Total Body Photography, Dermoscopy and Other Selected Noninvasive Dermatologic Tests
Number: 0188
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Scope of Policy
This Clinical Policy Bulletin addresses total body photography, dermoscopy, and other selected noninvasive dermatologic tests.
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Medical Necessity
Aetna considers total body photography (TBP) and dermoscopy (also known as total body imaging, digital epiluminescence microscopy (DELM), epiluminescence microscopy [ELM], incidence light microscopy, skin videomicroscopy, melanomography, in-vivo cutaneous surface microscopy, dermatoscopy, and magnified oil immersion diascopy) (e.g., MoleSafe) medically necessary when used for evaluation of members with a history or close family history of any of the following conditions:
- Atypical nevi; or
- Dysplastic nevi; or
- Melanoma; or
- Non-melanoma skin cancers.
Repeat studies are not typically required more frequently than every 24 months.
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Experimental, Investigational, or Unproven
The following interventions are considered experimental, investigational, or unproven because the effectiveness of these approaches has not been established:
- AdvanceAD-Tx (Castle Biosciences) for the management of atopic dermatitis
- AURA (Vita Imaging)
- Computerized TBP systems (e.g., MelaFind, MoleMapCD, MoleMate) because they have not been shown to provide better health outcomes than conventional TBP;
- Dermoscopy for assessment of vulvar intraepithelial neoplasia;
- Dermoscopy for delineation of basal cell carcinoma for Mohs micrographic surgery;
- Dermoscopy for evaluation of non-parasitic skin infections;
- Hand-held fluorescent molecular imaging (e.g., the Orlucent system) for evaluation of early tissue re-modeling that signals a mole’s transition to atypia because of a lack of evidence of its effectiveness;
- Skin-surface collection of mRNA using an adhesive patch (e.g., Mind.Px) because its predictive clinical value in the selection of biologic therapy to treat psoriasis has not been established.;
- TBP and dermoscopy for all other indications;
- The following interventions (not an all-inclusive list) for evaluating dysplastic and atypical nevi for early detection of malignant cutaneous melanomas because their clinical value for this indication has not been established:
- Confocal scanning laser microscopy;
- Dermtech Nevome;
- Electrical impedance devices;
- High-resolution (high-frequency) ultrasonography;
- Multi-photon laser scanning microscopy (also known as multi-photon fluorescence microscopy or multi-photon excitation microscopy);
- Multi-spectral image analysis;
- Non-invasive gene expression "patch biopsy" (e.g., DermTech Pigmented Lesion Assay (PLA));
- Optical coherence tomography;
- Reflectance confocal microscopy (RCM);
- Spectroscopy (electrical impedance and optical, e.g., Dermasensor);
- Teledermatology/teledermoscopy;
- Visual image analysis.
Background
Total body photography (TBP) and dermoscopy are noninvasive imaging techniques used to evaluate and monitor cutaneous lesions. These modalities are designed to support the early detection of skin cancers, including melanoma, by enabling longitudinal assessment of existing nevi and identification of new or changing skin lesions.
A skin lesion is a nonspecific term referring to any visible or palpable abnormality of the skin, which may be benign, premalignant, or malignant. Skin cancers are broadly categorized into melanoma and non-melanoma types. Non-melanoma skin cancers, most commonly basal cell carcinoma and squamous cell carcinoma, arise from cells within the epidermis and generally have less aggressive behavior than melanoma. These malignancies are strongly associated with cumulative ultraviolet radiation exposure. In contrast, melanoma arises from melanocytes and is less common but associated with higher morbidity and mortality. Melanoma typically presents as a pigmented lesion but may also appear amelanotic. It can arise on any skin surface and may be difficult to detect in early stages. Early surgical excision is associated with improved clinical outcomes, supporting the importance of early identification. Dysplastic and atypical nevi have been identified as markers of increased melanoma risk and may represent potential precursor lesions in some individuals. Therefore, patients with a personal or family history of melanoma, or with multiple atypical or dysplastic nevi, are considered higher risk and may benefit from closer dermatologic surveillance.
TBP, also referred to as mole mapping, uses digital imaging to record and store baseline and sequential photographs of the skin surface. These images may include both total body and single-lesion views and can be compared over time to assess for the development of new lesions or changes in existing lesions. TBP is particularly useful in individuals with numerous nevi, where longitudinal comparison may aid in the identification of clinically significant changes during follow-up examinations. Video-based imaging may also be used and is sometimes referred to as video-dermoscopy.
