Expression of novel neuroendocrine marker insulinoma-associated protein 1 (INSM1) in genitourinary high-grade neuroendocrine carcinomas: An immunohistochemical study with specificity analysis and comparison to chromogranin, synaptophysin, and CD56.

Confirmation of genitourinary high-grade neuroendocrine carcinomas (GU-HGNECs) often requires immunohistochemical staining. Here we evaluated a novel neuroendocrine marker, insulinoma-associated protein 1 (INSM1), in GU-HGNECs with comparison to chromogranin, synaptophysin and CD56. Immunohistochemical expression of INSM1, chromogranin, synaptophysin, and CD56 was evaluated in 39 GU-HGNECs using full tissue sections [4 in kidney, 28 in urinary bladder, and 7 in prostate; 31 small cell carcinomas (SmCCs), 6 large cell neuroendocrine carcinomas (LCNECs), 2 mixed SmCC-LCNECs]. In 33 SmCCs/components, INSM1 showed similar sensitivity (93.9 %) to chromogranin (87.8 %), synaptophysin (93.9 %) and CD56 (87.8 %), and stained a similar percentage of tumor cells (52 %) to chromogranin (49 %) and CD56 (52 %), but lower than synaptophysin (87 %) (p < 0.0001). In 8 LCNECs/components, INSM1 is similar to chromogranin, synaptophysin or CD56 in sensitivity (62.5 %, 62.5 %, 75 %, 62.5 %, respectively) and the mean percentage of positively stained tumor cells (21 %, 44 %, 48 %, 37 %, respectively). INSM1 is more sensitive for SmCCs than LCNECs (93.9 % vs. 62.5 %, p = 0.015). INSM1 showed 97.4 % specificity upon analyzing 273 genitourinary non-neuroendocrine tumors on tissue microarrays. Our study indicates that INSM1 is a sensitive marker for genitourinary HGNECs with high specificity. For genitourinary SmCCs, INSM1 shows similar sensitivity to chromogranin, synaptophysin and CD56 but stains a lower percentage of tumor cells than synaptophysin. For genitourinary LCNECs, INSM1 showed similar sensitivity to chromogranin, synaptophysin and CD56. INSM1 is more sensitive for genitourinary SmCCs than LCNECs. Our result and literature review indicate that whether INSM1 is more sensitive than conventional neuroendocrine markers for HGNECs depends on the tumor primary sites.

GNAS gene is an important regulator of insulin secretory capacity in pancreatic ß-cells.

BACKGROUND: Type 2 diabetes (T2D) is a complex polygenic disease with unclear mechanism. In an attempt to identify novel genes involved in ß-cell function, we harness a bioinformatics method called Loss-of-function tool (LoFtool) gene score. METHODS: RNA-sequencing data from human islets were used to cross-reference genes within the 1st quartile of most intolerant LoFtool score with the 100th most expressed genes in human islets. Out of these genes, GNAS and EEF1A1 genes were selected for further investigation in diabetic islets, metabolic tissues along with their correlation with diabetic phenotypes. The influence of GNAS and EEF1A1 on insulin secretion and ß-cell function were validated in INS-1 cells. RESULTS: A comparatively higher expression level of GNAS and EEF1A1 was observed in human islets than fat, liver and muscle tissues. Furthermore, diabetic islets displayed a reduced expression of GNAS, but not of EEF1A, compared to non-diabetic islets. The expression of GNAS was positively correlated with insulin secretory index, GLP1R, GIPR and inversely correlated with HbA1c. Diabetic human islets displayed a reduced cAMP generation and insulin secretory capacity in response to glucose. Moreover, siRNA silencing of GNAS in INS-1 cells reduced insulin secretion, insulin content, and cAMP production. In addition, the expression of Insulin, PDX1, and MAFA was significantly down-regulated in GNAS-silenced cells. However, cell viability and apoptosis rate were unaffected. CONCLUSION: LoFtool is a powerful tool to identify genes associated with pancreatic islets dysfunction. GNAS is a crucial gene for the ß-cell insulin secretory capacity.

A reciprocal regulatory loop between TAZ/YAP and G-protein Gαs regulates Schwann cell proliferation and myelination.

