Neuroendocrine differentiation in male breast carcinomas.

The presence of neuroendocrine differentiation, as expressed by cellular chromogranin immunoreactivity, was investigated in paraffin-embedded tissue material from 51 consecutive cases of male breast carcinoma. From six of these cases electron microscopic studies were included. Chromogranin-immunoreactive cells were present in solid cords and delineated tubular structures. Ultrastructurally, dense core secretory granules could be detected. The expression of neuroendocrine differentiation was 45%, which is between two and eight times higher than reported for female breast carcinomas by other investigators. The present findings suggest that male breast carcinoma is an exclusive tumour disease showing both similarities and discrepancies when compared to its female counterpart.     

Neuroendocrine differentiation and prognosis in breast adenocarcinoma

AIMS: Neuroendocrine differentiation has been detected, and its prognostic value studied, in a number of common human carcinomas. To date there are few detailed studies examining its relevance in breast carcinoma. In this study we evaluate the frequency and prognostic importance of neuroendocrine differentiation in breast adenocarcinoma. METHODS AND RESULTS: The presence of neuroendocrine differentiation, defined as positive reactivity for three markers, neuron-specific enolase (NSE), chromogranin A and/or synaptophysin, has been evaluated in 99 patients with primary operable breast cancer using standard immunocytochemical techniques. A consecutive cohort of patients were selected from the Nottingham/Tenovus series. Comprehensive patient and tumour records have been maintained, and patients were followed up according to a defined protocol. Eighteen cases were positive for NSE, 10 for chromogranin A and 13 for synaptophysin. Eleven percent were positive with more than one neuroendocrine marker. No significant association was found between neuroendocrine differentiation and tumour size, grade, stage or the prevalence of vascular invasion. There was no significant difference in either overall or disease-free survival between patients with or without neuroendocrine differentiation. CONCLUSIONS: In this study we confirm that neuroendocrine differentiation can be identified in a subset (10-18%) of human breast carcinomas. This phenomenon appears to have no relationship to established prognostic factors or patient outcome.     

Neuroendocrine differentiation in prostatic carcinoma

Specimens from 53 cases of prostatic carcinoma obtained during total prostatectomy or transurethral resection of prostate were analyzed for neuroendocrine differentiation with immunocytochemical tests for serotonin, neuron-specific enolase, and chromogranin as well as with the Churukian-Schenk argyrophil reaction. Forty-seven per cent (25 of 53) of the prostatic carcinomas were positive for neuroendocrine differentiation, usually with an overlapping combination of these techniques. Nine per cent (five cases) contained areas with numerous neuroendocrine cells, 11 per cent (six cases) had focal scattered neuroendocrine cells, and 26 per cent (14 cases) had rare neuroendocrine cells. The positive cases spanned the histologic spectrum of prostatic adenocarcinoma; histologically none resembled a carcinoid tumor or a small cell carcinoma. Positive cases were further studied with a battery of antisera to 12 polypeptide hormones. Immunoreactivity to only bombesin (one case) and calcitonin (two cases) was detected. In five cases, neuroendocrine differentiation was studied by electron microscopy and verified at the ultrastructural level.     

前列腺癌的神经内分泌分化

一、良性前列腺中的神经内分泌细胞 正常前列腺主要由分泌细胞和基底细胞组成,可在HE染色下由普通显微镜分辨。另外还有散在微量的神经内分泌细胞（neuroendocfine cell,NE细胞）,该细胞仅能由电镜分辨,或者通过免疫组织化学方法用特异性标记物如嗜铬粒素A（CgA）、突触素（Syn）、神经元特异性烯醇化酶（NSE）等识别。前列腺的NE细胞具有上皮性、神经性和内分泌性特征,散在分布于前列腺,但在移行区和外周区比在中心区更多见。NE细胞的这种分布,可能与前列腺增生和前列腺癌有关。     

