There are no clear histopathological parameters determining the risk of lymph node (LN) metastases and appropriateness of completion prophylactic right hemicolectomy (RHC) in patients with appendiceal neuroendocrine neoplasms (ANENs).

The PubMed, Cochrane Library, Embase, Web of Science and SCOPUS databases were searched up to November 2018. Quality/risk of bias was assessed using the Newcastle-Ottawa Scale (NOS).

A total of 526 articles were screened. In 11 adult and 3 paediatric studies, 602 and 77 unique patients, respectively, with ANEN and undergoing RHC, were included. The rate of LN metastases for a cutoff size >10 mm was 48.6% (vs 12.1% for lesions <10 mm) among adult patients, with an odds ratio (OR) of 4.8 (95% CI, 1.5-15.8). For 20 mm size cutoff, these figures were 61% (vs 28.2% for lesions <20 mm) with an OR of 3.2 (95% CI, 1.3-7.8). Vascular-, lymph vessel- and perineural invasions were identified as predictive factors for LN metastases in adult patients. In paediatric patients, there were no strong morphological predictors for LN metastases. The 10-year disease-specific survival (DSS) for adult patients without LN metastases was 99.2% vs 95.6% in patients with LN (OR: 0.2; 95% CI, 0.02-2.4). The complication rate of prophylactic RHC was 11.4%.

This meta-analysis demonstrates that tumour size >20 mm as well as >10 mm and/or vascular-, lymph vessel- and perineural invasions are associated with increased risk for LN metastases in adult patients with ANEN. The prognostic value of LN positivity remains to be determined in further studies with long-term follow-up.

Appendiceal neoplasms are identified in 0.9 to 1.4% of appendiceal specimens, and the incidence is increasing. It has long been professed that neuroendocrine tumors (formerly carcinoids) are the most common neoplastic process of the appendix; recent data, however, has suggested a shift in epidemiology. Our intent is to distill the complex into an algorithm, and, in doing so, enable the surgeon to seamlessly maneuver through operative decisions, treatment strategies, and patient counseling. The algorithm for evaluation and treatment is complex, often starts from the nonspecific presenting complaint of appendicitis, and relies heavily on often subtle histopathologic differences.

Gastrointestinal neuroendocrine neoplasms (GI-NENs) are increasingly being recognised, while appendiceal NENs (aNENs) currently constitute the third most common GI-NEN. Appendiceal NENs are generally considered to follow an indolent course with the majority being localised at diagnosis. Thus, the initial surgical approach is not that of a planned oncological resection. Due to the localised nature of the disease in the majority of cases, subsequent biochemical and radiological assessment are not routinely recommended. Histopathological criteria (size, mesoappendiceal invasion, Ki-67 proliferation index, neuro- and angio-invasion) are mainly used to identify those patients who are also candidates for a right hemicolectomy. Goblet cell carcinoids are a distinct entity and should be treated as adenocarcinomas. Despite the absence of any substantial prospective data regarding optimal management and follow-up, recent consensus statements and guidelines have been published. The purpose of this review is to overview the published studies on the diagnosis and management of appendiceal NENs and to suggest a possible management protocol.

Two cases of multiple carcinoid tumors of the rectum with numerous micronests of carcinoid tumors are reported. The patients were 51- and 58-year-old males. Many carcinoid tumors and numerous carcinoid micronests were found in the resected rectum; the total number of carcinoid tumors, groups of micronests, and solitary micronests was 69 in the first case and 62 in the second case. The micronests, consisting of a few to many endocrine cells, were observed in the lamina propria, muscularis mucosa, and/or submucosa. Micronests increased in number, gathered and formed carcinoid tumors, which were up to 8 mm in diameter. It was found that a nest of the carcinoid tumors in the lamina propria showed continuity with the endocrine cells of a crypt in the different carcinoid tumors in both cases. The carcinoid tumor and micronest infiltrated the nerves and ganglions in the muscularis mucosa and submucosa. Nests of the carcinoid tumors and micronests were surrounded by S-100-positive cells. Lymph node metastases of the carcinoid tumor were found in both cases. Rectal carcinoid tumors may originate from endocrine cells of the crypts, and multiple carcinoid tumors may occur heterogeneously.

