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 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.     

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.     

Neuroendocrine differentiation in adrenocortical carcinoma. New immunohistochemical findings supported by electron microscopy.

Ten adrenocortical carcinomas including two tumors with clinically detectable corticosteroid production, were immunohistochemically analyzed for their intermediate filament proteins, and for neuroendocrine markers. Keratins were present in 6 of 10, vimentin in all 10, and the 68 kilodalton kD neurofilament subunit protein in 6/10 tumors. Keratins numbers 8 and 18 were most prevalent, whereas only traces of keratins 19 and 7 were found. Eight tumors were positive for synaptophysin at least focally, and 3 showed extensive positivity in more than 30% of tumor cells. The tumors showed approximately similar levels of neuron-specific enolase (NSE) expression as judged by immunohistochemistry. Chromogranin was not detected, and there was no immunoreactivity for 3 neuropeptides (calcitonin, gastrin, somatostatin). In normal adrenal cortex, neuron-specific enolase, synaptophysin and neurofilaments were restricted to the nerves seen between the cortical cells. Electron microscopy revealed clusters of dense-core granules in 4 of 5 tumors, consistent with neuroendocrine granules. These results indicate that adrenocortical carcinomas may show signs of neuroendocrine differentiation and share some features with the adrenal medullary tumors.     

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 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 breast lesions

A review of neuroendocrine features in breast carcinomas is presented and markers for neuroendocrine cells are discussed. Immunostaining for neuron specific enolase is the best screening marker for neuroendocrine cells in breast carcinomas, but immunoreactivity for hormones is not present in all neuron specific enolase (NSE) positive cases. Normal myoepithelial cells are also NSE positive. Thirty per cent of breast carcinomas are NSE positive. Biochemical demonstration of ACTH, PTH and calcitonin, and immunohistochemical demonstration of ACTH, bombesin, serotonin, prolactin, gastrin, VIP, leu-enkephalin, pancreatic polypeptide, beta-endorphin and sub P has been reported in breast carcinomas. Neuroendocrine cells have not been convincingly demonstrated in the normal breast or in benign breast lesions.     

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 a case of acinic cell carcinoma of the parotid gland

We report a case of acinic cell carcinoma of the parotid gland with neuroendocrine differentiation. Light microscopically, the tumor appeared as clear cell-type acinic cell carcinoma. In addition, the tumor showed neurosecretory features such as Grimelius positivity and the presence of neurosecretory granules by electron microscopy. We suggest that a tumor cell arising from a stem cell can show simultaneous differentiation to both neuroendocrine and acinic cells.     

Neuroendocrine differentiation in pure type mammary mucinous carcinoma is associated with favorable histologic and immunohistochemical parameters.

Mucinous carcinoma of the breast is a specific good prognostic type malignancy occurring in elderly patients. Neuroendocrine differentiation has long been described in mucinous carcinoma, but the significance of such finding is uncertain. We evaluated the neuroendocrine differentiation profiles of 38 cases of pure mucinous carcinoma and compared the clinicopathological differences between those with and those without neuroendocrine differentiation. The parameters assessed included patients' age, tumor size, nuclear grade, axillary lymph node status at time of diagnosis, percentage area of intratumoral mucin, and the expression of estrogen and progesterone receptors, cerbB2 oncoprotein, and three neuroendocrine markers, namely neurone-specific enolase, chromogranin, and synaptophysin by immunohistochemistry. Patients' outcome and follow-up period were also documented. Of the 38 cases of pure mucinous carcinoma, 28, 11 and six cases showed positive staining for 1, 2 and 3 of the neuroendocrine markers. For all the groups with variable neuroendocrine differentiation and compared to those without such differentiation, they all showed older patients' age, higher proportion of tumors with lower nuclear grade, lower incidence of axillary lymph node metastasis, a higher progesterone receptor, and lower cerbB2 oncoprotein expression. No difference was detected between tumor size, intratumoral mucinous area, and estrogen receptor status. In all, 37 patients did not have distant metastases or local recurrences at the end of follow-up period, while one patient with coexisting high-grade ductal carcinoma in situ at time of diagnosis died of breast carcinoma. Our findings suggest that the identification of neuroendocrine differentiation in pure mucinous carcinoma is associated with more favorable histologic and immunohistochemical parameters.     