Neuroendocrine differentiation in carcinomas of the breast: a study of 51 cases

A group of human breast carcinomas shows morphologic and histochemical evidence of neuroendocrine (NE) differentiation. This study presents a structural, immunologic, and electron microscopic analysis of 51 cases in order to establish positive criteria for identification of these tumors, their incidence, variants, and biological behavior. Argyrophilia (by the Grimelius procedure), presence of chromogranin A and/or B, and of synaptophysin are the most reliable histochemical features, correlating with the ultrastructural demonstration of dense-core secretory granules and of clear vesicles of the synaptic type. Structural features alone may be suggestive, but do not prove NE differentiation, which has to be established by additional techniques. Seven histologic types were identified, but those herein described as types A, B, and C, which show cohesive, mucoid, and mixed patterns, respectively, comprise the vast majority of the tumors. Rare NE carcinomas of the breast show structural similarities to Merkel cell and oat cell carcinomas, and behave as highly aggressive tumors. Type B (mucinous) tumors proved to be relatively indolent, while the most frequent types of endocrine tumors (types A and C) have an intermediate grade of malignancy. The analysis of a consecutive series of 100 cases of breast cancer indicates that about 8% of breast carcinomas display some degree of NE differentiation.     

Neuroendocrine differentiation in basal cell carcinoma

Basal cell carcinoma (BCC) is the prototypical basaloid tumor of the skin. It may show various patterns simulating other cutaneous tumors due to its pleomorphism. It may have an unusal pattern of differentiation such as squamous, sebaceous, apocrine, eccrine, pilar, and endocrine differentiation. In order to establish the relative frequency of neuroendocrine differentiation in BCC, we performed a retrospective study of 33 consecutive BCCs using conventional immunohistochemistry with two neuroendocrine antibodies: Chromogranine A and synaptophysine. The age of the patients ranged from 17–83 years with mean of 65 years. The male to female ratio was 16:17. In immunohistochimestry, Chromogranine A was seen in 72.2% (24/33) while Synaptophysine was positive in 9.09% (3/33). Their expression was cytoplasmic and membranous and was seen in the periphery of these tumors in the overlying cells. Positive staining of chromogranine A was high (75–100% of tumors cells) in 9%, intermediate (25–75% of tumors cells) in 33% of cases and relatively low (<25%) in 30.3% of cases.     

卵巢粘液性肿瘤的神经内分泌分化

目的探讨卵巢粘液性肿瘤的神经内分泌分化与肿瘤分化程度、组织发生的关系。方法用免疫组织化学和免疫组织化学与组织化学联合染色方法观察７３例卵巢粘液性肿瘤（良性：３２例,交界性：２０例,恶性：２１例）病变组织中的神经内分泌细胞的形态、分布和数量。结果良性、交界性、恶性三种病变组织中ＣｇＡ和５ＨＴ的检出率分别依次为６２５％、７５０％、７６０％和３１３％、４００％、３９０％。但这些神经内分泌细胞（ＮＥＣ）的数量和分布未见明显的规律性。在４例肠型的良性肿瘤组织中见到较多ＣｇＡ阳性细胞,分布在粘液上皮的基底部,阳性率＞３０％,光镜下频繁观察到胞浆中同时含ＣｇＡ和ＰＡＳ两种阳性颗粒的中间型细胞。结论卵巢粘液性肿瘤随分化程度下降,神经内分泌细胞的检出率逐渐增加。４例肠型的良性肿瘤组织中频繁观察到胞浆中同时含ＣｇＡ和ＰＡＳ两种阳性颗粒的中间型细胞,提示这些肿瘤可能起源于具有多方向分化能力的干细胞,它们与卵巢粘液性肿瘤伴神经内分泌分化之间的确切关系,尚待研究。     

Neuroendocrine differentiation in cervical carcinoma.

