTR3 transcripts were completely absent. In breast cancer tissue, SSTR subtypes were transcribed independently of patient age, menstrual status, diagnosis, histological grade, and levels of estrogen receptor and progesterone receptor. The probability of finding transcripts for SSTR subtypes, P, was ranked differently for the three types of tumor tissues. For breast cancer, P2 > P3 = P1 > P4; for carcinoid tumors, P2 > P1 > P3 = P4; and for renal cell tumors, P2 > P1 > P4 > P3.

Copresence of prostaglandin EP 2 and EP 3 receptors on gastric enterochromaffin-like cell carcinoid in African rodents

Background & Aims: Prostaglandins (PGs) have important roles in the regulation of gastric acid secretion. The aim of this study was to examine the possible presence of PG receptors on the gastric enterochromaffin-like (ECL) carcinoid of Mastomys natalensis, which might be a useful model of normal ECL cells. Methods: A [ 3H]PGE 2 binding experiment was performed by using the ECL tumor membrane, and intracellular signal transduction was studied in the cells. In addition, Northern blot analysis using EP 2 and EP 3 receptor complementary DNAs was conducted. Results: [ 3H]PGE 2 specifically bound to the tumor cell membrane, and the binding was displaced by various PGs with a potency order of PGE 1 = PGE 2 > enprostil >PGF 2α. Although PGE 1 and PGE 2 stimulated 5′-cyclic adenosine monophosphate (cAMP) production, neither PGF 2α nor enprostil had any effect. On the other hand, all of PGE 1, PGE 2, PGF 2α, and enprostil attenuated the forskolin-induced cAMP production. Moreover, enprostil inhibited histamine release induced by forskolin. However, on pertussis toxin treatment, PGE 2 paradoxically enhanced the forskolin-induced increase of cAMP production. Finally, the presence of EP 2 and EP 3 receptor messenger RNAs was confirmed by RNA blot analysis. Conclusions: The ECL carcinoid tumor cells of Mastomys seem to possess two subtypes of PGE receptor: EP 2 linked to cAMP production and EP 3 coupled with inhibitory guanosine 5′-triphosphate-binding proteins mediating the inhibition of cAMP production.

Immunohistochemical and fine structural characterization of primary carcinoid tumors of the larynx.

Carcinoid tumors belong to the group of neuroendocrine tumors of epithelial origin, i.e., neuroendocrine carcinomas. These neoplasms usually occur in the gastrointestinal tract or bronchial system but are very rare neoplasms in the larynx. Since carcinoid tumors in this latter site may appear to be undifferentiated by light microscopy, they may possibly be misinterpreted and their neuroendocrine characteristics may remain unrecognized. Using immunohistochemical methods, three carcinoid tumors were studied and showed positive immunostaining for markers of epithelial origin (cytokeratins, epithelial membrane antigen, carcino-embryonic antigen) and, in particular, for markers of neuroendocrine differentiation (chromogranin, synaptophysin, neuron-specific enolase). All tumors expressed calcitonin-, serotonin- and adrenocorticotropic-hormone-like immunoreactivity. In contrast, three poorly differentiated squamous cell carcinomas showed positive immunostaining for epithelial markers but did not show any immunoreactivity with markers of endocrine characteristics. Fine structurally, carcinoid tumor cells contained neurosecretory-type granules scattered throughout the cytoplasm. The present study demonstrated that (1) carcinoid tumors of the larynx possess distinct immunohistochemical characteristics that allow a clear classification, (2) it is advisable to use a battery of primary antibodies rather than rely on specificity and sensitivity of a single marker to establish diagnosis and (3) the fine structural demonstration of neurosecretory-type granules serves as a reliable adjunct to diagnosis.

Ovarian Carcinoid with Severe Constipation Due to Peptide YY Production

We report a patient with primary trabecular carcinoid of the ovary with severe constipation probably due to peptide YY production by the tumor. A 43-year-old female had complained of severe constipation for several months and was found to have a left ovarian tumor. The surgically resected tumor was diagnosed as trabecular carcinoid by light microscopic examination. The carcinoid tumor cells were intensely and uniformly stained by the Grimelius technique. Immunohistochemically, the tumor cells were strongly positive for peptide YY, which has a strong inhibitory action on intestinal motility. The patient has been free from constipation since the removal of the tumor. The present case supports previously reported findings that not typical carcinoid syndrome but rather severe constipation accompanies primary trabecular carcinoid of the ovary, and that peptide YY is presumably the cause of the constipation.

