Bronchial carcinoids with S-100 positive sustentacular cells. A comparative study with gastrointestinal carcinoids, pheochromocytomas and paragangliomas.

Fourty-six bronchial carcinoids, twelve tumourlets and twenty areas of neuroendocrine cell dysplasia (NED) were immunohistochemically evaluated for various neuroendocrine markers, S-100 protein (S-100), myelin basic protein, intermediate filaments, actin, Leu-7 and several neurohormonal polypeptides. Eighteen of the bronchial carcinoids (39.1%) showed a biphasic cell pattern, with abundant stellate-shaped S-100 positive cells (SC). SC were not reactive for chromogranin A, myelin basic protein, cytokeratins, neurofilaments, glial fibrillary acidic protein or actin, and were only occasionally weakly positive for vimentin. SC were not detected in the tumourlets nor in the NED observed. For comparison a group of other neuroendocrine tumours (11 gastrointestinal carcinoids, 4 pheochromocytomas and 4 paragangliomas) were immunostained for S-100, chromogranin A and actin. SC similar to the ones detected in the bronchial carcinoids could be detected in appendiceal carcinoids, paragangliomas and in two out of four pheochromocytomas. Our present data are in keeping with a Schwannian/sustentacular nature of SC rather than that of a histiocytic or myoepithelial nature. We suggest that SC-rich bronchial carcinoids are biphasic tumours, which could be designed "paraganglioid" bronchial carcinoids. The relationship between SC-rich bronchial carcinoids and tumourlets/NED is a matter of further investigation: SC-rich bronchial carcinoids may either differentiate in a biphasic pattern during tumoural growth or may not be histogenetically related to tumourlets.

Amidated joining peptide in the human pituitary, gut, adrenal gland and bronchial carcinoids. Immunocytochemical and immunochemical evidence.

The distribution of the proopiomelanocortin-derivated amidated joining peptide (JP-N) was examined in the human pituitary gland, adrenal gland, gut and in three bronchial carcinoids. Double immunostaining showed coexistence of immunoreactive JP-N and other proopiomelanocortin derivatives, e.g., ACTH, beta-endorphin, Pro-tau-MSH, in the pituitary gland and adrenal medulla. The JP-N immunoreactive cells in the adrenal medulla were identified as a subpopulation of adrenaline-producing cells by means of an antiserum against phenylethanolamine N-methyltransferase. In the gut immunoreactive JP-N was costored with somatostatin in endocrine cells. Using radioimmunoassay, JP-N was found in higher concentrations than ACTH and alpha-MSH in the gut but not in the adrenal gland. Gel chromatography of gastric antrum and adrenal gland extracts showed three and two dominating components of immunoreactive JP-N, respectively, but under reduced conditions most of the immunoreactive material appeared as of low molecular weight in both extracts. In conclusion, immunoreactive JP-N is a major product from the processing of proopiomelanocortin in human extrapituitary tissues. The molecular forms of immunoreactive JP-N correspond to previous findings in the human pituitary gland.

An unusual case of bronchial carcinoid predominantly consisting of large cells.

A 58-year-old woman presented an unusual variant of bronchial carcinoid. A tumor measuring 20 x 25 mm was recognized upon gross examination in the upper lobe of the right lung. Microscopically, the tumor consisted of large polyhedral cells with a pseudoglandular arrangement similar to pheochromocytoma cells. Immunohistochemically, the tumor cells contained serotonin, S-100 protein and neuron-specific enolase. Thus, we consider this neoplasm to be a large cell variant of bronchial carcinoid which, to our knowledge, has not been described in the literature.

[Bronchial carcinoid and small cell lung cancer--neuroendocrine tumors. Immunohistochemical studies]. / Rakowiak oskrzela i rak drobnokomórkowy pluca--nowotwory ukladu neuroendokrynnego. Badania immunohistochemiczne.

Selected neoplastic markers (NSE, gastrin, CEA, calcitonin, keratin) were studied in pulmonary specimens from 5 patients with bronchial carcinoid, 20--with small cell lung cancer (SCLC), and 2 with solid tumors. In patients with carcinoid and SCLC NSE and gastrin markers were found--characteristic for neuroendocrine neoplasia. The author discuss the usefulness of immunohistochemistry in differential diagnostics of pulmonary malignancy.

[Morphologic and tumor-marker studies of human planocellular carcinoma of the bronchi in xenografts]. / Humán laphámsejtes hörgörák xenograftok morphologiai és tumor marker vizsgálata.

