Primary ovarian carcinoid tumor showing unusual histology and nuclear accumulation of β-catenin

Carcinoid tumor of the ovary is uncommon. We herein report a very rare case of primary ovarian carcinoid tumor with aggressive histology and an unusual immunophenotype. A 21-year-old woman presented with a palpable abdominal mass. Computed tomographic scan revealed a large, extensively necrotic solid mass in the left ovary. The patient underwent a left salpingo-oophorectomy. Grossly, the left adnexa showed a large, vaguely lobulated ovarian tumor measuring 22×15×13 cm. Histologically, the tumor had a readily identifiable neuroendocrine growth pattern, but some areas showed solid growth pattern associated with mild nuclear pleomorphism and multiple foci of punctate necrosis. Furthermore, mitotic figures were recognized in 8 per 10 high-power fields, and a few foci of large coagulative tumor necrosis were also noted. In addition, the tumor tissue exhibited uniform, strong nuclear β-catenin immunoreactivity, indicating the nuclear accumulation of β-catenin in the individual tumor cells. In summary, we described the first case of primary ovarian carcinoid tumor with loss of neuroendocrine growth pattern, increased mitotic activity and large areas of coagulative tumor necrosis. According to the WHO classification of pulmonary carcinoid tumor, this case may be classified as “atypical” carcinoid. However, currently, no primary ovarian atypical carcinoid exists in the classification system. Due to its rarity, there are no established diagnostic criteria and clinical data on patient outcomes for ovarian carcinoid tumors with aggressive histology. Additional reports are clearly necessary. We also showed for the first time the nuclear accumulation of β-catenin in carcinoid tumor cells, suggestive of a role for β-catenin in the tumorigenesis of ovarian atypical carcinoid tumor or its aggressive histology.     

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.     

Differential expression of neural-cadherin in pulmonary epithelial tumours

Aims:  Neural (N)-cadherin belongs to a group of transmembrane molecules with a crucial role in tissue morphogenesis and maintenance of an epithelioid phenotype and increased N-cadherin expression is implicated in tumour progression and dedifferentiation. The aim was to determine whether evaluation of N-cadherin in pulmonary tumours might assist in identifying lesions with more aggressive potential.
Methods and results:  One hundred and fifty-five pulmonary lesions were analysed for N-cadherin expression using immunohistochemistry, including neuroendocrine hyperplasia ( n  = 3), typical carcinoid ( n  = 59), atypical carcinoid ( n  = 12), small cell lung carcinoma ( n  = 11), large cell neuroendocrine carcinoma ( n  = 12), adenocarcinoma ( n  = 35) and squamous cell carcinoma ( n  = 23). Lymph node status was correlated with immunohistochemical expression. N-cadherin expression was demonstrated in all cases of neuroendocrine hyperplasia, 96% of typical carcinoids, 83% of atypical carcinoids, 63% of the small cell lung carcinomas and 32% of large cell neuroendocrine carcinomas. Over 90% of the adenocarcinomas and 100% of the squamous cell carcinomas were negative. Increased N-cadherin expression in typical carcinoids was associated with negative lymph node status ( P  < 0.001).
Discussion:  N-cadherin is differentially expressed in pulmonary tumours and is predominantly observed in neuroendocrine lung lesions with high expression in typical and atypical pulmonary carcinoids. The level of expression of N-cadherin between types of lung tumours does not appear to indicate malignant potential or aggressive behaviour.     

Kidney carcinoid tumor: Histological,immunohistochemical and ultrastructural features

Primary carcinoid tumor of the kidney is uncommon. Only limited morphologic studies have been reported in the literature. In general, renal carcinoid tumor reveals typical morphological features as present in carcinoid tumors in the other organs, i.e. growing as trabeculae intermixed with nests of monotonous cuboidal cells that show “salt and pepper” nuclear appearance. As reported in other organs, different morphological expressions may also present in renal carcinoid tumors, such as papillary, pseudoglandular or solid growth patterns and clear/eosinophilic cytoplasmic changes. These morphological variations may mimic other benign and malignant primary neoplasms in the kidney. Therefore, in some cases, ancillary studies are necessary or even crucial to differentiate carcinoid tumors from other primary renal neoplasms.

