Expression of Hedgehog signalling molecules in microcystic adnexal carcinoma.

BACKGROUND: Microcystic adnexal carcinoma (MAC) is a rare skin neoplasm that has not been characterized on a molecular basis. AIM: To assess expression profiles of Hedgehog (HH) signalling molecules in MAC and control tumours. METHODS: Immunohistochemistry was performed for Sonic Hedgehog (SHH), Indian Hedgehog (IHH), Patched 1 (PTCH1) and Smoothened (SMO) on patient MAC tissue (n = 26) and control tumour tissue, including syringoma (SyG; n = 11), trichoepithelioma (TE; n = 11) and basal cell carcinoma (BCC; n = 12) tissues. RESULTS: Patched 1 and SMO immunoreactivity was significantly higher in BCC than in SyG, TE or MAC (P < 0.001 and P < 0.03, respectively). The highest IHH expression was observed in BCC and TE compared with SyG and MAC (P < 0.04). Notably, the highest SHH protein expression was observed in SyG compared with MAC, TE and even BCC (P < 0.001). In patients with MAC, SMO immunoreactivity significantly (r = 0.51; P < 0.01) correlated with PTCH1 expression. Further correlation studies did not show significant associations between the HH expression markers assessed (P > 0.05). CONCLUSION: Our results indicate that alterations of the HH signalling are unlikely to play a major role in the pathogenesis of MAC, which is in contrast to the morphologically similar BCC and TE. Our observation provides additional information to the limited molecular pathology knowledge on this rare tumour.

Expression of Lefty predicts Merkel cell carcinoma-specific death.

BACKGROUND: Lefty and Nodal are transforming growth factor ß-related proteins, which, beside their role in determination of laterality during embryogenesis, have also been linked with cancer progression. OBJECTIVES: Prompted by the observed significant left-sided laterality of Merkel cell carcinoma (MCC), we addressed whether Lefty and Nodal are expressed in MCC and correlated expression patterns with clinical parameters such as MCC laterality and patient outcome. METHODS: Expression of Lefty and Nodal in primary MCC was assessed in 29 patients by immunohistochemistry. The histology (H-)score was calculated and correlated with clinical parameters. RESULTS: The median (range) H-score of Lefty and Nodal was 17.6 (0-291) and 74.9 (0.7-272), respectively. There was a significant correlation between Lefty expression and Nodal expression (correlation coefficient of 0.60, P = 0.0006). There was no significant correlation between Lefty expression and Nodal expression with either tumour laterality, gender, age, Merkel cell polyomavirus status, disease stage, anatomical localization of primary tumours or disease relapse. On univariate analysis, low Lefty expression and Nodal expression were significantly associated with MCC-specific death (P = 0.010 and P = 0.019, respectively). On univariate analysis, low Lefty expression was the only significant independent predictor for MCC-specific death (P = 0.025) as indicated by an odds ratio of 14 (95% CI: 1.43-137.33). CONCLUSIONS: Lefty and Nodal are frequently expressed in MCC, but not correlated with tumour laterality. Importantly, our data suggest that a low level of Lefty expression in primary MCC is a strong predictor of MCC-specific death.

Left-sided laterality of Merkel cell carcinoma in a German population: more than just sun exposure.

BACKGROUND: Lateral distribution of cancer has been observed previously. Most evident is this laterality in ultraviolet (UV)-induced skin cancer, based on an unequally distributed UV exposure. OBJECTIVES: The aim of this study was to explore whether patients from Germany also show asymmetrical lateral distribution of Merkel cell carcinoma (MCC). METHODS: In total, 115 patients with MCC were studied for laterality of the primary tumour. Correlation of clinical variables with lateral distribution of MCC was investigated as well. RESULTS: In 64/115 (55.7%) patients, primary tumours were present on the left side, in 37/115 (32.2%) on the right side, and in 14/115 (12.2%) in the midline (P < 0.0001). Excluding the latter localization occurrence of left-sided MCCs (64 of 101/63.4%) was significantly (P = 0.0072) more often observed (1.73-fold) when compared to right-sided tumours (37 of 101/36.6%). The excess of left-sided tumours was found on the head with a left-right ratio of 1.8, trunk of 8, arm of 1.2, and leg of 1.8. There was no significant association between laterality and gender, age, MCPyV status, and anatomic localization of primary tumours including the occurrence in sun-exposed sites. CONCLUSIONS: Occurrence of left-sided MCCs was significantly more often observed when compared to right-sided tumours. Laterality was not associated with tumour presentation at chronically ultraviolet-exposed sites. Hence, the reason for laterality in MCC remains obscure, but likely goes beyond UV exposure.

Prognostic relevance of high atonal homolog-1 expression in Merkel cell carcinoma.

BACKGROUND: It has recently been reported that atonal homolog 1 (ATOH1) gene is down-regulated in Merkel cell carcinoma (MCC) and thus may represent a tumor suppressor gene. OBJECTIVES: We aimed to test for ATOH1 gene mutations and expression levels in MCC tissues and cell lines. METHODS: Genomic DNA isolation and amplification via PCR was successfully performed in 33 MCCs on formalin-fixed paraffin-embedded tissue and three MCC cell lines, followed by Sanger sequencing of the whole ATOH1 gene to detect genomic aberrations. ATOH1 mRNA levels were determined by RT-PCR. Immunohistochemistry of ATOH1 was performed to quantify protein expression in tumor samples and cell lines. RESULTS: Neither in any of the 33 MCC tissue samples nor in the three cell lines ATOH1 mutations were present. ATOH1 was expressed in all lesions, albeit at different expression levels. Univariate analysis revealed that the total immunohistology score significantly correlated with the occurrence of tumor relapse (r = 0.57; P = 0.0008). This notion was confirmed in multivariate analysis suggesting that ATOH1 expression is a potential independent predictor for tumor relapse in MCC patients (P = 0.028). MCC-related death also correlated with ATOH1 expression (r = 0.4; P = 0.025); however, ATOH1 expression did not retain its predictive value in the regression model. CONCLUSIONS: In contrast to anecdotal reports ATOH1 expression is not lost by genetic alterations in MCC. However, protein expression of ATOH1 is increased in advanced MCC indicating that ATOH1 is involved in MCC progression.