Dermoscopy for melanoma detection and triage in primary care: a systematic review.

OBJECTIVE: Most skin lesions first present in primary care, where distinguishing rare melanomas from benign lesions can be challenging. Dermoscopy improves diagnostic accuracy among specialists and is promoted for use by primary care physicians (PCPs). However, when used by untrained clinicians, accuracy may be no better than visual inspection. This study aimed to undertake a systematic review of literature reporting use of dermoscopy to triage suspicious skin lesions in primary care settings, and challenges for implementation. DESIGN: A systematic literature review and narrative synthesis. DATA SOURCES: We searched MEDLINE, Cochrane Central, EMBASE, Cumulative Index to Nursing and Allied Health Literature, and SCOPUS bibliographic databases from 1 January 1990 to 31 December 2017, without language restrictions. INCLUSION CRITERIA: Studies including assessment of dermoscopy accuracy, acceptability to patients and PCPs, training requirements, and cost-effectiveness of dermoscopy modes in primary care, including trials, diagnostic accuracy and acceptability studies. RESULTS: 23 studies met the review criteria, representing 49 769 lesions and 3708 PCPs, all from high-income countries. There was a paucity of studies set truly in primary care and the outcomes measured were diverse. The heterogeneity therefore made meta-analysis unfeasible; the data were synthesised through narrative review. Dermoscopy, with appropriate training, was associated with improved diagnostic accuracy for melanoma and benign lesions, and reduced unnecessary excisions and referrals. Teledermoscopy-based referral systems improved triage accuracy. Only three studies examined cost-effectiveness; hence, there was insufficient evidence to draw conclusions. Costs, training and time requirements were considered important implementation barriers. Patient satisfaction was seldom assessed. Computer-aided dermoscopy and other technological advances have not yet been tested in primary care. CONCLUSIONS: Dermoscopy could help PCPs triage suspicious lesions for biopsy, urgent referral or reassurance. However, it will be important to establish further evidence on minimum training requirements to reach competence, as well as the cost-effectiveness and patient acceptability of implementing dermoscopy in primary care. TRIAL REGISTRATION NUMBER: CRD42018091395.

Propranolol in the treatment of infantile haemangiomas: lessons from the European Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce survey.

BACKGROUND: Oral propranolol is widely prescribed as first-line treatment for infantile haemangiomas (IHs). Anecdotally, prescribing practice differs widely between centres. OBJECTIVES: The Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce was founded to establish patterns of use of propranolol in IHs. METHODS: Participating centres entered data on all of their patients who had completed treatment with oral propranolol for IHs, using an online data capture tool. RESULTS: The study cohort comprised 1097 children from 39 centres in eight European countries. 76·1% were female and 92·8% had a focal IH, with the remainder showing a segmental, multifocal or indeterminate pattern. The main indications for treatment were periocular location (29·3%), risk of cosmetic disfigurement (21·1%) and ulceration and bleeding (20·6%). In total 69·2% of patients were titrated up to a maintenance regimen, which consisted of 2 mg kg(-1) per day (85·8%) in the majority of cases. 91·4% of patients had an excellent or good response to treatment. Rebound growth occurred in 14·1% upon stopping, of whom 53·9% were restarted and treatment response was recaptured in 91·6% of cases. While there was no significant difference in the treatment response, comparing a daily maintenance dose of < 2 mg kg(-1) vs. 2 mg kg(-1) vs. > 2 mg kg(-1) , the risk of adverse events was significantly higher: odds ratio (OR) 1 vs. adjusted OR 0·70, 95% confidence interval (CI) 0·33-1·50, P = 0·36 vs. OR 2·38, 95% CI 1·04-5·46, P = 0·04, Ptrend < 0·001. CONCLUSIONS: The PITCH survey summarizes the use of oral propranolol across 39 European centres, in a variety of IH phases, and could be used to inform treatment guidelines and the design of an interventional study.

Mutations in AEC syndrome skin reveal a role for p63 in basement membrane adhesion, skin barrier integrity and hair follicle biology.

BACKGROUND: AEC (ankyloblepharon-ectodermal defects-clefting) syndrome is an autosomal dominant ectodermal dysplasia disorder caused by mutations in the transcription factor p63. Clinically, the skin is dry and often fragile; other features can include partial eyelid fusion (ankyloblepharon), hypodontia, orofacial clefting, sparse hair or alopecia, and nail dystrophy. OBJECTIVES: To investigate how p63 gene mutations affect gene and protein expression in AEC syndrome skin. METHODS: We performed microarray analysis on samples of intact and eroded AEC syndrome skin compared with control skin. Changes were verified by quantitative real-time reverse transcription-polymerase chain reaction and, for basal keratinocyte-associated genes, by immunohistochemistry and analysis of microdissected skin. RESULTS: We identified significant upregulation of six genes and downregulation of 69 genes in AEC syndrome skin, with the main changes in genes implicated in epidermal adhesion, skin barrier formation and hair follicle biology. There was reduced expression of genes encoding the basement membrane proteins FRAS1 and collagen VII, as well as the skin barrier-associated small proline-rich proteins 1A and 4, late cornified envelope protein 5A, hornerin, and lipid transporters including ALOX15B. Reduced expression of the hair-associated keratins 25, 27, 31, 33B, 34, 35, 81 and 85 was also noted. We also confirmed similar alterations in gene expression for 26 of the 75 genes in eroded AEC scalp skin. CONCLUSIONS: This study identifies specific changes in skin structural biology and signalling pathways that result from mutant p63 and provides new molecular insight into the AEC syndrome phenotype.

