Pulsed Dye Laser-mediated Photodynamic Therapy is Less Effective than Conventional Photodynamic Therapy for Actinic Field Cancerization: A Randomized Half-side Comparative Study.

Previous research presents pulsed dye laser-mediated photodynamic therapy as a promising alternative to conventional red-light photodynamic therapy. In this study, 60 patients with 2 or more actinic keratoses randomly received either of these treatments on each side of the head. A physician blinded to the treatment evaluated treatment response at 6 months for each lesion, as completely, partially or not healed. Significantly lower complete clearance rates (10.3% vs 44.9%) and lesion-specific complete clearance rates were found for pulsed dye laser-mediated photodynamic therapy (47.9%) vs conventional red-light photodynamic therapy (73.4%). Significantly lower pain scores were found for pulsed dye laser-mediated photodynamic therapy, with a mean numerical rating of 2.3, compared with 4.1 for conventional red-light photodynamic therapy. The study population had a mean of 7.9 lesions, and 78% of patients had been treat-ed previously for actinic keratoses on the treatment area. To conclude, in a population with severe sun dam-age, pulsed dye laser-mediated photodynamic therapy seems less effective than conventional red-light photo-dynamic therapy. Pulsed dye laser-mediated photodynamic therapy may still be a treatment option for patients who are not compliant with conventional red-light photodynamic therapy.

Merkel Cell Carcinoma Treatment in Finland in 1986-2016-A Real-World Data Study.

Merkel cell carcinoma (MCC) is a rare cutaneous carcinoma that has gained enormous interest since the discovery of Merkel cell polyoma virus, which is a causative oncogenic agent in the majority of MCC tumours. Increased research has focused on effective treatment options with immuno-oncology. In this study, we reviewed the real-world data on different treatments given to MCC patients in Finland in 1986-2016. We used the Finnish Cancer Registry database to find MCC patients and the Hospital Discharge Register and the Cause-of-Death Register to obtain treatment data. We identified 376 MCC patients and 33 different treatment entities and/or combinations of treatment. An increase was noted in the incidence of MCC since 2005. Therefore, the cohort was divided into two groups: the "early" group with time of diagnosis between years 1986 and 2004 and the "late" group with time of diagnosis between 2005 and 2016. The multitude of different treatment combinations is a relatively new phenomenon; before the year 2005, only 11 treatments or treatment combinations were used for MCC patients. Our data show that combining radiation therapy with simple excision provided a survival advantage, which was, however, lost after adjustment for stage or age. Our registry study serves as a baseline treatment efficacy comparison as we move into the age of immunotherapy in MCC. Standardizing the treatment of MCC patients in Finland requires more work on awareness and multidisciplinary co-operation.

The expression of terminal deoxynucleotidyl transferase and paired box gene 5 in Merkel cell carcinomas and its relation to the presence of Merkel cell polyomavirus DNA.

BACKGROUND: Merkel cell carcinoma (MCC) tumor samples frequently express B-lymphoid lineage markers. However, the reasons for expression of specific B-lymphoid lineage markers are still unclear. We studied the expression of TdT and PAX5 (two B-cell lymphoid lineage markers) in a large pool of MCC tissue microarray samples. METHODS: Immunoexpression and staining intensities of TdT and Pax-5 were statistically correlated with patient, tumor, Merkel cell polyomavirus (MCV), and disease-specific parameters. RESULTS: In a cohort of 117 MCC patients and their corresponding tumor samples, TdT was expressed in 37 (31.6%) samples and PAX5 in 26 (22.2%). Simultaneous immunostaining for TdT and PAX5 was observed in 13 (11.1%) samples. A statistically significant relationship was observed between MCV virus copy number and positive TdT expression (P = 0.0056). Similarly, a significant relationship was also observed between positive TdT and tumor MCV virus positivity (P = 0.000495). CONCLUSION: We observed frequent TdT and PAX5 immunoexpression in MCC tumor samples. However, simultaneous immunoexpression of these markers was scarce. TdT expression was statistically significantly associated with MCV positivity. The absence of a statistically significant association between tumor parameters and disease progression markers undermines the systemic use of these markers in clinical practice.

History of chronic inflammatory disorders increases the risk of Merkel cell carcinoma, but does not correlate with Merkel cell polyomavirus infection.

