High frequency ultrasound for the diagnosis of skin cancer in adults

Background: Early accurate detection of all skin cancer types is essential to guide appropriate management and to improve morbidity and survival. Melanoma and squamous cell carcinoma (SCC) are high risk skin cancers which have the potential to metastasise and ultimately lead to death, whereas basal cell carcinoma (BCC) is usually localised with potential to infiltrate and damage surrounding tissue. Anxiety around missing early curable cases needs to be balanced against inappropriate referral and unnecessary excision of benign lesions. Ultrasound is a non-invasive imaging technique which relies on the measurement of sound wave reflections from the tissues of the body. At lower frequencies, the deeper structures of the body such as the internal organs can be visualised, while high frequency ultrasound (HFUS) with transducer frequencies of at least 20MHz, has a much lower depth of tissue penetration but produces a higher resolution image of tissues and structures closer to the skin surface. Used in conjunction with clinical or dermoscopic examination of suspected skin cancer, or both, HFUS may offer additional diagnostic information compared to other technologies. Objectives: To determine the diagnostic accuracy of HFUS to assist in the diagnosis of (a) melanoma and intraepidermal melanocytic variants, (b) cutaneous squamous cell carcinoma (cSCC), and (c) basal cell carcinoma (BCC) in adults. Search methods: We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; EMBASE; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles. Selection criteria: Studies evaluating HFUS (>= 20 MHz) in adults with lesions suspicious for melanoma, cSCC or BCC, compared with a reference standard of histological confirmation or clinical follow-up. Data collection and analysis: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). Due to scarcity of data and poor quality of studies, no meta-analysis was undertaken for this review. For illustrative purposes, estimates of sensitivity and specificity were plotted on coupled forest plots. Main results: Six studies were included, providing 29 datasets, 20 for diagnosis of melanoma (1125 lesions and 242 melanomas) and 9 for diagnosis of BCC (993 lesions and 119 BCCs). No data relating to the diagnosis of cSCC were identified. Studies were generally poorly reported limiting judgements of methodological quality. Half of studies did not set out to establish test accuracy and all should be considered preliminary evaluations of the potential usefulness of HFUS. There were particularly high concerns for applicability of findings due to selective study populations and data driven thresholds for test positivity. Studies reporting qualitative assessments of HFUS images excluded up to 22% of lesions (including some melanomas) due to them not being visualised by the test. Derived sensitivities for qualitative HFUS characteristics were at least 83% (95% CI 75% to 90%) for the detection of melanoma; the combination of three features (lesions appearing hypoechoic, homogenous and well defined) demonstrating 100% sensitivity in two studies, with variable corresponding specificities of 33% (95% CI 20% to 48%) and 73% (95% CI 57% to 85%) (Lower limits of the 95% CIs for sensitivities were 94% and 82% respectively). Quantitative measurement of HFUS outputs in two studies enabled decision thresholds to be set to achieve 100% sensitivity; specificities were 93% (95% CI 77% to 99%) and 65% (95% CI 51% to 76%). It was not possible to make summary statements regarding HFUS accuracy for the diagnosis of BCC due to highly variable sensitivities and specificities. Authors' conclusions: Insufficient data are available on the potential value of HFUS in the diagnosis of melanoma or BCC. Given the between study heterogeneity, unclear to low methodological quality and limited volume of evidence, no implications for practice can be drawn. The main value of the preliminary studies included may be in provision of guidance on the possible components of future diagnostic rules for diagnosis of melanoma or BCC using HFUS that require future evaluation. A prospective evaluation of HFUS added to visual inspection and dermoscopy alone in a standard health care setting with a clearly defined and representative population of participants would be required for a full and proper evaluation of accuracy

Reflectance confocal microscopy for diagnosising keratinocyte skin cancers in adults