Authors have studied the morphology of 10 human planocellular bronchus carcinoma xenografts parallel with that of the donor tumour. The expression of cytokeratin, epithelial membrane antigen and carcinoembryonic tumour markers was also studied and compared. The histological structure and marker expression of xenografts did not change as compared to the donor tissue. Tumour cells were characterized by cytokeratin rather than epithelial membrane antigen. Carcinoembryonic antigen positivity occurred mainly in well-differentiated tumours. The cellular heterogeneity of human planocellular bronchus carcinomas was found to occur also in xenograft tumours.

Multiple forms of parathyroid hormone-like proteins in a human tumour.

The extensive chromatographic characterization of four parathyroid hormone (PTH)-like proteins in a human bronchial carcinoid tumour associated with humoral hypercalcaemia and severe osteitis fibrosa is described. PTH-like bioactivity was detected in acetic acid extracts of the tumour using an in-vitro osteo-sarcoma cell bioassay. The active tumour proteins were positively charged at physiological pH and had apparent Mr of approximately 29,000, 16,000, 4000-9000 and less than 4000. The proteins were immunologically distinct from PTH, but each stimulated PTH-sensitive adenylate cyclase in cultured osteoblastic cells. There was no evidence of PTH gene expression by the tumour. These proteins represent different molecular forms of PTH-related protein.

Adenoid cystic carcinoma of the trachea and main-stem bronchus. A clinical, histopathologic, and immunohistochemical study.

Twelve cases of adenoid cystic carcinoma of the trachea and main-stem bronchus were histologically analyzed, and the results were examined with reference to the growth pattern of the tumor and the prognosis. The tumors were histologically classified into tubular, cribriform, and solid subtypes. Three histologic grades were established: grade I, tumors with tubular and cribriform subtypes but without solid subtype; grade II, tumors with tubular and cribriform subtypes in which the solid subtype comprised less than 20% of the area; grade III, tumors in which the solid subtype comprised more than 20% of the area. Three gross infiltrating types were established: type I, entirely intraluminal; type II, predominantly intraluminal; type III, predominantly extraluminal. In most cases histologic grade correlated with gross tumor type; that is, grades, I, II, and III were grossly types I, II, and III, respectively. The tumors infiltrating along the tracheobronchial wall were of the tubular or cribriform subtype, but not of the solid subtype. In two patients who died of distant metastasis, the histologic studies revealed the solid subtype. Immunohistochemical analysis demonstrated that the tubular subtype was the most differentiated form and the solid subtype, the most undifferentiated form. The histologic subtype of adenoid cystic carcinoma of the tracheobronchial tree was an important factor in the growth pattern of the tumor and the prognosis.

Bronchopulmonary carcinoids and regional lymph node metastases. A quantitative pathologic investigation.

Bronchopulmonary carcinoid tumors are tumors with a low malignant potential. They metastasize in 5-15% of cases. Accurate histologic preoperative prediction of the presence of regional lymph node metastases is not possible at this time. A retrospective quantitative pathologic analysis was performed to investigate the possibility of predicting the presence or absence of regional lymph node metastases in 24 patients with bronchopulmonary carcinoid tumors. The results of univariate analysis showed that large tumor size was associated significantly more frequently with regional lymph node metastases than small tumor size (P less than 0.01). The other quantitative features, ie, a larger mean nuclear area, higher standard deviation of the nuclear area and the presence of an aneuploid DNA index, were frequently associated with regional lymph node metastases, but this tendency was not significant. In multivariate analysis the combination of tumor size and mean nuclear area predicted the presence or absence of regional lymph node metastases correctly in 80 and 94% of the cases, respectively. These results indicate that the combination of tumor size and mean nuclear area may serve as a guideline to predict the presence of regional lymph node metastases.

Dendritic cells in bronchial adenocarcinoma.

We studied 28 bronchial adenocarcinomas (including 11 bronchiolo-alveolar carcinomas) stained for S-100 protein by the PAP technique in order to visualize dendritic cells in the neoplastic area. Dendritic cells were found in all cases varying in number from single to multiple and from region to region. Bronchiolo-alveolar carcinomas contained a similar quantity of these cells. The most numerous dendritic cells up to several scores per microscopical low-power field almost in all fragments of the tumour were found in three adenocarcinomas with numerous foci of the squamous cell metaplasia. Normal and metaplastic squamous epithelium of the bronchial mucosa did not show the presence of dendritic cells.

[Study of 2 markers, keratin and neuron-specific enolase, in bronchial cancers]. / Etude de 2 marqueurs, la kératine et la NSE dans les cancers bronchiques.

