J.E. Osborne

Vitamin D and systemic cancer: is this relevant to malignant melanoma?

Summary 1,25‐dihydroxyvitamin D3[1,25(OH)2D3] is a well‐known potent regulator of cell growth and differentiation and there is recent evidence of an effect on cell death, tumour invasion and angiogenesis, which makes it a candidate agent for cancer regulation. The classical synthetic pathway of 1,25(OH)2D3 involves 25‐ and 1α‐hydroxylation of vitamin D3, in the liver and kidney, respectively, of absorbed or skin‐synthesized vitamin D3. There is recent focus on the importance in growth control of local metabolism of 1,25(OH)2D3, which is a function of local tissue synthetic hydroxylases and particularly the principal catabolizing enzyme, 24‐hydroxylase. The classical signalling pathway of 1,25(OH)2D3 employs the vitamin D nuclear receptor (VDR), which is a transcription factor for 1,25(OH)2D3 target genes. Effects of this pathway include inhibition of cellular growth and invasion. Cytoplasmic signalling pathways are increasingly being recognized, which similarly may regulate growth and differentiation but also apoptosis.

An evaluation of the revised seven-point checklist for the early diagnosis of cutaneous malignant melanoma.

Summary The seven‐point checklist has been widely advocated as a sensitive screening test for malignant melanoma. A number of groups have questioned the sensitivity of this system, especially in the detection of early lesions. We have assessed the sensitivity and specificity of the revised seven‐point checklist when applied to lesions seen in our department over a 26‐month period and compared it with the American ABCDE evaluation system. All melanomas (n= 65) were detected using the revised seven‐point checklist and all were found to have at least one of the three major criteria defined by that system. Five (7·7%) melanomas were not picked up by the ABCDE checklist. Of 100 randomly selected patients who attended the clinic during the same period, with clinically diagnosed benign pigmented lesions, 63 had at least one major feature of the revised seven‐point checklist. Forty (62%) of the melanomas, compared with only (4%) of the benign lesions, had more than one major feature. This study confirms the sensitivity of the revised seven‐point checklist in the diagnosis of cutaneous malignant melanoma.

Vitamin D receptor gene polymorphisms, particularly the novel A-1012g promoter polymorphism, are associated with vitamin D3 responsiveness and non-familial susceptibility in psoriasis

Psoriasis is a genetically determined disease characterized by hyperproliferation and disordered maturation of the epidermis. Th1 lymphocytes are implicated in its pathogenesis. The vitamin D receptor (VDR) is a candidate modifying gene, having immunosuppressive effects and being involved in anti-proliferative and pro-differentiation pathways in keratinocytes. There is suggestive evidence that the A allele of the A-1012G polymorphism is associated with down-regulation of the Th1 response, via GATA-3. The F and T alleles of Fok1 and Taq1 have been associated with increased VDR activity. The present study aimed to test the hypothesis that the A allele of A-1012G is protective for occurrence and severity of psoriasis and enhances therapeutic response to vitamin D analogues and that these effects would be additive to those of Fok1 and Taq1. The study group comprised 206 psoriasis patients who had received topical calcipotriol treatment and 80 controls. There was no significant linkage disequilibrium between any pair of the three polymorphic sites (P=0.3–0.8). The A, F and T alleles were positively associated with calcipotriol response: AA genotype (compared to AG/GG), odds ratio (OR)=2.18 (P=0.04); TT, OR=1.97 (P=0.03); AAFF genotype combination, OR=4.11 (P=0.03); AATT, OR=5.64 (P=0.005); and FFTT, OR=3.22 (P=0.01). Comparing patients without, to patients with, a family history of psoriasis, the A allele was under represented (P=0.01) and the AAFF genotype combination even more so (compared to residual genotypes) (OR=0.24; P=0.005). AAFF was also under-represented in patients without a family history compared to controls (OR=0.31; P=0.04). There were no associations of family history with Fok1 and Taq1. There were no associations of severity of psoriasis with any polymorphism. In conclusion, the A-1012G, Fok1 and Taq1 VDR polymorphisms were associated with response to calcipotriol. A-1012G and Fok1 were associated with susceptibility to non-familial psoriasis.

