Increased incidence of melanoma in children and adolescents in Finland in 1990-2014: nationwide re-evaluation of histopathological characteristics.

BACKGROUND: Changes in the incidence of melanoma in children and adolescents have been reported in Europe and in the USA in the recent decades. AIMS: The aim of this study was to examine the incidence of paediatric and adolescent melanomas in Finland in 1990-2014, and the associated clinical and histopathological characteristics to reveal temporal trends, such as changes in diagnostic sensitivity of Spitzoid melanomas. METHODS: Information on 122 patients diagnosed with cutaneous melanoma at 0-19 years of age in Finland in 1990-2014 were retrieved from the Finnish Cancer Registry. 73 primary melanoma archival samples were re-evaluated by two dermatopathologists to allow comparability over time. RESULTS: A 5.6% annual increase was observed in the incidence of melanoma among children and adolescents during the study period. Fifty-six tumours were confirmed as malignant melanomas in the re-evaluation. After correction for tumour misclassification in the Cancer Registry, the age-adjusted annual incidence was estimated to have increased from 1.4/1 000 000 in 1990-1994 to 5.8/1 000 000 in 2010-2014. The change in incidence was most prominent among adolescents and in Spitzoid melanoma subtype. Melanomas diagnosed 1990-2002 and 2003-2014 did not differ in terms of their clinicopathological characteristics or prognosis (hazard ratio for melanoma-related death 1.53, 95% CI 0.30 to 7.88). Spitzoid melanomas were diagnosed at a younger age, were of higher stage and had higher Clark level than other melanomas, yet the hazard ratio for death was 0.52 (95% CI 0.10 to 2.58) for Spitzoid versus other melanomas. CONCLUSIONS: The incidence of cutaneous melanoma has clearly increased among the young in Finland, especially among adolescents. No evidence for overdiagnosis of Spitzoid melanomas as the underlying cause of the increased incidence was observed.Key messageA nationwide retrospective re-evaluation of the cutaneous melanomas recorded in the Finnish Cancer Registry among patients aged 0-19 years in Finland in 1990-2014 revealed an approximately 4-fold increase in the incidence. The increase in the incidence was most prominent among adolescents and in the Spitzoid melanoma subtype. Our results contrast those reported in other countries, where the incidence of melanoma among adolescents has declined.

Different expression of BRAFV600E, ALK and PD-L1 in melanoma in children and adolescents: a nationwide retrospective study in Finland in 1990-2014.

BACKGROUND: Pediatric melanoma may have a different biological background and more favorable prognosis compared with melanoma in adults. The aim of this study was to investigate melanoma in children and adolescents in the Finnish population in terms of incidence, clinical course, treatment, prognosis and BRAFV600E-, ALK- and PD-L1-positivity of the primary tumors. MATERIALS AND METHODS: Primary tumor samples and clinical records of all patients aged 0-19 years diagnosed with cutaneous melanoma in Finland in 1990-2014 were collected using the Finnish Cancer Registry database, Finnish hospitals and private pathology laboratories. BRAFV600E, ALK and PD-L1 were analyzed from 54 primary tumors and BRAFV600E from six metastasis samples. RESULTS: A total of 122 patients diagnosed with cutaneous melanoma were retrieved from the Cancer Registry database. The primary tumor samples of 73 patients were obtained for the review, and 56 cases were included in the study. The incidence of pediatric melanoma increased from 0.02 to 0.1/100 000 during the period 1990-2014. Spitzoid melanoma was the most common subtype (66%). The 10-year cancer-specific survival (CSS) was 88.7% in all patients. The 10-year-CSS did not differ in SLNB-positive or -negative groups. BRAFV600E was positive in 48%, ALK in 9% and PD-L1 in 2% of the tumors. BRAFV600E mutation was associated with 83% of melanoma deaths. CONCLUSIONS: Young melanoma patients had more favorable prognosis and a different staining profile for BRAFV600E, ALK, and PD-L1 in primary tumor than reported in adults. SLNB status was not an indicator for survival. BRAFV600E-positive patients have worse prognosis and could benefit from surveillance and treatment similarly to adults.

Circulating levels of VEGFR-1 and VEGFR-2 in patients with metastatic melanoma treated with chemoimmunotherapy alone or combined with bevacizumab.

There are no identified biomarkers that could predict response to antiangiogenic or traditional chemoimmunotherapy in metastatic melanoma. We hypothesized that soluble angiogenic factor receptors might help us to identify patients responsive to treatment. A series of 48 patients with stage IV melanoma participating in two phase II clinical trials were included. The trials included treatment with carboplatin, vinorelbine, and subcutaneous interleukin-2 (n=22) or treatment with bevacizumab, dacarbazine, and low-dose interferon-α2a (n=26).Serum samples were prospectively collected and soluble vascular endothelial growth factor receptor 1 (s-VEGFR-1) and 2 (s-VEGFR-2) were measured before starting the trial treatment and during response evaluation.There was a trend toward longer overall survival among patients with higher-than-median serum VEGFR-1 levels (21.3 months) compared with 12.3 months in patients with low pretreatment s-VEGFR-1 levels (P=0.146). Pretreatment s-VEGFR-2 levels did not correlate to survival. Serum VEGFR-2 levels decreased during therapy in 44% of the patients and increased in 56% of the patients. VEGFR-2 increased in 78% (14 of 18) of the patients who progressed during therapy (P=0.017). VEGFR-2 decrease was associated with clinical benefit in 65% of the patients (11 of 17) and with progression in only four patients (P=0.016).High pretreatment levels of s-VEGFR-1 are associated with improved prognosis among patients with metastatic melanoma independently on therapy, whereas increased VEGFR-2 levels during therapy are associated with disease progression. These markers might be useful in selecting patients responsive to antiangiogenic therapy.