Herewith, we report two primary renal carcinoid tumors with long follow-up, one showed typical morphological features of carcinoid tumor, and the second one revealed some uncommon histological findings. To differentiate these carcinoid tumors from other primary renal neoplasms and confirm neuroendocrine differentiation, immunohistochemical studies are valuable. In case 2 immunohistochemical stain results were not definitive and electron microscopy was performed confirming the diagnosis of carcinoid tumor.     

Lectin expression in carcinoid tumours of the gastrointestinal tract

The binding of peroxidase-conjugated Dolichos biflorus (DBA), Triticum vulgaris (WGA), Canavalia ensiformis (Con A), Arachis hypogaea (PNA), Lotus tetragonolobus, and Bandeiraea simplicifolia I (BSAI) to gastrointestinal carcinoid tumours was studied. The results indicate that carcinoid tumour cells express certain carbohydrates similar to those present in the adjacent surface epithelium. The differences in the lectin-binding properties of carcinoid tumours of different sites of the gastrointestinal tract are closely related to the regional differences in the lectin binding of adjacent surface epithelium. These observations therefore form a useful basis for further studies in the application of lectin histochemistry to elucidate the histogenesis of carcinoid tumours.     

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.     

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.     

Pigmented spindle cell carcinoid tumour of the thymus with ectopic adrenocorticotropic hormone secretion: report of a rare variant and differential diagnosis of mediastinal spindle cell neoplasms

AIMS: A variety of histological variants of thymic carcinoid tumour have been described. A rare case of pigmented spindle cell carcinoid tumour of the thymus is documented and compared with the reported cases of thymic pigmented carcinoid tumour in the literature, with a discussion of the differential diagnosis of spindle cell tumours of the mediastinum. METHODS AND RESULTS: A thymic tumour with ectopic adrenocorticotropic hormone (ACTH) secretion was resected from a 24-year-old man suffering from Cushing's syndrome. Histological, immunohistochemical, and ultrastructural studies revealed an ACTH-producing spindle cell carcinoid tumour harbouring pigmented melanocytes. Among four thymic pigmented carcinoid tumours reported before, only one was similar to the present case by being also an ACTH-secreting pigmented spindle cell thymic carcinoid tumour. The clinicopathological features of this tumour distinguish it from a spindle cell thymoma, spindle cell thymic carcinoma, and other mediastinal spindle cell tumours. CONCLUSIONS: This case illustrates an extremely rare variant of thymic carcinoid tumour exhibiting a spindle cell morphology and harbouring pigmented melanocytes. Awareness of this histological variant is important in the differential diagnosis of spindle cell tumours of the mediastinum.     

Peripheral small-cell carcinoma of the lung resembling carcinoid tumor. A clinical and pathologic study of 14 cases

We studied 14 small-cell, epithelial tumors of the lung with histologic features intermediate between typical carcinoid tumor and undifferentiated small-cell carcinoma. All of the tumors arose in the periphery of the lung beyond a segmental bronchus and were excised. Histologically, three of the tumors were low grade and 11 were high grade. The low-grade tumors had an organoid pattern comprising more than half of the area examined histologically, less than five mitoses per 10 high-power fields, individual cell necrosis, and nuclear pleomorphism of less than half of the cells. The high-grade tumors had the opposite characteristics. Distinction of these peripheral tumors from typical carcinoid tumors and from undifferentiated small-cell carcinomas is established after excision and cannot be made reliably on the findings of a transbronchial or needle biopsy. Prognosis was worse than that for typical carcinoid tumors but better than that for undifferentiated small-cell carcinomas.     

The topographical and age distributions of neuroendocrine cells in the normal human appendix

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.     

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.     