Background Early accurate detection of all skin cancer types is important to guide appropriate management and to improve morbidity and survival. Basal cell carcinoma (BCC) is usually a localised skin cancer but with potential to infiltrate and damage surrounding tissue, whereas squamous cell carcinoma (cSCC) and melanoma are higher risk skin cancers with the potential to metastasise and ultimately lead to death. When used in conjunction with clinical or dermoscopic suspicion of malignancy, or both, reflectance confocal microscopy (RCM) may help to identify those eligible for non-surgical treatment without the need for a diagnostic biopsy, particularly in people with suspected BCC. Any potential benefit must be balanced against the risk of any misdiagnoses. Objectives 1) To determine the diagnostic accuracy of RCM for the detection of BCC, cSCC, or any skin cancer in adults with a) suspicious lesion and b) lesions that are difficult to diagnose (equivocal); and 2) to compare its accuracy with that of usual practice (visual inspection or dermoscopy, or both). Search methods We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; EMBASE; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles. Selection criteria Studies of any design that evaluated the accuracy of RCM alone, or RCM in comparison to visual inspection or dermoscopy, or both, in adults with lesions suspicious for skin cancer compared with a reference standard of either histological confirmation or clinical follow-up, or both. Data collection and analysis Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). We contacted authors of included studies where information related to the target condition or diagnostic threshold were missing. We estimated summary sensitivities and specificities using the bivariate hierarchical model. For computation of likely numbers of true positive, false positive, false negative, and true negative findings in the'Summary of findings' tables, summary sensitivity and specificity estimates were applied to lower quartile, median and upper quartiles of the prevalence observed in the study groups. We also investigated the impact of observer experience. Main results Ten studies reporting on a total of 11 study cohorts were included. All 11 cohorts reported data for the detection of BCC, including 2037 lesions (464 with BCC); and four cohorts reported data for the detection of cSCC, including 834 lesions (71 with cSCC). Only one study also reported data for the detection of BCC or cSCC using dermoscopy, limiting comparisons between RCM and dermoscopy. Studies were at high or unclear risk of bias across almost all methodological quality domains, and were of high or unclear concern regarding applicability of the evidence. Selective participant recruitment, unclear blinding of the reference test, and exclusions due to image quality or technical difficulties were observed. It is unclear whether studies are representative of populations eligible for testing with RCM, and test interpretation was often undertaken using images, remotely from the patient and the interpreter blinded to clinical information that would normally be available in practice. Meta-analysis found RCM to be more sensitive but less specific for the detection of BCC in studies of participants with equivocal lesions (sensitivity 94%, 95% CI 79% to 98%; specificity 85%, 95% CI 72% to 92%; n = 3 studies) compared to studies that included any suspicious lesion (sensitivity 76%, 95% CI 45% to 92%; specificity 95%, 95% CI 66% to 99%; n = 4 studies), although confidence intervals were wide. At the median prevalence of disease of 12.5% observed in studies including any suspicious lesion, applying these results to a hypothetical population of 1000 lesions results in 30 BCCs missed with 44 false positive results (lesions misdiagnosed as BCCs). At the median prevalence of disease of 15% observed in studies of equivocal lesions, 9 BCCs would be missed with 128 false positive results in a population of 1000 lesions. Across both sets of studies, up to 15% of these false positive lesions were observed to be melanomas mistaken for BCCs. There was some suggestion of higher sensitivities in studies with more experienced observers. Summary sensitivity and specificity could not be estimated for the detection of cSCC due to paucity of data. Authors' conclusions There is insufficient evidence for the use of RCM for the diagnosis of BCC or cSCC in either population group. A possible role for RCM in clinical practice is as a tool to avoid diagnostic biopsies in lesions with a relatively high clinical suspicion of BCC. The potential for, and consequences of, misclassification of other skin cancers such as melanoma as BCCs requires further research. Importantly, data are lacking that compare RCM to standard clinical practice (with or without dermoscopy)

Exfoliative cytology for the diagnosis of basal cell carcinoma and other skin cancers in adults

Background: Early accurate detection of all skin cancer types is essential to guide appropriate management and to reduce morbidity and improve survival. Basal cell carcinoma (BCC) is usually localised to the skin with potential to infiltrate and damage surrounding tissue, while cutaneous squamous cell carcinoma (cSCC) and melanoma have a much higher potential to metastasise and ultimately lead to death. Exfoliative cytology is a non–invasive test that uses the Tzanck smear technique to identify disease by examining the structure of cells obtained from scraped samples. This simple procedure is a less invasive diagnostic test than a skin biopsy, and for BCC has the potential to provide an immediate diagnosis that avoids an additional visit to clinic to receive skin biopsy results. This may benefit patients scheduled for either Mohs micrographic surgery or non–surgical treatments such as radiotherapy. A cytology scrape can never give the same information as a skin biopsy, however, so it is important to know more about which skin cancer situations it may be helpful. Objectives: The primary objective was to determine the diagnostic accuracy of exfoliative cytology for the detection of basal cell carcinoma (BCC) in adults. Secondary objectives were to determine diagnostic accuracy for the detection of i) cutaneous squamous cell carcinoma, ii) invasive melanoma and atypical intraepidermal melanocytic variants, and iii) any skin cancer, including keratinocyte skin cancer, invasive melanoma and atypical intraepidermal melanocytic variants, or any other skin cancer. Search methods: We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; EMBASE; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We also studied the reference lists of published systematic review articles. Selection criteria: Studies evaluating exfoliative cytology in adults with lesions suspicious for BCC, cSCC or melanoma, compared with a reference standard of histological confirmation. Data collection and analysis: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). Where possible we estimated summary sensitivities and specificities using the bivariate hierarchical model. Main results: This review reports on nine studies with a total of 1655 lesions including 1120 BCCs (14 datasets), 401 lesions with 44 cSCCs (two datasets), and 200 lesions with 10 melanomas (one dataset). Three of these datasets (one each for BCC, melanoma, and any malignant condition) were derived from one study which also performed a direct comparison with dermoscopy. Studies were of moderate to poor quality providing inadequate descriptions of participant selection, thresholds used to make cytological and histological diagnoses, and blinding. Reporting of patients’ prior referral pathways was particularly poor, as were descriptions of the cytodiagnostic criteria used to make diagnoses. No studies evaluated the use of exfoliative cytology as a primary diagnostic test for detecting BCC or other skin cancers in lesions suspicious for skin cancer. Pooled data from seven studies using standard cytomorphological criteria (but various stain methods) to detect BCC in patients with a high clinical suspicion of BCC estimated the sensitivity and specificity of exfoliative cytology as 97.5% (95% CI: 94.5 to 98.9%) and 90.1% (95% CI: 81.1 to 95.1%) respectively. When applied to a hypothetical population of 1000 clinically suspected BCC lesions with a median observed BCC prevalence of 86%, exfoliative cytology would miss 21 BCCs and would lead to 14 false positive diagnoses of BCC. No false positive cases were histologically confirmed to be melanoma. Insufficient data are available to make summary statements regarding the accuracy of exfoliative cytology to detect melanoma or cSCC, or its accuracy compared to dermoscopy. Authors' conclusions: The utility of exfoliative cytology for the primary diagnosis of skin cancer is unknown, as all included studies focused on the use of this technique for confirming strongly suspected clinical diagnoses. For the confirmation of BCC in lesions with a high clinical suspicion, there is evidence of high sensitivity and specificity for exfoliative cytology. Since decisions to treat low risk BCCs are unlikely in practice to require diagnostic confirmation given that clinical suspicion is already high, exfoliative cytology might be most useful for cases of BCC where the treatments being contemplated require a tissue diagnosis (e.g. radiotherapy). The small number of included studies, poor reporting and varying methodological quality means that no strong conclusions can currently be drawn to guide clinical practice. Despite insufficient data on the use of cytology for cSCC or melanoma, it is unlikely that cytology would be useful in these scenarios since preservation of the architecture of the whole lesion that would be available from a biopsy provides crucial diagnostic information. Given the paucity of good quality data, appropriately designed prospective comparative studies may be required to evaluate both the diagnostic value of exfoliative cytology by comparison to dermoscopy, and its confirmatory value in adequately reported populations with a high probability of BCC scheduled for further treatment requiring a tissue diagnosis