Thymic carcinoma: proposal for pathological TNM and staging.

Recently, Yamakawa et al. following Masaoka's clinical staging of thymic epithelial tumors, proposed a TNM classification and staging system for thymic epithelial tumors including thymoma and thymic carcinoma. The present authors consider that division of thymomas into circumscribed types (either encapsulated or non-encapsulated but confined to within the thymus) and those invasive to adjacent organs or structures is sufficiently practical, and that a staging system is applicable to thymic carcinoma, carcinoid tumors and germ cell tumors of the anterior mediastinum, which are more malignant than thymoma. Therefore, the utility of the Yamakawa/Masaoka TNM and staging system was evaluated and a modification proposed based on experience with 16 thymic carcinomas. Although there were no cases at stage II, the survival curves obtained using the proposed modified system were more clearly separated between stages I and III or IV and between stages III and IV than the curves obtained using the Yamakawa/Masaoka system. However, the differences were not significant because of the small number of cases included. A statistically significant difference was noted between the survival curves for patients who underwent complete and incomplete surgical resection of the tumor. The utility of this proposed TNM and staging system must be evaluated by other investigators, since no cases of small cell carcinoma, lymphoepithelioma-like carcinoma, sarcomatoid carcinoma and clear cell carcinoma were included in this series, all of which are considered to have high-grade histology. An evaluation of carcinoid tumor and germ cell tumor of the anterior mediastinum must also be made.

Characterization of a Human Pancreatic Carcinoid in Vitro

The study of functioning human endocrine tumors has been hampered by a lack of suitable in vitro models. We have established the first permanent cell line of a human pancreatic carcinoid tumor (BON) in culture. BON cells grow in monolayer culture and form colonies in soft agar. Injection of BON cells into nude mice produces transplantable tumors in a dose-dependent fashion. The histology of tumors in athymic mice from injection of dispersed, cultured BON cells is similar to the original histology of the resected tumor. Significant amounts of neurotensin, pancreastatin, and serotonin (5-HT) are demonstrated in the cells by radioimmunoassay (RIA) and the presence of chromogranin A, bombesin, and 5-HT is confirmed by immunocytochemistry. Numerous round and pleomorphic dense-core neurosecretory granules are present on electron microscopy. Functional receptors for acetylcholine, 5-HT, isoproterenol, and somatostatin are present on cultured cells. BON cells possess a specific transport system for uptake of 5-HT from the medium; this uptake system may be a route for regulation of autocrine effects of 5-HT on carcinoid cells. This unique human carcinoid tumor cell line should provide the opportunity for new insight into the biology of carcinoid tumors and of specific intracellular mechanisms for secretagogue action in the release of amines and peptides.

Functioning ovarian carcinoids induce severe constipation.

Five patients with ovarian carcinoid who had severe constipation for a long period preoperatively showed marked reduction of this symptom postoperatively. Because this phenomenon was believed to be caused by some biologically active substance rather than a mechanical effect of the tumor, reactivity to 17 amine and peptide hormones was studied immunohistochemically in these patients. Numerous peptide YY (PYY)-positive cells were detected, with PYY-positive cells representing more than 50% of all carcinoid tumor cells in each patient. PYY, which has a pharmacologic inhibitory action on intestinal motility, was presumably the cause of the constipation in these patients.

Amine metabolism in human midgut carcinoid tumour cells

Amine metabolism in human midgut carcinoid tumour cells

An assessment of involucrin as a diagnostically useful immunohistochemical marker in lung tumours

A previous report has described involucrin as a specific immunohistochemical marker of squamous differentiation in lung carcinomas. The aim of our study was to examine the expression of this antigen in a wide variety of lung tumours, with particular attention to its potential value in the typing of biopsy specimens. We found that immunostaining for involucrin was common in squamous carcinomas but was also found in adenocarcinomas, adenosquamous carcinomas, large cell carcinomas and carcinosarcomas. Small cell carcinomas, carcinoid tumours and mesotheliomas were negative. Contrary to previous claims, this marker appears to have little diagnostic utility in the typing of lung tumours.