The neuroendocrine epithelial neoplasms (NENs) include well-differentiated neuroendocrine tumors (WDNETs) and poorly differentiated neuroendocrine carcinomas (PDNECs). Whereas PDNECs are highly lethal, with localized Merkel cell carcinoma somewhat of an exception, WDNETs exhibit a range of "indolent" biologic potentials-from benign to widely metastatic and eventually fatal. Within each of these 2 groups there is substantial morphologic overlap. In the metastatic setting, the site of origin of a WDNET has significant prognostic and therapeutic implications. In the skin, Merkel cell carcinoma must be distinguished from spread of a visceral PDNEC. This review intends to prove the thesis that determining the site of origin of a NEN is clinically vital and that diagnostic immunohistochemistry is well suited to the task. It will begin by reviewing current World Health Organization terminology for the NENs, as well as an embryologic and histologic pattern-based classification. It will present population-based data on the relative frequency and biology of WDNETs arising at various anatomic sites, including the frequency of metastases of unknown primary, and comment on limitations of contemporary imaging techniques, as a means of defining the scope of the problem. It will go on to discuss the therapeutic significance of site of origin. The heart of this review is a synthesis of data compiled from >100 manuscripts on the expression of individual markers in WDNETs and PDNECs, as regards site of origin. These include proteins that are considered "key markers" and others that are either useful "secondary markers," potentially very useful markers that need to be further vetted, or ones that are widely applied despite a lack of efficacy. It will conclude with my approach to the metastatic NEN of unknown origin.

Endocrine tumors of Meckel's diverticulum are rare. Their clinical and pathological characteristics are not well known, making it difficult to assess the best strategy for therapeutic management.

Eight cases of endocrine tumors of Meckel's diverticulum, submitted to surgical resection in our institution between 1977 and 2009, were studied. Clinical charts were reviewed; classification, grading, and staging were performed according to recent international recommendations. Five cases, including two associated with the carcinoid syndrome, were revealed by mesenteric mass or liver metastases; three cases were diagnosed incidentally at laparotomy or laparoscopy.

All cases presented as typical well-differentiated midgut endocrine tumors. Five cases were associated with mesenteric lymph node metastases; three presented with liver metastases. Seven cases were classified as well-differentiated endocrine carcinomas, one as well-differentiated endocrine tumor of benign behavior.

All tumors >1 cm, but one, had regional or distant disease. All patients had complete surgical resection of the primary. One patient deceased after 25 months; the others were alive after 12-101 months.

In conclusion, endocrine tumors of Meckel's diverticulum are rarely symptomatic and often diagnosed at an advanced stage. All tumors measuring more than 1 cm in diameter must be resected according to oncological principles.

Sustentacular cells are found in approximately half of pulmonary carcinoid tumours. However, most studies of sustentacular cells have used the less-specific antibody to the S100 protein, and any correlation between the presence of sustentacular cells and other clinicopathological factors is unclear. The aim of this study was to analyse the significance of sustentacular cells in pulmonary neuroendocrine carcinomas (NECs).

A Sox10 antibody was used to investigate 113 pulmonary NECs. Sustentacular cells were observed in 66.7% of typical carcinoid (TC) and 58.3% of atypical carcinoid (AC) cases, but not in high-grade NECs. Sustentacular-rich tumours had a statistically significant correlation with peripheral locations. We found no statistical differences in age, gender, smoking history, overall survival, or the occurrence of lymph node metastasis. In all but one case, when sustentacular cells were present in the primary site, they were also present in the metastatic lymph nodes. The presence of sustentacular cells differed in morphological subtypes, with the spindle pattern being the most common subtype.

Sox10-positive sustentacular cells were observed in carcinoid tumours but not in high-grade NECs. Sustentacular-rich carcinoid tumours did not show a correlation with the occurrence of lymph node metastasis or survival. The sustentacular cells found differed in morphological subtypes.

