Significance of chromogranin A and synaptophysin in medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) is a relatively rare thyroid carcinoma of C-cell deviation and produces and secrete calcitonin (CT) and chromogranin A (CgA) into the blood. Thus, both CT and CgA are immunohistochemical and serum markers for MTCs. MTC occurs in both sporadic and inheritable cases and the hallmark of inheritable cases in multiple endocrine neoplasm 2 (NEN2) is MTC. MEN2 cases represent 30% of MTCs through germline RET protooncogene mutation and occur in younger ages involving bilateral thyroid lobes. Sporadic cases are 70% of cases of solitary tumor and occur in older ages. CgA and synaptophysin (SPY) are the two, most widely used and reliable immunohistochemical markers for neuroendocrine tumors including MTCs. This study aimed to detect different immunohistochemical staining patterns for CgA and SPY between non-symptomatic small, microscopic lesions and invading larger aggressive tumors in both MEA2 cases and sporadic cases. There was different CgA and SPY immunostaining in MEA2 cases where small tumors (≤ 0.3 cm) were lesser immunostained for CgA and SPY, despite strong staining for CT, compared to the larger (≥ 0.5cm) tumors, stronger immunostained for CgA. There was also different CgA and SPY immunohistochemical staining in sporadic cases between small lesion (≤ 0.5 cm) and larger tumors (≥ 1.0cm). One small sporadic tumor (0.5 x 0.3 cm) was strongly and weakly, patchy (about 10% of tumor tissue) stained for CgA and SPY, respectively, while larger sporadic tumors were diffusely, stronger stained for CgA and SPY. Therefore, stronger CgA and SPY immunostaining for larger tumors in both MEA2 and sporadic cases may be used as independent aggressive immunohistochemical markers for MTCs.

Chromogranin A Expression in Rectal Neuroendocrine Tumors Is Associated With More Aggressive Clinical Behavior and a Poorer Prognosis.

Although rectal neuroendocrine tumors (NETs) with an L-cell phenotype and small size are generally less clinically serious, the new 2019 World Health Organization (WHO) classification system has categorized all of these lesions as malignant. Identifying biomarkers of rectal NETs is thus important for stratifying their clinical behavior. Chromogranin A protein expression was assessed in 538 endoscopically or surgically resected rectal NETs and compared with clinicopathologic factors to identify its clinical and prognostic significance. All of the rectal NETs analyzed (100%) were synaptophysin positive, but chromogranin A labeling was only detected in 111 cases (20.6%). Chromogranin A expression in the rectal NETs was more commonly associated with older age (50 y and older; P=0.013), male sex (P=0.002), radical resection (P=0.003), large tumor size (≥1 cm; P=0.038), muscularis propria invasion (P=0.002), lymphovascular (P=0.014) and perineural (P<0.001) invasion, an involved resection margin (P=0.028), and lymph node metastasis (P=0.003). Patients with chromogranin A expression had higher plasma chromogranin A levels (P=0.023) than those without chromogranin A expression during follow-up. The 10-year disease-free survival rate in rectal NET patients with chromogranin A expression (91.5%) was significantly shorter than the negative cases (99.7%) by both univariate (hazard ratio=14.438; 95% confidence interval: 2.911-71.598; P<0.001) and multivariate (hazard ratio=12.099; 95% confidence interval, 2.044-71.608; P=0.006) analyses. In summary, rectal NETs that are positive for chromogranin A are less common than those with synaptophysin expression and show more aggressive clinical behavior. Chromogranin A is therefore a prognostic indicator of higher recurrence risk in patients with endoscopically or surgically resected rectal NETs.

Morphologic Spectrum of Neuroendocrine Tumors of the Prostate: An Updated Review.

CONTEXT.­: The incidence of neuroendocrine tumors of the prostate increases after hormonal therapy. Neuroendocrine tumors possess a broad spectrum of morphologic features and pose challenges in the pathologic diagnosis and clinical management of patients. OBJECTIVE.­: To present a brief updated summary of neuroendocrine tumors of the prostate with an overview of their histopathologic and immunohistochemical profiles and differential diagnoses. DATA SOURCES.­: Literature review, personal experience in the daily practice of pathologic diagnosis, and laboratory research. CONCLUSIONS.­: Our understanding of neuroendocrine tumors of the prostate classification and diagnosis continues to evolve. These advances benefit the risk stratification and management of prostate cancer.

