neuroendocrine cell

Thu, 29 Jul 2010 07:11:02 -0400





Abstract

To elucidate the relationship between del(5q) and the clinical and histological features of small cell neuroendocrine lung carcinoma, 33 tissue samples from patients with this tumor were evaluated. By using fluorescence in situ hybridization, del(5q) was identified in almost 50% of cases (15/33, 45%). Clinically, patients with tumors showing del(5q) were older (mean age = 71 years) with a correspondingly greater pack-year smoking history (mean = 61) than patients with tumors (mean age = 59 years, mean pack-years = 44) without del(5q). Histologically, tumors with del(5q) had a greater frequency of spindle cell morphology (11/14 [79%] vs 6/16 [38%], P < .025) than those without del(5q). This is the first study to find an association between del(5q) and tumor histology in small cell neuroendocrine lung carcinoma.

Discussion

Evidence regarding the prognostic influence of NE markers in human carcinomas is confusing. For example, in prostate cancer both the increased and decreased immunoexpression of NE marker serotonin have been associated with advanced or aggressive disease [6,7]. In undifferentiated endometrial carcinomas, NE markers had no prognostic significance [19]. In addition, the clinical behaviour of breast carcinomas with NE differentiation is not well established [20]. The current paper examines the expression of NE markers (serotonin, CD56, chromogranin A, synaptophysin and NSE) in RCC with a special reference for patient survival.

Serotonin is a monoamine neurotransmitter mediating a wide range of physiological actions in the human body. Among others it is implicated in psychiatric and neurological disorders and also plays a fundamental role in tumour growth, differentiation and gene expression [8]. Serotonin has been proposed to take part in the autocrine loops of growth factors, contributing to cell proliferation in aggressive tumours such as small cell lung carcinoma. By contrast, serotonin can inhibit tumour growth, which is thought to be related to its vasoconstrictive effect [10]. It has been shown that decreased serotonin immunoexpression is associated with the progression of prostate cancer [7]. Furthermore, serotonin receptor overexpression is demonstrated in high-grade tumours and serotonin seems to stimulate prostate cancer cells [6]. In RCC, it has been shown that plasma serotonin levels are decreased in patients with metastases but there was no significant association between plasma serotonin level and the extent of the disease [11]. In a previous study of 10 patients with advanced RCC, no immunoexpression of serotonin was detected [12]. In the current study, the immunostaining for serotonin was uncommon, and only 8% of tumours were serotonin immunopositive. The discrepancy in detected immunoexpression with the earlier study [12] might be because of different stage groups and a larger study population. The immunoreactivity for serotonin was detected only in localised or locally advanced disease. None of the tumours with distal metastases were immunopositive for serotonin. However, in terms of patient survival, the immunohistochemical expression of serotonin in RCC seems to have no clinical significance.

CD56 is a member of the immunoglobulin superfamily. Only 15% of conventional RCCs express CD56 and the positivity is associated with poor patient outcome [14]. In addition, the expression of CD56 has been associated with a higher risk of adrenal gland and central nervous system metastases, tumour size, renal vein involvement, perirenal invasion and aggressive Fuhrman grade [14] The current data, however, did not support this observation (data not shown). In our study, there was immunostaining for CD56 in 18% of clear cell RCCs, which is consistent with the earlier study. However, the same frequency of CD56 positivity in papillary and chromophobic RCCs was also detected. The expression of CD56 was not associated with stage or grade. Despite a shorter mean survival for CD56 positive tumours, the expression of CD56 was not a significant predictive marker for RCC in the current study.

NSE is a rather non-specific marker of NE differentiation, which can be found in a variety of normal and neoplastic NE cells as well as in any type of neoplasms even of non-NE origin [15,13]. Elevated serum NSE levels can be detected in 27-80% of patients with RCC [16,17] and seem to be associated with patient outcome [17]. After the treatment of RCC, serum levels of NSE decrease and it has been suggested that this could be a useful marker in the surveillance of RCC [16]. The immunoreactivity for NSE in RCC has been found to be up to 100% [12,17]. In our study, half of tumours were immunopositive for NSE. The immunoreactivity for NSE did not associate with stage or grade. Positivity for NSE was more common in clear cell carcinomas than other subtypes of RCCs. Immunostaining for NSE was not a prognostic factor in RCC-specific survival. In our study population, the expression of NSE was not as common as in previous studies and did not show any prognostic significance in RCC.

Chromogranin A was originally identified as a major soluble protein in adrenal medullary chromaffin granules many decades ago [21]. It has been intensively studied with respect of its physiological role and pathological expression in tumours [22]. In a previous study, serum chromogranin A was found to be elevated in 14% of RCC patients without any prognostic significance in RCC [17]. The immunohistochemical reactivity for chromogranin A has been detected in 4% of RCC patients [17] or the tumours have been wholly immunonegative for chromogranin A [12]. In our study, we found no immunoreactivity for chromogranin A in RCCs, which is consistent with the latter study.

Synaptophysin is a transmembrane glycoprotein of presynaptic vesicles of nerve endings [23,24]. It is regarded as one of the most specific markers of NE differentiation. The immunoexpression of synaptophysin has previously been described in undifferentiated endometrial carcinomas where it did not seem to have a significant prognostic potential [19]. To our knowledge, this is the first study describing the immunostaining of synaptophysin in RCC. In our study, immunostaining for synaptophysin was rare (only 1% of the tumours). Interestingly, the prognosis of patients with synaptophysin immunopositive tumours was excellent. Both patients whose primary RCC tumour showed an immunopositivity for synaptophysin are still alive after 10 and 17 years follow-up. The TNM classes for these synaptophysin immunopositive tumours were pT1aN0M0 and pT3aN0M0. Synaptophysin positivity in RCC may be associated with good prognosis, but as an uncommon phenomenon, this observation should be further studied with large number of RCC tumours.

Conclusions

To conclude, the immunohistochemical expression of NE markers was quite common in RCC. The current study showed that serotonin, CD56, chromogranin A, synaptophysin and NSE were not potential prognostic markers in RCCs. The outcome of an individual patient with RCC is still to be evaluated with traditional clinicopathological markers such as stage and grade.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

HR, SK and PH evaluated the immunohistochemical staining. HR performed statistical analyses. All authors revised the manuscript and approved the final manuscript.

Acknowledgements

We would like to thank Ms. Mirja Vahera and Ms. Erja Tomperi at Department of Pathology, Oulu University for their skilful technical assistance with immunohistochemical stainings and Dr. Heikki Tokola for encouraging us to study NE markers in RCCs.

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