Schwann cell (SC) myelination in the peripheral nervous system is essential for motor function, and uncontrolled SC proliferation occurs in cancer. Here, we show that a dual role for Hippo effectors TAZ and YAP in SC proliferation and myelination through modulating G-protein expression and interacting with SOX10, respectively. Developmentally regulated mutagenesis indicates that TAZ/YAP are critical for SC proliferation and differentiation in a stage-dependent manner. Genome-wide occupancy mapping and transcriptome profiling reveal that nuclear TAZ/YAP promote SC proliferation by activating cell cycle regulators, while targeting critical differentiation regulators in cooperation with SOX10 for myelination. We further identify that TAZ targets and represses Gnas, encoding Gαs-protein, which opposes TAZ/YAP activities to decelerate proliferation. Gnas deletion expands SC precursor pools and blocks peripheral myelination. Thus, the Hippo/TAZ/YAP and Gαs-protein feedback circuit functions as a fulcrum balancing SC proliferation and differentiation, providing insights into molecular programming of SC lineage progression and homeostasis.

Neuroendocrine markers and sustentacular cell count in benign and malignant pheochromocytomas - a comparative study.

Pheochromocytomas are rare tumours with uncertain clinical behaviour. Histological separation between benign and malignant pheochromocytomas is usually difficult. The utilization of PASS criteria (Pheochromocytoma of the Adrenal Gland Scaled Score) has not provided a solid basis for separating benign from malignant tumours. The aim of this study was to investigate immunohistochemical markers (chromogranin, synaptophysin, S-100 and Ki-67) to find out if they could provide useful diagnostic and/or prognostic data in a series of 62 pheochromocytomas (5 cases followed an aggressive clinical course). Chromogranin and synaptophysin immunoreactivity proved to be diagnostically useful, allowing, together with the absence of immunoreactivity for inhibin and melan A, an unequivocal diagnosis of pheochromocytoma. The pattern of staining did not provide, however, significant prognostic information. The mean count of sustentacular S-100 positive cells was lower in malignant than in benign pheochromocytomas but the frequent architectural variability and the haemorrhagic and cystic changes make it very difficult to achieve a precise and reproducible count in the majority of tumours. Without questioning that the occurrence of metastases and/or recurrent disease still remains the only unquestionable criterion for diagnosing a malignant pheochromocytoma, we think that the combined use of the PASS score and Ki-67 index provides useful information for diagnosing malignancy.

Dysregulated expression of secretogranin III is involved in neurotoxin-induced dopaminergic neuron apoptosis.

The neurotoxins paraquat (PQ) and dopamine (DA or 6-OHDA) cause apoptosis of dopaminergic neurons in the substantia nigra pars compacta (SNpc), reproducing an important pathological feature of Parkinson's disease (PD). Secretogranin III (SCG3), a member of the multifunctional granin family, plays a key role in neurotransmitter storage and transport and in secretory granule biogenesis, which involves the uptake of exogenous toxins and endogenous "toxins" in neuroendocrine cells. However, the molecular mechanisms of neurotoxin-induced apoptosis in dopaminergic neurons and the role of SCG3-associated signaling pathways in neuroendocrine regulation are unclear. To address this, we used PQ- and DA-induced apoptosis in SH-SY5Y human dopaminergic cells as an in vitro model to investigate the association between SCG3 expression level and apoptosis. SCG3 was highly expressed in SH-SY5Y cells, and SCG3 mRNA and protein levels were dramatically decreased after PQ treatment. Apoptosis induced by PQ is associated with caspase activation and decreased SCG3 expression, and restoration of SCG3 expression is observed after treatment with caspase inhibitors. Overexpressed SCG3 in nonneuronal cells and endogenous SCG3 in SH-SY5Y cells are cleaved into specific fragments by recombinant caspase-3 and -7, but the fragments were not detected in PQ-treated SH-SY5Y cells. Therefore, SCG3 may be involved in apoptosis signal transduction as a caspase substrate, leading to loss of its original biological functions. In addition, SCG3 may be a pivotal component of the neuroendocrine pathway and play an important role in neuronal communication and neurotransmitter release, possibly representing a new potential target in the course of PD pathogenesis.