Insulinoma-associated Protein 1 (INSM1) in Thoracic Tumors is Less Sensitive but More Specific Compared With Synaptophysin, Chromogranin A, and CD56.

OBJECTIVE: Recognition of neuroendocrine differentiation is important for tumor classification and treatment stratification. To detect and confirm neuroendocrine differentiation, a combination of morphology and immunohistochemistry is often required. In this regard, synaptophysin, chromogranin A, and CD56 are established immunohistochemical markers. Insulinoma-associated protein 1 (INSM1) has been suggested as a novel stand-alone marker with the potential to replace the current standard panel. In this study, we compared the sensitivity and specificity of INSM1 and established markers. MATERIALS AND METHODS: A cohort of 493 lung tumors including 112 typical, 39 atypical carcinoids, 77 large cell neuroendocrine carcinomas, 144 small cell lung cancers, 30 thoracic paragangliomas, 47 adenocarcinomas, and 44 squamous cell carcinomas were selected and tissue microarrays were constructed. Synaptophysin, chromogranin A, CD56, and INSM1 were stained on all cases and evaluated manually as well as with an analysis software. Positivity was defined as ≥1% stained tumor cells in at least 1 of 2 cores per patient. RESULTS: INSM1 was positive in 305 of 402 tumors with expected neuroendocrine differentiation (typical and atypical carcinoids, large cell neuroendocrine carcinomas, small cell lung cancers, and paraganglioma; sensitivity: 76%). INSM1 was negative in all but 1 of 91 analyzed non-neuroendocrine tumors (adenocarcinomas, squamous cell carcinomas; specificity: 99%). All conventional markers, as well as their combination, had a higher sensitivity (97%) and a lower specificity (78%) for neuroendocrine differentiation compared with INSM1. CONCLUSIONS: Although INSM1 might be a meaningful adjunct in the differential diagnosis of neuroendocrine neoplasias, a general uncritical vote for replacing the traditional markers by INSM1 may not be justified.

Childhood adrenocortical tumor: A clinical and immunohistochemical study of 13 cases.

The aim of the study was to investigate the molecular mechanisms in childhood adrenocortical tumors (ACTs), which is still unclear.A total of 9 girls and 4 boys with ACTs were enrolled. Relevant clinical features were obtained from records. Immunohistochemistry of vimentin, chromogranin A, S100, synaptophysin, cytokeratin (CK), type 2 3ß-hydroxysteroid dehydrogenase (3ßHSD), cytochrome P45017α, p53, p21, p27, cyclin D1, Ki-67, insulin growth facter-2 (IGF-2), and ß-catenin were undertaken for 13 tumors and 3 adjacent normal tissues. TP53 mutations in exon 2-11 were analyzed for 6 tumors and 3 blood samples.Virilization was the most common presentation (8/13, 61.5%). Immunohistochemically, p53 was positive in 8 of 13 ACTs and none in controls while p21 was positive in 12 of 13 ACTs and none in controls (P = .0036). Ki-67 was positive in 10 of 13 ACTs, but not in normal tissues (P = .0089). Although the expression of p27, cyclin D1, IGF-2 and ß-catenin were similar between the ACTs and controls, ß-catenin was noted in nuclear of 3 ACTs but not in controls. The difference of type 2 3ßHSD and P450c17α was not significant (P > .05, respectively). Four variants of TP53 were identified in the 6 tumors. C215G variant was found in 5 of 6 while A701G and G743A variants were found in 1 case, respectively. A novel C680G variant was also noted in 1 case. It was notable that C215G variant was found in the blood mononuclear cell of 3 patients.In conclusion, p53 variant and p21 overexpression, and abnormal ß-catenin distribution may be involved in the etiology and mechanism of childhood ACTs.

Immunohistochemical expression patterns of S100, synaptophysin, chromogranin A and neuron specific enolase in predicting malignant behaviour in paragangliomas.

