Endocrine cell hyperplasia and appendiceal carcinoids

As endocrine tumours in a number of organs may arise in a background of hyperplasia, the density of endocrine cells in appendices from ten patients with carcinoid tumours was compared with that in appendices from ten age- and sex-matched control patients. Crypt and lamina propria endocrine cells were quantified separately. The density of argentaffin endocrine cells in the crypts was significantly higher in appendices with carcinoid tumours when compared with the controls. No difference was found in non-argentaffin endocrine cells, and no difference was found in either argentaffin or argyrophil endocrine cells in the lamina propria. While it is possible that carcinoid tumours induce an increase in the number of enterochromaffin (EC) cells in the background mucosa, it is considered more likely that EC cell hyperplasia predisposes to the development of carcinoid tumours of the appendix.     

Prealbumin in the diagnosis of bronchopulmonary carcinoid tumours.

The reliability of prealbumin as a diagnostic marker was studied in 60 cases of bronchopulmonary carcinoid tumours. There were differences in the incidence of positivity between typical and atypical carcinoids (well differentiated neuroendocrine carcinomas). Seventy five per cent of the carcinoid tumours were positive for prealbumin; (86.7% typical and 63.3% atypical carcinoids). In 15 cases, which were Grimelius negative, 10 were prealbumin positive. Only 8.3% carcinoids were negative with both prealbumin and Grimelius stains. Ten squamous, 10 adeno- and 10 small cell carcinomas showed only occasional scattered prealbumin positive cells. It is concluded that prealbumin is a useful marker for bronchopulmonary carcinoid tumours. It is cheap, readily available, and should be considered part of routine diagnostic procedures for the diagnosis of carcinoid tumours.     

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.     

Mucosal argyrophil endocrine cells in pernicious anaemia and upper gastrointestinal carcinoid tumours.

The number and density of argyrophil endocrine cells were morphometrically calculated in gastric fundal mucosal biopsy specimens taken from 64 patients with pernicious anaemia (five with gastric carcinoids, 15 with nodular argyrophil cell hyperplasia, 44 with diffuse argyrophil cell hyperplasia) and from 14 healthy controls. Similar calculations were also made on the ileal mucosa away from the tumour of 10 patients with ileal carcinoids and 10 controls. In the stomach, the argyrophil cell counts were twice as high in the patients with pernicious anaemia than in controls and the densities in the whole mucosa or in the epithelial structures were similarly three to five times higher. The cell counts in the patients showed positive correlation with the serum gastrin concentration. The patients with nodular argyrophil cell hyperplasia and gastric carcinoids formed a uniform group with the highest cell counts and serum gastrin concentrations; the difference between the groups was in the longer duration of pernicious anaemia in the patients with carcinoid tumours. On the other hand, no endocrine cell hyperplasia was seen in those with ileal carcinoids. It is concluded that fundal mucosal endocrine cells show an increase in patients with pernicious anaemia that is related to the gastrin concentration. This phenomenon may favour the development of hyperplastic endocrine cell nodules and, eventually, carcinoid tumours.     

Signet-ring cell carcinoid of the gallbladder

A case of signet-ring cell carcinoid of the gallbladder is reported. The tumour diffusely infiltrated the gallbladder wall and extensively ulcerated the mucosa. Neoplastic nests were composed of numerous signet-ring cells mixed with clear endocrine cells. The latter expressed chromogranin A, gastrin and somatostatin and contained neurosecretory granules. The diagnostic problem of differentiating between signet-ring cell carcinomas and composite adenocarcinoma-carcinoid tumours is discussed.     

Electron microscopic characteristics of carcinoid tumors of varying localization and degree of differentiation

Results of an electron-microscopic study of 15 carcinoid tumours of different sites were compared to those of histological and histochemical investigation. Highly differentiated tumours (6 observation had pronounced tissue and organ-specific features, contained a high number of argentaffin and/or argyrophilic endocrine granules in all cells. Moderately differentiated tumours (3 observations) showed a typical structure and abundance of secretory granules in the cytoplasm; when the chromatin of their nuclei became coarse, consisting of large clumps, karyolemma invaginations and bulging appeared, this being a sign of malignization. These nuclei changes progressed in the poorly differentiated tumours, number of secretory granules decreased (they were absent in 50% of cells). Argentaffin carcinoid of the appendix, intestine and cecum contained mainly serotonin granules (diameter 200-350 nm) and small number of polypeptide hormones granules (diameter less than 200 nm). The inverse correlation between the granules was observed in the bronchial carcinoid.     

