Environmental Exposures Such as Smoking and Low Vitamin D Are Predictive of Poor Outcome in Cutaneous Melanoma rather than Other Deprivation Measures.

A lack of basic resources within a society (deprivation) is associated with increased cancer mortality, and this relationship has been described for melanoma. We have previously reported the association of smoking and low vitamin D levels with melanoma death. In this study, we further explored the associations of these with melanoma in addition to deprivation and socio-economic stressors. In this analysis of 2,183 population-ascertained primary cutaneous melanoma patients, clinical, demographic, and socio-economic variables were assessed as predictors of tumor thickness, melanoma death and overall death. Using the Townsend deprivation score, the most deprived group did not have thicker tumors compared to the least deprived. Of the World Health Organization 25x25 risk factors for premature death, smoking and body mass index (BMI) were independently associated with thicker tumors. Low vitamin D was also independently associated with thicker tumors. No socio-economic stressors were independent predictors of thickness. Smoking was confirmed as a key predictor of melanoma death and overall death, as were low vitamin D levels, independent of other measures of deprivation. Neither BMI nor the Townsend deprivation score were predictive in either survival analysis. We report evidence for the role of smoking, vitamin D, and BMI in melanoma progression independent of a postcode-derived measure of deprivation.

Associations of pigmentary and naevus phenotype with melanoma risk in two populations with comparable ancestry but contrasting levels of ambient sun exposure.

BACKGROUND: People at high risk of developing melanoma are usually identified by pigmentary and naevus phenotypes. OBJECTIVE: We examined whether associations of these phenotypes with melanoma risk differed by ambient sun exposure or participant characteristics in two population-based, case-control studies with comparable ancestry but different ambient sun exposure. METHODS: Data were analysed from 616 cases and 496 controls from the Australian Melanoma Family Study and 2012 cases and 504 controls from the Leeds (UK) case-control study. Questionnaire, interview and dermatological skin examination data were collected using the same measurement protocols. Relative risks were estimated as odds ratios using unconditional logistic regression, adjusted for potential confounders. RESULTS: Hair and skin colour were the strongest pigmentary phenotype risk factors. All associations of pigmentary phenotype with melanoma risk were similar across countries. The median number of clinically assessed naevi was approximately three times higher in Australia than Leeds, but the relative risks for melanoma associated with each additional common or dysplastic naevus were higher for Leeds than Australia, especially for naevi on the upper and lower limbs. Higher naevus counts on the head and neck were associated with a stronger relative risk for melanoma for women than men. The two countries had similar relative risks for melanoma based on self-reported naevus density categories, but personal perceptions of naevus number differed by country. There was no consistent evidence of interactions between phenotypes on risk. CONCLUSIONS: Classifying people at high risk of melanoma based on their number of naevi should ideally take into account their country of residence, type of counts (clinical or self-reported), body site on which the naevus counts are measured and sex. The presence of naevi may be a stronger indicator of a genetic predisposition in the UK than in Australia based on less opportunity for sun exposure to influence naevus development.

Squamous and Neuroendocrine Specific Immunohistochemical Markers in Head and Neck Squamous Cell Carcinoma: A Tissue Microarray Study.

The performance characteristics of neuroendocrine-specific and squamous-specific immunohistochemical markers in head and neck squamous cell carcinomas (SCC), in particular in oropharyngeal tumors in this era of human papillomavirus (HPV)-induced cases, are not well-established. The differential diagnosis for poorly differentiated SCCs, for nonkeratinizing oropharyngeal SCCs, and for other specific SCC variants such as basaloid SCC and undifferentiated (or lymphoepithelial-like) carcinomas includes neuroendocrine carcinomas. Given that neuroendocrine carcinomas of the head and neck are aggressive regardless of HPV status, separating them from SCC is critically important. In this study, we examined the neuroendocrine markers CD56, synaptophysin, and chromogranin-A along with the squamous markers p40 and cytokeratin 5/6 in a large tissue microarray cohort of oral, oropharyngeal, laryngeal, and hypopharyngeal SCCs with known HPV results by RNA in situ hybridization for the oropharyngeal tumors. Results were stratified by site and specific SCC variant. The neuroendocrine stains were rarely expressed in SCC (<1% overall) with CD56 the least, and chromogranin-A the most, specific markers. Further, p40 and cytokeratin 5/6 were very consistently expressed in all head and neck SCC (>98% overall), including very strong, consistent staining in oropharyngeal HPV-related nonkeratinizing SCC. Undifferentiated (or lymphoepithelial-like) carcinomas of the oropharynx are more frequently p40 or cytokeratin 5/6 negative or show only weak or focal expression. In summary, markers of neuroendocrine and squamous differentiation show very high specificity and sensitivity, respectively, across the different types of head and neck SCC.

