Molecular pathology of c-kit proto-oncogene and development of gastrointestinal stromal tumors

The study evaluates faecal immunoreactive lipase (IRL) measurement in spot stool samples as an index of exocrine pancreatic function in patients with cystic fibrosis (CF). Stool samples (211) from 183 healthy volunteers (age range: 2 days-14.2 years) showed a normal log distribution of IRL values with a median concentration of 71.4 micrograms/g (range: 0.53-4160 micrograms/g). In 156 stool samples from 58 patients with proven CF, the median IRL concentration of 0.4 microgram/g (range: 0.003-107 micrograms/g) was significantly lower (P < 0.001) than that of normal controls. In healthy controls, IRL levels were age related with significantly higher levels (P < 0.001) shortly after birth compared to older children. Stimulation of the exocrine pancreas by oral milk feeding resulted in a significant (P < 0.001) increase in a faecal IRL concentration. Faecal IRL concentrations in meconium were very low and of the same magnitude as in patients with CF. CONCLUSION: Faecal IRL determination had a high diagnostic sensitivity (87%) and excellent diagnostic specificity (97%) in patients with CF. A negative test result (PVneg. 99%) virtually excluded CF under screening conditions.     

Telomerase activity in gastrointestinal stromal tumors

BACKGROUND: Telomerase activity has been observed in 80-90% of carcinomas derived from various organs. However, to the authors' knowledge this report is the first assessment of telomerase activity in gastrointestinal stromal tumors (GISTs). METHODS: Telomerase activity was analyzed by the telomerase repeat amplification protocol assay in 29 tumors from 26 patients (23 primary tumors from 22 patients, 1 pair of primary and metastatic tumors from 1 patient, and 4 metastatic tumors from 3 patients). Phenotypes, tumor cell proliferation, and overexpression of p53 protein were evaluated immunohistochemically. RESULTS: Seven of 24 primary tumors (29%) and 5 of 5 metastatic tumors (100%) showed telomerase activity. Telomerase activity positive (+) GISTs were significantly larger (P < 0.05) and showed a significantly higher rate of proliferation than telomerase activity negative (-) tumors (P < 0.0001). All telomerase activity (+) GISTs were classified histologically as high risk tumors. Conversely, 15 of the 17 telomerase (-) GISTs were classified histologically as low risk tumors (P < 0.0001). With regard to p53 immunoreactivity, two and seven telomerase activity (+) tumors showed diffuse and sporadic positivity, respectively, whereas only five telomerase activity (-) tumors showed only focal or sporadic positivity. Telomerase activity was correlated significantly with poor prognosis (P < 0.05) in the patients in whom the primary GISTs were evaluated (n = 23). CONCLUSIONS: Telomerase activity may be a useful marker for evaluating the malignant potential of GIST. A distinct subgroup of GISTs is a target for therapy with a telomerase inhibitor.     

Muscle differentiation and clinicopathologic features of gastrointestinal stromal tumors

We analyzed 46 gastrointestinal stromal tumors (GISTs) using a panel of antibodies to determine the frequency of smooth muscle differentiation and the relationship of immunophenotype to histopathologic features and clinical behavior. Thirty-six GISTs were classified as benign or malignant based exclusively on clinical behavior; a 2-year minimum follow-up was required for benign lesions. GISTs were immunopositive in the following categories: vimentin 45 of 46, desmin nine of 45, muscle-specific actin (MSA) 36 of 46, alpha-smooth muscle actin (SMA) 34 of 46, chicken gizzard actin-7 zero of 38, cytokeratin two of 46, S100 protein six of 46, glial fibrillary acidic protein (GFAP) zero of 46, synaptophysin zero of 46, and chromogranin one of 46. At least one muscle marker was positive in 39 of 46 tumors. Five GISTs were MSA positive/SMA negative, and three were MSA negative/SMA positive. All desmin-positive cases reacted with MSA or SMA. Eight GISTs were positive for vimentin, MSA, SMA, and desmin, whereas seven were vimentin positive only. Compared with the latter, the former tended to be smaller, less often necrotic, and clinically benign (p less than 0.05 for each). All vimentin-positive only GISTs were malignant. Immunohistochemical features did not correlate with tumor site, cellularity, nuclear pleomorphism, or mitotic rate. Benign GISTs were less cellular than were malignant GISTs (p less than 0.05), but they did not differ statistically in degree of nuclear pleomorphism, necrosis, mitotic rate, or size. We conclude that (a) 85% of GISTs react with at least one muscle antibody; (b) immunohistochemical features are unrelated to anatomic site; (c) SMA is, in effect, as sensitive as MSA, whereas desmin is less sensitive; and (d) simultaneous vimentin, MSA, SMA, and desmin positivity correlates with a benign outcome.     