Immunohistochemical markers of small cell carcinoma and related neuroendocrine tumours of the lung

A selected group of 263 pulmonary neuroendocrine tumours comprised 156 small cell carcinomas, five combined cell carcinomas, nine atypical carcinoid/small cell carcinomas, 32 atypical carcinoids, ten large cell/small cell carcinomas, and 51 carcinoid tumours. These were compared with a group of 109 non-small cell carcinomas, using four markers of neuroendocrine differentiation to determine differences in reactivity between the two groups and among the variants of neuroendocrine tumour. The antibodies used were neuron-specific enolase (NSE), protein gene product (PGP) 9.5, human bombesin, and the C-terminal flanking peptide of human bombesin (CTP). Most small cell carcinomas, carcinoid tumours, and atypical carcinoid variants showed immunoreactivity for both NSE and PGP 9.5 but a significant number of non-small cell carcinomas, mainly squamous cell carcinomas, were also positive (11 and 35 per cent, respectively). Bombesin was specific for neuroendocrine tumours, being demonstrable in 35 per cent carcinoids and 24 per cent small cell carcinomas, but staining was focal and often confined to scattered cells. Diffuse strongly positive immunoreactivity for CTP was seen in the majority of malignant neuroendocrine tumours, but only 12 per cent of carcinoid tumours were positive and non-small cell carcinomas were negative. CTP is therefore of potential value as a specific marker of malignant neuroendocrine tumours, particularly if the amount of biopsy material is limited and the tumour is an unusual variant, such as atypical carcinoid or large cell-small cell carcinoma.     

Glandular duodenal carcinoid--a somatostatin rich tumour with neuroendocrine associations

The clinical and pathological features of four cases of duodenal carcinoid tumour are presented. All four tumours showed a glandular pattern, and in three cases this was associated with psammoma bodies. In three tumours somatostatin was identified by immunocytochemistry in most tumour cells. In two cases the duodenal tumours were associated with von Recklinghausen's disease and phaeochromocytoma. The importance of these unusual features is discussed, and it is suggested that these glandular carcinoids are a specific subgroup of endocrine cell tumours which appear to have potentially important clinical and pathological associations.     

Serotonin in tubular adenomas,adenocarcinomas and endocrine tumours of the stomach

Summary Serotonin was examined immunohistochemically in seven tubular adenomas, 194 adenocarcinomas and 41 endocrine cell tumours of the stomach. In tubular adenomas, serotonin-containing cells showing argentaffinity were present in the lower portion of the adenomatous glands and were considered to be an expression of intestinal character. Scattered serotonin-containing tumour cells were found in 60 (30.9%) of 194 adenocarcinomas regardless of their histological type. Cell fusions between carcinoma and enterochromaffin (EC) cells might be a possible mechanism for the occurrence of serotonin-containing cells within the tumour. In 17 (54.8%) of 31 endocrine cell carcinomas, serotonin-containing tumour cells were observed in a variable degree in contrast to the absence of these cells in classical carcinoid. Moreover, diffuse serotonin reactivity was found in four cases of scirrhous endocrine cell carcinoma. The histogenesis and the occurrence of serotonin-containing cells in each type of gastric tumour is also discussed.Supported in part by Grant-in-Aid for Cancer Research from the Ministry of Education, Science and Culture     

Duodenal and ampullary carcinoid tumors

Summary Twelve duodenal carcinoid tumours are presented, 4 of them located in the ampulla. Symptoms included the Zollinger-Ellison syndrome (4 patients), the carcinoid syndrome (1 patient), mechanical obstruction (3 patients), bleeding (1 patient) and abdominal pain (1 patient). Two further tumours were detected by chance.Three patients with the Zollinger-Ellison syndrome had additional endocrine tumours characteristic of the MEN I syndrome. In 2 of them the duodenal carcinoids were of very small size and were multiple. They were observed in close proximity to focal areas of endocrine cell hyperplasia.Immunohistochemical investigations showed gastrin and somatostatin to be the predominant polypeptide hormones produced by these tumours. No somatostatinoma syndrome was encountered. In half of our cases additional production of insulin, VIP or even calcitonin in smaller amounts was found.Two of our patients had cutaneous manifestations of von Recklinghausen's disease and in both of them the carcinoid was located in the ampulla. One of these patients also had a pheochromocytoma.     

ECTOPIC ACTH-MSH PRODUCING CARCINOID TUMOR WITH MULTIPLE ENDOCRINE HYPERPLASIA IN A CHILD

An autopsy case of a 9-year-old Japanese girl revealed a carcinoid tumor originating in the duodenum and hyperplasia of the multiple endocrine organs as manifested by ectopic ACTH syndrome, carcinoid syndrome and giantism. The tumor cells were positive for histochemical argyrophile reaction and two types of secretary granules were identified by electron microscopy. Biochemical assay revealed the production of AGTH and β-MSH by the tumor cells. Other changes of multiple endocrine organs included acidophll dominant hyperplasia of the pituitary, diffuse hyperplasia of the thyroid, chief cell hyperplasia of the parathyroid, hyperplasia of the islets of Langerhans and the adrenal cortex. This case was considered to be a type of multiple endocrine adenomatosis including carcinoid tumor. The relationship between the carcinoid tumor and multiple endocrine adenomatosis was discussed.     