BACKGROUND: We aimed to assess the connection between chronic inflammatory disorders (CIDs) and Merkel cell carcinoma (MCC). METHODS: Merkel cell carcinoma cases diagnosed in 1978-2009 were extracted from the Finnish Cancer Registry and controls from the Population Registry. Information on reimbursed CIDs was linked to clinicopathological data including Merkel cell polyomavirus (MCV) status by qPCR and immunohistochemistry for the large T antigen of MCV (LTA), Ki-67 and tumour-infiltrating lymphocytes. RESULTS: Chronic inflammatory disorders increased the risk of MCC significantly (odds ratio (OR) 1.39, 95% confidence interval (CI) 1.03-1.88), specifically connective tissue/systemic diseases (OR 1.75, 95% CI 1.09-1.80) and diabetic conditions (OR 1.51, 95% CI 1.03-2.22). Chronic inflammatory disorders associated with larger tumour diameter (P=0.02) and higher Ki-67 expression (P=0.005). The expression of LTA was seen significantly more often in the absence of CIDs (P=0.05). CONCLUSIONS: Patients with CID are at significantly higher risk for aggressive MCC. Merkel cell polyomavirus positivity is more common in MCC patients unafflicted by CID.

Post-transplant Merkel Cell Carcinoma.

Malignant tumours are the foremost complications of immunosuppressive treatment. They are a major challenge for organ transplant recipients and their treating physicians. This paper reviews the aetiology and current treatment of an unusual neuroendocrine skin cancer, Merkel cell carcinoma (MCC), caused by a Merkel cell polyomavirus infection. MCC occurs more frequently than expected in immunosuppressed subjects, especially in organ transplant recipients. The current literature comprises reports of 79 organ transplant recipients with MCC. The risk of MCC in organ transplant recipients is increased up to 66-182-fold compared with the general population. In addition to the increased risk of developing MCC, immunosuppressed individuals have poorer MCC-specific survival. The aim of this review article is to familiarize organ transplant doctors with this unique and clinically challenging skin cancer, and to provide recent data on the diagnosis and current treatment recommendations for an immunosuppressed population.

Joint occurrence of Merkel cell carcinoma and non-Hodgkin lymphomas in four Nordic countries.

The objective of this study was to assess the reciprocal association between non-Hodgkin lymphoma (NHL) and Merkel cell carcinoma (MCC) using the data of four Nordic Cancer Registries. Data for this study were drawn from the Danish, Finnish, Norwegian, and Swedish cancer registries. Standardized incidence ratios (SIRs) for MCC among NHL patients, and for NHL among MCC patients, were calculated. There were 109 838 individuals with NHL and 1411 individuals with MCC, of which 28 had joint occurrence of NHL and MCC. In 18 cases, NHL was diagnosed first, and in 10 cases, MCC was diagnosed first. The SIR for MCC after NHL was 4.34 (95% confidence interval 2.57-6.85). The SIR for NHL after MCC was 3.13 (1.50-5.77). Although the absolute frequency of joint occurrence of MCC and NHL is low, individuals suffering from one of the cancer forms have an increased risk of the other.

miRNA-34a underexpressed in Merkel cell polyomavirus-negative Merkel cell carcinoma.

Merkel cell polyomavirus (MCV) is frequently detectable in Merkel cell carcinoma (MCC) tumors, but the significance of MCV infection is not yet totally understood. Thus far, no key regulatory miRNA has been identified for MCC tumorigenesis. However, distinct miRNA expression profiles have been suggested for MCV-positive and MCV-negative tumors. We used microarray hybridization to identify miRNA expression differences in MCC tumor samples according to MCV status and further validated these results by quantitative reverse transcription polymerase chain reaction (qRT-PCR). When compared with MCV-negative tumors, we detected overexpression of miR-34a, miR-30a, miR-142-3p, and miR-1539 in those MCV positives. In addition, slight underexpression was detectable in MCV-positive tumors of miR-181d. We confirmed the distinct expression of miRNAs in MCV-positive and MCV-negative tumors and confirmed statistically significant underexpression of miR-34a in MCV-negative tumors by both array analysis and qRT-PCR. Neither tumor location nor development of metastases affected miRNA expression.

RB1 gene in Merkel cell carcinoma: hypermethylation in all tumors and concurrent heterozygous deletions in the polyomavirus-negative subgroup.