Secretogranin III is an astrocyte granin that is overexpressed in reactive glia.

Astrocytes release peptide and nonpeptide transmitters that influence neuronal development, function, and plasticity. However, the molecular components of the astroglial secretory pathways in vivo are largely unknown. Here, we analyze in astrocytes the production, expression regulation, trafficking, and release of secretogranin III (SgIII), a member of the multifunctional granin family. We show that astroglial cells in culture synthesize and release a nonprocessed form of SgIII. In vivo studies show that many neuronal populations produce and transport SgIII. In particular, the highest SgIII expression in the cerebral cortex in vivo is present in astroglial cells. Both SgIII protein and mRNA are abundantly detected in cortical astrocytes and in Bergmann glial cells. Moreover, the levels of SgIII mRNA and protein in reactive astrocytes, induced by perforating injury increase dramatically. These results implicate SgIII in the astrocyte secretory pathway in vivo and show that its expression is finely regulated during glial activation. The robust expression of SgIII in astrocytes and its regulation in the injured brain suggest both intracellular and extracellular roles for this glial granin in the physiology and repair/damage of neuronal circuits.

Secretogranin III directs secretory vesicle biogenesis in mast cells in a manner dependent upon interaction with chromogranin A.

Mast cells are granular immunocytes that reside in the body's barrier tissues. These cells orchestrate inflammatory responses. Proinflammatory mediators are stored in granular structures within the mast cell cytosol. Control of mast cell granule exocytosis is a major therapeutic goal for allergic and inflammatory diseases. However, the proteins that control granule biogenesis and abundance in mast cells have not been elucidated. In neuroendocrine cells, whose dense core granules are strikingly similar to mast cell granules, granin proteins regulate granulogenesis. Our studies suggest that the Secretogranin III (SgIII) protein is involved in secretory granule biogenesis in mast cells. SgIII is abundant in mast cells, and is organized into vesicular structures. Our results show that over-expression of SgIII in mast cells is sufficient to cause an expansion of a granular compartment in these cells. These novel granules store inflammatory mediators that are released in response to physiological stimuli, indicating that they function as bona fide secretory vesicles. In mast cells, as in neuroendocrine cells, we show that SgIII is complexed with Chromogranin A (CgA). CgA is granulogenic when complexed with SgIII. Our data show that a novel non-granulogenic truncation mutant of SgIII (1-210) lacks the ability to interact with CgA. Thus, in mast cells, a CgA-SgIII complex may play a key role in secretory granule biogenesis. SgIII function in mast cells is unlikely to be limited to its partnership with CgA, as our interaction trap analysis suggests that SgIII has multiple binding partners, including the mast cell ion channel TRPA1.

Regional adaptations in PSD-95, NGFI-A and secretogranin gene transcripts related to vulnerability to behavioral sensitization to amphetamine in the Roman rat strains.

Genetically selected for high or low two-way active avoidance, Roman high-avoidance (RHA) and Roman low-avoidance (RLA) rats differ in their central dopaminergic activity, sensation/novelty- and substance-seeking profiles. These animals are, therefore, well suited to identify anatomical and neurochemical concomitants of behavioral sensitization, a phenomenon linked to addictive liability. We submitted inbred RHA (RHA-I), inbred RLA (RLA-I) and Sprague-Dawley-OFA (SD-OFA) rats to a sensitization regimen with amphetamine and studied the behavioral response to an amphetamine challenge after a 2-week withdrawal period. The expression patterns of nerve growth factor inducible clone A (NGFI-A), secretogranin, post-synaptic density protein of 95 Kd (PSD-95), prodynorphin and proenkephalin mRNA were also analyzed using in situ hybridization, after the challenge with amphetamine. RHA-I rats showed stronger sensitization than SD-OFA rats. RLA-I rats did not show sensitization but were hyper-reactive to amphetamine. Expression of behavioral sensitization in RHA-I rats activated secretogranin and PSD-95 mRNA in the nucleus accumbens core. On the other hand, high induction of NGFI-A mRNA in the central amygdala was observed in RLA-I rats when they experienced amphetamine for the first time in the challenge. Our results reveal that 1) the acute locomotor response to amphetamine does not predict vulnerability to behavioral sensitization and 2) differences in vulnerability to sensitization may involve distinctive cellular adaptations at particular brain locations which may be related to addictive vulnerability.