Ultrasound, CT, MRI, or PET-CT for staging and re-staging of adults with cutaneous melanoma.

BACKGROUND: Melanoma is one of the most aggressive forms of skin cancer, with the potential to metastasise to other parts of the body via the lymphatic system and the bloodstream. Melanoma accounts for a small percentage of skin cancer cases but is responsible for the majority of skin cancer deaths. Various imaging tests can be used with the aim of detecting metastatic spread of disease following a primary diagnosis of melanoma (primary staging) or on clinical suspicion of disease recurrence (re-staging). Accurate staging is crucial to ensuring that patients are directed to the most appropriate and effective treatment at different points on the clinical pathway. Establishing the comparative accuracy of ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET)-CT imaging for detection of nodal or distant metastases, or both, is critical to understanding if, how, and where on the pathway these tests might be used. OBJECTIVES: Primary objectivesWe estimated accuracy separately according to the point in the clinical pathway at which imaging tests were used. Our objectives were:• to determine the diagnostic accuracy of ultrasound or PET-CT for detection of nodal metastases before sentinel lymph node biopsy in adults with confirmed cutaneous invasive melanoma; and• to determine the diagnostic accuracy of ultrasound, CT, MRI, or PET-CT for whole body imaging in adults with cutaneous invasive melanoma:○ for detection of any metastasis in adults with a primary diagnosis of melanoma (i.e. primary staging at presentation); and○ for detection of any metastasis in adults undergoing staging of recurrence of melanoma (i.e. re-staging prompted by findings on routine follow-up).We undertook separate analyses according to whether accuracy data were reported per patient or per lesion.Secondary objectivesWe sought to determine the diagnostic accuracy of ultrasound, CT, MRI, or PET-CT for whole body imaging (detection of any metastasis) in mixed or not clearly described populations of adults with cutaneous invasive melanoma.For study participants undergoing primary staging or re-staging (for possible recurrence), and for mixed or unclear populations, our objectives were:• to determine the diagnostic accuracy of ultrasound, CT, MRI, or PET-CT for detection of nodal metastases;• to determine the diagnostic accuracy of ultrasound, CT, MRI, or PET-CT for detection of distant metastases; and• to determine the diagnostic accuracy of ultrasound, CT, MRI, or PET-CT for detection of distant metastases according to metastatic site. SEARCH METHODS: We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; Embase; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists as well as published systematic review articles. SELECTION CRITERIA: We included studies of any design that evaluated ultrasound (with or without the use of fine needle aspiration cytology (FNAC)), CT, MRI, or PET-CT for staging of cutaneous melanoma in adults, compared with a reference standard of histological confirmation or imaging with clinical follow-up of at least three months' duration. We excluded studies reporting multiple applications of the same test in more than 10% of study participants. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2)). We estimated accuracy using the bivariate hierarchical method to produce summary sensitivities and specificities with 95% confidence and prediction regions. We undertook analysis of studies allowing direct and indirect comparison between tests. We examined heterogeneity between studies by visually inspecting the forest plots of sensitivity and specificity and summary receiver operating characteristic (ROC) plots. Numbers of identified studies were insufficient to allow formal investigation of potential sources of heterogeneity. MAIN RESULTS: We included a total of 39 publications reporting on 5204 study participants; 34 studies reporting data per patient included 4980 study participants with 1265 cases of metastatic disease, and seven studies reporting data per lesion included 417 study participants with 1846 potentially metastatic lesions, 1061 of which were confirmed metastases. The risk of bias was low or unclear for all domains apart from participant flow. Concerns regarding applicability of the evidence were high or unclear for almost all domains. Participant selection from mixed or not clearly defined populations and poorly described application and interpretation of index tests were particularly problematic.The accuracy of imaging for detection of regional nodal metastases before sentinel lymph node biopsy (SLNB) was evaluated in 18 studies. In 11 studies (2614 participants; 542 cases), the summary sensitivity of ultrasound alone was 35.4% (95% confidence interval (CI) 17.0% to 59.4%) and specificity was 93.9% (95% CI 86.1% to 97.5%). Combining pre-SLNB ultrasound with FNAC revealed summary sensitivity of 18.0% (95% CI 3.58% to 56.5%) and specificity of 99.8% (95% CI 99.1% to 99.9%) (1164 participants; 259 cases). Four studies demonstrated lower sensitivity (10.2%, 95% CI 4.31% to 22.3%) and specificity (96.5%,95% CI 87.1% to 99.1%) for PET-CT before SLNB (170 participants, 49 cases). When these data are translated to a hypothetical cohort of 1000 people eligible for SLNB, 237 of whom have nodal metastases (median prevalence), the combination of ultrasound with FNAC potentially allows 43 people with nodal metastases to be triaged directly to adjuvant therapy rather than having SLNB first, at a cost of two people with false positive results (who are incorrectly managed). Those with a false negative ultrasound will be identified on subsequent SLNB.Limited test accuracy data were available for whole body imaging via PET-CT for primary staging or re-staging for disease recurrence, and none evaluated MRI. Twenty-four studies evaluated whole body imaging. Six of these studies explored primary staging following a confirmed diagnosis of melanoma (492 participants), three evaluated re-staging of disease following some clinical indication of recurrence (589 participants), and 15 included mixed or not clearly described population groups comprising participants at a number of different points on the clinical pathway and at varying stages of disease (1265 participants). Results for whole body imaging could not be translated to a hypothetical cohort of people due to paucity of data.Most of the studies (6/9) of primary disease or re-staging of disease considered PET-CT, two in comparison to CT alone, and three studies examined the use of ultrasound. No eligible evaluations of MRI in these groups were identified. All studies used histological reference standards combined with follow-up, and two included FNAC for some participants. Observed accuracy for detection of any metastases for PET-CT was higher for re-staging of disease (summary sensitivity from two studies: 92.6%, 95% CI 85.3% to 96.4%; specificity: 89.7%, 95% CI 78.8% to 95.3%; 153 participants; 95 cases) compared to primary staging (sensitivities from individual studies ranged from 30% to 47% and specificities from 73% to 88%), and was more sensitive than CT alone in both population groups, but participant numbers were very small.No conclusions can be drawn regarding routine imaging of the brain via MRI or CT. AUTHORS' CONCLUSIONS: Review authors found a disappointing lack of evidence on the accuracy of imaging in people with a diagnosis of melanoma at different points on the clinical pathway. Studies were small and often reported data according to the number of lesions rather than the number of study participants. Imaging with ultrasound combined with FNAC before SLNB may identify around one-fifth of those with nodal disease, but confidence intervals are wide and further work is needed to establish cost-effectiveness. Much of the evidence for whole body imaging for primary staging or re-staging of disease is focused on PET-CT, and comparative data with CT or MRI are lacking. Future studies should go beyond diagnostic accuracy and consider the effects of different imaging tests on disease management. The increasing availability of adjuvant therapies for people with melanoma at high risk of disease spread at presentation will have a considerable impact on imaging services, yet evidence for the relative diagnostic accuracy of available tests is limited