Malignant salivary gland tumours of the larynx: a single institution review.

Malignant salivary gland tumours of the larynx are very rare, with limited reports of clinical outcomes. We present the decade-long experience of a single institution. A 10-year retrospective chart review of a tertiary head and neck cancer centre was performed. Index patients were identified from a review of a pathology database, and reviewed by a head and neck pathologist. Patient demographics, presenting signs and symptoms, treatment modalities and clinical outcomes were extracted from electronic medical records. Six patients were included, with an age range of 44 to 69. All six had malignant laryngeal salivary gland tumours. Pathologies included: three adenoid cystic carcinoma (2 supraglottic, 1 subglottic), one mucoepidermoid carcinoma (supraglottic), one epithelial-myoepithelial carcinoma (supraglottic) and one adenocarcinoma (transglottic). All were treated with surgery (2 endolaryngeal, 4 open) and five of six with the addition of adjuvant therapy (4 radiotherapy, 1 concurrent chemoradiation). One patient had smoking history; no patients had significant alcohol history. With 4.5 years of median follow-up, none of the patients has had recurrence or local/distant metastasis. Salivary gland tumours of the larynx present in mid to late-age, and can be successfully managed with a multi-modality approach, resulting in excellent local and regional control rates.

Vitamin D, vitamin A, the primary melanoma transcriptome and survival.

Survival from melanoma is influenced by several, well-established clinical and histopathological factors, e.g. age, Breslow thickness and microscopic ulceration. We (the Section of Epidemiology and Biostatistics, University of Leeds) have carried out research to better understand the biological basis for these observations. Preliminary results indicated a protective role for vitamin D in melanoma relapse and that higher vitamin D was associated with thinner primary melanomas. Funding from the British Skin Foundation enabled JNB to establish a study of the effects of vitamin A in melanoma. The results suggested that vitamin A could reduce the protective effect of vitamin D in terms of overall survival. Therefore, we propose that vitamin D3 supplementation alone might be preferable to combined multivitamin preparations, where vitamin D supplementation is deemed to be appropriate. Proving a causal link between vitamin D and melanoma-specific survival is challenging. We have shown limited evidence of causation in a Mendelian randomization experiment (described in more detail later). Recent work in Leeds has also shown that higher vitamin D may be protective for microscopic ulceration. Taken together, vitamin D appears to be associated with less aggressive primary melanomas and may itself influence outcome. We continue to explore the role of vitamin D in melanoma survival and the optimum levels that might be crucial.

Non-epithelial tumors of the larynx: a single institution review.

AIM: Non-epithelial tumors of the larynx are rare and encompass a wide range of pathology. We present the decade-long experience of a single institution to define clinical presentations and outcomes. MATERIAL AND METHODS: This is a ten year retrospective chart review of a tertiary head and neck cancer center. Index patients were identified from a review of a pathology database, and patient demographics, presenting signs and symptoms, treatment modalities, and clinical outcomes were extracted from electronic medical records. Epithelial tumors (squamous cell carcinoma, spindle cell carcinoma, and salivary tumors), granulomas, sarcoidosis, papilloma, and amyloidosis were all excluded. RESULTS: Twenty-four patients with ages ranging from 2months-old to 84years were identified. Malignant lesions (11) included chondrosarcoma (6), Kaposi's sarcoma (2), metastatic melanoma, synovial cell sarcoma, and T cell neoplasm. Six were operated upon endolaryngeally, but four required either upfront or salvage total laryngectomy. Two received adjuvant therapy. Benign lesions (13) included hemangioma (4), granular cell tumor (3), myofibroblastic tumor (2), schwannoma (2), chondroma, and ossifying fibromyxoid tumor. Nine underwent endolaryngeal operations, and four were managed medically or with observation. None have required aggressive open resection or total laryngectomy. CONCLUSION: Treatment approach of non-epithelial tumors of the larynx depends on the site and extent of the tumor, histology, and sensitivity of adjuvant therapy. Benign tumors can be managed without need for aggressive resection thereby sparing laryngeal function.