Prognostic significance of neuroendocrine expression in lymph node-positive prostate cancer.

OBJECTIVES: To evaluate the expression of chromogranin A, a marker for neuroendocrine (NE) differentiation, in patients with lymph node-positive prostate cancer to determine its prognostic significance. NE cells are involved in cellular growth and differentiation in both normal and pathologic conditions of the prostate. METHODS: We reviewed the data of 140 patients with lymph node-positive prostate adenocarcinoma treated with radical prostatectomy and pelvic lymphadenectomy. The median follow-up was 10.9 years (range 0.8 to 19.7). Immunohistochemical staining for chromogranin A was evaluated in areas of benign epithelium, primary prostate cancer, and lymph node metastasis. The association between chromogranin A expression and the clinical and pathologic factors (preoperative serum prostate-specific antigen and prostatectomy Gleason score and stage) and clinical outcomes, including overall and recurrence-free survival, was evaluated. RESULTS: Staining was positive in 86% of benign areas, 61% of primary cancer specimens, and 12% of lymph node deposits. The preoperative serum prostate-specific antigen level and pathologic stage and grade of the primary tumor did not show any statistically significant correlation with NE staining in any of the areas. Only NE expression in the primary tumor was associated with clinical recurrence, with a 10-year recurrence-free survival rate for those with less than 5% staining of 67% compared with 35% for those with 5% staining or greater (P = 0.03). Furthermore, after adjusting for age, greater NE expression in the primary tumor (relative risk 2.15, P = 0.02) and lymph node deposit (relative risk 2.03, P = 0.03) was associated with poorer overall survival. CONCLUSIONS: NE expression in the primary tumor and lymph node metastasis of patients with node-positive prostate cancer may provide additional prognostic stratification.

Utility of molecular genetic signatures in the delineation of gastric neoplasia.

BACKGROUND: Current techniques to define gastric neoplasia are limited but molecular genetic signatures can categorize tumors and provide biological rationale for predicting clinical behavior. We identified three gene signatures: Chromogranin A (CgA), MAGE-D2 (adhesion), and MTA1 (metastasis) that define gastrointestinal (GI) carcinoids and hypothesize that their expression can delineate gastric neoplasia. This strategy provides a molecular basis to define neuroendocrine gastric carcinoids (GCs), neuronal stromal tumors (GISTs), or epithelial cell (gastric adenocarcinomas [GCAs])-derived tumors. METHODS: Total RNA was isolated from 38 GCs: Type I/II (n = 7), Type III/IV (n = 6), GISTs (n = 12), GCAs (n = 13), and normal mucosa (n = 12). Quantitative reverse transcriptase polymerase chain reaction (Q RT-PCR) gene expression was quantified against glyseraldehyde-3-phosphate dehydrogenase (GAPDH) and CgA and MTA1 protein expression levels were analyzed by immunohistochemical analyses of a gastric neoplasia microarray. RESULTS: CgA was elevated in Type I/II (10-fold; P < .01) and Type III/IV (100-fold, P < .005), decreased in GISTs (100-fold, P < .03), and unchanged in GCAs. MAGE-D2 was 5-10-fold elevated (P < .05) in Type III/IV, GISTs, and GCAs but not in Type I/II tumors. MTA1 (> 5-fold, P < .01) was elevated in GCs (Type III/IV>I/II, P < .05), in GISTs (> 4-fold, P < .05), and GCAs. CgA protein levels were elevated in GCs (P < .005) but not in GISTs and GCAs. MTA1 levels were elevated in all tumors (P < .02) compared with normal, and especially with tumor invasion (P < .05). CONCLUSION: CgA discriminates GCs from other gastric neoplasms; overexpression of MAGE-D2 and MTA1 differentiate Type III/IV from Type I/II GCs. GISTs share similar expression patterns with Type III/IV GCs but have decreased CgA. MTA1 is a marker of tumor invasion.