Prognosis of gastrointestinal smooth-muscle (stromal) tumors: dependence on anatomic site

OBJECTIVES: To assess how the community urologist employs intravesical therapy in patients with transitional cell carcinoma (TCC) of the bladder because most data on intravesical therapy reflect the experience of major referral centers. METHODS: The medical records of 234 consecutive patients with TCC were reviewed. Sixty-nine patients received intravesical treatment before referral. The initial pathologic findings, the indication for treatment (eg, grade and stage, initial versus recurrent tumor), the schedule of intravesical therapy, and the drug selected for each course of treatment were assessed. RESULTS: A total of 1 39 courses of intravesical treatment were given to 69 patients; thus, the avarage number of courses was 2.02 per patient. The drug used was bacillus Calmette-Guerin (BCG) in 81 (58%), mitomycin C in 34 (24%), thiotepa in 16 (12%), Adriamycin in 4 (3%), and unknown in 4 (3%). Intravesical treatment was given after transurethral resection of the initial tumor in 33 patients; the initial pathologic finding was high grade (ie, grade 3 or carcinoma in situ) and/or Stage T1 in 22, TaG1-G2 in 9, and unknown in 2. One course of treatment was administered to 34 patients (49%) and two or more courses to 35 patients (51%). Eleven patients with TaG 1 -2 tumors were treated repetitively despite failure, with an average of 3.5 courses per patient; the drug used was BCG in 44%. Nineteen percent of patients received maintenance therapy. Intravesical therapy had to be discontinued in 10 patients because of side effects; 8 patients (12%) developed small contracted bladders and severe irritative symptoms, 3 required cystectomy despite the lack of bladder cancer. CONCLUSIONS: Intravesical therapy in community practice conforms with the generally accepted indications for high-grade and T1 disease. However, the use of BCG for low-grade TCC appears to be quite common. Repeated courses may result in significant side effects. We emphasize that excessive treatment should be avoided for low-grade, Ta lesions and BCG reserved for patients with TaG3, carcinoma in situ, or T1 TCC.     

A primary solitary tumor of the lesser omentum with immunohistochemical features of gastrointestinal stromal tumors

We here present a primary solitary tumor of the lesser omentum that was found in a 71-yr-old woman. Differential diagnosis could not be made preoperatively; therefore, histopathological examination including immunohistochemical studies were performed to determine the nature of the tumor. The resected specimen, measuring 17 cm at the largest point, consisted of the outer solid part and the inner multiloculated cysts. Microscopically, the tumor was characterized by interlacing bundles of elongated spindle cells, with the nuclei focally showing a palisading pattern. However, skeinoid fibers were not observed anywhere. One to three mitoses per 50 high power fields were observed. Immunohistochemically, the tumor was negative for S-100 protein and smooth muscle-specific actin, but stained positive for CD34. The microscopic features were consistent with those of potentially malignant gastrointestinal stromal tumors. Stromal tumors that represent the differentiation toward neither typical leiomyomas or schwannomas rarely occur in the lesser omentum with only one such instance having been reported to date. Due to this rarity, it is difficult to make the differential diagnosis preoperatively, even with existing imaging techniques, and predicting the clinical behavior of such omental tumors is also often difficult. Therefore, complete resection should be performed when such tumors are encountered in daily practice.     