Genomic alterations in head and neck squamous cell carcinoma determined by cancer gene-targeted sequencing.

BACKGROUND: To determine genomic alterations in head and neck squamous cell carcinoma (HNSCC) using formalin-fixed, paraffin-embedded (FFPE) tumors obtained through routine clinical practice, selected cancer-related genes were evaluated and compared with alterations seen in frozen tumors obtained through research studies. PATIENTS AND METHODS: DNA samples obtained from 252 FFPE HNSCC were analyzed using next-generation sequencing-based (NGS) clinical assay to determine sequence and copy number variations in 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. Human papillomavirus (HPV) status was determined by presence of the HPV DNA sequence in all samples and corroborated with high-risk HPV in situ hybridization (ISH) and p16 immunohistochemical (IHC) staining in a subset of tumors. Sequencing data from 399 frozen tumors in The Cancer Genome Atlas and University of Chicago public datasets were analyzed for comparison. RESULTS: Among 252 FFPE HNSCC, 84 (33%) were HPV positive and 168 (67%) were HPV negative by sequencing. A subset of 40 tumors with HPV ISH and p16 IHC results showed complete concordance with NGS-derived HPV status. The most common genes with genomic alterations were PIK3CA and PTEN in HPV-positive tumors and TP53 and CDKN2A/B in HPV-negative tumors. In the pathway analysis, the PI3K pathway in HPV-positive tumors and DNA repair-p53 and cell cycle pathways in HPV-negative tumors were frequently altered. The HPV-positive oropharynx and HPV-positive nasal cavity/paranasal sinus carcinoma shared similar mutational profiles. CONCLUSION: The genomic profile of FFPE HNSCC tumors obtained through routine clinical practice is comparable with frozen tumors studied in research setting, demonstrating the feasibility of comprehensive genomic profiling in a clinical setting. However, the clinical significance of these genomic alterations requires further investigation through application of these genomic profiles as integral biomarkers in clinical trials.

Prevalence and correlates of unmet supportive care needs in patients with resected invasive cutaneous melanoma.

BACKGROUND: Knowledge about supportive care needs in patients with cutaneous invasive melanoma is scarce. We examined the unmet needs of melanoma patients treated with surgery and factors associated with these needs to assist health professionals identify areas needing clinical attention. PATIENTS AND METHODS: Cross-sectional multisite survey of UK patients ascertained 3 months to 5 years after complete resection of stage I-III cutaneous melanoma. Participants completed the following validated questionnaires: Supportive Care Needs Survey (SCNS-SF34 with melanoma module), Hospital Anxiety and Depression Scale and 51-item Functional Assessment of Cancer Therapy-Melanoma quality-of-life scale. RESULTS: A total of 472 participants were recruited [319 (67%) clinical stage I-II). Mean age was 60 years (standard deviation = 14) and 255 (54%) were female. One hundred and twenty-three (27%) participants reported at least one unmet need (mostly 'low' level). The most frequently reported unmet needs were fears of cancer returning (n = 138, 29%), uncertainty about the future (n = 119, 25%), lack of information about risk of recurrence (n = 112, 24%) and about possible outcomes if melanoma were to spread (n = 91, 20%). One hundred and thirty-eight (29%) participants reported anxiety and 51 (11%) depression at clinical or subclinical levels. Patients with nodal disease had a significantly higher level of unmet supportive care needs (P < 0.001) as did patients with anxiety or depression (P < 0.001). Key correlates of the total SCNS-SF34 score for unmet supportive care needs were younger age (odds ratio, OR = 2.23, P < 0.001) and leaving school early (OR = 4.85, P < 0.001), while better emotional (OR = 0.89, P < 0.001) and social well-being (OR = 0.91, P < 0.001) were linked with fewer unmet needs. Neither patients' sex nor tumour thickness was associated with unmet needs. CONCLUSIONS: Around a quarter of melanoma patients may have unmet support needs in the mid to long term after primary treatment. In particular, patients who are younger, less educated, distressed or socially isolated could benefit from more support.

Plasma osteopontin concentrations in patients with cutaneous melanoma.