PURPOSE: The purpose of this study was to evaluate the role of immunohistochemical markers in the prediction of malignancy in paragangliomas. METHODS: Our institute's patient records between 1990-2012 were retrieved in order to identify patients who were treated for paragangliomas. Size and location of the tumour, existence of concurrent metastatic disease, patient demographics and survival were recorded. Haematoxylin-eosin stained slides were reviewed and all tumours were stained specifically for neuron specific enolase (NSE), chromogranin, synaptophysin and S100 protein positivity. Positivity and expression patterns of the above markers were evaluated and compared between malignant and benign tumours. Malignant behaviour was defined when patient had concurrent or subsequent lymph node involvement, local recurrence and/or metastases. RESULTS: A total of 22 patients with a diagnosis of paraganglioma were treated in our institutes. Female to male ratio was 1.75: 1. The mean age was 43.5 and 51.6 years for women and men, respectively. In 5 patients the tumors had malignant clinical behavior. Their mean size was 3.65 cm for benign and 4.56 cm for malignant neoplasms. NSE expression was diffuse in 47.1% and 0% for benign and malignant tumors, respectively (p=0.10). S100 expression in the periphery of the tumour was typical in 88.2% and 0% for benign and malignant tumors, respectively (p<0.001). CONCLUSION: Immunohistochemical profile from the combination of NSE, synaptophysin chromogranin and S100 staining patterns can serve as a cheap and valuable tool for correctly distinguishing between malignant and benign paragangliomas with high diagnostic accuracy.

Expression of neuroendocrine differentiation markers in lethal metastatic castration-resistant prostate cancer.

Neuroendocrine differentiation (NED) is a common phenomenon in prostate cancer, and it has been associated with poor prognosis in some studies of primary prostate cancer. Incidence and patterns of NED in metastatic prostate cancer sites have not been examined widely. In this study, we studied expression of three commonly used markers of NED (chromogranin A, neuron specific enolase and synaptophysin) in 89 metastases from 31 men that died of castration-resistant prostate cancer and underwent rapid autopsy, and in 89 hormone-naïve primary tumors removed by radical prostatectomy. In addition, we examined NED association with androgen receptor, ERG and Ki-67 expression in metastatic tumor sites. Morphologically, 1 of 31 cases was classified as small cell carcinoma, and the remaining 30 were classified as usual prostate adenocarcinoma using a recently proposed classification of prostate cancers with NED. Metastases showed more expression of neuron specific enolase and synaptophysin compared to prostatectomies (6.3% of cells vs. 1.0%, p < 0.001 and 4.0% vs. 0.4%, p < 0.001, respectively). At least focal expression of one of the markers was seen in 78% of metastases. Strong expression was relatively uncommon, seen in 3/89 (chromogranin A), 8/89 (neuron specific enolase), and 5/89 (synaptophysin) metastases. Expression of chromogranin A and synaptophysin correlated with each other (r = 0.64, p < 0.001), but expression of neuron specific enolase did not correlate with the two other markers. Extent of NED varied significantly between different metastatic sites in individual patients. Absent androgen receptor expression was associated with strong expression of chromogranin A (p = .02) and neuron specific enolase (p = .02), but not with focal expression of any marker. No clear association was found between expression of NE markers and ERG or Ki-67. In conclusion, NED is a common and heterogeneous phenomenon in metastatic, castration-resistant prostate cancer. NED is more often present in castration-resistant prostate cancer compared to hormone-naïve disease, and it is associated with androgen receptor negativity. More research is needed to understand significance of NED in the progression of prostate cancer.

Netazepide, a gastrin/cholecystokinin-2 receptor antagonist, can eradicate gastric neuroendocrine tumours in patients with autoimmune chronic atrophic gastritis.

AIMS: Netazepide, a gastrin/cholecystokinin 2 receptor antagonist, once daily for 12 weeks reduced the number of tumours and size of the largest one in 16 patients with autoimmune chronic atrophic gastritis (CAG), achlorhydria, hypergastrinaemia and multiple gastric neuroendocrine tumours (type 1 gastric NETs), and normalized circulating chromogranin A (CgA) produced by enterochromaffin-like cells, the source of the tumours. The aim was to assess whether longer-term netazepide treatment can eradicate type 1 gastric NETs. METHODS: After a mean 14 months off netazepide, 13 of the 16 patients took it for another 52 weeks. Assessments were: gastroscopy; gene-transcript expression in corpus biopsies using quantitative polymerase chain reaction; blood CgA and gastrin concentrations; and safety assessments. RESULTS: While off-treatment, the number of tumours, the size of the largest one, and CgA all increased again. Netazepide for 52 weeks: cleared all tumours in 5 patients; cleared all but one tumour in one patient; reduced the number of tumours and size of the largest one in the other patients; normalized CgA in all patients; and reduced mRNA abundances of CgA and histidine decarboxylase in biopsies. Gastrin did not increase further, confirming that the patients had achlorhydria. Netazepide was safe and well tolerated. CONCLUSIONS: A gastrin/cholecystokinin 2 receptor antagonist is a potential medical and targeted treatment for type 1 gastric NETs, and an alternative to regular gastroscopy or surgery. Treatment should be continuous because the tumours will regrow if it is stopped. Progress can be monitored by CgA in blood or biomarkers in mucosal biopsies.