The authors review the most important clinical aspects of carcinoid tumors. Carcinoid tumors originating in neuroendocrine cells are rare, usually slowly-growing neoplasms, however, they may present as aggressive and rapidly progressing tumors. Epidemiologic data indicates that their prevalence is gradually increasing, which may be explained, at least in part, by the development and wider use of advanced diagnostic methods. A considerable proportion of patients with neuroendocrine tumors are symptom-free, whereas others may have carcinoid syndrome or symptoms of other endocrine syndromes. Early diagnosis may be established by the measurement of biochemical markers (serum chromogranin A, urinary 5-hydroxyindoleacetic acid) and advanced localization methods. A considerable number of patients are diagnosed at the late stages of the disease; in these cases surgical cure is not possible but surgical and/or interventional radiologic procedures which reduce tumoral mass should be still considered. The most effective drugs for symptomatic treatment of carcinoid tumors are somatostatin analogues; in addition to their beneficial effect on clinical symptoms they may stabilize tumor growth for many years and, less frequently, may produce tumor regression. The use of chemotherapeutic agents is considered in patients with aggressive, rapidly growing and advanced tumors; initial findings with temozolomide and thalidomide in clinical trials raise the possibility that these chemotherapeutic agents may prove to be new therapeutic options. Radioisotope-labeled peptide receptor therapy with 131 I-MIBG, 90 Y-DOTA-TOC or 177 Lu-DOTA-TOC may offer a highly effective option for patients with progressive and advanced stage of neuroendocrine tumors. Initial observations obtained in clinical trials with some tyrosine kinase inhibitors, antibodies against tyrosine kinases, and with inhibitors of mammalian target of rapamycin (mTOR) support the possibility that at least some of these new agents may have a role in future treatment options in patients with advanced neuroendocrine tumors.

There is an increased incidence of tumors among renal transplant patients, which are associated with immunosuppression. Carcinoids are rare neuroendocrine tumors that arise from the enterochromaffin cells. Although appendiceal carcinoid tumors are the commonest malignant neoplasms affecting the appendix, and mucinous cystadenoma is the commonest benign appendiceal neoplasm, they have not been reported in immunosuppressed patients. We present two renal transplant recipients who developed combined appendiceal carcinoid and mucinous cystadenoma.

Carcinoid tumors are rare, slow-growing neuroendocrine tumors arising from the enterochromaffin cells disseminated throughout the gastrointestinal and bronchopulmonary systems. Though they have been traditionally classified based on embryologic site of origin, morphologic pattern, and silver affinity, newer classification systems have been developed to emphasize the considerable clinical and histopathologic variability of carcinoid tumors found within each embryologic site of origin. These neoplasms pose a diagnostic challenge because they are often innocuous at the time of presentation, emphasizing the need for a multidisciplinary diagnostic approach using biochemical analysis, standard cross-sectional imaging, and newer advances in nuclear medicine. Similarly, treatment of both primary and disseminated carcinoid disease reflects the need for a multidisciplinary approach, with surgery remaining the only curative modality. The prognosis for patients with these tumors is generally favorable; however, it can be quite variable and is related to the location of the primary tumor, extent of metastatic disease at initial presentation, and time of diagnosis.

The generally indolent nature of neuroendocrine tumors is an advantage in the management of patients who have localized disease, and surgery alone is often curative. This same property presents a challenge in the treatment of patients who have metastatic disease, in whom standard cytotoxic chemotherapy has a limited benefit. In such patients, the use of somatostatin analogs, interferon, and the treatment of hepatic metastases may provide effective palliation. The highly vascular nature of carcinoid tumors has led to the investigation of antiangiogenic agents in this setting. Preliminary reports of activity associated with agents targeting the vascular endothelial growth factor pathway suggest that such strategies may play a role in the future treatment of patients who have this disease.