IFN-beta is a highly potent inhibitor of gastroenteropancreatic neuroendocrine tumor cell growth in vitro.

IFN-alpha controls hormone secretion and symptoms in human gastroenteropancreatic neuroendocrine tumors (GEP-NET) but it rarely induces a measurable tumor size reduction. The effect of other type I IFNs, e.g., IFN-beta, has not been evaluated. We compared the antitumor effects of IFN-alpha and IFN-beta in BON cells, a functioning human GEP-NET cell line. As determined by quantitative reverse transcription-PCR analysis and immunocytochemistry, BON cells expressed the active type I IFN receptor mRNA and protein (IFNAR-1 and IFNAR-2c subunits). After 3 and 6 days of treatment, IFN-beta significantly inhibited BON cell growth in a time- and dose-dependent manner. IC50 and maximal inhibitory effect on day 6 were 8 IU/mL and 98%, respectively. In contrast, the effect of IFN-alpha resulted significantly in a less potent effect (IC50: 44 IU/mL, maximal inhibition: 26%). IFN-alpha induced only cell cycle arrest, with an accumulation of the cells in S phase. IFN-beta, apart from a more potent delay in S-G2-M phase transit of the cell cycle, also induced a strong stimulation of apoptosis, evaluated by flow cytometry (Annexin V and 7-AAD) and measurement of the DNA fragmentation. Besides, only IFN-beta severely suppressed chromogranin A levels in the medium from BON cells after 6 days of treatment. In conclusion, IFN-beta is much more potent, compared with IFN-alpha, in its inhibitory effect on GEP-NET cell proliferation in vitro through the induction of apoptosis and cell cycle arrest. Further studies are required to establish whether IFN-beta has comparable potent tumor growth inhibitory effects in vivo.

Proteolytic processing and differential distribution of secretogranin-II in goldfish.

Secretoneurin (SN) is a 33-34 amino acid neuropeptide derived by endoproteolysis of secretogranin-II (SgII), a chromogranin. A multi-antigenic strategy was used to generate a rabbit polyclonal goldfish SN antiserum that was characterized for Western blot analysis. In the goldfish pituitary two intermediate proteins containing SN and likely processed from the 69.6-kDa SgII precursor were detected. No immunoreactive proteins were observed in the goldfish interrenal, ovary, cerebellum, and telencephalon whereas SgII mRNA was expressed in all these tissues. Immunoreactive levels of the approximately 57 kDa product were higher in the pars distalis (PD) than in the neurointermediate lobe (NIL). The abundance of the approximately 57 kDa protein indicates that this SgII-product containing the SN sequence is a major stored form in secretory granules of the goldfish pituitary. High expression and processing of SN in the hypothalamus and pituitary suggest important roles for SgII-derived peptides in neuroendocrine tissues.

Differential expression and processing of chromogranin A and secretogranin II in relation to the secretory status of endocrine cells.

Chromogranin A (CgA) and secretogranin II (SgII) are neuroendocrine secretory proteins that participate in regulation of the secretory pathway and also serve as precursors of biologically active peptides. To investigate whether there is a relationship between the expression, distribution, and processing of CgA and SgII and the degree of secretory activity, we employed two melanotrope subpopulations of the pituitary intermediate lobe that exhibit opposite secretory phenotypes. Thus, although one of the melanotrope subtypes shows high secretory activity, the other exhibits characteristics of a hormone storage phenotype. Our data show that SgII expression levels were higher in secretory melanotropes, whereas CgA expression showed similar rates in both cell subsets. The use of various antibodies revealed the presence of the unprocessed proteins as well as three CgA-derived peptides (67, 45, and 30 kDa) and six SgII-derived peptides (81, 66, 55, 37, 32, and 30 kDa) in both subpopulations. However, the smallest molecular forms of both granins predominated in secretory melanotropes, whereas the largest SgII- and CgA-immunoreactive peptides were more abundant in storage melanotropes, which is suggestive of a more extensive processing of granins in the secretory subset. Confocal microscopy studies showed that CgA immunoreactivity was higher in storage cells, but SgII immunoreactivity was higher in secretory melanotropes. Taken together, our results indicate that SgII and CgA are differentially regulated in melanotrope subpopulations. Thus, SgII expression is strongly related to the secretory activity of melanotrope cells, whereas CgA expression may not be related to secretory rate, but, rather, to hormone storage in this endocrine cell type.