Gain-of-function mutations in FcgammaRI of NOD mice: implications for the evolution of the Ig superfamily

It has been postulated that, during evolution of the Ig superfamily, modifications of the function of individual receptors might occur by acquisition of exons and their subsequent modification, though evidence of this is lacking. Here we have analysed the interaction of mouse IgG subclasses with high-affinity FcgammaRI (CD64) which contains three Ig-like domains and is important in innate and adaptive immunity. This analysis has identified a mechanism by which the postulated modification of newly acquired exons provides gains in function. Thus, the most widely distributed FcgammaRI allele in mice (e.g. BALB/c), bound only a single IgG subclass, IgG2a, with high affinity. However, non-obese diabetic (NOD) mice expressed a unique allele that exhibits broader specificity and, in addition to binding IgG2a, FcgammaRI-NOD bound monomeric IgG3 and bound IgG2b with high affinity, an IgG subclass not bound by FcgammaRI of other mouse strains, either as monomer or multivalent immune complexes. Analysis of mutants of FcgammaRI wherein segments of the interdomain junctions were exchanged between FcgammaRI-BALB and FcgammaRI-NOD identified these regions as having major influence in 'gain-of-function' by the NOD form of FcgammaRI. Nucleotide sequence analysis of intron/exon boundaries encoding the interdomain junctions of the FcgammaRI alleles showed these to have arisen by mutation to alter existing or create new mRNA splice donor/acceptor sites, resulting in generation of modified junctions.     

Detection and clinical correlations of ras gene mutations in human ovarian tumors

In epithelial ovarian neoplasms K-ras codon 12 gene mutations show a wide variation fluctuating between 4-39% in invasive carcinomas and 20-48% in borderline malignant tumors. In this study, we showed the pattern of point mutations in codon 12 of the K-ras, H-ras and N-ras genes, using polymerase chain reaction restriction fragment length polymorphism analysis in 74 tissue specimens of Greek patients with epithelial ovarian tumors. K-ras and H-ras gene mutations were detected in 11/48 (23%) and 3/48 (6%) cases with primary invasive ovarian carcinomas, respectively, while N-ras gene mutations were not found. No mutation of K-, H- and N-ras genes was detected in 23 ovarian cystadenomas. In 1 out of 3 borderline ovarian tumors (33%) we found an H-ras gene mutation. The prevalence of mutations in K-ras gene was 1/8 (13%) in mucinous, 7/29 (24%) in serous, 1/3 (33%) in endometrioid and 2/8 (25%) in clear-cell adenocarcinomas and in H-ras gene 1/8 (13%) in mucinous and 2/29 (7%) in serous adenocarcinomas. Analysis of the results revealed no significant correlation between ras gene mutations and clinicopathological parameters or clinical outcome of this primary invasive ovarian carcinoma population. Our present data suggest that ras gene mutations in invasive ovarian carcinomas occur in 29% of Greek patients and are not associated with the differentiation of the epithelial cells or the response of patients to adjuvant platinum-based chemotherapy.     

Characterization of gastrointestinal tumors

Transabdominal ultrasonography is used increasingly for the evaluation of gastrointestinal disorders in small animals, including neoplasms such as lymphosarcoma, carcinoma, and smooth muscle tumors (leiomyoma, leiomyosarcoma). An updated summary of the clinical studies currently investigating the use of ultrasonography to detect and to characterize gastrointestinal neoplasia is presented in this article.     

Intraoperative radiotherapy in gastrointestinal tumors

Intraoperative radiotherapy has proved its worth for curative and palliative treatment of gastrointestinal tumors. IORT indications comprise cancer of the stomach, of the pancreas and colorectal carcinomas. Most authors are cautious to apply it to carcinoma of the esophagus, of the small intestine and of the hepatobiliary system. IORT is applied as adjuvant treatment alone or in combination with postoperative external-beam photon irradiation +/- chemotherapy. There is evidence of an improved local control rate. Pain can be relieved in symptomatic patients by an IORT dose of > or = 20 Gy. Until now, however, there is no evidence of a prolonged relapse-free and overall survival.     