The vast majority of neuroendocrine neoplasms of the appendix are carcinoid tumors. Most are of enterochromaffin (EC) cell type, although rare examples are of L cell type. EC cell carcinoids of the appendix differ from those encountered elsewhere in the gastrointestinal system. For example, they are remarkably common given the small size of the appendix, are usually benign, occur in younger patients, and typically contain sustentacular cells that express S-100. Origin from subepithelial neuroendocrine cells could explain these characteristics. It has also been suggested that most appendiceal carcinoids are hyperplastic rather than neoplastic, although this hypothesis requires further study. Nevertheless, truly neoplastic EC cell carcinoids of the appendix undoubtedly occur, and those greater than 2 cm in diameter have a significant risk of producing distant metastases. Carcinoid syndrome is a very rare presentation. Tubular carcinoids are unusual benign neoplasms; it has been proposed that they represent L cell carcinoids with a predominant tubular pattern of growth. Goblet cell carcinoids tend not to produce a grossly visible tumor mass but diffusely infiltrate the wall. They typically exhibit tight clusters of goblet cells, usually with scattered neuroendocrine cells and sometimes with Paneth cells, sometimes surrounding a small lumen. They may behave as a low-grade malignancy. The distinction between goblet cell carcinoid and other types of tumor is of great importance because of the implications for treatment and prognosis. Frank adenocarcinoma can arise from goblet cell carcinoids, and tumors with both components are classified as mixed goblet cell carcinoid-adenocarcinoma. The carcinoma component of the latter determines their prognosis, which would be worse than for a goblet cell carcinoid alone.

Carcinoid tumors generally appear as yellow/gray or tan submucosal nodules. We experienced a case of pedunculated rectal carcinoid showing a mushroom-like appearance. The case was a forty years old woman who was admitted to our hospital due to rectal bleeding. Colonoscopy revealed a pedunculated polyp presenting a mushroom-shaped appearance measuring 13 mm in diameter in the rectum. The histological diagnosis of specimens obtained by biopsy was adenocarcinoma and transanal ultrasonography revealed the tumor localization within the submucosal layer in the rectum. Endoscopic mucosal resection (EMR) was performed. Histopathological examination established the diagnosis of carcinoid tumor in the rectum. Frequencies of the pedunculated type in rectal carcinoids were reported to be 2.4% to 7.1% in the literature. Because of its rarity, pedunculated configuration may confuse the endoscopic diagnosis of carcinoids. Treatment for carcinoids of 1 to 1.5 cm in size remains controversial. Although such tumors are technically respectable by EMR, careful attention must be paid in dealing with these tumors because there may be unexpected behaviors of the tumors.

We conducted a retrospective clinicopathologic and immunohistochemical study of the biologic significance of mesoappendix infiltration in 15 appendiceal neuroendocrine tumors selected from a series of 42 primary tumors. In all cases, the tumor was found incidentally and measured less than 2 cm (mean, 0.84 cm). In 13 cases, it was located in the tip of the appendix and in the midportion in 2. Histologically, none showed relationship with overlying mucosa. Necrosis was absent; mitotic figures were rare. The Ki-67 labeling index was low (1%-2%). In all cases, S-100 protein immunostaining disclosed positive elements with cytoplasmic dendritic processes closely intermingled with neuroendocrine neoplastic cells. All patients (8 males; 7 females; mean age, 38.2 years) underwent simple appendectomy. A right-sided hemicolectomy was performed subsequently in 1 case. After a mean follow-up of 52.6 months (range, 8-143 months), none had died of disease or had recurrent or metastatic disease. Our results confirm that appendiceal neuroendocrine tumors seem to have a different phenotype from those occurring in other gastrointestinal sites. Tumors less than 2 cm, even with mesoappendiceal infiltration, have an excellent prognosis, and simple appendectomy seems to be the appropriate therapeutic approach.

Intestinal carcinoids are potentially malignant neoplasms. Their histogenesis and pathogenesis are currently uncertain. The morphological and histochemical characteristics of twenty intestinal carcinoids are studied. The primary sites of three mucin-producing tumors were examined by electron microscope. Furthermore 11 appendiceal carcinoids were analysed by the polymerase chain reaction (PCR) for the detection of ras and p53 point mutations. Microscopically all carcinoids were of mixed type. Focal mucin production was evident in three carcinoids that metastasised to regional lymph nodes. HID-Alcian blue staining proved that mucin in both primary and secondary foci did not belong to the sulphated group. The secretory granules and mucin droplets found in a single neoplastic cell suggest that carcinoids of the small intestine and some of the appendix arise from the endoderm. Neither ras nor p53 mutations were detected. It seems that ras oncogenes are probably not involved in the pathogenesis of appendiceal carcinoids.