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 prostatic carcinomas. A retrospective autopsy study

Neuroendocrine differentiation in prostatic neoplasms has in the past been considered extremely uncommon. The histologic neuroendocrine patterns reported previously vary from small cell to carcinoidlike to mixed adenocarcinoma--small cell or carcinoid. The majority of the tumors reported are of the mixed variety. We reviewed 2648 autopsies, revealing 69 prostatic carcinomas, eight with neuroendocrine differentiation (five mixed adenocarcinoma--small-cell carcinoma, two "pure" small cell, and one "pure" carcinoidlike). The mean patient age was 69.5 years. One patient presented with markedly elevated serum corticotropin and another was severely hypercalcemic with elevated serum parathyroid hormone level. Three neoplasms were incidental autopsy findings. The mean survival time, after diagnosis, was 19 months for the other patients. Three of the cases were examined ultrastructurally and showed cytoplasmic processes containing membrane-bound granules in the neuroendocrine component. The areas with neuroendocrine differentiation were positive for markers as follows: neuron-specific enolase, seven of eight; prostate-specific antigen (PSA), none of eight; chromogranin A, seven of eight; synaptophysin, four of eight; and calcitonin, four of eight. Those neoplasms mixed with an adenocarcinoma component showed well-defined PSA positivity in the glandular elements. This study suggests that neuroendocrine differentiation in prostatic neoplasms may be more common than previously thought. Often, the areas with neuroendocrine differentiation are considered to represent poorly differentiated adenocarcinoma. It is important to recognize neuroendocrine components in prostatic carcinomas owing to prognostic and potential therapeutic implications.     

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 thymic epithelial tumors with special reference to thymic carcinoma and atypical thymoma

To determine the neuroendocrine (NE) features of thymic epithelial tumor, immunohistochemistry and electron microscopy studies were performed on eight NE tumors (thymic carcinoids) and 26 non-NE tumors (nine thymic carcinomas, five atypical thymomas, and 12 thymomas other than lymphocytic thymoma). Immunohistochemical studies were performed with antibodies against general markers for NE cells (synaptophysin, a subunit of a guanine nucleotidebinding protein, Go, and small-cell lung carcinoma cluster 1 antigen), and a broad panel of antibodies for hormonal substances. Thymic carcinoid showed synchronous diffuse immunoreactivity for the three NE markers and contained cells that were positive for a variety of hormonal products: human chorionic gonadotropin (hCG) a-subunit (eight of eight), hCG β-subunit (three of eight), adrenocorticotropic hormone (ACTH) (three of eight), calcitonin (two of eight), calcitonin gene-related peptide (two of eight), and serotonin (one of eight). Conversely, although positivity for NE markers was neither synchronous nor diffuse in non-NE tumors, seven of nine thymic carcinomas, three of five atypical thymomas (focal or dispersed distribution), and none of the five thymomas were positive for at least two of these NE markers. A small number of neoplastic cells were positive for hCGa-subunit or ACTH in three thymic carcinomas and one atypical thymoma. Ultrastructurally, dense core granules (DCG) were much more frequent in thymic carcinoid, but several DCG-like granules were identified in 12 of 13 non-NE tumors with or without immunoexpression of NE markers. The presence of focal or dispersed NE cells in thymic carcinoma and atypical thymoma may reflect multidirectional differentiation within the tumor, which, like cytological atypia, epithelial CD5 expression, and lack of immature T cell infiltration, may be another feature of this group at thymic tumors.     

Neuroendocrine liver metastasis in gastric mixed adenoneuroendocrine carcinoma with trilineage cell differentiation: a case report

Mixed adenoneuroendocrine carcinoma (MANEC) is a rare disease, which mostly occurs in the gastroin testinal tract and pancreas. Here we report a case of gastric MANEC with tri-lineage differentiation in which only the neuroendocrine component had metastasized to the liver. Liver and gastric masses were detected by abdominal computed tomography, and the preoperative relationship between liver and gastric masses was unknown. The histopathological analysis after operation confirmed the gastric mass to be MANEC, whereas the liver mass was actually the metastatic neuroendocrine component of the gastric MANEC. In the pathologic diagnosis, tri-lineage differentiation, including tubular adenocarcinoma, neuroendocrine carcinoma and squamous cell carcinoma was observed in the gastric MANEC tissues. The mitotic and Ki-67 labeling indexes of the resected tumor tissue were high, and thus, the tumor was classified as a grade G3 neuroendocrine carcinoma, which has a poor prognosis. Multiple low-density masses were found in the right lobe of the liver 2.5 months after operation.