The use of teledermatology for the diagnosis of skin cancer in adults

Background: Early accurate detection of all skin cancer types is essential to guide appropriate management and to improve morbidity and survival. Melanoma and squamous cell carcinoma (SCC) are high risk skin cancers which have the potential to metastasise and ultimately lead to death, whereas basal cell carcinoma (BCC) is usually localised with potential to infiltrate and damage surrounding tissue. Anxiety around missing early curable cases needs to be balanced against inappropriate referral and unnecessary excision of benign lesions. Teledermatology provides a way for generalist clinicians to access the opinion of a specialist dermatologist for skin lesions that they consider to be suspicious without referring the patients concerned through the normal referral pathway. Teledermatology consultations can be ‘store-and-forward’ with electronic digital images of a lesion sent to a dermatologist for review at a later time, or can be live and interactive consultations using video conferencing to connect the patient, referrer and dermatologist in real time. Objectives: To determine the diagnostic accuracy of teledermatology for the detection of any skin cancer (melanoma, BCC or cSCC) in adults, and to compare its accuracy with that of in-person diagnosis. Search methods: We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; EMBASE; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles. Selection criteria: Studies evaluating skin cancer diagnosis for teledermatology alone, or in comparison with face-to-face diagnosis by a specialist clinician, compared with a reference standard of histological confirmation or clinical follow-up and expert opinion. Studies evaluating the referral accuracy of teledermatology compared with a reference standard of face-to-face diagnosis by a specialist clinician were also included. Data collection and analysis: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). We contacted authors of included studies where information related to the target condition of any skin cancer was missing. Data permitting, we estimated summary sensitivities and specificities using the bivariate hierarchical model. Due to scarcity of data, no covariate investigations were undertaken for this review. For illustrative purposes, estimates of sensitivity and specificity were plotted on coupled forest plots for diagnostic threshold and target condition under consideration. Main results: Twenty-two studies were included reporting diagnostic accuracy data for 4057 lesions and 879 malignant cases (16 studies) and referral accuracy data for reported data for 1449 lesions and 270 ‘positive’ cases as determined by the reference standard face-to-face decision (six studies). Methodological quality was variable with poor reporting hindering assessment. The overall risk of bias was rated as high or unclear for participant selection, reference standard and participant flow and timing in at least half of all studies; the majority were considered at low risk of bias for the index test. The applicability of study findings were of high or unclear concern for the majority of studies in all domains assessed due to the recruitment of study participants from secondary care settings or specialist clinics rather than from the primary or community-based settings in which teledermatology is more likely to be used and due to the acquisition of lesion images by dermatologists or in specialist imaging units rather than by primary care clinicians. Seven studies provided data for the primary target condition of any skin cancer (1588 lesions and 638 malignancies). For the correct diagnosis of lesions as malignant using photographic images, summary sensitivity was 94.9% (95% CI 90.1 to 97.4%) and summary specificity 84.3% (95% CI 48.5 to 96.8%) (from four studies). Individual study estimates using dermoscopic images or a combination of photographic and dermoscopic images generally suggested similarly high sensitivities with highly variable specificities. Limited comparative data suggested similar diagnostic accuracy between teledermatology assessment and in-person diagnosis by a dermatologist; however, data were too scarce to draw firm conclusions. For the detection of invasive melanoma or atypical intraepidermal melanocytic variants both sensitivities and specificities were more variable. Sensitivities ranged from 59% (95% CI 42% to 74%) to 100% (95% CI 54% to 100%) and specificities from 30% (95% CI 22% to 40%) to 100% (95% CI 93% to 100%), with reported diagnostic thresholds including the correct diagnosis of melanoma, classification of lesions as ‘atypical’ or ‘typical as well as the decision to refer or to excise a lesion. Referral accuracy data comparing teledermatology against a face-to-face reference standard suggested good agreement for lesions considered to require some positive action by face to face assessment (sensitivities of over 90%). For lesions considered of less concern when assessed face-to-face (e.g. for those not recommended for excision or referral), agreement was more variable with teledermatology specificities ranging from 57% (95% CI 39 to 73%) to 100% (95% CI 86% to 100%), suggesting that remote assessment is more likely recommend excision, referral or follow-up compared to in-person decisions. Authors' conclusions: Studies were generally small and heterogeneous and methodological quality was difficult to judge due to poor reporting. Bearing in mind concerns regarding the applicability of study participants and of lesion image acquisition in specialist settings, our results suggest that teledermatology can correctly identify the majority of malignant lesions. Using a more widely defined threshold to identify ‘possibly’ malignant cases or lesions that should be considered for excision is likely to appropriately triage those lesions requiring face-to-face assessment by a specialist. Despite the increasing use of teledermatology on an international level, the evidence base to support its ability to accurately diagnose lesions and to triage lesions from primary to secondary care is lacking and further prospective and pragmatic evaluation is needed