Molecular alterations of neuroendocrine tumours of the lung

Neuroendocrine tumours of the lung comprise low [typical carcinoid (TC)], intermediate [atypical carcinoid (AC)] and high‐grade [small‐cell lung cancer (SCLC) and large‐cell neuroendocrine carcinoma (LCNEC)] malignancies, while a pre‐invasive lesion [diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH)] may generate a subset of peripheral carcinoid tumours. These neoplasms are differentiated conventionally based on mitotic rate, presence of necrosis and cytological details, according to the 2015 World Health Organisation (WHO) classification. Clinical data and molecular alterations distinguish carcinoids and high‐grade carcinomas into two separate categories. Previous studies have demonstrated a significantly higher rate of chromosomal aberrations in carcinomas (e.g. 3p and 17p deletions), but restriction of multiple endocrine neoplasia type 1 (MEN1) mutations to carcinoids. High‐grade carcinomas are also characterised by TP53 and RB1 gene inactivation. In this review, a critical analysis of the diagnostic and prognostic role of Ki67 labelling index and a concise discussion of the most relevant findings regarding molecular characterisation of lung neuroendocrine neoplasms are reported. In addition, we illustrate how the development of promising therapeutic strategies based on the identification of molecular targets (mTOR inhibitors in carcinoids and targeting of the Notch ligand DLL3 in SCLC) may require the assessment of predictive biomarkers, even in the group of neuroendocrine tumours of the lung.     

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.     

Endocrine cell carcinoma of the gallbladder

An endocrine cell carcinoma in the gallbladder of a 59-year-old woman is reported. The morphological features of this diagnosis are compared with 14 previously reported primary gallbladder carcinoid tumours that had metastasized. The histogenesis and current classification of endocrine cell tumours is discussed.     

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.     

An unusual cause of tricuspid and pulmonary valve stenosis and regurgitation

Carcinoid heard disease is a frequent sequela to metastatic carcinoid tumour. This rare condition has a typical pathological presentation with characteristic macroscopic and microscopic findings. We present here a case detailing the classical findings of carcinoid heart disease in a tricuspid valve.     

Adenocarcinoid of the vermiform appendix

Summary Four cases of adenocarcinoid of the appendix were studied. Two tumours were found among 28 cases primarily diagnosed as appendiceal carcinoids. They showed characteristic histological structures with features of both a conventional carcinoid tumour and a mucinproducing adenocarcinoma with goblet cells. All tumours were small and ill-defined; three were associated with fibrous obliteration of the appendiceal lumen. All were diagnosed incidentally by the pathologist in appendices removed en passant or because of acute appendicitis. Three of the tumours appeared well differentiated with a low degree of malignancy similar to that of the conventional carcinoid tumour. In one case however, the tumour was less differentiated with atypical foci and a high mitotic count and had metastasised to peritoneum and both ovaries.     

Strumal carcinoid of the ovary associated with hyperinsulinaemic hypoglycaemia and cutaneous melanosis

Using immunohistochemical techniques ovarian carcinoid tumours can be shown to contain a wide variety of neuro-hormonal peptides but clinical effects, apart from the carcinoid syndrome, are very rare. Non-islet cell tumours with documented hyperinsulinaemic hypoglycaemia are also rare. This is the first recorded case of an ovarian strumal carcinoid associated with hyperinsulinaemic hypoglycaemia. Concurrent skin hyperpigmentation is believed to have resulted from the effects of tumour derived α-melanocyte stimulating hormone or an antigenically similar, biologically active peptide.     

Widespread neuroendocrine malignancy within the central nervous system: a diagnostic conundrum.

A 75 year old female presented with a sellar tumour, and was subsequently found also to have a cauda equina tumour, a parietal dural tumour, a pontine tumour, an intradural spinal tumour, and several vertebral body tumours. Histological examination revealed a neuroendocrine tumour forming cell nests surrounded by reticulin. There was moderate nuclear pleomorphism, prominent mitoses, and focal necrosis. Immunohistochemistry showed diffuse positive staining with cytokeratins, chromogranin and 5-hydroxytryptamine, and focal positive staining with S100. This case is an unusual and ultimately insoluble, diagnostic problem; however, the differential diagnoses include pituitary carcinoma, malignant paraganglioma, and atypical carcinoid.