Carcinoid tumours are enigmatic, slow growing malignancies which occur most frequently (74%) in the gastrointestinal tract. In recent years, it has become apparent that the term 'carcinoid' represents a wide spectrum of different neoplasms originating from a variety of different neuroendocrine cell types. Carcinoid lesions are usually identified histologically by their affinity for silver salts, by general neuroendocrine markers, or more specifically by immunocytochemistry using antibodies against their specific cellular products. Within the gut, the most frequent sites are the small bowel (29%), the appendix (19%) and rectum (13%). Clinical manifestations are often vague or absent. Nevertheless, in approximately 10% of patients the tumours secrete bioactive mediators which may engender various elements of characteristic carcinoid syndrome. In many instances the neoplasms are detected incidentally at the time of surgery for other gastrointestinal disorders. The tendency for metastatic spread correlates with tumour size, and is substantially higher in lesions larger than 2.0 cm. An association with noncarcinoid neoplasms is ascribed in 8-17% of lesions. Treatment consists of radical surgical excision of the tumour, although gastric (type I and II) and rectal carcinoids may be managed with local excision. Overall 5-year survival is excellent for carcinoids of the appendix (86%) and rectum (72%), whereas small intestinal (55%), gastric (49%) and colonic carcinoids (42%) exhibit a far worse prognosis.

To determine the prevalence of sustentacular cells across the range of pulmonary neuroendocrine tumours: typical and atypical carcinoid tumours and large cell and small cell neuroendocrine carcinomas.

Sustentacular cells were sought in 80 pulmonary neuroendocrine tumours by immunolabelling for S100 protein, nerve growth factor receptor and glial fibrillary acidic protein. Intratumoural macrophages and Langerhans cells were identified with the KP 1 (CD68) and CD1A antibodies. S100-positive sustentacular cells were present in 25 of 30 typical carcinoids, 200 of 25 atypical tumours, six of 10 large cell carcinomas and six of 15 small cell lesions. They were most numerous in the typical carcinoids but very few in the small cell carcinomas, their prevalance being clearly related to grade of differentiation and, in particular, to the degree of architectural organization.

Sustentacular cells are often found in pulmonary neuroendocrine tumours, especially better-differentiated lesions with a well-developed architecture. their prevalence clearly reflecting the degree of structural organization. Whether their prevalence is a useful prognostic indicator within a particular group of such tumours, such as the atypical carcinoids or the large cell carcinomas, as appears to be the case with paragangliomas, is unclear.

This paper reports on two patients with carcinoid tumours of the gall bladder who presented to the Aberdeen hospitals during the period 1970 to 1990 and reviews all previously reported cases in published works.

A retrospective study of 41 patients with histologically confirmed diagnosis of appendix carcinoid tumors was undertaken by reviewing the surgical records at Massachusetts General Hospital.

There were 8 male and 33 female patients (mean age 32 years). Twenty-two patients (54%) presented with signs and symptoms suggestive of acute appendicitis. In 19 patients (46%) the lesions were discovered incidentally. The tumors were located in 32 patients at the tip, in 6 patients in the middle third, and in 3 patients at the base of the appendix. The tumor was less than 1 cm in diameter in 32 patients, between 1 and 2 cm in 7 patients, and was bigger than 2 cm in 2 patients. In 29 patients, the depth of tumor penetration was confined to the submucosa or to the muscle layers of the appendix, and in 8 patients the serosa was involved. In 4 patients, evidence of tumor extension into the meso-appendicular fat was present, including one patient with a tumor bigger than 2 cm and local lymph-node metastases. Forty patients underwent appendectomy alone. One patient with a tumor size bigger than 2 cm in diameter with positive lymph nodes in the mesoappendix underwent secondary right hemicolectomy. Complete follow-up was achieved in 35 patients, and all patients remained free of tumor recurrence.