Smartphone applications for triaging adults with skin lesions that are suspicious for melanoma

Background: Melanoma accounts for a small proportion of all skin cancer cases but is responsible for the majority of skin cancer-related deaths. Early detection and treatment can improve survival. Smartphone applications are readily accessible and potentially offer an instant risk assessment of the likelihood of malignancy, so that the right people seek further medical attention from a clinician for more detailed assessment of the lesion. There is, however, a risk that melanomas will be missed and treatment delayed if the application reassures the user that their lesion is low risk. Objectives: To determine the diagnostic accuracy of smartphone applications to rule out cutaneous invasive melanoma and intraepidermal melanocytic variants in adults with concerns about suspicious skin lesions. Search methods: We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; Embase; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles. Selection criteria: Studies of any design evaluating smartphone applications intended for use by individuals in a community setting who have lesions that might be suspicious for melanoma or intraepidermal melanocytic variants compared with a reference standard of histological confirmation or clinical follow-up and expert opinion. Data collection and analysis: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). Due to scarcity of data and poor quality of studies, no meta-analysis was undertaken for this review. For illustrative purposes, estimates of sensitivity and specificity were plotted on coupled forest plots for each application under consideration. Main results: This review reports on two cohorts of lesions published in two studies. Both studies were at high risk of bias from selective participant recruitment, and high rates of non-evaluable images. Concerns about applicability of findings were high due to inclusion only of lesions already selected for excision in a dermatology clinic setting, and image acquisition by clinicians rather than by smartphone app users. Data for five mobile phone applications were reported for 332 suspicious skin lesions with 86 melanomas across the two studies. Across the four artificial intelligence-based applications which classified lesion images (photographs) as melanomas (one application) or as high risk or ‘problematic’ lesions (three applications) using a pre-programmed algorithm, sensitivities ranged from 7% (95% CI: 2%, 16%) to 73% (95% CI: 52%, 88%) and specificities from 37% (95% CI: 29% to 46%) to 94% (95% CI: 87%, 97%). The single application using store-and-forward review of lesion images by a dermatologist had a sensitivity of 98% (95% CI: 90%, 100%) and specificity 30% (95% CI: 22%, 40%). The number of test failures (lesion images analysed by the applications but classed as ‘not evaluable’ and excluded by the study authors) ranged from 3 to 31 (or 2% to 18% of lesions analysed). The store-and-forward application had one of the highest rates of test failure (15%). At least one melanoma was classed as ‘not evaluable’ in three of the four application evaluations. Authors' conclusions: Smartphone applications using artificial intelligence-based analysis have not yet demonstrated sufficient promise in terms of accuracy, and are associated with a high likelihood of missing melanomas. Applications based on store-and-forward images could have a potential role in the timely presentation of people with potentially malignant lesions by facilitating active self-management health practices and early engagement of those with suspicious skin lesions; however, they may incur a significant increase in resource and workload. Given the paucity of evidence and low methodological quality, no implications for practice can be drawn. Nevertheless, this is a rapidly advancing field and new and better applications with robust reporting of studies could change these conclusions substantially

Visual examination and dermoscopy, alone or in combination, for the diagnosis of keratinocyte skin cancers in adults