Ectopic ACTH-MSH producing carcinoid tumor with multiple endocrine hyperplasia in a child.

An autopsy case of a 9-year-old Japanese girl revealed a carcinoid tumor originating in the duodenum and hyperplasia of the multiple endocrine organs as manifested by ectopic ACTH syndrome, carcinoid syndrome and giantism. The tumor cells were positive for histochemical argyrophile reaction and two types of secretory granules were identified by electron microscopy. Biochemical assay revealed the production of ACTH and beta-MSH by the tumor cells. Other changes of multiple endocrine organs included acidophil dominant hyperplasia of the pituitary, diffuse hyperplasia of the thyroid, chief cell hyperplasia of the parathyroid, hyperplasia of the islets of Langerhans and the adrenal cortex. This case was considered to be a type of multiple endocrine adenomatosis including carcinoid tumor. The relationship between the carcinoid tumor and multiple endocrine adenomatosis was discussed.     

Histidine decarboxylase expression in pancreatic endocrine cells and related tumors

Histidine decarboxylase (HDC) is an enzyme for decarboxylating l-histidine to histamine and is expressed in various types of cells including neuroendocrine tumors. Recent findings have demonstrated a high percentage of HDC immunoreactivity in many neuroendocrine tumors, including carcinoid tumors, small cell carcinomas of the lung, pheochromocytomas, and medullary carcinomas of the thyroid. HDC immunostaining was applied to pancreatic islet cells and related tumors to explore possible expression of HDC as a wide spectrum marker for neuroendocrine differentiation. A total of 24 cases (22 pancreatic endocrine neoplasms, one small cell carcinoma of the pancreas, and one mixed exocrine-endocrine carcinoma) along with normal pancreatic tissue were immunostained with the anti-HDC antibody. In a normal pancreas, a double immunostaining revealed possible colocalization of HDC with glucagon- or insulin-positive cells in the islets. Seventeen of 22 pancreatic endocrine neoplasms (77%) were found to be positive for HDC, and no distinct relation to hormonal activity was observed. One small cell carcinoma was strongly positive to HDC. One non-functional tumor with mixed exocrine and endocrine components showed a diffuse positive immunostaining for HDC, and some neoplastic glucagon- or somatostatin (SRIF)-positive cells coexpressed HDC. In conclusion, we demonstrated that the majority of pancreatic endocrine tumors expressed HDC, and we suggest that HDC is a wider new marker for neuroendocrine differentiation.     

THE RELATIONSHIP OF GASTROINTESTINAL ENDOCRINE CELLS TO GASTRIC EPITHELIAL CHANGES WITH SPECIAL REFERENCE TO GASTRIC CANCER

Using advanced gastric adenocarcinoma and carcinoid as human material and gastric adenocarcinoma in rats induced by MNNG and in mice by localized X-irradiation of the stomach as experimental material, a pathological study was made on the relationship of gastric endocrine cells to gastric cancer. The results of the present study suggest that most of the endocrine cells in the cancer tissue are derived from the didte rentiation of cancer cells. Therefore, the following three may be given as the aformentioned relationship, that is, 1) carcinoid of endocrine cell origin, 2) endocrine cell carcinoma showing undifferentiated adenocarcinoma, and 3) endocrine cell cloning developed from the differentiation of cancer cell of adenocarcinoma. There is the possibility that most of 2) are of 3) origin and thus 2) and 3) should be discriminated from 1), having a functioning tumor in rare cases. The significance of reactive hyperplasia of endocrine cells in the non-metaplastic mucosa of the stomach around cancer and atypical epithelium is not yet determined, but that of EC cell seems at least to be related with the development of intestinal metaplasia in the gastric mucosa.     

The relationship of gastrointestinal endocrine cells to gastric epithelial changes with special reference to gastric cancer.

Using advanced gastric adenocarcinoma and carcinoid as human material and gastric adenocarcinoma in rats induced by MNNG and in mice by localized X-irradiation of the stomach as experimental material, a pathological study was made on the relationship of gastric endocrine cells to gastric cancer. The results of the present study suggest that most of the endocrine cells in the cancer tissue are derived from the differentiation of cancer cells. Therefore, the following three may be given as the aformentioned relationship, that is, 1) carcinoid of endocrine cell origin, 2) endocrine cell carcinoma showing undifferentiated adenocarcinoma, and 3) endocrine cell cloning developed from the differentiation of cancer cell of adenocarcinoma. There is the possibility that most of 2) are of 3) origin and thus 2) and 3) should be discriminated from 1), having a functioning tumor in rare cases. The significance of reactive hyperplasia of endocrine cells in the non-metaplastic mucosa of the stomach around cancer and atypical epithelium is not yet determined, but that of EC cell seems at least to be related with the development of intestinal metaplasia in the gastric mucosa.     