TBP is used to document baseline cutaneous findings and facilitate longitudinal comparison of lesions over time. This approach is particularly relevant for individuals with numerous nevi or those at increased risk for melanoma, including patients with a personal or family history of melanoma or dysplastic nevi.
Evidence from a systematic review of 14 studies (n ≈ 12,082) found that use of TBP was associated with detection of melanomas at earlier stages, including a higher proportion of in situ melanomas and lower Breslow thickness compared with individuals not undergoing TBP surveillance. Hornung et al. (2021) noted that TBP may support early detection in high-risk populations; however, heterogeneity in study methods and limitations in study quality were identified.
Additional observational data suggest that TBP may reduce unnecessary biopsies by confirming lesion stability over time, particularly in patients with numerous nevi. However, variability exists in implementation, imaging protocols, and follow-up intervals (Truong et al., 2016).
Dermoscopy, also known as total body imaging, digital epiluminescence microscopy (DELM), epiluminescence microscopy (ELM), incidence light microscopy, skin videomicroscopy, melanomography, in-vivo cutaneous surface microscopy, and dermatoscopy, is a noninvasive diagnostic technique that utilizes magnification and specialized lighting to visualize subsurface structures within the epidermis and superficial dermis that are not detectable by the unaided eye. This method serves as an adjunct to clinical examination, while histopathologic evaluation of biopsied tissue remains the gold standard for diagnosis (Weber et al., 2018; Kato et al., 2019). Although oil can be applied to enhance translucency, it is unnecessary when using polarized light systems.
Dermoscopes, such as the FDA-cleared DermLite, can be used independently or in conjunction with cameras, software, and computerized systems to capture and store images for longitudinal evaluation, with MicroDERM and MoleMax being examples of a digital dermoscope and software system. Typically, dermoscopy provides approximately 10× or greater magnification, allowing for detailed assessment of patterns and structures that are imperceptible to the naked eye. Even though most malignant melanocytic lesions can be identified based on unaided visual inspection alone, many lesions are not readily distinguished by examination with the naked eye.
Since its introduction, dermoscopy has undergone extensive improvements; the instruments have become more readily available, and the diagnostic indications, benefits, and limitations have been better delineated. Dermoscopy has developed into a powerful tool to discriminate between melanocytic and non-melanocytic pigmented skin lesions and to distinguish benign from malignant melanocytic lesions to avoid inopportune surgical treatments for low-risk lesions. Although dermoscopy does not show 100% sensitivity in diagnosing cutaneous malignant melanoma (CMM), it is more accurate than unaided visual inspection in detecting thin CMM. Features of pigmented lesions identified by dermoscopy should be integrated with data from the history and physical examination.
Evidence has demonstrated that dermoscopy improves diagnostic accuracy for melanoma and other skin cancers compared with clinical examination alone. A systematic review and meta-analysis demonstrated that dermoscopic structures are associated with increased diagnostic accuracy for melanoma detection (Williams et al., 2021). In addition, prior studies have shown that dermoscopy increases sensitivity and specificity and enables identification of thinner melanomas compared with naked-eye examination (Yélamos et al., 2019). However, the diagnostic performance of dermascopy is influenced by clinician expertise.
Glud et al. (2009) noted that dermoscopy is considered the gold standard for the clinical assessment of pigmented skin lesions. In expert hands, this instrument improves both sensitivity and specificity for the diagnosis of melanoma; however, the outcome is highly dependent on the skills and experience of the examiner. Spectrophotometric intra-cutaneous analysis (SIAscopy) is a new, commercially available method for analyzing pigmented skin lesions non-invasively. The diagnosis is based on objective features such as the presence of dermal pigment, vascularity of the lesion, and the integrity of collagen. These researchers examined the usefulness of SIAscopy for the clinical diagnosis of malignant melanoma in a prospective, unbiased manner. They enrolled 65 patients with 83 lesions, where the diagnosis of melanoma could not be ruled out based on clinical evaluation by a non-dermatologist. All lesions were investigated by dermoscopy and SIAscopy and subsequently excised. Histopathologically, 12 lesions were diagnosed as malignant melanoma. Both dermoscopy and SIAscopy overestimated the proportion of possible malignant lesions (n = 24 and n = 41, respectively) and had sensitivities of 92% and 100%, respectively. The specificity of dermoscopy in this study was 81% compared to 59% for SIAscopy. These findings showed that dermoscopy remains the best diagnostic tool for the pre-operative diagnosis of pigmented skin lesions.