Background Early accurate detection of all skin cancer types is important to guide appropriate management, to reduce morbidity and to improve survival. Basal cell carcinoma (BCC) is almost always a localised skin cancer with potential to infiltrate and damage surrounding tissue, whereas a minority of squamous cell carcinoma (cSCC) and invasive melanoma are higher risk skin cancers with the potential to metastasise and cause death. Dermoscopy has become an important tool to assist specialist clinicians in the diagnosis of melanoma, and is increasingly used in primary care settings. Dermoscopy is a precision-built handheld illuminated magnifier that allows more detailed examination of the skin down to the level of the superficial dermis. Establishing the value of dermoscopy over and above visual inspection for the diagnosis of BCC or cSCC in primary and secondary care settings is critical to understanding its potential contribution to appropriate skin cancer triage, including referral of higher risk cancers to secondary care, the identification of low risk skin cancers that might be treated in primary care and to provide reassurance to those with benign skin lesions who can be safely discharged. Objectives To determine the diagnostic accuracy of visual inspection and dermoscopy, alone or in combination, for the detection of a) BCC and b) cSCC, in adults. Studies were separated according to whether the diagnosis was recorded face-to-face (in-person) or based on remote (image-based) assessment. Search methods We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; Embase; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles. Selection criteria Studies of any design that evaluated visual inspection and/or dermoscopy in adults with lesions suspicious for skin cancer, compared with a reference standard of either histological confirmation or clinical follow-up. Data collection and analysis Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). We contacted authors of included studies where information related to the target condition or diagnostic threshold were missing. We estimated accuracy using hierarchical summary ROC methods. Analysis of studies allowing direct comparison between tests was undertaken. To facilitate interpretation of results, we computed values of sensitivity at the point on the SROC curve with 80% fixed specificity and values of specificity with 80% fixed sensitivity. We investigated the impact of in-person test interpretation; use of a purposely developed algorithm to assist diagnosis; and observer expertise. Main results A total of 24 publications reporting on 24 study cohorts were included, providing 27 visual inspection datasets (8805 lesions; 2579 malignancies) and 33 dermoscopy datasets (6855 lesions; 1444 malignancies). The risk of bias was mainly low for the index test (for dermoscopy evaluations) and reference standard domains, particularly for in-person evaluations, and high or unclear for participant selection, application of the index test for visual inspection and for participant flow and timing. Concerns regarding the applicability of study findings were scored as ‘high’ or 'unclear' concern for almost all studies across all domains assessed. Selective participant recruitment, lack of reproducibility of diagnostic thresholds and lack of detail on observer expertise were particularly problematic. The detection of BCC was reported in 28 datasets; 15 on an in-person basis and 13 image-based. Analysis of studies by prior testing of participants and according to observer expertise was not possible due to lack of data. Studies were primarily conducted in participants referred for specialist assessment of lesions with available histological classification. No clear differences in accuracy were noted between dermoscopy studies undertaken in-person and those which evaluated images. The lack of effect observed is likely due to other sources of heterogeneity, including variations in the types of skin lesion studied, in dermatoscopes used, in the use of algorithms and varying thresholds for deciding on a positive test result. Meta-analysis found in-person evaluations of dermoscopy (7 evaluations; 4683 lesions and 363 BCCs) to be more accurate than visual inspection alone for the detection of BCC (8 evaluations; 7017 lesions and 1586 BCCs), with an RDOR of 8.2 (95% CI: 3.5 to 19.3; P < 0.001). This corresponds to predicted differences in sensitivity of 14% (93% vs 79%) at a fixed specificity of 80% and predicted differences in specificity of 22% (99% vs 77%) at a fixed sensitivity of 80%. Very similar results were observed for the image-based evaluations. When applied to a hypothetical population of 1000 lesions, of which 170 are BCC (based on median BCC prevalence across studies), an increased sensitivity of 14% from dermoscopy would lead to 24 fewer BCCs missed, assuming 166 false positive results from both tests. A 22% increase in specificity from dermoscopy with sensitivity fixed at 80% would result in 183 fewer unnecessary excisions assuming 34 BCCs missed for both tests. There was not enough evidence to assess the use of algorithms or structured checklists for either visual inspection or dermoscopy. Insufficient data were available to draw conclusions on the accuracy of either test for the detection of cSCC. Authors’ conclusions Dermoscopy may be a valuable tool for the diagnosis of BCC as an adjunct to visual inspection of a suspicious skin lesion following a thorough history-taking including assessment of risk factors for keratinocyte cancer. The evidence primarily comes from secondary care (referred) populations and populations with pigmented lesions or mixed lesion types. There is no clear evidence supporting the use of currently available formal algorithms to assist dermoscopy diagnosis

Dermoscopy, with and without visual inspection, for the diagnosis of melanoma in adults