In an immunohistochemical study 31 patients with bronchial cancer (squamous cell 9, large cell 4, small intermediate cell 11 and oat cell 7) were investigated for keratin and NSE. Keratin seems to be a valuable marker since only oat cell cancers and 45% of small intermediate cell cancers were negative. In contrast, marking with NSE seems to be non-discriminating. The low value of NSE as marker was confirmed by 133 serum NSE assays performed in 39 bronchial cancer patients. Although NSE values were significantly higher in oat cell cancer, in any given patient serum assays can, at best, detect relapses.

Chromogranin as a marker of neuroendocrine cells in cytologic material--an immunocytochemical study.

Cytologic material, including fine-needle aspirations, bronchial brushings, body cavity fluids, and tissue imprints from 39 neuroendocrine and 26 nonneuroendocrine tumors, was stained for chromogranin by the immunoperoxidase technic. Our results suggest that chromogranin is useful in identifying primary as well as metastatic neuroendocrine lesions from a variety of body sites. All lymphoid proliferations and carcinomas, including small-cell anaplastic carcinomas of the lung (oat-cell carcinomas), were negative. Chromogranin appears to be a useful marker in diagnostic cytology. This technic can be applied to routinely prepared cytologic material.

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.

Bombesin in human neuroendocrine (NE) neoplasms.

Bombesin is a 14 amino acid peptide isolated from amphibian skin which was found to have stimulatory effects upon gastric and pancreatic secretions, release of gastrointestinal hormones, gallbladder contraction and bronchoconstriction. It is present in amphibian gastric endocrine cells, avian proventriculus endocrine cells and avian brain. In mammals it is present mainly in nerve cells and fibers. The only mammalian endocrine cell shown to date to have bombesin is the P-cell in fetal lung. Bombesin is also found in mammalian brain, with its highest concentration in the hypothalamus. We examined several groups of human neuroendocrine neoplasms for the presence of bombesin by immunohistochemistry. Our findings indicate that bombesin is present 68% of bronchial carcinoids, 65% of pulmonary neuroendocrine carcinomas, 62% of neuroendocrine carcinomas of the skin, 5-10% of pheochromocytomas and extraadrenal paragangliomas and 35% of gastrointestinal carcinoids and neuroendocrine carcinomas. Parallel studies in a wide variety of non neuroendocrine neoplasms failed to reveal the presence of bombesin. We conclude that bombesin is a highly specific marker of neuroendocrine differentiation and thus a valuable tumor marker. Furthermore, its specificity compares favorably with another neuroendocrine marker, neuron specific enolase, an enzyme thought to be present only in neural tissues and neuroendocrine cells but recently found in non neural human tissues and non neuroendocrine neoplasms.

Cushing's syndrome produced by a bronchial carcinoid tumor.

A case of bronchial carcinoid tumor with ectopic corticotropin production is described. Cushing's syndrome refractory to therapy, including pituitary irradiation and hypophysectomy, had been present for 12 years before the neoplasm was discovered at autopsy. The tumor was a small nodule localized in the pulmonary parenchyma and an adjacent hilar lymph node. Corticotropin, serotonin, and neuron-specific enolase were localized in the neoplasm by immunoperoxidase staining.

Isolation and sequence analysis of human bombesin-like peptides.

The decapeptide form of human gastrin releasing peptide was isolated from acid extracts of liver tissue containing a metastatic human bronchial carcinoid tumor. A larger form also was isolated and partially characterized. During gel permeation chromatography the major immunoreactive peak eluted in the same region as synthetic gastrin releasing decapeptide while a second minor immunoreactive peak eluted near gastrin releasing peptide. Bombesin-like immunoreactivity (BLI) was purified by successive applications to reverse phase high pressure liquid chromatography (HPLC) columns. After four successive HPLC purifications a single peak of bombesin-like immunoreactivity was detected. Amino acid analysis, microsequence analysis and coelution with synthetic peptide indicated that the predominant form present in metastatic tumor tissue was identical to the decapeptide form of canine gastrin-releasing peptide. The less abundant form was purified by cation exchange chromatography followed by reverse phase high pressure liquid chromatography. Partial microsequence analysis of this peptide, through the first 11 residues, was Val-Pro-Leu-Pro-Ala-Gly-Gly-Gly-Thr-Val-Leu. This sequence differed from that of hog heptacosapeptide gastrin releasing peptide at positions 1,3,4 and 5 and from the canine peptide as positions 1,3,5, and 7.