The initial effects on workload and outcome of a public education campaign on early diagnosis and treatment of malignant melanoma in Leicestershire.

We report our experience of the initial effects of a publicity campaign directed at early presentation of malignant melanoma in Leicestershire. The campaign resulted in a dramatic increase in workload and, at the pigmented lesion clinic, the numbers of new patients rose from 12.3 to 54.5 per clinic. There was a large rise in the number of new melanomas presenting in Leicestershire: from 1.02 per week before the campaign to 1.88 per week in the immediate postpublicity period. This was statistically significant (P<0.001), Although there was also an apparently encouraging rise in the percentage of thinner ‘good prognosis’ tumours, it was not possible to isolate this statistically from a pre‐existing trend.

Cytochrome P450 CYP2D6 genotypes: association with hair colour, Breslow thickness and melanocyte stimulating hormone receptor alleles in patients with malignant melanoma.

We previously identified associations between polymorphism in the cytochrome P450 CYP2D6 gene and outcome in several cancers. We have now examined the hypothesis that homozygosity for the mutant alleles, CYP2D6*4 and CYP2D6*3, is associated with susceptibility and outcome in malignant melanoma. Outcome was assessed by Breslow thickness. We first confirmed previous reports that these mutant alleles are associated with increased susceptibility to malignant melanoma. For example, the frequency of homozygosity for CYP2D6*4 was significantly greater (P = 0.006, chi-squared 1 d.f. = 7.4, odds ratio 2.2, 95% confidence interval 1.2, 3.9) in cases (9.1%) than in control individuals (4.3%). The frequency of homozygosity for the mutant alleles was next examined in the malignant melanoma cases grouped on the basis of characteristics associated with malignant melanoma risk. Homozygosity was significantly more common (P = 0.038) in cases with red/blonde hair than in those with brown/black hair. We found no associations between the CYP2D6 genotype and sex, skin type or eye colour. The possible association of CYP2D6 with outcome was assessed by comparing genotype frequencies in patients with tumours of Breslow thickness < 1.5 mm with those whose tumours were > or = 1.5 mm. In patients with red/blonde, but not brown or black hair, homozygosity for CYP2D6*4 was significantly associated with thicker lesions in a multivariate model (P = 0.036). We further examined the association of CYP2D6*4 homozygosity with red/blonde hair by classifying patients on the basis of homo- or heterozygosity for wild-type or val92met, asp294his or asp84glu melanocyte stimulating hormone receptor (MC1R) alleles. None of the nine patients with brown/black hair with the asp294his allele were homozygotes for CYP2D6*4. By contrast, in the patients with red/blonde hair, three of five cases with asp294his were homozygotes for the mutant CYP2D6 allele. The difference in the frequency of CYP2D6*4 homozygotes in the red/blonde cases with wild-type MC1R alleles compared with those with asp294his was significant (exact P = 0.029). No associations between val92his or asp84glu and CYP2D6 alleles were identified.

Comparison of diagnostic accuracy for cutaneous malignant melanoma between general dermatology, plastic surgery and pigmented lesion clinics

Summary Background Since the 1980s there have been dedicated pigmented lesion clinics (PLCs) in the U.K. Important considerations when comparing the efficacy of the PLC with other referral clinics include diagnostic accuracy.

Clinical correlates of Breslow thickness of malignant melanoma

Background  Breslow thickness is a major predictor of prognosis in cutaneous malignant melanoma (MM) and patients continue to present with thick lesions, which have a poorer prognosis.

False negative clinical diagnoses of malignant melanoma.