AIMS: To examine neuroendocrine differentiation, as shown by chromogranin A (CGA) expression, in cervical carcinomas. METHODS: Sixty seven cervical carcinomas were studied and were classified as adenocarcinomas, adenosquamous carcinomas or squamous cell carcinomas based on the assessment of haematoxylin and eosin staining and stains for mucin. Where features of glandular differentiation were identified, sections were also stained for evidence of intestinal type mucin. CGA immunostaining was done and the results were graded on a three point scale: 0, + (1-5% of cells positive) and ++ (> 5% of cells positive). These findings were then analysed with respect to lymph node status, tumour differentiation and clinical outcome. RESULTS: There were 32 adenocarcinomas, 18 adenosquamous carcinomas and 17 squamous cell carcinomas. Positive staining was seen in 14 (20.9%) cases, of which four were strongly positive. All but one case were either adenocarcinomas or adenosquamous carcinomas. There was a trend for CGA positivity to be related to intestinal differentiation but this failed to reach statistical significance. No correlation could be demonstrated between CGA staining and lymph node status, tumour differentiation and clinical outcome. CONCLUSIONS: Neuroendocrine differentiation is common in cervical carcinomas where there is evidence of glandular differentiation. Whilst the numbers in this study are relatively small, the presence of neuroendocrine cells in otherwise typical carcinomas does not seem to have any association with clinical behaviour.     

Neuroendocrine differentiation in human prostatic carcinoma.

Endocrine-paracrine (APUD, neuroendocrine) cells are located in the prostatic ductal and acinar epithelium. These cells are of the open and closed type and have dendritic processes. There is a wide range of secretory granule morphology presumably indicating a variety of different cell "types." Secretory immunoreactive peptides include serotonin, calcitonin (and related peptides), somatostatin, bombesin-like, thyroid-stimulating hormone-like (beta chain), and alpha-glycoprotein chain-like. These cells may function by endocrine, paracrine, neurocrine, and lumencrine mechanisms and play an important regulatory role both during growth and differentiation of the prostate as well as in the secretory process of the mature gland. Neuroendocrine differentiation in prostatic carcinoma is a frequent occurrence and manifests itself in several forms, including (1) small cell carcinoma, (2) carcinoid and carcinoid-like tumors, and (3) conventional adenocarcinoma with focal neuroendocrine differentiation. This latter pattern is the most common, and there is evidence that all or nearly all prostatic adenocarcinomas show at least some focal neuroendocrine differentiation. A review of the world's literature on this topic is included. Neuroendocrine differentiation generally portends a poorer prognosis but may also correlate directly with the grade. There is some evidence to suggest that neoplastic cells with neuroendocrine differentiation are resistant to hormonal therapy. Eutopic and ectopic hormone production may allow screening for prostatic carcinoma and/or monitoring for recurrence of prostatic carcinomas. Finally, the more basic implications of endocrine-paracrine cells and neuroendocrine differentiation are speculated on in reference to prostatic carcinogenesis and autocrine/paracrine tumor growth factor activity.     

Neuroendocrine lesions of the genitourinary tract

Neuroendocrine differentiation in tumors of the upper and lower urinary tracts, prostate, and testis is rare. The current review surveys the most significant pathologic and clinical features of primary neuroendocrine lesions at these sites, with emphasis on the cell types from which they derive. As many tumors in this spectrum often bear strong morphologic resemblance to similar neoplasms in other organs, the importance of considering secondary involvement of the genitourinary tract cannot be overstated.     

Neuroendocrine differentiation in endocrine and nonendocrine lung carcinomas

Bronchial carcinoids and small cell lung cancer (SCLC) are currently recognized as neuroendocrine (NE) neoplasms. However, non-SCLC (NSCLC) may also express NE properties. Paraffin-embedded sections of a comprehensive panel of 113 lung carcinomas were analyzed for the expression of three general markers common to all NE cells, namely, chromogranin A, Leu-7 and neuron-specific enolase (NSE), five specific NE secretory products, and four other tumor markers by immunohistochemistry using the sensitive avidin-biotinylated peroxidase technique. The authors were able to demonstrate the following: (1) most, but not all carcinoids and SCLCs expressed multiple NE markers in a high percentage of tumor cells; (2) up to a half of NSCLC cases contained small subpopulations of cells expressing NE in a high percentage of tumor cells; (2) up to half of NSCLC cases contained small subpopulations of cells expressing NE markers; and (3) occasional NSCLCs showed staining patterns indistinguishable from SCLC. Specifically, 7 of 77 NSCLCs expressed four or more NE markers. NE markers in NSCLCs were more commonly expressed in adenocarcinomas and large cell carcinomas and rarely in squamous cell carcinomas. For comparison, the mean number of NE markers expressed by all cases of NSCLC was 1.5, carcinoids 6.0, and SCLCs 3.8. Individual "marker counts" were not useful in categorizing lung tumors as carcinoids and SCLC versus NSCLC. Instead, 95% of the tumors were correctly classified, applying a statistical model created from staining indices of the three general NE markers (chromogranin A, Leu-7, NSE) and three other tumor markers (carcinoembryonic antigen, keratin, vimentin). Because NSCLCs with NE features might have different clinical characteristics than other NSCLCs, immunohistochemistry provides an effective manner to identify this biologically interesting subset of NSCLCs in routine paraffin sections.     