An effective circulating tumour marker is needed for melanoma especially with the advent of targeted therapies. Gene expression studies examining primary melanomas have shown that increased expression of osteopontin (SPP1) is associated with poor prognosis. Studies subsequently reported higher blood levels in melanoma patients with metastatic disease than those without. This study was designed to determine whether osteopontin plasma concentrations in disease-free patients after initial treatment predict survival. An enzyme-linked immunosorbent assay (ELISA) was used to measure osteopontin levels in stored plasma samples (N=215) from participants in the Leeds Melanoma Cohort. AJCC stage at sampling was statistically significant associated with osteopontin levels (p=0.03). Participants with untreated stage IV disease at sampling (n=10) had higher median osteopontin levels compared to those with treated stage I-III disease (n=158) (p<0.001) confirming previous findings. There was a trend for increased risk of death with increasing osteopontin levels but this was not statistically significant. If a level of 103.14 ng/ml (95th centile of healthy controls) was taken as the upper end of the normal range then 2.5% of patients with treated stage I-III (4/110), 17.6% of patients with untreated stage III (3/17) and 30% of patients with untreated stage IV disease (3/10) had higher levels. These findings suggest that plasma osteopontin levels warrant investigation as a tumour marker in a larger study in which the significance of change in levels over time should be studied in relation to detectable disease recurrence.

An exploration of reported mortality from cutaneous squamous cell carcinoma using death certification and cancer registry data.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is increasing in incidence but mortality rates are low. Identifying high-risk tumours is important when rationalizing clinical review for patients with cSCC. OBJECTIVES: To assess the accuracy of death certification in cases of reported fatal cSCC and to identify risk factors for fatal cSCC. METHODS: A retrospective, observational study of cases of fatal cSCC over 11 years (1993-2004) in Leeds, identified in cancer registry and death certification data. RESULTS: Fifty-eight patients were recorded by the registry as having fatal cSCC in this period. Review of case notes and pathology specimens, where available (34 cases), confirmed that 21/34 patients had died of cSCC. Five were on the ear and none on the lip. Four patients had been treated for leukaemia or lymphoma and one was a renal transplant recipient. On pathology review five patients proved to have had malignant adnexal tumours rather than cSCC, and one a melanoma. In addition, three patients had disease of the ear canal or vulva. CONCLUSIONS: A proportion of deaths were falsely attributed to cSCC as a result of inaccurate histological diagnosis. Some fatalities were related to tumours in sites known to be at higher risk, and a significant proportion was postulated to be related to immunosuppression. In those cases attributed to cSCC in which this could be assessed, the majority were American Joint Committee on Cancer stage 2 and only 24% were in high-risk sites.

Cutaneous adverse events associated with vemurafenib in patients with metastatic melanoma: practical advice on diagnosis, prevention and management of the main treatment-related skin toxicities.

Until recently, no effective treatment was available for patients with metastatic malignant melanoma, and median overall survival was little more than 6 months with the current standard of care, dacarbazine. In 2012, the first specific BRAF mutation inhibitor, vemurafenib, was licensed for the monotherapy of adults with BRAF V600 mutation-positive unresectable or metastatic melanoma. Like other targeted therapies, vemurafenib is associated with a predictable pattern of adverse events, including skin toxicities. We review the most common cutaneous adverse events associated with vemurafenib, based on data from clinical trials, and our own experiences of treating patients in trials and clinical practice. Overall, these toxicities are not preventable, but they rarely necessitate permanent treatment discontinuation and are generally manageable with dose modification and supportive care. We provide a treatment algorithm offering guidance on the most appropriate approach to managing the main skin toxicities to help clinicians unfamiliar with this novel agent to become confident in using vemurafenib effectively in the management of patients with metastatic melanoma.

The determinants of periorbital skin ageing in participants of a melanoma case-control study in the U.K.