The false negative rate for the clinical diagnosis (FNR) for malignant melanoma is reported to be of the order of 20–50%. The aim of this study was to investigate possible predictor variables for FNR, with particular reference to the features and score of the seven‐point check‐list within the total population (778) of histologically proved malignant melanomas presenting in Leicestershire between 1982 and 1996. The FNR was 18.5%. The check‐list would have failed as a referral indication in only 0.8–1.1% of the lesions. The major check‐list features occurred more commonly than the minor features, excepting size ≥ 7 mm, confirming the diagnostic importance of the major criteria. The FNR was unaffected by age or sex. More rarely involved sites had higher rates (31–42%), and the face was a particularly difficult diagnostic site. Clinical features of lesions associated with a higher FNR were lack of irregular pigmentation and shape, altered sensation, the presence of inflammation and size < 7 mm. The FNR was inversely related to the total score and major feature score, but directly related to the minor score. The minor features, in addition to the major features, are potentially valuable in avoiding false negative diagnoses and we suggest their retention as part of the check‐list. There was only one patient, in whom the diagnosis of melanoma was initially missed and who was not biopsied on presentation to hospital, who re‐presented after 1 year. However, the study illustrates the importance of avoiding a false negative diagnosis as there was marked delay in the excision of such lesions.

The unfavorable effect of the A allele of the vitamin D receptor promoter polymorphism A-1012G has different mechanisms related to susceptibility and outcome of malignant melanoma.

The A allele of the A-1012G (rs4516035) vitamin D receptor (VDR) promoter polymorphism is associated with increased susceptibility and worsened outcome in malignant melanoma (MM). The A allele contains a GATA-3 binding site. There is a second polymorphism in the same promoter region, G-1520C (rs7139166), and there is potential for another GATA binding site in the G allele. Here, we tested the hypothesis that the G-1520A-1012 haplotype might be a greater risk factor for MM than A-1012 alone. The A allele of A-1012G was preferentially linked to G of G-1520C and was more frequent in MM patients (P=0.011) but G of G-1520C was not (P=0.756). The CA haplotype was a very significant risk factor for MM (P=0.0001) while the CG haplotype was protective (P=0.014, combined model P=0.00002). There was no effect of GA haplotype (P=0.931), suggesting that that the difference in frequencies of the A allele between patients and controls was accounted for by the differences in frequencies of the CA haplotype. The A allele of A-1012G was more frequent in patients with metastasis (P=0.054) than MM patients without metastasis, as was the G allele of G-1520C (P=0.028). The GA haplotype was more frequent in patients with metastasis (P=0.015), while frequencies of CA were similar. We suggest that the different roles of the A allele of A-1012G in susceptibility and metastasis risk may be a function of the availability of transcription factors in the differing cellular backgrounds related to susceptibility and progression of MM.

Skin cancer screening and surveillance

It has been suggested that the burden of skin cancer might be lowered through effective primary prevention measures with particular emphasis on reduction of sun exposure starting in childhood, and secondary preventive strategies focusing on early detection. Public education and screening may assist earlier diagnosis and treatment and possibly result in improved survival. In the U.K. there have been several public education campaigns focusing on the personal recognition of the early signs and symptoms of malignant melanoma (MM), but little similar attention to nonmelanoma skin cancer (NMSC). There are no formal screening programmes for skin cancer in the U.K. and international guidelines concerning clinical skin examination lack consensus. Recently, the American College of Preventive Medicine recommended screening of populations at high risk of MM. However, in Australia, general population screening has not been recommended due to the lack of rigorously acquired evidence. In the U.K., referral of suspected malignancies is either via dermatology and plastic surgery clinics or, in the case of MM, to pigmented lesion clinics (PLCs). Recent Government guidelines state that patients with suspected skin cancer, with the exception of basal cell carcinomas (BCCs), should be seen by a specialist within 2 weeks of referral by their General Practitioner (GP). Currently there is little evidence to show that early detection reduces morbidity and mortality from skin cancer. There is some evidence that the public education campaigns for MM have resulted in increased numbers of thin lesions presenting, and one study in Scotland showed improved survival, but only in females. In contrast, the Cancer Research Campaign was unable to detect any significant reduction in MM mortality as a result of a health education programme for early detection, although there is likely to be a long lag time between the initiation of any programme and changes in incidence or mortality. However, surveillance of high-risk groups has been shown to detect MM at an earlier stage than otherwise would have occurred. The aims of this review are to describe accepted criteria for successful screening and to consider whether skin cancer fulfils them; to define high-risk groups that may benefit most from screening; to examine the effectiveness of reported screening programmes, in terms of detection rates; and finally, to review future developments that may further refine the identification of high risk groups.