Chromogranin A expression in familial versus sporadic prostate cancer.

OBJECTIVES: To evaluate whether a significant difference in chromogranin A (CgA) levels exist between patients with familial and sporadic cancer. METHODS: The study included 146 patients with clinically localized prostate adenocarcinoma (Stage T2N0M0), who underwent radical prostatectomy between June 1999 and June 2004. Patients were considered to have a positive family history for prostate cancer when the index patient confirmed the diagnosis of prostate cancer in a first-degree relative (brother or father). On the day of surgery, a blood sample for the determination of serum prostate-specific antigen and CgA levels (radioimmunoassay) was obtained from all patients. In a subgroup of 20 patients, CgA mRNA expression was also evaluated by reverse transcriptase-polymerase chain reaction at the prostatic tissue level. RESULTS: A positive familial history was found in 28 (19.2%) of the 146 patients. The mean patient age in the familial group was significantly (P < 0.0001) lower than that in the sporadic group. No significant difference between the familial and sporadic groups was found in terms of prostate-specific antigen level (P = 0.9625) or Gleason score distribution (P = 0.4891). The familial group had significantly (P = 0.0013) lower serum CgA levels (43.3 +/- 12.7 ng/mL, median 39.9) compared with the sporadic group (55.9 +/- 19.4 ng/mL, median 54.1). The familial group also had significantly (P = 0.0432) lower expression of tissue CgA mRNA compared with the sporadic group. CONCLUSIONS: The result of significantly lower CgA expression in familial compared with sporadic prostate cancer cases suggests that neuroendocrine activity is not increased in familial cases and also confirms that familial cancer is not a more aggressive disease.

Immunohistochemical expressions of cytokeratins, mucin core proteins, p53, and neuroendocrine cell markers in epithelial neoplasm of appendix.

Epithelial neoplasms of appendix are infrequent, and their pathological features are not fully characterized. We collected 33 cases of appendiceal tumors and examined immunohistochemically the expression of cytokeratins (CK, CK7, and CK20), mucin core protein (MUC1, MUC2, MUC5AC, and MUC6), E-cadherin, chromogranin A, and p53 protein. Gene analysis of TP53 was also conducted on exons 5 to 8. Clinically, mucinous tumors were predominant in females. Immunohistochemically, all the tumors expressed CK20, whereas CK7 was positive in one third of the cases. Similarly, MUC2 was expressed in all the tumors, whereas MUC1 and MUC5AC were detected in about a half of the cases. Although chromogranin A-positive cells are generally sparse in normal appendix, they were more common in mucinous tumors than in nonmucinous tumors. Contrary to the previous data reported (Mod Pathol 2002;15:599-605), mucinous carcinoma exhibited a higher frequency of p53-positive cells (mean 29%) compared with mucinous adenoma (2.8%) (P < .001), whereas nonmucinous tumors showed high levels of p53-positive cells to similar extent (51%-67%) in both adenoma and carcinoma. The high expression of p53 protein coincided with the presence of mutations in multiple sites of TP53 gene in mucinous tumors. This is the first report that characterized the immunophenotypic profile of appendiceal epithelial neoplasms with an emphasis of a higher frequency of p53 positivity in mucinous carcinoma cases compared with mucinous adenoma in the appendix.

Multimodality treatment of neuroendocrine tumors of the thymus.

BACKGROUND: Neuroendocrine tumors of the thymus are rare neoplasms. Four patients with this tumor who underwent multimodality treatment are presented and the literature is briefly reviewed. METHODS: The medical records of all patients treated for neuroendocrine tumors of the thymus from 1979 to 2002 were reviewed. Tumors were classified using a slight modification of the World Health Organization criteria. RESULTS: The patients' median age was 38 years. All patients underwent extensive excision of the tumor. Histological diagnosis was atypical carcinoid (2), typical carcinoid (1), and small cell carcinoma (1). All patients developed recurrence(s). One patient died 132 months after diagnosis. The remaining three patients are alive with no symptoms at 135, 99, and 35 months, respectively, after diagnosis. Two patients with recurrences have been on treatment with Octreotide LAR with satisfactory results. One patient is free of disease. CONCLUSIONS: Neuroendocrine tumors of the thymus are potentially aggressive tumors. Radical resection is the treatment of choice. The encouraging results obtained by administration of Octreotide LAR in two of our patients warrant further investigation.

