Nuclear pleomorphism in typical carcinoid tumours of the lung: problems in frozen section interpretation

Pulmonary typical carcinoid tumours are generally easy to diagnose with their uniform cells, carcinoid growth pattern and lack of mitoses. However, nuclear pleomorphism, which is common in other neuroendocrine tumours, is not emphasized in pulmonary carcinoid tumours. Three cases of typical carcinoid tumours, because of marked nuclear pleomorphism on frozen section, were misdiagnosed as non-small cell carcinomas.     

Mucin producing carcinoid tumours of the vermiform appendix.

Six cases of an unusual mucoid variant of carcinoid tumour of the appendix are reported. These lesions are small, detected incidentally, and carry a good prognosis. Their histological features are distinctive and differ from those of ordinary carcinoid tumours and adenocarcinoma. They have been confused with adenocarcinoma, sometimes resulting in radical surgery. Surgery beyond appendicectomy is probably unwarranted in these cases. The mucin secreted by goblet cells of the normal mucosal epithelium and by the cells of these carcinoid tumours have certain histochemical similarities.     

The oncoproteins c-erb-B2, c-fos and the tumour suppressor protein p53 in human embryos and fetuses

 Oncoproteins and tumour-suppressor proteins are thought to possess an antagonistic function in the regulation of growth and differentiation processes during embryonic and fetal development. In contrast, in the adult, tumour growth is associated with the overexpression of oncoproteins or the malfunction of tumour-suppressor proteins. We examined the occurrence of the tumour proteins c-erb-B2 and c-fos and the tumour-suppressor protein p53 in 17 human embryos and fetuses with the help of immunohistochemistry. C-erb-B2 was detected mainly in embryonic tissue that are not known for c-erb-B2-overexpression in tumours in the adult. In contrast, c-fos was almost always located in fetal tissues corresponding to its location in adult tumours. Staining for p53 was found in a wide variety of embryonic and fetal tissues. C-erb-B2 and p53 were localized in the same tissue structures of the developing skin, heart and muscle. In other tissues, e.g. muscle and bone, c-fos was found together with p53, suggesting an antagonistic action of these proliferative and antiproliferative factors. Furthermore, c-erb-B2, c-fos and p53 appear to be important for growth and differentiation processes in human development as the occurrence of these proteins was not only restricted to specific tissues but also to specific stages of development of these tissues. Accepted: 30 September 1996     

Sox10-positive sustentacular cells in neuroendocrine carcinoma of the lung

Tsuta K, Raso M G, Kalhor N, Liu D C, Wistuba I I & Moran C A
(2011) Histopathology  58, 276–285
Sox10‐positive sustentacular cells in neuroendocrine carcinoma of the lung Aims: 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). Methods and results: 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. Conclusions: 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.     

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.     

Morphologie, DNA-Zytophotometrie und Prognose gastrointestinaler neuroendokriner Tumoren (Karzinoide)

A total of 123 manifestations (97 primary tumours and 26 metastases) of neuroendocrine tumours of the gastrointestinal tract observed in 95 patients was investigated for the prognostic value of clinical, histological and DNA cytophotometric parameters. Metastases almost exclusively occurred among ileal carcinoids, which also were responsible for all 14 cases of lethal outcome observed during the follow-up period of mean 42 months. Aneuploid DNA values could be determined significantly more frequently among ileal than in non-ileal carcinoids and showed - upon analysis of the total group of gastrointestinal neuroendocrine tumours - a significant correlation to lethal course of disease. In addition, among 18 cases with primary and secondary carcinoid manifestations available for DNA cytophotometry, an association between the DNA content of metastatic neuroendocrine tumours and prognosis came to light. When applied to the group of ileal neoplasms, however, the parameter DNA content did not allow a better prognostic assessment.     

Thymic neuroendocrine tumours

Thymic epithelial tumours include the subcategory of thymic neuroendocrine neoplasms, which comprise a spectrum of entities that mirrors their counterparts in the lung, i.e. typical carcinoid, atypical carcinoid, large cell neuroendocrine carcinoma and small cell carcinoma. These tumours are classified according to the current WHO classification for lung tumours, and their relevant histomorphological and immunohistochemical criteria will be discussed in this brief review. Thymic neuroendocrine neoplasms do, however, also have clinical and molecular characteristics which set them apart from their pulmonary relatives, and recent research has provided valuable insights into possible molecularly-informed classification systems, which broadly align with classical categories, but also show some discrepancies. The most salient recent studies in that respect will also be discussed, as will the avenues for locally ablative therapy and possibilities for systemic treatment.     