BACKGROUND: Skin ageing is said to be caused by multiple factors. The relationship with sun exposure is of particular interest because the detrimental cutaneous effects of the sun may be a strong motivator to sun protection. We report a study of skin ageing in participants of an epidemiological study of melanoma. OBJECTIVES: To determine the predictors of periorbital cutaneous ageing and whether it could be used as an objective marker of sun exposure. METHODS: Photographs of the periorbital skin in 1341 participants were graded for wrinkles, degree of vascularity and blotchy pigmentation and the resultant data assessed in relation to reported sun exposure, sunscreen use, body mass index (BMI), smoking and the melanocortin 1 receptor (MC1R) gene status. Data were analysed using proportional odds regression. RESULTS: Wrinkling was associated with age and heavy smoking. Use of higher sun-protection factor sunscreen was protective (P = 0·01). Age, male sex, MC1R variants ('r', P=0·01; 'R', P=0·02), higher reported daily sun exposure (P=0·02), increased BMI (P=0·01) and smoking (P=0·02) were risk factors for hypervascularity. Blotchy pigmentation was associated with age, male sex, higher education and higher weekday sun exposure (P=0·03). More frequent sunscreen use (P=0·02) and MC1R variants ('r', P=0·03; 'R', P=0·001) were protective. CONCLUSIONS: Periorbital wrinkling is a poor biomarker of reported sun exposure. Vascularity is a better biomarker as is blotchy pigmentation, the latter in darker-skinned individuals. In summary, male sex, sun exposure, smoking, obesity and MC1R variants were associated with measures of cutaneous ageing. Sunscreen use showed some evidence of being protective.

Melanoma sentinel node biopsy and prediction models for relapse and overall survival.

BACKGROUND: To optimise predictive models for sentinal node biopsy (SNB) positivity, relapse and survival, using clinico-pathological characteristics and osteopontin gene expression in primary melanomas. METHODS: A comparison of the clinico-pathological characteristics of SNB positive and negative cases was carried out in 561 melanoma patients. In 199 patients, gene expression in formalin-fixed primary tumours was studied using Illumina's DASL assay. A cross validation approach was used to test prognostic predictive models and receiver operating characteristic curves were produced. RESULTS: Independent predictors of SNB positivity were Breslow thickness, mitotic count and tumour site. Osteopontin expression best predicted SNB positivity (P=2.4 × 10⁻7), remaining significant in multivariable analysis. Osteopontin expression, combined with thickness, mitotic count and site, gave the best area under the curve (AUC) to predict SNB positivity (72.6%). Independent predictors of relapse-free survival were SNB status, thickness, site, ulceration and vessel invasion, whereas only SNB status and thickness predicted overall survival. Using clinico-pathological features (thickness, mitotic count, ulceration, vessel invasion, site, age and sex) gave a better AUC to predict relapse (71.0%) and survival (70.0%) than SNB status alone (57.0, 55.0%). In patients with gene expression data, the SNB status combined with the clinico-pathological features produced the best prediction of relapse (72.7%) and survival (69.0%), which was not increased further with osteopontin expression (72.7, 68.0%). CONCLUSION: Use of these models should be tested in other data sets in order to improve predictive and prognostic data for patients.

Association of MC1R variants and host phenotypes with melanoma risk in CDKN2A mutation carriers: a GenoMEL study.

BACKGROUND: Carrying the cyclin-dependent kinase inhibitor 2A (CDKN2A) germline mutations is associated with a high risk for melanoma. Penetrance of CDKN2A mutations is modified by pigmentation characteristics, nevus phenotypes, and some variants of the melanocortin-1 receptor gene (MC1R), which is known to have a role in the pigmentation process. However, investigation of the associations of both MC1R variants and host phenotypes with melanoma risk has been limited. METHODS: We included 815 CDKN2A mutation carriers (473 affected, and 342 unaffected, with melanoma) from 186 families from 15 centers in Europe, North America, and Australia who participated in the Melanoma Genetics Consortium. In this family-based study, we assessed the associations of the four most frequent MC1R variants (V60L, V92M, R151C, and R160W) and the number of variants (1, ≥2 variants), alone or jointly with the host phenotypes (hair color, propensity to sunburn, and number of nevi), with melanoma risk in CDKN2A mutation carriers. These associations were estimated and tested using generalized estimating equations. All statistical tests were two-sided. RESULTS: Carrying any one of the four most frequent MC1R variants (V60L, V92M, R151C, R160W) in CDKN2A mutation carriers was associated with a statistically significantly increased risk for melanoma across all continents (1.24 × 10(-6) ≤ P ≤ .0007). A consistent pattern of increase in melanoma risk was also associated with increase in number of MC1R variants. The risk of melanoma associated with at least two MC1R variants was 2.6-fold higher than the risk associated with only one variant (odds ratio = 5.83 [95% confidence interval = 3.60 to 9.46] vs 2.25 [95% confidence interval = 1.44 to 3.52]; P(trend) = 1.86 × 10(-8)). The joint analysis of MC1R variants and host phenotypes showed statistically significant associations of melanoma risk, together with MC1R variants (.0001 ≤ P ≤ .04), hair color (.006 ≤ P ≤ .06), and number of nevi (6.9 × 10(-6) ≤ P ≤ .02). CONCLUSION: Results show that MC1R variants, hair color, and number of nevi were jointly associated with melanoma risk in CDKN2A mutation carriers. This joint association may have important consequences for risk assessments in familial settings.