Detection of infrequent and multiple K-ras mutations in human tumors and tumor-adjacent tissues

A sensitive method was developed and applied to examine the distribution of K-ras gene mutations in histologically differing areas of lung tissues obtained from lung cancer patients. This method, which combines polymerase chain reaction (PCR), mutation allele enrichment (MAE), and denaturing gradient gel electrophoresis (DGGE), allows detection of one K-ras mutant allele present in 10(4) to 10(5) wild-type alleles. It was applied to analyze mutations in codon 12 of the K-ras gene in 43 tissue sites microdissected from paraffin-embedded sections obtained from 8 archival cases of lung cancer, all previously shown to have codon 12 K-ras mutations by direct sequencing. In four cases, mutations were detected only in the tumor, while in the other four cases, the same mutations were also found in tissues adjacent to tumors, using the MAE + DGGE method. No mutations were detected among normal-appearing cells in areas distant from the tumors in any of the cases studied. These findings demonstrate that K-ras mutations can be detected at low frequencies in normal-appearing cells from tissues adjacent to the tumor in some lung cancer cases. In addition, this approach also allowed detection of multiple mutations in colorectal tissues obtained from colorectal cancer patients. Thus, the MAE + DGGE method may be applicable to study of K-ras mutations in premalignant or morphologically suspicious lesions in bronchial mucosa or other types of human cancer.     

Malignant stromal tumors of the stomach

BACKGROUND/AIMS: The purpose of this paper is to expose our experience in malignant stromal tumors of the stomach. METHODOLOGY: We present 16 cases of malignant stromal tumors of the stomach, operated on in our hospital from 1977 to 1995. Age, sex, symptoms and signs, standard laboratory tests, diagnostic methods, location, size, infiltration of other organs, proliferating activity, treatment and survival rate are analyzed. Immune staining was performed using the avidin-biotin-peroxidase method, with the S-100 1/8000 and muscular actin 1/50 antiserum. All patients underwent surgical treatment, and neither chemotherapy nor radiotherapy were used. RESULTS: Thirteen patients died 5 to 78 months after surgery, and the other 3 are alive and free of disease 74, 48 and 38 months after resection, respectively. Five year survival rate was 37.5%. The most important prognostic factors were tumor size, infiltration of neighboring organs and high mitotic index. CONCLUSION: All the clinical data, survival rates and prognostic factors are similar to other published cases. Surgery is the first step in the treatment of these tumors, as the role of other therapeutic options is not well known yet.     

Prevalence of G-to-T transversions among K-ras oncogene mutations in human colorectal tumors in Yugoslavia

Human colorectal carcinoma tissue sampled from 37 patients, routinely graded into Dukes' stages A, B and C and histologically examined for the level of differentiation, were analyzed for the presence of point mutations in the K-ras oncogene. Seventeen cases out of the 37 analyzed were found to have a mutation in either the 12th or the 13th codon of the K-ras gene, giving an overall frequency of mutation of 46%. The incidence of mutations in Dukes' stages A, B and C was 33, 46 and 58% respectively. Although the frequency of mutation appears to be similar to that reported for the USA population, the spectrum of point mutations in codons 12 and 13 of the K-ras gene in the Yugoslav population appears to differ significantly. G-to-T transversions make up 77% of all mutations present, with the distribution as follows: 18% at the first base and 59% at the second base of codons 12 and 13. G-to-A transitions at the second base is the only other mutation identified, occurring mainly in codon 13 in colorectal tumors of all 3 stages.     

CD117: a sensitive marker for gastrointestinal stromal tumors that is more specific than CD34

Interaction between dopaminergic and corticoliberinergic integrative systems in the process of situation alimentary conditioning, was studied in dogs with chemotrodes indwelled in the caudate nucleus head. Following the CRF administration, the cortisol and catecholamine levels were determined in the blood of intact dogs and in the dogs with 6-OHDA impairment of the substantia nigra. The findings suggest that an interaction between the CRF and dopaminergic systems occurs in the neostriatum.     