The prevalence, prognostic significance and hormonal content of endocrine cells in gastric cancer

Twenty-six of 100 cases of gastric adenocarcinoma contained argyrophil cells. All these tumours were carcino-embryonic antigen positive and 13 contained variable amounts of gastro-enteropancreatic peptides and amines. There was no significant difference in mucin type, extent or incidence of intestinal metaplasia between tumours with and those without endocrine cells. The prognosis for both groups was similarly poor, contrasting with that for carcinoid and atypical carcinoid. Endocrine cell hyperplasia was evident in the adjacent mucosa in some of the cases of endocrine positive tumours. There was no association between achlorhydria and the presence of endocrine cells in the tumours. The origin of the neoplastic endocrine cells remains speculative, occurring either as a mutation of a single stem cell or as a synchronous malignant transformation of two epithelial cell types exposed to a particular carcinogenic factor(s). Adenocarcinomas containing endocrine cells appear to be as biologically aggressive as the usual adenocarcinomas of the stomach and therefore should be treated in a like manner.     

Pulmonary carcinoid tumours: a comparative regional study.

Twenty-two pulmonary carcinoid tumours (18 central, 4 peripheral) were seen in this department over an 11-year period. The majority of the tumours displayed a mixed pattern on microscopic examination, and cell-nest formation was a prominent feature in sixteen. The findings are at variance with the results of a similar series reported from Japan and suggest that there is regional variation in the tumour pattern of pulmonary carcinoids. Various aspects of the histopathology are discussed, and a causal relationship between ossification of bronchial cartilage in these tumours and locally produced calcitonin is postulated.     

hASH1基因与肺神经内分泌肿瘤的关系

肺神经内分泌肿瘤(neuroendocrine tumor，NET)是由具有多向分化潜能的肿瘤细胞组成，这些肿瘤细胞具有分泌多种活性激素的功能。肺NET的发生、发展与hASH1(human achaete-scute homologue 1), MEN1(multiple endocrine neoplasia type 1), pRB和E2F1等基因相关，其中hASH1基因成为近年来研究的热点，该基因能促进肺NET的内分泌分化，降低肿瘤的分化程度，并且有临床资料显示hASH1基因的表达还与小细胞肺癌的低生存率有关，可以作为临床预后的一个标准。     

Dual carcinoid/epithelial neoplasia of the appendix

We report a series of 13 lesions of the human vermiform appendix in which a carcinoid component was associated with a separate non-carcinoid epithelial component that included an adenoma-like lesion of the mucosal epithelium. We use the term dual carcinoid/epithelial neoplasia to describe this phenomenon. The carcinoid component was insular/trabecular in nine cases, tubular in one case and of goblet cell type in three. The epithelial component was a mucinous cystadenoma in four, a mucinous tumour of uncertain malignant potential in three, and a mucinous cystadenocarcinoma in six. No intermediate cell population was seen and in three cases the carcinoid and epithelial components were in different parts of the appendix, leading us to suggest that these lesions may be true 'collision' tumours in which two neoplasms have arisen in the same organ. The prognosis appears to be no worse than for either of the components alone, but conclusions regarding these lesions must be guarded on account of their rarity and the small numbers available for study.     

Absence of overexpression of p53 protein by intestinal carcinoid tumours

A recessive gene on chromosome 17 encodes a protein, known as p53, which normally acts to regulate the cell cycle, its mutation and overexpression being amongst the commonest genetic abnormalities in human malignant neoplasms. As detected by immunolabelling using the anti-p53 protein antibody D07, overexpression was absent from a series of 22 intestinal carcinoid tumours (ten ileal, nine appendiceal, and three colorectal), nine overtly malignant, but was readily demonstrable in five of five colorectal adenocarcinomas, five of six cloacogenic carcinomas, and four of five squamous carcinomas of the anal canal used as controls. These observations are in keeping with previous similar studies of pulmonary carcinoid tumours and suggest possible differences in the pathogenesis of such neoplasms in comparison with non-endocrine differentiated tumours arising at equivalent sites.     

