Markers neuron-specific enolase

Neuroendocrine/neurosecretion markers Neuron-specific enolase (NSE) (38)... 

The usual carcinoid tumor is sofid and yeUow-tan in appearance. Tumor cells exhibit a monotonous morphology, with pink granular cytoplasm and round nuclei with infrequent mitoses. Most carcinoids can be recognized by their reactions to silver stains and to neuroendocrine cell markers, such as chromogranin and neuron-specific enolase. Ultra-structuraUy, carcinoids possess numerous membrane-bound, electron-dense neurosecretory granules. These granules contain peptide hormones and bioactive amines, which can occasionally be identified by immunocytochemi-cal techniques. 

Attempts are being made to identify more sensitive and specific markers for carcinoids. For example, measurement of chromogranin A in serum is reported to be more sensitive than urinary 5-HIAA in detecting carcinoid tumors and may reflect tumor size, but specificity is lower. Plasma levels of neuron-specific enolase, neuropeptide K, and substance P have also been suggested as diagnostic and prognostic markers in carcinoid tumors. 

Lucker, E., Eigenbrodt, E., Wenisch, S., Failing, K., Leiser, R., and Bulte, M. 1998. Development of an integrated procedure for the detection of central nervous tissue in meat products using cholesterol and neuron-specific enolase as markers. /. Food I rot. 62,268-276. 

Neuron-specific and non-neuron-specific enolase isoenzymes have been used as markers to distinguish neurons from nonneuronal cells (e.g., glial cells that are physically and metabolically supportive cells of neurons) by im-munocytochemical techniques. Neuron-specific enolase is extremely stable and resistant to a number of in vitro treatments (e.g., high temperature, urea, chloride) that inactivate other enolases. The functional significance of these isoenzymes is not known. 

The enolase enzymes comprise five different forms, each of which is composed of three homodimers and two hybrids. Neuron-specific enolase (NSE) is found in a variety of normal and neoplastic neuroendocrine cells and predominates in the brain. Originally believed to be a specific marker for neuroendocrine differentiation, it has subsequently been observed that NSE can be found in virtually any type of neoplasm. Because of this, it is a poor antibody to use to screen for neuroendocrine differentiation. Overall a poor marker for detection of neuroendocrine differentiation because of its lack of specificity, NSE may be useful in combination with other more specific antibodies such as chromogranin and synaptophysin for the appropriate neuroendocrine morphologic identification and documentation of immunostaining. 

Immunohistochemical staining is fairly consistent and straightforward in ONE. The tumor cells are positive for synaptophysin and neuron-specific enolase and, occasionally, for chromogranin (Fig. 9.5). Up to 30% of cases may be positive for CAM 5.2. However, ONEs are uniformly negative for epithelial membrane antigen, muscle markers, and CD 99 (MIC-2). Elongated cells often observed at the periphery of the lobules, so-called sus-tentacular cells, are positive for S-100 protein and glial fibrillary acidic protein (Fig. 9.6, Tables 9.4 and 9.5). 

The tumors are positive for synaptophysin, chromogranin, and neuron-specific enolase and may express a variety of hormones (growth hormone, prolactin, TSH, ACTH, and FSH). A few are hormone negative and are designated as null-cell adenomas. Almost all are positive for CAM 5.2, either focally or diffusely, and about half are positive for AE 1/3. They are negative for cytokeratin 7, 19, and 20, as well as S-100 protein. Pituitary transcription factor-1 is selectively expressed in tumors that express growth hormone, prolactin, and TSH. No diagnostic molecular markers are currently in use for sporadic pituitary lesions. ... 

These three neuroendocrine tumors of the larynx all display positivity for typical neuroendocrine markers such as chromogranin, synaptophysin, and neuron-specific enolase. They may also be positive for carcinoembryonic antigen (CEA) or epithelial membrane antigen (EMA). Atypical carcinoid and SCNEC can also express other neuroendocrine markers such as serotonin, calcitonin, and somatostatin. TTE-1 is probably not a useful marker to distinguish metastatic pulmonary small cell carcinoma from primary tumors in the head and neck because up to 50% of extrapulmonary small cell carcinomas are positive for TTR-l.i 8... 

FIGURE 10.4 Distribution of markers in pituitary adenomas. CHR-A, chromogranin A KER (CAMS.2), keratins detected with monoclonal antibody CAMS.2 SYNAP, synaptophysin NSE, neuron-specific enolase KER (AE1/AE3), keratins detected with antibodies AE1 and AE3 HBME-1 CK7, cytokeratin 7 CK19, cytokeratin 19 CFAP, glial fibrillary acid protein. 

FIGURE 10.38 Distribution of markers in pancreatic endocrine tumors. SYN, synaptophysin NSE, neuron-specific enolase LMWCK, low-molecular-weight cytokeratin CgA, chromogranin A PC2, pro-convertase 2 PCM, peptidylglycine alpha-amidating enzyme PC3, proconvertase 3 NFP, neurofilament protein HCC(a), human chorionic gonadotropin alpha VIM, vimentin. 