Neuroendocrine differentiation in human prostatic tumor models.

Neuroendocrine (NE) cells can be identified in benign and malignant prostatic epithelia. Factors regulating their presence and their functions are poorly understood, mainly due to a lack of suitable experimental models. Fifteen in vitro and in vivo prostatic cancer tumor models, including a number of newly established in vivo models, were studied immunohistochemically for the presence of NE cells under different hormonal conditions. None of the in vitro models (PC-3, DU 145, LNCaP, and TSU) contained NE cells. Five of the seven xenograft models established at this laboratory contained NE cells. In three of these, NE cells were found only in the initial mouse passages. In the other two (PC-295 and PC-310), the NE phenotype was stable. NE features were confirmed by transmission electron microscopy and by Western analysis of chromogranin A expression. Immunohistochemical double-labeling experiments confirmed that NE cells in prostate cancer are post-mitotic (no Ki-67 expression) and do not express the androgen receptor. In the PC-295 and PC-310 models, short-term androgen withdrawal resulted in a rapidly increased number of NE cells. A time course experiment with PC-295-bearing mice strongly suggests that this increase occurred by induction of NE differentiation rather than by rapid proliferation and subsequent differentiation or selective persistence. In conclusion, these models are suitable to resolve fundamental questions with regard to the presence and functions of NE cells in human prostate cancer.     

Neuroendocrine differentiation in carcinoma of the breast. Tyramide signal amplification discloses chromogranin A-positive tumour cells in more breast tumours than previously realized

The aim of the study was to determine if, by means of tyramide signal amplification (TSA), the presence of chromogranin A (CgA)-positive tumour cells could be demonstrated in breast cancer cases found to be negative by conventional immunohistochemical staining. Sections from 44 cases of breast cancer (28 infiltrating ductal carcinomas, 2 lobular carcinomas, 4 ductal carcinomas in situ (DCIS), 7 lobular carcinomas in situ (LCIS), and 3 mucinous carcinomas) were stained for CgA by conventional immunohistochemical methods and by immunohistochemistry with TSA. The sections were also histologically graded and their oestrogen receptor (ER), progesterone receptor (PgR) and HER-2 oncogene status was recorded. Five of the tumours showed CgA-positive staining with the polyclonal antibody 430 with conventional methods. Thirty cases showed CgA-immunoreactive tumour cells after immunohistochemical staining with the polyclonal antibody 430 with TSA. However, eight of these also showed faint staining with the negative control antibody X0936 with TSA. One case showed immunopositivity for CgA using a monoclonal antibody without tyramide amplification and only a further two cases were positive when TSA was applied. The presence of CgA appears to be associated with a lower histological grade and may be more often found in oestrogen receptor-positive tumours.     

Neuroendocrine differentiation in hyalinizing trabecular tumor of the thyroid

The presence of neuroendocrine cells is putative in thyroid hyalinizing trabecular tumor (HTT), although this entity requires a differential diagnosis from paraganglioma or medullary carcinoma of the thyroid, due to similarity of the growth pattern of the cells. Here, we present a case of HTT with a mixture of endocrine cells stained positive for somatostatin, chromogranin A and Grimelius silver impregnation. The histology and results of other immunostainings were consistent with the features typical for HTT. In the world literature to date, only two cases of HTT with endocrine cells, including the current case, have been reported. Nevertheless, the cases may indicate the diversified differentiation of cells in HTT and may, in part, account for the resemblance of HTT to paraganglioma and medullary carcinoma.