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Phakomatosis pigmentovascularis is a diagnosis that denotes the coexistence of pigmentary and vascular birthmarks of specific types, accompanied by variable multisystem involvement, including CNS disease, asymmetrical growth, and a predisposition to malignancy. Using a tight phenotypic group and high-depth next-generation sequencing of affected tissues, we discover here clonal mosaic variants in gene PTPN11 encoding SHP2 phosphatase as a cause of phakomatosis pigmentovascularis type III or spilorosea. Within an individual, the same variant is found in distinct pigmentary and vascular birthmarks and is undetectable in blood. We go on to show that the same variants can cause either the pigmentary or vascular phenotypes alone, and drive melanoma development within pigmentary lesions. Protein structure modeling highlights that although variants lead to loss of function at the level of the phosphatase domain, resultant conformational changes promote longer ligand binding. In vitro modeling of the missense variants confirms downstream MAPK pathway overactivation and widespread disruption of human endothelial cell angiogenesis. Importantly, patients with PTPN11 mosaicism theoretically risk passing on the variant to their children as the germline RASopathy Noonan syndrome with lentigines. These findings improve our understanding of the pathogenesis and biology of nevus spilus and capillary malformation syndromes, paving the way for better clinical management., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Competing interests: PH is Clinical Advisor for Skin Cancer to Check4Cancer, a company that offers teledermatoscopic analysis of pigmented skin lesions (https://www.check4cancer.com), and is a medical advisor to MedX, the Canadian company with the IP for the SIAscope (https://medxhealth.com/default.aspx)., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Background: GPs need to recognise significant pigmented skin lesions, given rising UK incidence rates for malignant melanoma. The 7-point checklist (7PCL) has been recommended by NICE (2005) for routine use in UK general practice to identify clinically significant lesions which require urgent referral., Aim: To validate the Original and Weighted versions of the 7PCL in the primary care setting., Design and Setting: Diagnostic validation study, using data from a SIAscopic diagnostic aid randomised controlled trial in eastern England., Method: Adults presenting in general practice with a pigmented skin lesion that could not be immediately diagnosed as benign were recruited into the trial. Reference standard diagnoses were histology or dermatology expert opinion; 7PCL scores were calculated blinded to the reference diagnosis. A case was defined as a clinically significant lesion for primary care referral to secondary care (total 1436 lesions: 225 cases, 1211 controls); or melanoma (36)., Results: For diagnosing clinically significant lesions there was a difference between the performance of the Original and Weighted 7PCLs (respectively, area under curve: 0.66, 0.69, difference = 0.03, P<0.001). For the identification of melanoma, similar differences were found. Increasing the Weighted 7PCL's cut-off score from recommended 3 to 4 improved detection of clinically significant lesions in primary care: sensitivity 73.3%, specificity 57.1%, positive predictive value 24.1%, negative predictive value 92.0%, while maintaining high sensitivity of 91.7% and moderate specificity of 53.4% for melanoma., Conclusion: The Original and Weighted 7PCLs both performed well in a primary care setting to identify clinically significant lesions as well as melanoma. The Weighted 7PCL, with a revised cut-off score of 4 from 3, performs slightly better and could be applied in general practice to support the recognition of clinically significant lesions and therefore the early identification of melanoma.

This study explores the relationship between different types of spitzoid tumours, spindle cell naevus of Reed and spitzoid melanomas. Clinical and histopathological data were retrospectively reviewed from our hospital database in Cambridge from January 2006 to July 2009. Clinical images, where available, were recorded. Search headings from our pathology database included 'spitzoid tumours', 'Spitz naevi', 'atypical spitzoid tumours', spitzoid tumours of uncertain malignant potential ('STUMP'), 'spindle cell naevus of Reed' and 'spitzoid melanomas'. The total number of spitzoid tumours was 118 comprising Spitz naevi (72), atypical spitzoid tumours (30), spitzoid melanomas (eight), and other naevi with spitzoid features (eight). In total, 60% of Spitz naevi were diagnosed clinically and 50% reported a history of change with spitzoid melanoma, compared with 32% with Spitz naevi. In all, 60% of Spitz naevi and atypical spitzoid tumours were pigmented in contrast with spitzoid melanomas (83%). Variegated pigmentation was found in 20% of Spitz naevi and atypical spitzoid tumours, however, no spitzoid melanomas had mixed pigmentation. There were 30 atypical spitzoid tumours (9 M : 21 F); 16 occurred on the lower limbs, peaking in the 20-30-years age group. There were eight patients with spitzoid melanomas with a 7:1 F : M ratio, 50% of which were diagnosed clinically. Of the 34 spindle cell naevus of Reed (10 M : 24 F), 31 were misdiagnosed, most commonly as melanoma. Reed naevi peaked in the 30-40 year age group and on the upper limbs and lower limbs in the 20-30-years age group. In summary, age and sex appeared helpful in distinguishing benign from malignant spitzoid tumours, however history was less discriminatory. Spitzoid melanomas, most of which were pigmented occurred more commonly in females. Atypical spitzoid tumours were more common in females and pathologists favoured malignancy in this group beyond 20 years of age., (© 2012 The Authors. Australasian Journal of Dermatology © 2012 The Australasian College of Dermatologists.)