Background: Melanoma has one of the fastest rising incidence rates of any cancer. It accounts for a small percentage of skin cancer cases but is responsible for the majority of skin cancer deaths. Although history-taking and visual inspection of a suspicious lesion by a clinician are usually the first in a series of ‘tests’ to diagnose skin cancer, dermoscopy has become an important tool to assist diagnosis by specialist clinicians and is increasingly used in primary care settings. Dermoscopy is a magnification technique using visible light that allows more detailed examination of the skin compared to examination by the naked eye alone. Establishing the additive value of dermoscopy over and above visual inspection alone across a range of observers and settings is critical to understanding its contribution for the diagnosis of melanoma and to future understanding of the potential role of the growing number of other highresolution image analysis techniques. Objectives: To determine the diagnostic accuracy of dermoscopy for the detection of cutaneous invasive melanoma and atypical intraepidermal melanocytic variants in adults, and to compare its accuracy with that of visual inspection alone. Studies were separated according to whether the diagnosis was recorded face-to-face (in-person) or based on remote (image-based) assessment. Search methods: We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; Embase; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles. Selection criteria: Studies of any design that evaluated dermoscopy in adults with lesions suspicious for melanoma, compared with a reference standard of either histological confirmation or clinical follow-up. Data on the accuracy of visual inspection, to allow comparisons of tests, was included only if reported in the included studies of dermoscopy. Data collection and analysis: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). We contacted authors of included studies where information related to the target condition or diagnostic threshold were missing. We estimated accuracy using hierarchical summary ROC methods. Analysis of studies allowing direct comparison between tests was undertaken. To facilitate interpretation of results, we computed values of sensitivity at the point on the SROC curve with 80% fixed specificity and values of specificity with 80% fixed sensitivity. We investigated the impact of in-person test interpretation; use of a purposely developed algorithm to assist diagnosis; observer expertise; and dermoscopy training. Main results: A total of 104 study publications reporting on 103 study cohorts with 42,788 lesions (including 5700 cases) were included, providing 354 datasets for dermoscopy. The risk of bias was mainly low for the index test and reference standard domains and mainly high or unclear for participant selection and participant flow. Concerns regarding the applicability of study findings were largely scored as ‘High’ concern in three of four domains assessed. Selective participant recruitment, lack of reproducibility of diagnostic thresholds and lack of detail on observer expertise were particularly problematic. The accuracy of dermoscopy for the detection of invasive melanoma or atypical intraepidermal melanocytic variants was reported in 86 datasets; 26 for evaluations conducted in-person (dermoscopy added to visual inspection) and 60 for image-based evaluations (diagnosis based on interpretation of dermoscopic images). Analyses of studies by prior testing revealed no obvious effect on accuracy; analyses were hampered by the lack of studies in primary care, lack of relevant information and the restricted inclusion of lesions selected for biopsy or excision. Accuracy was higher for in-person diagnosis compared to image-based evaluations (relative diagnostic odds ratio (RDOR) of 4.6; 95% CI 2.4, 9.0, P<0.001). Accuracy was compared for (a) in-person evaluations of dermoscopy (26 evaluations; 23,169 lesions and 1664 melanomas) versus visual inspection alone (13 evaluations; 6740 lesions and 459 melanomas) and for (b) image-based evaluations of dermoscopy (60 evaluations; 13,475 lesions and 2851 melanomas) versus image-based visual inspection (11 evaluations; 1740 lesions and 305 melanomas). For both comparisons, meta-analysis found dermoscopy to be more accurate than visual inspection alone, with RDORs of (a) 4.7 (95% CI: 3.0 to 7.5; P < 0.001) and (b) 5.6 (95% CI: 3.7 to 8.5; P < 0.001). These effects correspond to predicted differences in sensitivity of (a) 16% (95% CI: 8%, 23%) (92% for dermoscopy+visual inspection vs 76% for visual inspection) and (b) 35% (95% CI 24% to 46%) (81% for dermoscopy vs 47% for visual inspection) at a fixed specificity of 80%; and topredicted differences in specificity of (a) 20% (95% CI 7%, 33) (95% for dermoscopy plus visual inspection vs 75% for visual inspection) and (b) 40% (95% CI 27, 57) (82% for dermoscopy vs 42% for visual inspection) at a fixed sensitivity of 80%. Using the median prevalence of disease in each set of studies ((a) 12% for in-person and (b) 24% for image-based) for a hypothetical population of 1000 lesions, an increase in sensitivity of (a) 16% (in-person) and (b) 35% (image-based) from using dermoscopy at a fixed specificity of 80% equates to a reduction in the number of melanomas missed of (a) 19 and (b) 81 with (a) 176 and (b) 152 false positive results. An increase in specificity of (a) 20% (in-person) and (b) 40% (image-based) at a fixed sensitivity of 80% equates to a reduction in the number of unnecessary excisions from using dermoscopy of (a) 176 and (b) 304 with (a) 24 and (b) 48 melanomas missed. The use of a named or published algorithm to assist dermoscopy interpretation (as opposed to no reported algorithm or reported use of pattern analysis) had no significant impact on accuracy either for in-person (RDOR 1.4, 95% CI 0.34, 5.6; P=0.17) or image-based (RDOR 1.4, 95% CI 0.60, 3.3; P=0.22) evaluations. This result was supported by subgroup analysis according to algorithm used. Higher accuracy for observers reported as having high experience and for those classed as ‘expert consultants’ in comparison to those considered to have less experience in dermoscopy was observed, particularly for image-based evaluations. Evidence for the effect of dermoscopy training on test accuracy was very limited but suggested associated improvements in sensitivity. Authors' conclusions: Despite the observed limitations in the evidence base, dermoscopy is a valuable tool to support the visual inspection of a suspicious skin lesion for the detection of melanoma and atypical intraepidermal melanocytic variants, particularly in referred populations and in the hands of experienced users. Data to support its use in primary care is limited however it may assist in triaging suspicious lesions for urgent referral when employed by suitably trained clinicians. Formal algorithms may be of most use for dermoscopy training purposes and for less expert observers, however reliable data comparing approaches using dermoscopy in-person are lacking