Tissue Chromogranin A Expression during Prostate Cancer Progression: Prediction of Chemosensitivity.

PURPOSE: We investigated the clinical significance of chromogranin A (CgA) expression as a neuroendocrine (NE) marker during prostate cancer (PCa) progression, especially as a potential predictor of chemotherapeutic response in castration-resistant PCa (CRPC) patients based on immunohistochemical findings. MATERIALS AND METHODS: Sixteen CRPC patients who underwent combination (docetaxel/estramustine/ carboplatin; DEC) chemotherapy were retrospectively studied. Immunostaining of CgA was performed using prostate biopsy samples obtained at the initial PCa diagnosis, during androgen deprivation therapy, at the time of CRPC diagnosis, and after 2 cycles of DEC therapy. The positive rate was expressed as the mean percentage of positively stained tumor cells against the total number of tumor cells. Differences in positive rates among the treatment courses were compared using a Mann-Whitney test. RESULTS: The mean percentage of CgA-positive PCa cells increased in a stepwise manner until CRPC development and then significantly decreased after DEC therapy. Subanalysis of CgA at CRPC diagnosis showed a more evident reduction of CgA expression after DEC therapy in patients who also had a high level of CgA as compared to those with a low CgA level (P = .003). Likewise, longer prostate-specific antigen progression-free survival was related to CRPC and high CgA (P = .028). CONCLUSION: NE differentiation of PCa cells is accelerated despite androgen deprivation and reaches a peak at the time of CRPC diagnosis. Although further studies using larger samples are needed, CgA expression in CRPC may be a candidate tissue biomarker to reflect the chemotherapy sensitivity of individual PCa cells.

[The role of chromogranin-A and its derived peptide, WE-14 in the development of type 1 diabetes mellitus]. / A kromogranin-A és a belole lehasadó WE-14 szerepe az 1-es típusú cukorbetegség kialakulásában.

Chromogranin-A is a member of the granine protein family. It is produced in neuroendocrine cells via secretory granules. Many cleavage proteins are formed from chromogranin-A, from which some have well known biological activity, while the function of others is not yet fully known. Serum chromogranin-A levels are used in neuroendocrine tumour diagnostics. Recent studies showed that one of its cleavage protein, WE-14 may also play a role in the development of type 1 diabetes. WE-14 may function as an autoantigen for T-cells involved in the destruction of ß-cells. This mechanism was previously observed only in non-obese diabetic mice. Novel results show that WE-14 also serves as a target for autoreactive cells in newly diagnosed type 1 diabetic patients as well, which reaction can be increased with transglutaminase. In this paper the authors summarize the recent knowledge about chromogranin-A and its potential role in the pathomechanism of type 1 diabetes mellitus.

Mixed medullary-papillary carcinoma of the thyroid: report of two cases and review of the literature.

Papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC) are two distinct types of thyroid carcinoma with considerable difference in terms of cellular origin, histopathological appearance, clinical course and prevalence. The histogenetic origin and possible molecular mechanisms responsible for the development of mixed medullary-papillary carcinoma of the thyroid are still unclear. The most widely accepted hypotheses considering co-occurrence of MTC and PTC are stem cell theory, collision effect theory and hostage theory. Herein we describe two rare cases of mixed medullary-papillary thyroid carcinoma with co-occurrence of MTC and PTC which developed with concomitant MEN 2A and different sites of lymph node metastasis in the first patient, while with atypical clinical presentation in the second patient. In conclusion, co-expression of thyroglobulin, synaptophysin and chromogranin by the papillary component of mixed tumor seems to support stem cell theory in our first case, whereas positive staining for calcitonin but not for thyroglobulin in the medullary component of the tumor along with separation of these two tumors from each other by a normal thyroid tissue seem to indicates the likelihood of collision effect theory in our second case.