Sequestration of the tumor suppressor retinoblastoma protein (RB) by the Merkel cell polyomavirus (MCV) is a crucial step in the pathogenesis of Merkel cell carcinoma (MCC). RB expression is frequently lost, particularly in MCV-negative MCC tumors, through yet unknown mechanisms. We compared the genomic copy number changes of 13 MCV-positive and 13 -negative MCC tumors by array comparative genomic hybridization. The analysis revealed increased genomic instability, amplification of 1p34.3-1p34.2, and losses of 11p in the absence of MCV infection. Deletions of the RB1 locus were also detected at high rates in MCV-negative tumors. None of the tumors with heterozygous RB1 losses expressed RB in immunohistochemistry. RB1 promoter hypermethylation was studied with a methylation-specific multiplex ligation-dependent probe amplification technique. The RB1 promoter was methylated in all tumor specimens at CpG islands located close to the ATG start codon, albeit at low levels. The pattern of hypermethylation was similar in all MCC samples, despite RB expression, survival or MCV status. In conclusion, the frequent heterozygous losses of the RB1 locus could partly explain the decreased RB expression in MCV-negative MCC tumors, although the effects of RB1 mutations, coinciding promoter hypermethylation and, for example, miRNA regulation, cannot be excluded.

Bcl-2 expression indicates better prognosis of Merkel cell carcinoma regardless of the presence of Merkel cell polyomavirus.

Merkel cell carcinoma (MCC) is an aggressive dermal tumour of neuroendocrine origin. The recently found Merkel cell polyomavirus (MCV) integrates clonally in the tumour genome, which suggests an important role in the pathogenesis of the disease. Previous small-scale studies have detected anti-apoptotic protein bcl-2 in 80 % of MCC tumours, but its correlation to the prognosis of MCC remains controversial. Our aim was to clarify the correlation of immunohistochemical expression of bcl-2 to MCV presence and MCC prognosis. We analyzed 116 primary MCC specimens with corresponding clinical data by immunohistochemistry for bcl-2. The presence of MCV DNA had been analyzed by quantitative PCR for 108 tumours. The correlations were analyzed statistically. Of the primary MCC samples, 85 % were bcl-2 positive. No significant differences in MCV DNA occurred between the bcl-2-positive and bcl-2-negative tumours. Local and systemic metastasis was more common in patients with bcl-2 negative tumours (33 %) than in patients with bcl-2-positive tumours (12 %; p = 0.04) at the time of diagnosis. The mean overall survival was higher in patients with bcl-2-positive tumours than of those with negative tumours (mean survival 1,814 days (5.0 years) vs. 769 days (2.1 years), p = 0.01). Bcl-2 positivity indicates better clinical stage at the time of diagnosis and a longer survival in MCC.

Increased incidence of Merkel cell carcinoma among younger statin users.

BACKGROUND: Statins (HMG-CoA-reductase inhibitors) are suggested to act as a predisposing factor for autoimmune diseases, have immunomodulatory effects, and possibly prevent some cancer types - the sum of these effects is unknown in cancers of viral aetiology, such as Merkel cell carcinoma (MCC). Aim of our study was to find out whether statin users in Finland have an increased incidence of MCC. PATIENTS AND METHODS: A cohort of 224715 male and 230220 female statin users during 1994-2007 was identified from the Prescription Register of the National Social Insurance Institution. This cohort was followed up through the Finnish Cancer Registry for MCC up to 2009. RESULTS: There were altogether 50 cases of MCCs, while the expected number of cases, calculated on the basis of the MCC incidence in comparable Finnish population, was 39.9 (SIR 1.25, 95% CI 0.93-1.65). The standardized incidence ratio (SIR) for MCC in ages <60 years was 3.16 (95% CI 0.65-9.23), in ages 60-74 years 1.94 (95% CI 1.23-2.90) and in ages ≥75 years 0.89 (95% CI 0.57-1.31). The relative risk of MCC decreased significantly, 0.79 fold (95% CI 0.67-0.92), at each 5 year step when moving towards older age groups. There was no significant variation in SIR related to years since starting the statin use, or between the genders. CONCLUSIONS: MCC is the first neuroendocrine cancer linked to statin use. The association is statistically significant and biologically plausible through immunomodulatory effects of statins. The excess of MCCs was observed in atypically young patients, a similar phenomenon as noted earlier in patients with immunocompromising states.