Treatment and outcomes of melanoma in Asia: Results from the National Cancer Centre Singapore.

BACKGROUND: Acral melanoma (AM) and mucosal melanoma (MM) make up more than half of melanomas in Asia but comprise only 5% of cases in Caucasians, where cutaneous melanoma (CM) predominates. AM and MM are thought to be genetically and biologically distinct from CM. We report the characteristics and outcomes of melanoma patients from the National Cancer Centre Singapore. METHODS: Case records of 210 patients treated between 2002 and 2014 were reviewed. RESULTS: Median follow-up was 2.5 years. CM, AM and MM made up of 37.6%, 33.8% and 16.2% of cases, respectively, with 6.2% each having ocular melanoma and unknown primary. Caucasians made up 16.2% of patients, accounting for 36.7% of CM but only 2.8 of AM and 2.9% of MM. Patients with MM (2.9% stage I, 14.7% stage IV) presented with higher American Joint Committee on Cancer (AJCC) stage than those with AM (16.9% stage I, 5.6% stage IV) or CM (24.1% stage I, 8.9% stage IV) (P = 0.01). Median overall survival (OS) was 5.7 years for all patients, and 1.0 year for metastatic disease. Considering stage I-III disease, multivariable Cox regression analysis demonstrated age ≥60 years and higher stage to be independent adverse prognostic factors for RFS and OS. Sentinel lymph node biopsy, undertaken for 56 stage I-III patients (25 AM, 31 CM) did not influence outcome. CONCLUSION: Our study reinforces the known unique clinicopathologic features of melanomas in Asians where AM and MM predominate. Age and stage remain the most critical prognostic factors across all subtypes.

SETD2 histone modifier loss in aggressive GI stromal tumours.

BACKGROUND: GI stromal tumours (GISTs) are clinically heterogenous exhibiting varying degrees of disease aggressiveness in individual patients. OBJECTIVES: We sought to identify genetic alterations associated with high-risk GIST, explore their molecular consequences, and test their utility as prognostic markers. DESIGNS: Exome sequencing of 18 GISTs was performed (9 patients with high-risk/metastatic and 5 patients with low/intermediate-risk), corresponding to 11 primary and 7 metastatic tumours. Candidate alterations were validated by prevalence screening in an independent patient cohort (n=120). Functional consequences of SETD2 mutations were investigated in primary tissues and cell lines. Transcriptomic profiles for 8 GISTs (4 SETD2 mutated, 4 SETD2 wild type) and DNA methylation profiles for 22 GISTs (10 SETD2 mutated, 12 SETD2 wild type) were analysed. Statistical associations between molecular, clinicopathological factors, and relapse-free survival were determined. RESULTS: High-risk GISTs harboured increased numbers of somatic mutations compared with low-risk GISTs (25.2 mutations/high-risk cases vs 6.8 mutations/low-risk cases; two sample t test p=3.1×10-5). Somatic alterations in the SETD2 histone modifier gene occurred in 3 out of 9 high-risk/metastatic cases but no low/intermediate-risk cases. Prevalence screening identified additional SETD2 mutations in 7 out of 80 high-risk/metastatic cases but no low/intermediate-risk cases (n=29). Combined, the frequency of SETD2 mutations was 11.2% (10/89) and 0% (0/34) in high-risk and low-risk GISTs respectively. SETD2 mutant GISTs exhibited decreased H3K36me3 expression while SETD2 silencing promoted DNA damage in GIST-T1 cells. In gastric GISTs, SETD2 mutations were associated with overexpression of HOXC cluster genes and a DNA methylation signature of hypomethylated heterochromatin. Gastric GISTs with SETD2 mutations, or GISTs with hypomethylated heterochromatin, showed significantly shorter relapse-free survival on univariate analysis (log rank p=4.1×10-5). CONCLUSIONS: Our data suggest that SETD2 is a novel GIST tumour suppressor gene associated with disease progression. Assessing SETD2 genetic status and SETD2-associated epigenomic phenotypes may guide risk stratification and provide insights into mechanisms of GIST clinical aggressiveness.

Cutaneous versus non-cutaneous angiosarcoma: clinicopathologic features and treatment outcomes in 60 patients at a single Asian cancer centre.

BACKGROUND: Angiosarcoma (AS) is an uncommon soft tissue sarcoma with dismal prognosis that presents either cutaneously (C-AS) or non-cutaneously (NC-AS). We compared the clinical features and treatment outcomes between these 2 groups. METHODS: A single-centre study evaluating 60 AS patients between 2002 and 2012 was performed. RESULTS: The median age was 70 years. C-AS of the scalp or face comprised 66% of patients. C-AS patients were older than NC-AS (median age 74 vs. 56 years; p < 0.001). Proportionately more C-AS patients presented with non-metastatic disease (86 vs. 50%; p = 0.007). Amongst resected C-AS and NC-AS patients, rates of positive surgical margins (53 vs. 50%; p = 1.00) and adjuvant therapy (25 vs. 43%; p = 0.626) were not significantly different, though proportionately fewer C-AS patients relapsed (36 vs. 78%; p = 0.038). Paclitaxel was the most common agent in first line palliative systemic therapy, achieving an objective response rate of 56%. Median overall survival was 11.2 months, with no significant difference between C-AS and NC-AS (11.3 vs. 9.8 months; p = 0.895). CONCLUSION: Distinct from AS in the West, our series demonstrates a clear preponderance of scalp AS. Disparities in clinical characteristics between C-AS and NC-AS did not translate into survival differences.

Localized gastrointestinal stromal tumor of the rectum: An uncommon primary site with prominent disease and treatment-related morbidities.

Well-established clinicopathological variables used in the risk stratification of gastrointestinal stromal tumor (GIST) may not completely predict rectal GIST, an uncommon and poorly studied GIST subset. The aim of the present study was to determine the patterns of relapse and morbidities associated with recurrence in rectal GIST. A single-institution retrospective study between 2002 and 2011 was conducted, identifying 9 patients (8%) with localized rectal GIST, while comparing small intestinal (n=37) and gastric (n=63) GIST (median age, 60 years). Rectal GIST tumors were smaller compared to small intestinal/gastric GIST (P=0.044). The number of mitoses per 50 high-power field (HPF) did not differ by primary site. In general, 73% of patients were high-risk, as defined by the National Institutes of Health (NIH) consensus criteria, however, only 25% received adjuvant imatinib. Fewer rectal GIST patients achieved negative surgical margins compared to small intestinal/gastric GIST (67 vs. 92%; P=0.054). Of the 9 patients with localized rectal GIST 6 had peri-operative tumor rupture, anastomotic breakdown or required anal sphincter-compromising surgery. At the time of the first relapse, 83% of the recurrences were local failures for rectal GIST, compared to 21% for small intestinal/gastric GIST (P=0.005). The median relapse-free survival was 51 months for the entire cohort, and 54, 36 and 56 months for rectal, small intestinal and gastric GIST, respectively (P=0.468). Rectal GIST was found to be associated with high rates of local relapse and significant morbidity, despite being significantly smaller compared to GIST of other sites. A multimodality peri-operative therapeutic approach may be required to improve outcomes.