A. Zero of 10 squamous carcinomas, 4 of 26 adenocarcinomas, and 0 of 11 large cell undifferentiated carcinomas showed immunostaining for Leu7. Six of 10 squamous carcinomas, 15 of 26 adenocarcinomas, and 7 of 11 large cell undifferentiated carcinomas showed immunostaining for neuron-specific enolase. Six of 10 squamous carcinomas, 16 of 26 adenocarcinomas, and 7 of 11 large cell undifferentiated carcinomas showed immunostaining for synaptophysin. Overall, 34 of 47 (79%) carcinomas without neuroendocrine features expressed at least one neuroendocrine immunohistochemical marker. Nineteen of 19 (100%) of neuroendocrine carcinomas expressed at least one neuroendocrine marker. 

The bottom line for pathologists is that lung neoplasms that are not classified by histologic criteria as being a neuroendocrine neoplasm may express neuroendocrine markers by immunohistochemistry. A summary of these studies showing the frequency of expression of chromogranin A, synaptophysin, neuron-specific enolase, and Leu7 is shown in Fig. 12.41. 

Detection of the latter three markers, alone or in combination, provides for the reliable identification of PNSTs if all myogenous and epithelial determinants are concurrently absent. In particular, neurilemmoma essentially always shows diffuse and intense reactivity for S-100 protein, but neurofibromas are more heterogeneous immunohistologically. Other determinants also have been detected in selected PNSTs including glial fibrillary acidic protein, neuron-specific enolase, and nerve growth factor receptor. 

Nash SV, Said JW. Gastroenteropancreatic neuroendocrine tumors. A histochemical and immunohistochemical study of epithelial (keratin proteins, carcinoembryonic antigen) and neuroendocrine (neuron-specific enolase, bombesin and chromo-granin) markers in foregut, midgut, and hindgut tumors. Am J Clin Pathol. 1986 86 415-422. 

The immunohistochemical demonstration of the specific endocrine cell peptides allows the classification of the pancreatic endocrine neoplasms (PENs). However, it is not always possible to demonstrate these in PENs. Therefore it is of diagnostic importance to use broad-spectrum endocrine cell markers for the general identification of the endocrine nature of islet cells and PENs. These protein markers, localized in the secretory granules in the cytosol or in the cellular membrane, are present in most (rarely in all) normal and neoplastic endocrine cells. The markers most commonly used in routine histopathology have been the secretory granule proteins chromogranin and synaptophysin and the cytosolic enzyme neuron-specific enolase (NSE). Of these, chromogranin is the most specific but its sensitivity is about 80% to 90% (Fig. 15.2). 

Kosmahl M, Wagner J, Peters K, et ak Serous cystic neoplasms of the pancreas an immunohistochemical analysis revealing al-pha-inhibin, neuron-specific enolase, and MUC6 as new markers. Am J Surg Pathol. 2004 28 339-346. 

Inhibin A is also a sensitive marker of Sertoli cell differentiation (>90% positive). Sertoli cell tumor including its large cell calcifying variant stains variably positive with antibodies to vimentin, cytokeratin, S-100, synaptophy-sin, chromogranin, and neuron-specific enolase. Cytokeratin immunoreactivity in Sertoli cell tumors is usually stronger than that seen in Leydig cell tumors. Immunoreactivity for FLAP is not seen in Sertoli cell tumors. 

Although NB has a neuronal phenotype, it does not have a specific immunohistochemical profile. Neuroblasts are reactive for a variety of markers that characterize neuronal differentiation including neuron-specific enolase (Fig.17.2), CD57, CD56, protein gene product... 

Neuroblastic tumors express neuronal markers of varying sensitivity and specificity neuron-specific enolase, leu-7, protein gene product 9.5, synaptophysin, chromogranin, and other markers. 

DSRCT has a distinctive immunohistochemical profile with coexpression of epithelial and mesenchymal markers. Vimentin, cytokeratin, epithelial membrane antigen, desmin, neuron-specific enolase, and WTl reactivity are characteristic. The immunohistochemical profile compiled from seven published series is shown in Figure 17.20.Nearly all cases express vimentin (Fig. 17.21), and both keratin (Fig. 17.22) and epithelial membrane antigen (Fig. 17.23) are expressed... 

Immunohistochemistry is an invaluable adjunct technique because of the potential for many different neoplasms to display a rhabdoid appearance. Figure 17.27 shows an immunohistogram of the most frequently found markers in MRT, compiled from four series. 793,i97,200 MRT is typically a polyphenotypic neoplasm with coexpression of vimentin (Fig. 17.28) at least one epithelial marker such as cytokeratin (Fig. 17.29) or epithelial membrane antigen (Fig. 17.30) neuroectodermal markers such as neuron-specific enolase, synaptophysin... 

While neuron-specific enolase (NSE) has been described as a marker of neuronal tumors in reviews and texts, this author finds that it has better uses than this. The shortcoming for neuronal tumors is its propensity to also stain glial tumors, which commonly need to be distinguished from neuronal tumors. 7 Experimental IFIC stains such as Neu-N identify neurons by showing their on-target nuclear features rather than their cytoplasmic or confusing surface features. " 425 cases refractory to immu-nohistochemical stains, electron microscopy positively identifies Nissl substance, neurofilaments, neurosecretory granules, and synapses in neoplastic cells. 

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