Increased chromogranin A and neuron-specific enolase in rats with chronic nonbacterial prostatitis induced by 17-beta estradiol combined with castration.

Although chronic nonbacterial prostatitis (CNBP) is a common diagnosis in middle-aged men, the etiology of this disease remains poorly understood. Neuroendocrine cells play an important role in the neuroendocrine regulation of the prostate, and chromogranin A (CgA) and neuron-specific enolase (NSE) are regarded as classic markers of neuroendocrine cells. This study aimed to determine CgA and NSE levels in a CNBP rat model to evaluate the role of neuroendocrine cells in the pathogenesis of CNBP. For developing a CNBP rat model, we examined the ability of 17-beta estradiol and surgical castration alone or in combination to induce CNBP. Histologic inflammation of the prostate was assessed in CNBP-induced rats by hematoxylin-eosin staining, whereas CgA and NSE protein levels were assessed by immunohistochemistry, Western blot analysis, and enzyme-linked immunosorbent assays. Our results showed that 17-beta estradiol combined with castration successfully induced CNBP and that CgA and NSE levels were increased in the prostate of CNBP rats as compared to those without CNBP. These findings indicate that the neuroendocrine regulation mediated by neuroendocrine cells may be involved in the pathogenesis of CNBP.

Expression of neuroendocrine markers in different molecular subtypes of breast carcinoma.

BACKGROUND: Carcinomas of the breast with neuroendocrine features are incorporated in the World Health Organization classification since 2003 and include well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine carcinomas/small cell carcinomas, and invasive breast carcinomas with neuroendocrine differentiation. Neuroendocrine differentiation is known to be more common in certain low-grade histologic special types and has been shown to mainly cluster to the molecular (intrinsic) luminal A subtype. METHODS: We analyzed the frequency of neuroendocrine differentiation in different molecular subtypes of breast carcinomas of no histologic special type using immunohistochemical stains with specific neuroendocrine markers (chromogranin A and synaptophysin). RESULTS: We found neuroendocrine differentiation in 20% of luminal B-like carcinomas using current WHO criteria (at least 50% of tumor cells positive for synaptophysin or chromogranin A). In contrast, no neuroendocrine differentiation was seen in luminal A-like, HER2 amplified and triple-negative carcinomas. Breast carcinomas with neuroendocrine differentiation presented with advanced stage disease and showed aggressive behavior. CONCLUSIONS: We conclude that neuroendocrine differentiation is more common than assumed in poorly differentiated luminal B-like carcinomas. Use of specific neuroendocrine markers is thus encouraged in this subtype to enhance detection of neuroendocrine differentiation and hence characterize the biological and therapeutic relevance of this finding in future studies.

Nicotine in cigarettes promotes chromogranin A production by human periodontal ligament fibroblasts.

OBJECTIVE: The body produces chromogranin A (ChgA) in response to stress as an adaptive reaction. While ChgA is used as an index of autonomic nervous system activity, it is also involved in the immunomodulation system, and an increase in its production in patients with periodontal disease and cigarette smokers has been reported. However, its production in periodontal tissue cells subjected to stress and its immunomodulatory action have not been clarified. To investigate the influence of nicotine on periodontal tissue, we measured ChgA production in nicotine-treated periodontal ligament fibroblasts. DESIGN: Using normal human periodontal ligament-derived fibroblasts (HPdLF) as a periodontal tissue model, untreated cells (control) and cells treated with 10 and 100nM nicotine sulfate corresponding to passive and active cigarette smoking, respectively, were cultured for a specific time. The ChgA level in the culture fluid was measured as ChgA production in HPdLF employing ELISA. ChgA gene expression was quantified employing qPCR. In addition, intracellular localisation was confirmed by immunohistochemical staining. RESULTS: In the control HPdLF group, a low level of ChgA was produced, and immunohistochemical ChgA-positive reactions were observed in the nucleus and cytoplasm. In the nicotine-treated HPdLF group, the ChgA mRNA expression level, protein production, and immunostaining-positive rate increased, and the levels were higher in the cells treated with 10nM nicotine corresponding to passive smoking than in the cells treated with 100nM nicotine corresponding to active smoking. CONCLUSION: Human periodontal ligament-derived fibroblasts (HPdLF) produced ChgA, and nicotine increased ChgA production.