Pseudoepitheliomatous, keratotic and micaceous balanitis after penile squamous cell carcinoma.

Pseudoepitheliomatous keratotic and micaceous balanitis (PKMB) is a rare form of balanitis, with only a handful of cases reported since the disease was first described. Although the condition has been described as benign, there is increasing evidence of its premalignant potential, with several of the reported cases progressing to verrucous or squamous cell carcinoma (SCC). We report a case of PKMB following penile SCC and discuss the literature on this rare condition.

Multiple primary malignancies in patients with Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare malignant cutaneous tumour, the incidence of which is increasing. Second malignancies have been reported to occur with high incidence in these patients. OBJECTIVES: We report the rate and nature of multiple malignancies in patients with MCC treated over a 10 year period in Addenbrooke's Hospital in Cambridge, United Kingdom, as well as the temporal relationship of these additional malignancies to the diagnosis of MCC. RESULTS: The 27 patients had an approximately equal sex incidence with a median age at diagnosis of 79 years. Seventy percent (n=19) of patients had a second primary malignant tumour; and 7 of these patients had two or more tumours in addition to the MCC. Eighteen patients had additional cutaneous malignancies: melanoma, squamous cell carcinoma and basal cell carcinoma, and 8 patients presented non-cutaneous malignancy including colorectal, haematological and breast tumours. Of the 28 additional tumours in our patients, half were diagnosed prior to presentation of MCC, 32% within 6 months of diagnosis, and 18% between 6 months and 3 years after diagnosis. Possible reasons for the high rate of additional tumours in this population are discussed. CONCLUSIONS: Our figures reflect a higher incidence of multiple malignancies in those with Merkel cell tumour than has previously been reported. This has important implications for the care and surveillance of these patients.

Smoking related COPD and facial wrinkling: is there a common susceptibility?

BACKGROUND: Cigarette smoking causes accelerated facial wrinkling and predisposes to chronic obstructive pulmonary disease (COPD). However, it has long been recognised that there is a subgroup of susceptible smokers who are at increased risk of developing airflow obstruction. We have tested the hypothesis that there is a common susceptibility for the development of COPD and facial wrinkling in cigarette smokers. METHODS: One hundred and forty nine current and ex-smokers were recruited from a family based study of COPD genetics, 68 (45.6%) of whom fulfilled the definition of COPD. 124 (83.2%) had no or minor facial wrinkling (Daniell /=IV). Generalised estimating equations were used to adjust for familial correlations between related individuals and the potential confounding effects of age and pack years smoked. RESULTS: Forced expiratory volume in 1 second (FEV(1)) was significantly lower in those with wrinkles than in those without (mean difference in FEV(1) % predicted -13.7%, 95% CI -27.5 to 0.0, p = 0.05) and facial wrinkling was associated with a substantially increased risk of COPD (adjusted OR 5.0, 95% CI 1.3 to 18.5, p<0.02). The Daniell score correlated with the extent of emphysema on the CT scan (p<0.05) and facial wrinkling was also associated with a greater risk of more extensive emphysema (adjusted OR 3.0, 95% CI 1.0 to 9.3, p = 0.05). CONCLUSION: Facial wrinkling is associated with COPD in smokers, and both disease processes may share a common susceptibility. Facial wrinkling in smokers may therefore be a biomarker of susceptibility to COPD.

Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency.

Germline mutations of the fumarate hydratase (FH, fumarase) gene are found in the recessive FH deficiency syndrome and in dominantly inherited susceptibility to multiple cutaneous and uterine leiomyomatosis (MCUL). We have previously reported a number of germline FH mutations from MCUL patients. In this study, we report additional FH mutations in MCUL and FH deficiency patients. Mutations can readily be found in about 75% of MCUL cases and most cases of FH deficiency. Some of the more common FH mutations are probably derived from founding individuals. Protein-truncating FH mutations are functionally null alleles. Disease-associated missense FH changes map to highly conserved residues, mostly in or around the enzyme's active site or activation site; we predict that these mutations severely compromise enzyme function. The mutation spectra in FH deficiency and MCUL are similar, although in the latter mutations tend to occur earlier in the gene and, perhaps, are more likely to result in a truncated or absent protein. We have found that not all mutation-carrier parents of FH deficiency children have a strong predisposition to leiomyomata. We have confirmed that renal carcinoma is sometimes part of MCUL, as part of the variant hereditary leiomyomatosis and renal cancer (HLRCC) syndrome, and have shown that these cancers may have either type II papillary or collecting duct morphology. We have found no association between the type or site of FH mutation and any aspect of the MCUL phenotype. Biochemical assay for reduced FH functional activity in the germline of MCUL patients can indicate carriers of FH mutations with high sensitivity and specificity, and can detect reduced FH activity in some patients without detectable FH mutations. We conclude that MCUL is probably a genetically homogeneous tumour predisposition syndrome, primarily resulting from absent or severely reduced fumarase activity, with currently unknown functional consequences for the smooth muscle or kidney cell.