Slow-release lanreotide treatment in endocrine gastrointestinal tumors

OBJECTIVES: Lanreotide is a somatostatin analogue whose activity persists for 10-14 days. In this study, we treated a group of patients with gastrointestinal endocrine tumors with lanreotide to assess its therapeutic efficacy and tolerability. METHODS: Eighteen patients, 12 male and six female, mean age 58 yr (range, 25-80 yr) were studied. Ten had carcinoid tumors, five had nonfunctioning endocrine tumors, two had glucagonomas, and the remaining one had a gastrinoma. All patients had somatostatin receptors, demonstrated by octreoscan scintigraphy. Lanreotide was administered intramuscularly at a dose of 30 mg every 10 days, for a mean of 12 months (range, 5-18 months). Fifteen of the 18 patients had been previously treated with octreotide. RESULTS: In patients with carcinoid tumors, lanreotide markedly reduced daily bowel movements and flushing episodes. A reduction was also observed in urinary serotonin and urinary 5-hydroxyindoleacetic acid, although it was not statistically significant. A marked reduction in symptoms, and in plasma glucagon and serum gastrin levels, was also observed in patients with glucagonoma and gastrinoma. In the five patients with nonfunctioning endocrine tumors, as in all the other 13 patients, no significant effects were noted in the size of the tumor. The administration of lanreotide did not cause side effects, apart from transient abdominal pain and pain at the injection site in two patients. Only in the patient with gastrinoma was lanreotide suspended, because of the appearance of attacks of marked hypoglycemia. In the 15 patients previously treated with octreotide, no differences in the effects were noted with lanreotide. CONCLUSIONS: Lanreotide has a satisfactory therapeutic efficacy and tolerability in the treatment of gastrointestinal endocrine tumors; its effects are similar to those of octreotide. However, unlike octreotide, it can be administered once every 10-14 days, instead of 2 or 3 times daily and for this reason, it is preferable in clinical practice.     

PTEN mutations in gliomas and glioneuronal tumors

Cytogenetic and loss of heterozygosity studies have suggested the presence of at least one tumor suppressor gene on chromosome 10 involved in the formation of high grade gliomas. Recently, the PTEN gene, also termed MMAC1 or TEP1, on chromosomal band 10q23 has been identified. Initial studies revealed mutations of PTEN in limited series of glioma cell lines and glioblastomas. In order to systematically evaluate the involvement of PTEN in gliomas, we have analysed the entire PTEN coding sequence by SSCP and direct sequencing in a series of 331 gliomas and glioneuronal tumors. PTEN mutations were detected in 20/142 glioblastomas, 1/7 giant cell glioblastomas, 1/2 gliosarcomas, 1/30 pilocytic astrocytomas and 2/22 oligodendrogliomas. No PTEN mutations were detected in 52 astrocytomas, 37 oligoastrocytomas, three subependymal giant cell astrocytomas, four pleomorphic xanthoastrocytomas, 15 ependymomas, 16 gangliogliomas and one dysembryoplastic neuroepithelial tumor. In addition, all tumors were examined for the presence of homozygous deletions of the PTEN gene; these were detected in 7 glioblastomas that did not have PTEN mutations. Therefore, PTEN mutations occur in approximately 20% of glioblastomas but are rare in lower grade gliomas. These findings confirm that PTEN is one of the chromosome 10 tumor suppressor genes involved in the development of glioblastomas.     

Aspiration cytology in the diagnosis of gastrointestinal tumors

Early experiences with the new endoscopic aspiration cytology method in the diagnosis of gastrointestinal malignancies are discussed. It was performed in five patients in case of gastric and cardiac cancers and in fifteen ones of colon tumours. Results are compared with those of biopsies and brush cytologies. The new method is quick, reliable and suggested to be widely used in the gastrointestinal endoscopy.     