Expression of NCAM (CD56), chromogranin A, synaptophysin, c-KIT (CD117) and PDGFRA in normal non-neoplastic skin and basal cell carcinoma: an immunohistochemical study of 66 consecutive cases.

The expression of NCAM (CD56), chromogranin A, synaptophysin, c-KIT (CD117) and PDGFRA in normal non-neoplastic skin and basal cell carcinoma (BCC) has rarely been investigated. The author immunohistochemically examined the expression of these molecules in 66 consecutive cases of BCC. In non-tumorous skin, NCAM chromogranin A, synaptophysin, c-KIT and PDGFRA expression was seen in the basal cell of the epidermis. NCAM, c-KIT and PDGFRA expression was also seen in the sweat glands and outer cells of hair follicles, but chromogranin and synaptophysin expression was not identified in these structures. In BCC, NCAM expression was seen in 95 % (63/66 cases). Its expression was membranous. Chromogranin A expression was recognized in 27 % (18/66 cases). Its expression was cytoplasmic. Synaptophysin expression was seen in 18 % (12/66 cases). Its expression was membranous and cytoplasmic. c-KIT expression was noted in 93 % (61/66 cases). Its expression was membranous and focally cytoplasmic. PDGFRA expression was seen in 65 % (43/66 cases). Its expression was membranous and cytoplasmic. The expression of these molecules in normal non-tumorous skin is a new finding. The expression of c-KIT and PDGFRA in BCC is also a new finding. In conclusion, the author described the normal (non-neoplastic) distribution of NCAM, chromogranin A, synaptophysin, c-KIT and PDGFRA. In addition, the author showed that, in cutaneous BCC, the expression of NCAM and c-KIT was high (95 and 93 % respectively), PDGFRA was intermediate (65 %), and chromogranin A and synaptophysin was relatively low (27 and 18 %, respectively).

Neuroendocrine differentiation does not have independent prognostic value in conservatively treated prostate cancer.

In vitro studies have implicated neuroendocrine differentiation in the development of hormone resistant prostate cancer following administration of androgen blockers. Studies on clinical material are equivocal. We wished to understand the significance of neuroendocrine differentiation in our large and well-characterised cohort of clinically localised prostate cancer, treated conservatively. Immunohistochemical expression of chromogranin-A was assessed semi-quantitatively on tissue samples of 806 patients in a tissue microarray approach. The correlation of expression with 10-year prostate cancer survival was examined. Multivariate analysis including contemporary Gleason score was performed and sub-group analysis of early hormone treated patients was also undertaken. Chromogranin-A expression correlated with high Gleason score (χ(2) = 28.35, p < 0.001) and early prostate cancer death (HR = 1.61, 95 %CI = 1.15-2.27, p < 0.001). In univariate analysis, NE differentiation correlated significantly with outcome (HR = 1.61, 95 % CI 1.15-2.27, p < 0.001) However in multivariate analysis including Gleason score, chromogranin-A expression was not an independent predictor of survival (HR = 0.97, 95 %CI = 0.89-1.37, p = 0.87). Although chromogranin-A expression was higher in patients with early hormone therapy (χ(2) = 7.25, p = 0.007), there was no association with prostate cancer survival in this sub-group (p = 0.083). Determination of neuroendocrine differentiation does not appear to have any bearing on the outcome of prostatic carcinoma and does not add to the established prognostic model.

Immunohistochemical verification of ductal differentiation in prostate cancer.

Recent studies have shown that patients with prostate carcinomas exhibiting ductal differentiation have an unfavourable prognosis compared with those with purely acinar adenocarcinomas. We studied the expression of nine immunohistochemical markers to evaluate their value in delineating carcinomas with and without ductal differentiation. Thirteen tumours showing cellular characteristics and growth patterns typical of ductal differentiation were identified among 110 analysed prostatectomy specimens. The levels of cytoplasmic expression of chromogranine A (69% vs 19%, p = 0.0003) and nuclear expression of p53 (76% vs 12%, p < 0.0001) as well as nuclear expression of Ki-67 (69% vs 26%, p = 0.0047) in the tumour cells, were found to be statistically significantly different in the two tumour categories. Assessment of chromogranine A, p53 and Ki-67 in prostate carcinoma may serve as useful adjunctive diagnostic tools for delineating more aggressive prostate cancer cases exhibiting ductal differentiation.