A phase II trial of bevacizumab with dacarbazine and daily low-dose interferon-alpha2a as first line treatment in metastatic melanoma.

Metastatic melanomas are hypervascular tumours with poor prognosis. We hypothesized that treatment of metastatic melanoma with a combination of bevacizumab, a monoclonal antibody against vascular endothelial growth factor, dacarbazine (DTIC) and low-dose interferon alpha-2a (IFN-alpha2a) might lead to a synergistic inhibition of angiogenesis and regression of tumours. Patients with metastatic melanoma were treated with bevacizumab (5 mg/kg every 2 weeks), DTIC (200 mg/m days 1-5 every 4 weeks) and IFN-alpha2a (three MIU subcutaneously daily from day 15 onwards). Patients exhibiting response or stable disease after 6 months were treated with bevacizumab+/-IFN-alpha2a until disease progression. The primary study objectives were progression-free survival (PFS), overall survival and safety. Twenty-six patients were accrued. Response rate was 23% (two complete responses, four partial responses), and six patients showed stable disease. The median PFS for all patients was 2.3 months and for responders 8.1 months. The median overall survival for all patients was 11.5 months. Four life-threatening adverse events were seen: two pulmonary thromboembolisms, an intracerebral haemorrhage, and one grade 4 hypertension. One of the pulmonary emboli and the intracerebral haemorrhage were observed > or =3 months after the last bevacizumab-DTIC dose. Serum matrix metalloproteinase-9 and vascular endothelial growth factor levels changed during therapy. There was a trend towards favourable PFS among patients with only minimal or moderate change in these marker expression levels. The present regimen was active in this patient group but was also associated with remarkable vascular events.

Head and neck cutaneous melanoma: a retrospective observational study on 146 patients.

BACKGROUND: Sentinel node biopsy (SNB) is a novel staging technique in cutaneous melanoma, but it is more challenging in the head and neck (H&N) than in the trunk and extremities. The aim of this study was to investigate the utility of SNB in patients with clinical stage I-II H&N cutaneous melanoma, with emphasis on disease outcome. PATIENTS AND METHODS: Twenty five patients with H&N melanoma of >1.0 mm in Breslow depth underwent SNB and were compared to 121 historic H&N melanoma patients, who had either undergone routine prophylactic neck dissection or had been observed without any invasive nodal staging. RESULTS: Sixteen percent of the SNB patients were sentinel-positive and there have been no false-negative cases. In the Kaplan-Meier analysis, there were no significant differences between the study groups in melanoma-specific overall survival. Among the entire cohort, melanoma-specific overall survival rate was 67.1% at 5 years and 61.9% at 10 years. Predictive factors for worsen survival were nodal micrometastases, male sex, scalp location, thick primary lesion and ulceration. DISCUSSION: SNB is a reliable and mini-invasive approach for the nodal staging of H&N cutaneous melanoma. Traditional neck dissection is recommended only for therapeutic purposes in clinically node-positive or sentinel-positive patients.

Serum VEGF-C is associated with metastatic site in patients with malignant melanoma.

Vascular endothelial growth factor-C (VEGF-C) is involved in lymphatic metastatic spread. Metastatic site is a prognostic factor in melanoma. We assessed whether serum levels of VEGF-C are associated with metastatic sites or prognosis in patients treated for stage IV melanoma. The study included 64 patients, who received dacarbazine or four-drug chemotherapy (dacarbazine, vincristine, bleomycin and lomustine; BOLD) both combined with interferon-alfa. Serum samples for VEGF-C were analyzed by ELISA. The patients (n =22) with only skin and subcutaneous metastases had significantly lower mean VEGF-C levels (1 643 pg/ml) then the patients (n =42) with other distant metastases (2 584 pg/ml, Mann-Whitney, p =0.033). VEGF-C levels above the median (1 590 pg/ml) were significantly related to deep lymph node involvement (OR 3.763; 95% CI 1.038 - 13.646, p =0.034). There were no other significant associations between VEGF-C levels and tumour burden, nor were the levels significantly related to the response to therapy or survival. Those eight patients, who had received previous adjuvant IFN-alfa therapy had lower mean VEGF-C levels (1 738 pg/ml) as compared to those 56 patients without previous IFN-alfa therapy (2 335 pg/ml, ANOVA, p =0.026). This is the first study exploring serum VEGF-C in melanoma. VEGF-C might be involved in the deep lymphatic dissemination and progression of melanoma metastasis.

New prognostic factors and developing therapy of cutaneous melanoma.

The multiple molecular alterations underlying the neoplastic process and clinical characteristics of cutaneous melanoma are currently under intensive investigation. Recent studies have demonstrated that the levels of melanoma-associated proteins in tumor tissue or in patient serum can serve as new markers to predict disease outcome. Similarly, the expression of thousands of genes in melanoma tumors can be surveyed simultaneously using DNA arrays, allowing molecular profiling of individual tumors, which gives the possibility of classifying melanomas based on their biological diversity. Large clinical studies have also identified multiple prognostic factors, such as tumor ulceration, and led to development of a new, more precise melanoma staging system, which emphasizes the biological characteristics of the primary disease. These new findings may have an important role in earlier measurement of the clinical response and provide a basis for tailored melanoma therapy, the development of which will also be discussed in this review.