The authors conclude that appendiceal carcinoids are rare and most often are asymptomatic. Tumors of less than 1 cm are adequately managed by appendectomy alone. The appropriate treatment for tumors of 1 to 2 cm continues to be controversial. Right hemicolectomy is recommended for all tumors larger than 2 cm, whereas preference for an aggressive approach should be given in young patients.

A case of atypical carcinoid with peculiar histological and ultrastructural pattern and immunohistochemical phenotype is presented. The neoplasm is composed of three types of cells. Type 1 cells are small to medium sized, fusiform, with scarce cytoplasm and are arranged in fascicles. Type 2 cells are cuboidal and line acinar structures. Type 3 cells have more abundant eosinophilic cytoplasm, larger nuclei and are arranged in fascicles intersecting with fascicles of type 1 cells, and sometimes surround acinar structures. The three cell types are present both in the primary lesion and in its lymph node metastases. Immunohistochemistry demonstrates immunoreactivity of all cell types for general neuroendocrine markers. Cytokeratin immunoreactivity is more prominent in type 1 and 2 cells, and is only focally expressed in type 3 cells. Type 3 cells are also immunoreactive for glial fibrillary acidic protein (GFAP), alpha-actin, S-100 protein, vimentin. Electron microscopic examination confirms the neuroendocrine nature of the cells, and show that type 3 cells have prominent bundles of intermediate filaments, electron-dense granules and junctional complexes. To our knowledge, this is the first case of atypical lung carcinoid with GFAP immunoreactivity. The nature of type 3 GFAP positive cells is unclear. There are some clues pointing to their sustentacular nature, and other ones pointing to a myoepithelial origin, but the data are inconclusive. Type 3 cells may be the malignant counterpart of sustentacular cells seen in typical carcinoids, but their GFAP positivity and the presence of electron-dense granules are very unique features, which differentiates them from sustentacular cells. Alternatively, their unusual GFAP + immunohistochemical phenotype may be due to aberrant expression of cytoskeletal proteins.

For a study of histogenesis of intestinal carcinoids a collection of 5 classical small intestinal carcinoids, 6 appendiceal carcinoids and 9 pheochromocytomas, were evaluated. The tumors were identified by routine morphology, silver staining and chromogranin immunocytochemistry and were then examined with regard to the expression of intermediate filaments of cytokeratin type. Eight different antisera identifying individual or combinations of cytokeratins were employed. All classical small intestinal carcinoids displayed cytokeratin immunoreactivity and an almost identical cytokeratin reaction was observed in the normal enterocytes of the small intestinal mucosa. Of the individual cytokeratin types, number 18 was most heavily expressed. The appendiceal carcinoids, like the pheochromocytomas, almost totally lacked a cytokeratin staining despite a positive reaction in the mucosa of the appendix. This, in agreement with some previous studies, indicates that the small intestinal carcinoids are histogenetically related to the epithelial cells of the intestinal mucosa, while the appendiceal carcinoids have a different histogenesis and are more like pheochromocytomas. The appendiceal carcinoid may represent a distinct type of intestinal paraganglioma. This offers one explanation for the different biological behavior of appendiceal carcinoids in comparison with the other intestinal carcinoids.

The purpose of this study was to determine the histogenesis of jejunoileal and appendiceal carcinoids and to ascertain whether this could be useful in further explaining the pathology of these neoplasms.

Eight cases each of multiple jejunoileal carcinoids and appendiceal carcinoids together with their respective age-matched and sex-matched controls were stained with silver stains, chromogranin A, serotonin, and S-100. Histomorphometric evaluations of the endocrine cells in the mucosa adjacent to the carcinoids were carried out and compared with the respective controls using the Student's t test.

All the carcinoids from both groups stained for argyrophilia, argentaffinity, chromogranin A, and serotonin. Histomorphometric evaluations showed intraepithelial endocrine cell hyperplasia (IECH) in the jejunoileal carcinoid group (P = 0.007, chromogranin; P = 0.004, serotonin) but not in the appendiceal carcinoid group. On the other hand, subepithelial endocrine cell aggregates that were separate from the main tumor were seen in two cases of appendiceal carcinoids. With S-100, all appendiceal carcinoids showed intrinsic tumor positivity whereas the jejunoileal carcinoids did not.