Production of transferrable neuronotrophic growth factor by human carcinoid tumour cells in culture

Production of transferrable neuronotrophic growth factor by human carcinoid tumour cells in culture

TNM staging and long-term follow-up after sleeve resection for bronchogenic tumors

From 1960 to 1989, 145 patients (132 men and 13 women) with a mean age of 60.3 years underwent sleeve lobectomy or sleeve resection of a main bronchus for a bronchogenic tumor. Squamous cell carcinoma was predominantly found (116 patients, 80.0%), followed by carcinoid tumor in 13 patients (9.0%). Postoperative staging was: stage I, 61 patients (42.1%); stage II, 47 (32.4%); stage IIIA, 33 (22.8%); and stage IIIB, 4 (2.7%). Thirty-day mortality was 4.8% (7 patients). Follow-up was complete except for 1 patient who was lost to follow-up 4 years after operation. For the whole group, 5-, 10-, and 15-year survival rates were 49%, 37%, and 18%, respectively. Better survival was noted in patients with carcinoid tumor and squamous cell carcinoma. Considering 112 patients with T2 and T3 squamous cell carcinoma, 5- and 10-year survival rates for No disease (52 patients) were 59% and 47%, for N1 disease (51 patients) 21% and 0%, and for N2 disease (9 patients) 44% and 0%. Differences between N1 and N2 disease were not statistically significant. Survival after sleeve resection is best for carcinoid tumors and squamous cell carcinoma with negative nodes. Presence of N1 or N2 disease significantly worsens prognosis, with no 10-year survivors and no difference between N1 and N2 status.

Well-differentiated Neuroendocrine Carcinoma: A Designation Comes of Age

In this issue (see page 1053), Lequaglie and co-workers describe a retrospective analysis of their ten-year experience with resected, well-differentiated neuroendocrine carcinoma (WDNC). Their work confirms and extends the observations of others that WDNC is a clinicopathologic entity distinct from other neuroendocrine tumors of the lung, including carcinoid tumor and small cell lung carcinoma (SCLC). 1 Memoli VA Maurer LH. Retrospective histologic classification of long-term survivors with small cell carcinoma.. Lung Cancer. 1986; 2: 56 Google Scholar 2 Warren WH Memoli VA Jordan AG Gould VE. Re-evaluation of pulmonary neoplasms resected as small cell carcinoma: significance of distinguishing between well-differentiated and small cell neuroendocrine carcinomas.. Cancer. 1990; 65: 1003-1010 Crossref PubMed Scopus (34) Google Scholar Utilizing morphologic criteria defined by Gould et al, 3 Gould VE Linnoila RI Memoli VA Warren WH. Neuroendocrine components of the bronchopulmonary tract: hyperplasias, dysplasias and neoplasms.. Lab Invest. 1983; 49: 519-537 PubMed Google Scholar the authors identify 19 cases of resected WDNC. Significantly, while six of the first 12 cases were diagnosed as atypical carcinoids, the remaining six cases had originally been diagnosed as SCLC, thereby reinforcing the observation that some WDNCs are mistaken for SCLC. Refinements in the morphologic diagnosis of WDNC by Warren and co-workers 2 Warren WH Memoli VA Jordan AG Gould VE. Re-evaluation of pulmonary neoplasms resected as small cell carcinoma: significance of distinguishing between well-differentiated and small cell neuroendocrine carcinomas.. Cancer. 1990; 65: 1003-1010 Crossref PubMed Scopus (34) Google Scholar clearly demonstrate that, while the WDNC category encompasses tumors originally diagnosed as atypical carcinoids, it also includes tumors that may be incorrectly diagnosed as SCLC, particularly when diagnostic material is limited to small bronchoscopic biopsy specimens or cytologic preparations. In our experience, 1 Memoli VA Maurer LH. Retrospective histologic classification of long-term survivors with small cell carcinoma.. Lung Cancer. 1986; 2: 56 Google Scholar these cases represent a large majority of long-term survivors with a diagnosis of SCLC. Similar morphologic observations have been made in cytologic studies of bronchial specimens, and criteria have been established for the cytodiagnosis of WDNC. 4 Jordan AG Predmore L Sullivan MM Memoli VA. The cytodiagnosis of well differentiated neuroendocrine carcinoma.. Acta Cytol. 1987; 31: 464-470 PubMed Google Scholar