Epstein-Barr virus and CD21 expression in gastrointestinal tumors

OBJECTIVES: Animal inhalation studies and theoretical models suggest that the pattern of formation of benzene metabolites changes as exposure to benzene increases. To determine if this occurs in humans, benzene metabolites in urine samples collected as part of a cross sectional study of occupationally exposed workers in Shanghai, China were measured. METHODS: With organic vapour monitoring badges, 38 subjects were monitored during their full workshift for inhalation exposure to benzene. The benzene urinary metabolites phenol, catechol, hydroquinone, and muconic acid were measured with an isotope dilution gas chromatography mass spectroscopy assay and strongly correlated with concentrations of benzene air. For the subgroup of workers (n = 27) with urinary phenol > 50 ng/g creatinine (above which phenol is considered to be a specific indicator of exposure to benzene), concentrations of each of the four metabolites were calculated as a ratio of the sum of the concentrations of all four metabolites (total metabolites) and were compared in workers exposed to > 25 ppm v < or = 25 ppm. RESULTS: The median, 8 hour time weighted average exposure to benzene was 25 ppm. Relative to the lower exposed workers, the ratio of phenol and catechol to total metabolites increased by 6.0% (p = 0.04) and 22.2% (p = 0.007), respectively, in the more highly exposed workers. By contrast, the ratio of hydroquinone and muconic acid to total metabolites decreased by 18.8% (p = 0.04) and 26.7% (p = 0.006), respectively. Similar patterns were found when metabolite ratios were analysed as a function of internal benzene dose (defined as total urinary benzene metabolites), although catechol showed a more complex, quadratic relation with increasing dose. CONCLUSIONS: These results, which are consistent with previous animal studies, show that the relative production of benzene metabolites is a function of exposure level. If the toxic benzene metabolites are assumed to be derived from hydroquinone, ring opened products, or both, these results suggests that the risk for adverse health outcomes due to exposure to benzene may have a supralinear relation with external dose, and that linear extrapolation of the toxic effects of benzene in highly exposed workers to lower levels of exposure may underestimate risk.     

Induction of c-kit molecules on human CD34+/c-kit < low cells: evidence for CD34+/c-kit < low cells as primitive hematopoietic stem cells

c-kit, a receptor for stem cell factor, has been widely accepted as a distinctive marker for hematopoietic stem cells. However, the level of c-kit expression on pluripotent hematopoietic stem cells is still controversial in mice and humans. We purified CD34+/c-kit < low cells (phenotypically c-kit-negative but only detectable at the message level) from human cord blood and examined their maturational steps in relation to the expression of c-kit molecules. When the CD34+/c-kit < low cells were cultured with cytokines (flt 3 ligand, interleukin 6 and interleukin 7) plus immobilized anti-CD34 monoclonal antibody (to crosslink CD34 molecules), c-kit molecules were clearly induced within 24 h. The c-kit expression gradually increased until day 8. When CD34+/c-kit(low) or CD34+/c-kit+ cells that had been induced from CD34+/c-kit < low cells were resorted and recultured using a methylcellulose culture system, they showed the same colony-forming ability as the freshly isolated CD34+/c-kit(low) or CD34+/c-kit+ cells, respectively. Furthermore, CD34+/c-kit < low cells have a similar hematopoietic potential to CD34+/c-kit(low) cells in assays for long-term culture initiating cell and colony-forming unit culture generated from long-term cultures. These findings suggest that CD34+/c-kit < low cells mature into CD34+/c-kit(low) and CD34+/c-kit+ cells, and acquire the reactivity to various humoral hematopoietic stimuli. Moreover, CD34+/c-kit < low cells showed a low level of rhodamine 123 retention, suggesting that CD34+/c-kit < low cells have multidrug resistance. Therefore, the CD34+/c-kit < low cells without colony-forming unit-granulocyte-erythroid-macrophage-megakaryocyte activity are also a pluripotent hematopoietic stem cell population, and the expression of c-kit on c-kit < low cells is the first maturational step of hematopoiesis.     

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.