The finding of IECH with multiple jejunoileal carcinoids suggests that these carcinoids arise from a field effect. The absence of IECH with appendiceal carcinoids as well as their association with subepithelial endocrine cell aggregates and their intimate relationship with Schwann cell processes suggests that appendiceal carcinoids arise from a more discrete unit, the subepithelial neuroendocrine complex.

Twenty-two appendiceal carcinoid tumours, comprising 10 classical carcinoids, six tubular carcinoids and six goblet cell carcinoids were examined by histochemistry and immunohistochemistry. All of the tumours showed evidence of neuroendocrine differentiation. Classical carcinoids were invariably intimately associated with S-100 protein positive cells, supporting an origin from sub-epithelial neuroendocrine cells. Both tubular and goblet cell carcinoids expressed cytoplasmic mucin and immunoglobulin A, and neither were associated with S-100 protein positive cells. These observations suggest that tubular and goblet cell carcinoids are derived from epithelial crypt stem cells.

In order to clarify the histogenesis of appendiceal carcinoid tumours, epithelial (ENC) and subepithelial (SNC) neuroendocrine cells were counted at four sites in 50 normal appendices stained by standard argyrophil and argentaffin techniques. In general, ENC were present in similar number at all sites within the appendix, whereas SNC were more numerous at the tip than at the base. The number of ENC was similar throughout life, apart from an increase in one neonate and some elderly patients, whereas SNC were maximal in young adults. Thus, the topographical and age distributions of SNC, but not those of ENC, parallels the topographical and age incidence of appendiceal carcinoid tumours, suggesting that most appendiceal carcinoid tumours arise from SNC rather than ENC.

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.

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.

Neoplastic proliferations of neuroendocrine cells (NE) may occur throughout the entire GI tract but affect particularly appendix and ileum ("midgut carcinoids"), rectum ("hindgut carcinoids"), as well as stomach and the duodenum ("foregut carcinoids"). Only more exceptionally, they arise in the esophagus, jejunum and colon. The NE tumors encompass a heterogeneous gross and microscopic structural spectrum, ranging from inconspicuous microproliferations ("mucous membrane nevi") to bulky tumor masses. Their growth patterns are usually characteristic and easily recognized. In doubtful cases their NE differentiation becomes established by a characteristic silver affinity, by the ultrastructurally observed presence of characteristic "endocrine" secretion granules, and by immunohistochemically detectable occurrence of "pan-NE markers" (neuron-specific enolase, chromogranins, and synaptophysin), biogenic amines (mainly serotonin), and neurohormonal peptides. Foregut carcinoids usually contain serotonin, gastrin, and somatostatin, midgut carcinoids often only serotonin and tachykinins, whereas the hindgut carcinoids as a rule are multihormonal with a wide spectrum of hormonal peptides, including even insulin. Most GI NE tumors are found in the appendix (50%) and the ileum (30%). Practically all (98%) of the appendiceal NE tumors are benign. They have recently been proposed as arising from apparently Schwann-cell-related NE cells in the submucosa, whereas the ileal--and probably also all the other non-appendiceal NE tumors--are derived from the totipotential cells in epithelial crypts of the mucosa. Among the ileal NE neoplasms a large number can metastasize and result in a fatal outcome. The ability to metastasize is related to the size and to the multiplicity of the primary tumors at the time of initial diagnosis and, to some extent, to their histopathologic growth pattern. Now, some relationship between the prognosis and the cytochemically assessed nuclear DNA content of the NE tumor cells has also been established; not less than about 1/4 to 1/3 seem to be aneuploid. Almost 90% of the rectal carcinoids are benign. Exceptionally, a highly malignant NE neoplasms can arise from the colon/rectum--as well as from the esophagus--composed of NE cells of small and intermediate size. The NE tumors of the stomach are often composed of ECL (enterochromaffin-cell-like) cells; such ECL cell carcinoids are related to atrophic gastritis with pernicious anemia; experimentally, they can be induced by hypergastrinemia in rats. Duodenal carcinoids often contain psammoma bodies and can be associated with neurofibromatosis.