Pleomorphic pineocytoma associated with normal pineal parenchyma: report of a case in a 70-year-old man.

Pineocytomas (PCs) most frequently occur in adults, but only three cases have been reported in women older than 70 years. In PCs, cytologic pleomorphism, accompanied by ganglion cells intensely expressing neuronal markers, has been described and the presence of pleomorphic cells may lead to an erroneous upgrading of the tumor. We report an unusual case of pleomorphic pineocytoma in an older patient who presented with a slowly growing tumor adjacent to residual pineal gland. The immunohistological markers of the tumoral tissue and the remnant normal pineal tissue were evaluated and compared. In the neoplasm, the large number of cells labeled for neuronal markers, including many pleomorphic cells, confirmed previous findings that a neuronal immunophenotype is common in PC. Reactivity for synaptophysin was stronger in the tumor than the pineal gland, whereas neurofilament protein reactivity was stronger in the pineal gland than the tumor. The neoplastic cells, but not the pineal gland, were reactive for chromogranin A. This dense core vesicle-associated protein immunolabeling is an interesting diagnostic marker for PCs, which makes it possible to distinguish normal pineal parenchyma with low or negative expression from tumoral tissue. This case illustrates that, even though PCs are low-grade tumors, they can increase in size and surgery appears a valuable option.

Increased neuroendocrine cells in resected metastases compared to primary colorectal adenocarcinomas.

Neuroendocrine differentiation has been described in rectal adenocarcinomas receiving neoadjuvant therapy prior to radical surgery, but its clinical relevance is controversial and no data are currently available in colorectal carcinoma metastases as compared to primary tumors. The presence of chromogranin A positive tumor cells was investigated by means of immunohistochemistry on surgical specimens from 54 primary colorectal carcinomas and their corresponding metastases, resected at diagnosis or during tumor progression. In 47 patients, tumor metastases were resected 1 month to 12 years after chemotherapy and/or radiotherapy, while in the remaining seven patients no additional therapy after primary surgery was performed. In primary tumors, neuroendocrine differentiation was found in 12/54 cases (22.2%) as compared to 25/54 metastatic lesions (46.3%; p = 0.01). The presence of neuroendocrine phenotype was not correlated with any clinical pathological parameter nor with a different proliferation index. However, patients having neuroendocrine cells in the primary tumor had a significantly shorter survival from the time of metastatic spread than those having not (33.3 vs. 55.5 months; p = 0.04). In summary, our data show that colorectal carcinoma metastases contain a higher percentage of neuroendocrine differentiated cells as compared to their corresponding primaries, a finding possibly related to the influence of chemotherapy in neuroendocrine differentiation during colorectal carcinoma progression.

Clinical significance of polymorphism and expression of chromogranin a and endothelin-1 in prostate cancer.

PURPOSE: We investigated the clinical significance of chromogranin A and endothelin-1 polymorphism and expression in prostate cancer. MATERIALS AND METHODS: We analyzed 2 CHGA polymorphisms by polymerase chain reaction-restriction fragment length polymorphism in DNA samples of 435 patients with prostate cancer and 316 age matched male controls. Chromogranin A and endothelin-1 expression was evaluated by immunohistochemistry in prostate specimens of 114 men with prostate cancer who underwent radical retropubic prostatectomy and in 27 with bladder cancer who underwent radical cystectomy and served as controls. RESULTS: For the CHGA Glu264Asp polymorphism men with the GG genotype were at 2.05 times higher risk for prostate cancer than men with the CC genotype (p = 0.014). In men with prostate cancer higher chromogranin A immunohistochemistry grade was associated with higher stage and higher Gleason score (p = 0.011 and 0.044, respectively). Multivariate analysis showed that chromogranin A immunohistochemistry grade was an independent variable for predicting biochemical failure after radical prostatectomy (p = 0.023). Higher endothelin-1 expression was observed in prostate cancers (p = 0.011), especially those with a higher Gleason score (p = 0.042). There was no significant relationship between chromogranin A polymorphisms, and chromogranin A and endothelin-1 expression. CONCLUSIONS: Polymorphism and expression of chromogranin A and endothelin-1 have clinical significance in prostate cancer. Chromogranin A expression was an independent predictor of biochemical failure after prostatectomy in patients with localized prostate cancer.