[The prognostic value of human neuroendocrine clone on colorectal carcinoma].

OBJECTIVE: To demonstrate the prognostic value of neuroendocrine clone on colorectal carcinoma. METHODS: The immunochemistry methods were used to investigate the percent of neuroendocrine carcinoma in 73 human colorectal carcinoma. Retrospective analysis and follow-up were carried out in all patients. RESULTS: In all 73 cases of colorectal carcinoma, the total percentage of neuroendocrine carcinoma was 17.8%. Neuroendocrine carcinoma included 11 synapse positive, 6 chromogranin positive and 4 both positive. The major factors related to the prevalence of neuroendocrine carcinoma were sex, age, tumor location and Dukes' stage. And the 1-year survival rate of the patients who suffered from neuroendocrine carcinoma is obviously lower than that of other colorectal carcinoma. CONCLUSIONS: The neuroendocrine carcinoma is a special kind of human colorectal carcinoma, and neuroendocrine clone may be a new marker of the malignant potency. The neuroendocrine clone has its prognostic value and may be a novel therapeutic target.

Neuroendocrine differentiation in primary Merkel cell carcinoma--possible prognostic significance.

BACKGROUND: The aim of this study was to examine the level of neuroendocrine differentiation to determine its association with clinicopathological parameters. PATIENTS AND METHODS: Twenty-five primary MCC samples were evaluated for neuroendocrine differentiation profiles by immunohistochemistry using antibodies to chromogranin-A, microtubule associated protein-2 and synaptophysin. The data were compared with clinical parameters to find out whether their expression correlates with prognosis. RESULTS: In general, MCC shows a high degree of neuroendocrine differentiation. A higher expression of chromogranin-A and synaptophysin associated with benign behaviour. Chromogranin-A appeared to be the most important one in predicting the course of disease. CONCLUSION: Low levels of neuroendocrine differentiation in MCC associates with poor prognosis. Chromogranin-A could be used to identify patients who might benefit from oncological treatments.

Expression of adhesion molecules and cytokeratin 20 in merkel cell carcinomas.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin. MCCs often show characteristic paranuclear dot-like immunopositivity for cytokeratin 20 (CK20), a globular aggregation of CK20 intermediate filaments. These aggregates typically form rhabdoid features and fibrous bodies and may be associated with a down-regulation in adhesion molecules (AMs). To date, the relationship between the expression of AMs and CK20 and clinicopathological findings in MCC has not been well examined. In this immunohistochemical study, we assessed the expression of AMs, CK20, and chromogranin A (CgA) on MCCs in 8 men and 23 women with this disease, and also characterized their clinicopathological features. This study is the largest of its kind that has been undertaken to date in Japanese patients. Compared to normal tissue, E-cadherin and alpha- and beta-catenins showed reduced membranous expression in 95.7%, 46.7%, and 45.2% of MCCs, respectively. Nuclear E-cadherin localization was seen in four tumors, all of which predominantly showed a CK20 dot pattern. However, there was no significant relationship between the membranous expression of AMs and a CK20 dot pattern. E-cadherin expression was significantly lower in tumors of > or =2 cm, and tumors negative for E-cadherin more frequently developed outside of the head and neck than within those regions. CgA was more intensely expressed in tumors with uniform nuclei and a dense lymphocytic infiltrate than in those that showed pleomorphisms and that had few, if any, infiltrating lymphocytes. These findings suggest that MCCs have a reduced expression of AMs and that down-regulation of E-cadherin expression may correlate with increased tumor aggressiveness. The fact that no significant relationship was demonstrable between the membranous expression of AMs and the CK20 expression pattern suggests that the mechanism of aggregation of intermediate filaments may be different in different types of tumors.