A case of multiple carcinoid tumors of the rectum with numerous proliferations of extraglandular endocrine cells is reported. The patient was 52-year-old man with five polypoid lesions in the rectum. The resected rectum contained five macroscopic carcinoid tumors, 36 microcarcinoids, and innumerous extraglandular endocrine cell proliferations. Endocrine cell microproliferations, in their early stage consisting of one to 15 micronests, were mainly located within the bundles of muscularis mucosae, having no contact with mucosal glandular structures. All of the immunohistochemically examined proliferations of extraglandular endocrine cells contained S-100 protein-positive dendritic cells, and some endocrine cells coexisted with submucosal ganglion cells. In contrast, there was no increase in intraglandular endocrine cells. The origin of rectal carcinoid tumor may be the extraglandular endocrine cells, a distinct compartment of mucosal endocrine cells of the rectum.

In a prospective study of 103 patients with carcinoid tumors consecutively referred for medical treatment, the most common sites of the primary tumors were the ileum (73%), bronchi (7%), and jejunum (4%). All patients had local metastases, and 96 (93%) also had liver metastases. The most common initial symptoms were diarrhea (32%), ileus (25%), and flush (23%). The overall frequency of diarrhea was 84% and of flush was 75%. Heart insufficiency caused by cardiac valve disease was seen in 33% of the patients. The carcinoid syndrome, including flush, diarrhea, and elevated urinary 5-hydroxyindole acetic acid (5-HIAA) concentrations, was manifested by 69 patients (67%), 64 of whom (93%) had carcinoid tumors of mid-gut origin. Elevated urinary 5-HIAA was found in 91 patients (88%), of which 89 displayed liver metastases. The plasma concentration of the tachykinin neuropeptide K (NPK) was elevated in 67 patients (66%), 63 of whom had tumors of the mid-gut region. Serum pancreatic polypeptide (PP) and human chorionic gonadotrophin alpha levels were elevated in 43% and 28% of the patients, respectively, and the highest levels were found in patients with metastatic bronchial carcinoid tumors. Thirty-nine of the 103 patients are now dead; 18 died of tumor progression, whereas 14 patients died of heart failure secondary to a carcinoid tricuspidal valve insufficiency. The estimated median survival from the time of histologic diagnosis was 14 years, and from the time of carcinoid syndrome was 8 years.

A specimen from the small intestine with multiple (three) classic carcinoid tumors and one appendiceal carcinoid tumor displaying argentaffinity, argyrophilia (Grimelius stain), and serotonin and neuron specific enolase immunoreactivity was examined by light microscopy with regard to the tumor cell histopathogenesis. The smallest tumor (diameter 0.5 cm) from the small intestine was cut into 512 and the appendiceal tumor into 511 serial sections, which were stained with the argyrophil technique. In the small intestine an increased number of endocrine cells and small proliferating aggregates of endocrine cells were observed among nonendocrine enterocytes in the crypts of Lieberkühn. They seemed to grow initially inside the crypts and to later infiltrate through the basement membrane into the lamina propria of the mucosa. This finding suggests that classic carcinoid tumors of the small intestine develop from mucosal endocrine (enterochromaffin) cells. Since proliferating argentaffin cells were also seen in the mucosal crypts in one of the other two carcinoid tumors (2 cm in diameter) in the same intestine specimen, it is suggested that when multiple carcinoid tumors occur in the small intestine they arise from multiple sites. There was no apparent connection between the mucosal crypts and the carcinoid tumor of the appendix. Thus in this particular case, the appendiceal carcinoid tumor did not appear to derive from the mucosal endocrine cells but from the subepithelial endocrine cells that are present in the lamina propria and submucosa of the appendix wall. Supporting this view is the fact that S-100 protein immunoreactive cells are found both in close relation to subepithelial endocrine cells and as an integral component of appendiceal carcinoid tumors.