Visual inspection for the diagnosis of cutaneous melanoma in adults

Background: Melanoma has one of the fastest rising incidence rates of any cancer. It accounts for a small percentage of skin cancer cases but is responsible for the majority of skin cancer deaths. History-taking and visual inspection of a suspicious lesion by a clinician is usually the first in a series of ‘tests’ to diagnose skin cancer. Establishing the accuracy of visual inspection alone is critical to understating the potential contribution of additional tests to assist in the diagnosis of melanoma. Objectives: To determine the diagnostic accuracy of visual inspection for the detection of cutaneous invasive melanoma and intraepidermal melanocytic variants in adults with limited prior testing and in those referred for further evaluation of a suspicious lesion. Studies were separated according to whether the diagnosis was recorded face-to-face (in-person) or based on remote (image-based) assessment. Search methods: We undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles. Selection criteria: Test accuracy studies of any design that evaluated visual inspection in adults with lesions suspicious for melanoma, compared with a reference standard of, either histological confirmation or clinical follow-up. Studies reporting data for ‘clinical diagnosis’ where dermoscopy may or may not have been used were excluded. Data collection and analysis: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS-2). We contacted authors of included studies where information related to the target condition or diagnostic threshold were missing. We estimated summary sensitivities and specificities per algorithm and threshold using the bivariate hierarchical model. We investigated the impact of: in-person test interpretation; use of a purposely developed algorithm to assist diagnosis; and observer expertise. Main results: Forty-nine publications reporting on a total of 51 study cohorts with 34,351 lesions (including 2499 cases) were included, providing 134 datasets for visual inspection. Across almost all study quality domains, insufficient information was provided in the majority of study reports to allow the risk of bias to be judged, while concerns regarding applicability of study findings were scored as ‘High’ in three of four domains assessed. Selective participant recruitment, lack of detail regarding the threshold for deciding on a positive test result, and lack of detail on observer expertise were particularly problematic. Attempts to analyse studies by degree of prior testing were hampered by a lack of relevant information and by the restricted inclusion of lesions selected for biopsy or excision. Accuracy was generally much higher for in-person diagnosis compared to image-based evaluations (relative diagnostic odds ratio of 8.54, 95% CI 2.89, 25.3, P<0.001). Meta-analysis of in-person evaluations that could be clearly placed on the clinical pathway showed a general trade-off between sensitivity and specificity, with the highest sensitivity (92.4%, 95% CI 26.2, 99.8%) and lowest specificity (79.7%, 95% CI 73.7, 84.7%) observed in participants with limited prior testing (n = 3 datasets). Summary sensitivities were lower for those referred for specialist assessment but with much higher specificities (e.g. sensitivity 76.7% (95% CI 61.7, 87.1%) and specificity 95.7% (95% CI 89.7, 98.3%) for lesions selected for excision, n = 8 datasets). These differences may be related to differences in the spectrum of included lesions, differences in the definition of a positive test result, or to variations in observer expertise. We did not find clear evidence that accuracy is improved by the use of any algorithm to assist diagnosis in all settings. Attempts to examine the effect of observer expertise in melanoma diagnosis were hindered due to poor reporting. Authors' conclusions: Visual inspection is a fundamental component of the assessment of a suspicious skin lesion; however, the evidence suggests that melanomas will be missed if visual inspection is used on its own. The evidence to support its accuracy in the range of settings in which it is used is flawed and very poorly reported. Although published algorithms do not appear to improve accuracy, there is insufficient evidence to suggest that the ‘no algorithm’ approach should be preferred in all settings. Despite the volume of research evaluating visual inspection, further prospective evaluation of the potential added value of using established algorithms according to the prior testing or diagnostic difficulty of lesions may be warranted

Smartphone applications for triaging adults with skin lesions that are suspicious for melanoma

Background: Melanoma accounts for a small proportion of all skin cancer cases but is responsible for most skin cancer‐related deaths. Early detection and treatment can improve survival. Smartphone applications are readily accessible and potentially offer an instant risk assessment of the likelihood of malignancy so that the right people seek further medical attention from a clinician for more detailed assessment of the lesion. There is, however, a risk that melanomas will be missed and treatment delayed if the application reassures the user that their lesion is low risk.Objectives: To assess the diagnostic accuracy of smartphone applications to rule out cutaneous invasive melanoma and atypical intraepidermal melanocytic variants in adults with concerns about suspicious skin lesions.Search methods: We undertook a comprehensive search of the following databases from inception to August 2016: Cochrane Central Register of Controlled Trials; MEDLINE; Embase; CINAHL; CPCI; Zetoc; Science Citation Index; US National Institutes of Health Ongoing Trials Register; NIHR Clinical Research Network Portfolio Database; and the World Health Organization International Clinical Trials Registry Platform. We studied reference lists and published systematic review articles.Selection criteria: Studies of any design evaluating smartphone applications intended for use by individuals in a community setting who have lesions that might be suspicious for melanoma or atypical intraepidermal melanocytic variants versus a reference standard of histological confirmation or clinical follow‐up and expert opinion.Data collection and analysis: Two review authors independently extracted all data using a standardised data extraction and quality assessment form (based on QUADAS‐2). Due to scarcity of data and poor quality of studies, we did not perform a meta‐analysis for this review. For illustrative purposes, we plotted estimates of sensitivity and specificity on coupled forest plots for each application under consideration.Main results: This review reports on two cohorts of lesions published in two studies. Both studies were at high risk of bias from selective participant recruitment and high rates of non‐evaluable images. Concerns about applicability of findings were high due to inclusion only of lesions already selected for excision in a dermatology clinic setting, and image acquisition by clinicians rather than by smartphone app users.We report data for five mobile phone applications and 332 suspicious skin lesions with 86 melanomas across the two studies. Across the four artificial intelligence‐based applications that classified lesion images (photographs) as melanomas (one application) or as high risk or 'problematic' lesions (three applications) using a pre‐programmed algorithm, sensitivities ranged from 7% (95% CI 2% to 16%) to 73% (95% CI 52% to 88%) and specificities from 37% (95% CI 29% to 46%) to 94% (95% CI 87% to 97%). The single application using store‐and‐forward review of lesion images by a dermatologist had a sensitivity of 98% (95% CI 90% to 100%) and specificity of 30% (95% CI 22% to 40%).The number of test failures (lesion images analysed by the applications but classed as 'unevaluable' and excluded by the study authors) ranged from 3 to 31 (or 2% to 18% of lesions analysed). The store‐and‐forward application had one of the highest rates of test failure (15%). At least one melanoma was classed as unevaluable in three of the four application evaluations.Authors' conclusions: Smartphone applications using artificial intelligence‐based analysis have not yet demonstrated sufficient promise in terms of accuracy, and they are associated with a high likelihood of missing melanomas. Applications based on store‐and‐forward images could have a potential role in the timely presentation of people with potentially malignant lesions by facilitating active self‐management health practices and early engagement of those with suspicious skin lesions; however, they may incur a significant increase in resource and workload. Given the paucity of evidence and low methodological quality of existing studies, it is not possible to draw any implications for practice. Nevertheless, this is a rapidly advancing field, and new and better applications with robust reporting of studies could change these conclusions substantially