Melanoma
Surveillance
Several observational studies have demonstrated lower Breslow depth and lower risk of advanced or fatal melanoma in screen detected melanomas using either monthly self-examination or regular clinical examination of skin. Specificity of screening is higher with clinical rather than self-examination and improves with increased clinician training. A German study reported a 47% decrease in melanoma mortality in a screened population at average risk.r
Australian studies have shown that six-monthly specialist skin examination, supported by dermoscopy and total body photography, is effective in reducing thickness of prospectively detected melanomas, and in reducing the number of ineffectual skin lesion excisions in those at very high risk of melanoma (CDKN2A pathogenic variant carriers or equivalent).r The intervention was also cost-effective. r Follow Cancer Council Australia UV related position statements opens in a new tab or window.
Relatives who are non-carriers of an identified familial CDKN2A pathogenic variant have a higher risk of cutaneous melanoma than the general population (but lower than carrier relatives), possibly due to inheritance of other less penetrant melanoma susceptibility variants and shared lifestyle and environmental risks. Annual melanoma surveillance may still be warranted for non-carrier relatives. (For melanoma risk estimation tools see Alfred Health - Melanoma risk calculator for health professionals opens in a new tab or window or QIMR Berghofer - Melanoma Risk Predictor opens in a new tab or window)
Pancreatic cancer
Surveillance
In a Dutch-based 20-year prospective follow-up study evaluating pancreatic screening with MRCP +/- EUS in CDKN2A carriers, 347 germline pathogenic variant carriers participated in surveillance and were followed for a median of 5.6 years (interquartile range 2.3 to 9.9 years).r The cumulative incidence of pancreatic ductal adenocarcinoma (PDAC) by age 70 years was 20.7%, with surveillance leading to detection of resectable, early stage PDAC. 80% of affected patients were found to have resectable disease, with a third of patients diagnosed with stage I PDAC.r This compared favourably with general population data where only 10-15% of pancreatic cancers are resectable at diagnosis. 5-year overall survival (OS) rate in the study population was 32.4% compared with 5% 5-year OS in sporadic PDACs.r This study primarily consisted of patients with the CDKN2A c.225_243del variant and therefore there is still some uncertainty regarding the generalisation of this data to support surveillance in all CDKN2A pathogenic variant carriers. This is due to undefined pancreatic risk in other CDKN2A variants. Pancreatic surveillance itself is effective as a screening tool.
If surveillance is undertaken, it should be done in a high-volume centre after discussion of the limitations of screening, including the risk of detecting benign or indeterminate pancreatic abnormalities, the potential complications of the surveillance modality used and the uncertainties about the benefit of surveillance (if any) on mortality and morbidity from pancreatic cancer. Most surveillance detected cystic lesions are small and will not warrant biopsy, surgical resection, or any other intervention. A community-based screening study of 75 high-risk individuals based on family history and underlying germline pathogenic variant (in a range of pancreatic cancer predisposition genes) detected pancreatic lesions in 58.7% of study participants on initial MRCP, with 52% representing simple cysts.r The remaining 5 (6.7%) study participants were further investigated with EUS+/- FNA biopsy confirming benign aetiology. One participant proceeded to pancreatoduodenectomy; pathology revealed an intraductal papillary mucinous neoplasm and a low-grade pancreatic intraepithelial neoplasia (PanIN-1A).r
Not smoking is recommended because pancreatic cancer has a known association with smoking and there are reports of an increased risk of smoking-related head-and-neck cancers in CDKN2A pathogenic variant positive families.r
Melanoma-astrocytoma syndrome
There are case reports of patients with multiple peripheral and central nervous system (CNS) tumours who have pathogenic variants in CDKN2A, known as melanoma-astrocytoma syndrome (MAS). There are less than 15 families with MAS in the world. CNS tumours reported include glioblastomas, gliosarcoma and astrocytoma.r This is exceedingly rare and there is no evidence for addition of CNS surveillance imaging. An NF1-like phenotype has been reported in multiple patients with MAS with propensity to develop neurofibromas and nerve sheath tumours.r
Genotype-phenotype correlation
CDKN2A encodes for two proteins, namely p16INK4A and p14ARF, critical for the regulation of cell cycle pathways.r There have been increasing reports of genotype-phenotype association based on the protein affected. Analysis of a Dutch CDKN2A cohort showed pancreatic cancer occurrence in 58% of families with p16 affecting variants but none in the p14 affecting families.r On the other hand, a majority of patients (93%) with MAS had a variant that altered p14.r These reports of genotype-phenotype correlation are limited by the small sample size and limited variants, especially in the Dutch cohort.r