Revised UK guidelines for the management of cutaneous melanoma 2010.

These guidelines for the management of cutaneous melanoma present an evidence-based guidance for treatment, with identification of the strength of evidence available at the time of preparation of the guidelines, and a brief overview of epidemiology, diagnosis, investigation, and follow-up.

A retrospective study addressed to understanding what predicts severe histological dysplasia/early melanoma in excised atypical melanocytic lesions.

BACKGROUND: Atypical naevi are common benign skin lesions but are also recognized both as precursors of and risk factors for melanoma. It is therefore imperative to excise those lesions that are either likely to progress or are already progressing to melanoma. Clinically, however, it may be difficult to distinguish these from benign atypical naevi with bland histology. OBJECTIVES: To analyse the clinical characteristics of excised melanocytic lesions and to identify the predictors of severe histological atypia/melanoma in situ and invasive melanoma. METHODS: The case notes of 434 patients who had melanocytic lesions removed at a pigmented lesion clinic were studied retrospectively. A single pathologist reviewed the excised lesions and clinical characteristics predictive of malignancy were identified. RESULTS: The best predictors of melanoma were older age, history of change and site on an extremity, but only older age was predictive of severe histological atypia/melanoma in situ as opposed to mild to moderate atypical histology. CONCLUSIONS: These results confirm the difficulty of differentiating accurately between benign atypical naevi and borderline lesions or early melanoma in a clinical setting. It is therefore necessary to have a sufficiently low threshold for excision to avoid missing early melanomas, particularly in older patients presenting with lesions on the extremities.

A child with laryngo-onychocutaneous syndrome partially responsive to treatment with thalidomide.

Laryngo-onychocutaneous syndrome (LOCS) is a condition characterized by erosive or ulcerative skin lesions associated with excessive granulation tissue, at sites of trauma such as the digits, elbows and knees. Similar lesions can occur within the conjunctival mucosa, leading to corneal scarring and blindness. The main complications, however, occur in the respiratory tract, where a similar process of erosions and subsequent formation of granulation tissue causes airway obstruction which may lead to premature death. LOCS is now believed to be a nonblistering variant of junctional epidermolysis bullosa and to date there are no efficacious treatments available. We report a 16-year-old girl with LOCS who failed to respond to methylprednisolone and cyclophosphamide, but had a partial response to oral thalidomide with marked decrease in granulation tissue and tracheal secretions. Interruption of treatment resulted in prompt resurgence of the granulation tissue which was again controlled by reintroduction of thalidomide. We propose that in the absence of effective therapies for LOCS, a trial of thalidomide in these patients should be considered.

Recent trends in cutaneous malignant melanoma in the Yorkshire region of England; incidence, mortality and survival in relation to stage of disease, 1993-2003.

The aim of this study was to investigate recent trends in incidence, mortality and survival in patients diagnosed with malignant melanoma (MM) in relation to stage (Breslow thickness). Cases of primary invasive and in situ MM diagnosed between 1st January 1993 and 31st December 2003 in the former Yorkshire Health Authority were identified from cancer registry data. Over the study period, the incidence of invasive MM increased from 5.4 to 9.7 per 100,000 in male subjects and from 7.5 to 13.1 per 100,000 in female subjects. Most of this increase was seen in thin tumours (< 1.5 mm). Thin tumours were more likely to be diagnosed in the younger age groups and be classified as superficial spreading melanoma. In situ melanoma rates increased only slightly. Over the same time period, mortality rates have been relatively constant in both male and female subjects. Five-year relative survival varied from 91.8% (95% CI 90.4-93.1) for patients with thin tumours to 41.5% (95% CI 36.7-46.3) for those with thick tumours. In multivariable analyses, Breslow thickness was the most important prognostic factor. Age, sex and level of deprivation were also identified as independent prognostic factors. The trends in incidence suggest that the increase is real, rather than an artefact of increased scrutiny, implying that primary prevention in the Yorkshire area of the UK has failed to control trends in incidence. Mortality, in contrast, appears to be levelling off, indicating that secondary prevention has been more effective.