Detection of endothelin immunoreactivity and mRNA in pulmonary tumours

Paraffin sections of 66 surgically resected lung tumours were immunostained with antisera to human endothelin-1 and to the C-terminal peptide of big endothelin. With both antisera, strong immunoreactivity was demonstrated in 11 of 15 squamous cell carcinomas and 11 of 16 adenocarcinomas. Focal immunoreactivity was seen in small cell carcinoma (2/12), large cell carcinoma (2/5), and carcinoid tumours (2/11). Four lymphomas and three sarcomas did not show endothelin immunoreactivity. Cryostat sections of 22 of the 66 tumours were hybridized with radiolabelled complementary RNA probes prepared from the 3' non-coding region of endothelin-1 cDNA, and the chromosomal genes encoding endothelin-2 and -3. In situ hybridization demonstrated the presence of endothelin mRNAs in 4 of 7 squamous cell carcinomas and in 5 of 8 adenocarcinomas, in a pattern similar to that shown by immunocytochemistry. No hybridization signals were obtained from the other types of tumours. In lung tissue adjacent to the tumours, endothelin-like immunoreactivity and mRNA were detected in pulmonary endocrine cells and, in some cases, other epithelial cells, and in alveolar capillary endothelial cells. This study demonstrates the expression of endothelin in a number of pulmonary tumours and suggests a possible role for this peptide in the growth and/or differentiation of these tumours.     

Cardiac metastasis from a bronchial carcinoid: report of a case presenting with diffuse thickening of the left ventricular wall

Bronchial carcinoids are low grade malignancies with an excellent prognosis and a low incidence of metastases. This report describes a case of a typical carcinoid tumour with metastases to the spine after four years and to the heart after eight years. Carcinoid tumours rarely metastasise to the heart and previous reports have identified gastrointestinal primaries as the source in most cases. This is the first published case of typical carcinoid tumour that metastasised to the heart from a bronchial primary.     

The demonstration of a subset of carcinoid tumours of the appendix by in situ hybridization using synthetic probes to proglucagon mRNA.

Previous studies using immunohistochemistry have shown variable hormone production by carcinoid tumours of the appendix. In order to confirm the existence of a specific subset of these tumours, in situ hybridization using synthetic oligonucleotide probes to detect pre-proglucagon and pre-proinsulin mRNA was performed in formalin-fixed, paraffin-embedded material from eight tubular carcinoids, 12 insulin carcinoids, and two mucinous carcinoids. The results were correlated with standard silver and mucin stains. All tubular carcinoids but none of the insular or mucinous carcinoids contained proglucagon mRNA. Proinsulin mRNA was not detected in any of the tumours. Tubular carcinoids of the appendix constitute a definable subset of appendiceal carcinoids which have a similar distribution and prognosis to typical insular carcinoids and can be diagnosed on haematoxylin and eosin-stained sections confirmed by routine special stains. The main need for recognition is to avoid confusion with mucinous carcinoids, which have a worse prognosis and may require more aggressive treatment.     

Sustentacular cells in pulmonary neuroendocrine tumours

AIMS: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.     

Argentaffin and non-argentaffin carcinoid tumours of the appendix

Tumours of the vermiform appendix were studied. The majority proved to be carcinoid tumours of the usual argentaffin-positive type but a substantial minority, generally tumours of minute size, were found to have a somewhat different histological pattern and were argentaffinnegative. Some contained argyrophil granules. The non-argentaffin tumours are considered to form a subgroup of carcinoid tumours.     

Expression of occludin in human rectal carcinoid tumours as a possible marker for glandular differentiation

AIMS: To examine whether or not the tight junction-associated transmembrane protein occludin is expressed in rosette or gland-like structures in human rectal carcinoid tumours. The tight junction is crucial for the formation and maintenance of organized tubular structures in glandular epithelia. Previous studies have reported the presence of glandular structures in carcinoid tumours, though they are not believed to arise from glandular epithelium. METHODS AND RESULTS: The expression profiles of occludin in 40 carcinoid tumours were examined immunohistochemically, using an anti-occludin monoclonal antibody. In eight (20%) samples of typical carcinoid tumours, a small number of rosette-like tubular structures outlined by occludin were detected. CONCLUSIONS: Tight junction-associated molecules, including occludin, are thought to be one of the most characteristic structural markers of polarized glandular structures. The results of the present study provide supportive evidence that carcinoid tumour cells are capable of glandular differentiation.     

Electrical excitability of oat cell carcinoma.

Cultured tumour cells from two oat cell carcinomas of the lung were demonstrated to generate all-or-nothing, short-duration action potentials similar to those previously reported in neurones, in bronchial carcinoid cells, and in a number of endocrine cells of proven or proposed neural ancestry. This observation provides new evidence to establish oat cell carcinomas and carcinoids as closely related tumours distinct from other pulmonary neoplasms, and raises the possibility of treating these tumours by manipulation of hormonal agents.