Histochemical and ultrastructural analyses of glandular differentiation in typical carcinoid tumor of the hindgut

Adenomatous differentiation of typical carcinoid tumors was examined by histochemical and ultrastructural studies on 33 cases of typical carcinoids of the hindgut. Of these 33 carcinoids, 12 (36%) showed a tubular and/or acinar pattern with production of mucus as a minor component. A few tumor cells with mucous globules were scattered among tubules in these carcinoids. Ultrastructurally, microvilli were seen along the luminal surface of tubules, with both numerous mucous globules in the supranuclear area and endocrine granules in basal sites of the same cells. These results indicate that even in typical carcinoid tumors, certain tumor cells have the features of goblet cells or the open type of endocrine cells. The findings of both mucous globules and endocrine granules in the same single cells indicate a close relationship between endocrine cells and mucus-producing and/or tubule-forming cells. It is concluded that pluripoten-tial ceils producing carcinoid tumors might be able to differentiate into three types of tumor cells: (i) endocrine cells without microvilli or mucus production; (ii) cells with microvilli and no mucus product; and (iii) mucus-containing cells with microvilli.     

Autoantibodies to epithelial cells in patients on long-term therapy with leucocyte-derived interferon-alpha (IFN-alpha).

During routine screening for anti-nuclear antibodies, using rat liver tissue as substrate, a reactivity against bile duct epithelium was observed in sera from carcinoid tumour patients given human leucocyte-derived IFN-alpha (HuLe IFN-alpha). In a retrospective study, initiated by this observation, the development of serum antibodies to bile duct epithelium was observed in nine out of 12 patients with carcinoid tumours and in three out of 14 patients with hairy-cell leukaemia during their treatment with HuLe IFN-alpha. However, no bile duct reactivity was observed in sera from carcinoid or hairy-cell leukaemia in patients given recombinant IFN-alpha. When analysing the reactivity of positive sera against a panel of rat and human tissues, a uniform reactivity was observed against simple epithelial cells lining the gastrointestinal tract, pancreatic secretory ducts, fallopian tube, kidney tubuli, mesothelium and also against carcinoid tumour cells. The mechanisms promoting autoreactivity against this simple epithelial cell autoantigen is so far unknown. The cytoplasmic as well as the restricted staining pattern of simple epithelial cells may indicate autoreactivity against certain cytoskeletal intermediate filaments, such as cytokeratin 19, 18 and 8, known to be exclusively present in simple epithelial cells and tumours derived from them.     

Serotonin immunoreactivity in pancreatic endocrine neoplasms (carcinoid tumors).

Primary serotonin secreting pancreatic endocrine neoplasms (carcinoid tumors) are extremely rare and may be associated with manifestations of the carcinoid syndrome. Two cases of primary carcinoid tumor of the pancreas with liver metastases showed clinical and biochemical features of the carcinoid syndrome. Both cases demonstrated strong positive immunoreactivity for serotonin within the tumor cells. In an attempt to determine the relationship between pancreatic carcinoid tumors and other pancreatic endocrine neoplasms, immunostains for serotonin were performed on 11 additional islet cell tumors and on non-neoplastic pancreatic tissues. These cases showed serotonin immunoreactivity within islet cell tumors (36%). In addition, focal staining for serotonin was present in non-neoplastic ducts and ductules (88%), acini (22%), and islets of Langerhans (33%). Based on these observations, specific criteria are suggested for the diagnosis of primary pancreatic carcinoid tumor.     

Morphology and staining patterns of endocrine cell tumours in the gut, pancreas and bronchus and their possible significance

We have studied 109 endocrine cell tumours of the gastrointestinal tract, pancreas and bronchus in terms of histological pattern and histochemical staining with immunocytochemical studies on seven tumours. As a result we believe that previous histological classifications need modification. 5-Hydroxytryptamine secreting tumours have a carcinoid (A1) pattern with, in some cases, an additional tubuloacinar element (A1A2) and definable histochemical reactions; well differentiated gastrinomas, insulinomas and glucagonomas are associated commonly, but not exclusively, with particular histological patterns and argyrophilia, but no such association exists for less differentiated tumours. This may be related to the synthesis of precursor hormones by less differentiated tumours. Mixed patterns are common, particularly in tumours of foregut derivation. Prospective studies planned to correlate histology, histochemistry, immunocytochemistry and ultrastructure are needed on all endocrine cell tumours.