Surveillance technologies have been developed to find skin cancer, particularly melanoma, early and to assist in identifying malignant skin lesions without using a biopsy or excising (removing) the lesion. However, more than 90% of melanomas that arise in the skin can be recognized with the naked eye. A biopsy is necessary when there is a sufficient index of suspicion. Histopathologic examination remains the gold standard for skin cancer diagnosis.
The combined use of TBP and digital dermoscopy, often referred to as the "two-step method", may be used for the surveillance of patients at high risk for melanoma. Prospective controlled data indicate that these integrated approaches can facilitate early melanoma detection in high-risk populations undergoing longitudinal monitoring (Hobelsberger et al., 2024).
Although TBP and dermoscopy provide clinically useful adjunctive information, they have limitations. A substantial proportion of melanomas can be identified by clinical examination alone, and neither modality has 100% sensitivity. Diagnostic accuracy is dependent on clinician experience and appropriate patient selection.
Variation in imaging protocols, interpretation criteria, and follow-up intervals may limit standardization across clinical settings. Additionally, these techniques may increase the number of biopsies in some settings without clearly improving melanoma detection rates, depending on implementation.
Histopathologic examination remains the gold standard for diagnosis of skin cancer, and noninvasive imaging should be used to support, but not replace, clinical judgment and biopsy when indicated.
Dermoscopy for Assessment of Vulvar Intraepithelial Neoplasia
De Giorgi et al. (2023) stated that vulvar intraepithelial neoplasia (VIN) is a vulvar skin lesion considered a precursor of vulvar squamous cell carcinoma (SCC). No characteristics have been discovered to-date that allows clinicians to differentiate between grades of VIN, such as correlating the thickness of involvement of the epithelium (VIN1, VIN2, and VIN3) to the dermoscopic pattern. In a retrospective study, these investigators correlated the clinical and dermoscopic features of VIN cases with histopathological findings, with the objective of identifying dermoscopic characteristics that allow them to differentiate between different grades of VIN. Clinical and dermoscopic characteristics, as well as histopathology data, were gathered from patients at 2 dermatology units in Italy between January 2020 and December 2021. The study population consisted of 20 patients with a histologically confirmed diagnosis of VIN. The mean age of subjects at the time of diagnosis was 55 years. At the dermoscopic level, VIN1 was characterized by a homogeneous erythematous area that completely involved the entire lesion, with a vascular pattern consisting of regular glomerular vessels. VIN3, was characterized by the presence of compact milky white areas that involved almost the entire lesion. VIN2 was characterized by the presence of non-compact white areas that allowed homogeneous erythematous areas to be observed transparently, without other distinguishing aspects. The authors concluded that although a definitive diagnosis and grading of VIN remains confirmed only histopathologically, the findings of this study revealed how dermoscopy may aid the differential diagnosis between the different grades of VIN; the presence of a compact milky white area that involves nearly the entire lesion should be interpreted as an alarming feature, while homogeneous erythematous areas or a glomerular vascular pattern are more typical of the 1st stage of this neoplasia. Moreover, these researchers stated that further studies are needed to better characterize the dermoscopic features of VIN and to corroborate these findings.
Dermoscopy for Delineation of Basal Cell Carcinoma for Mohs Micrographic Surgery
Litaiem et al. (2022) noted that several studies have examined the use of dermoscopy in the delineation of basal cell carcinoma (BCC) for Mohs micrographic surgery (MMS) with conflicting results. In a systematic review with meta-analysis, these investigators examined the effectiveness of dermoscopy-guided MMS in the treatment of BCC. They included all comparative studies, comparing cases of BCC treated using dermoscopy-guided MMS (or slow MMS) to those treated with curettage-guided MMS or "standard" MMS. A total of six studies, including 508 BCCs, were reviewed. The analysis found no statistically significant difference in the proportion of total margin clearance on the first MMS stage between BCCs removed using dermoscopy-guided MMS and those that had curettage or visual inspection. However, lateral margin involvement was significantly lower in BCCs that underwent dermoscopy-guided MMS. The authors concluded that dermoscopy allowed visualization of structures up to 1 mm into the dermis, making it rational to use for lateral margin evaluation. Currently, there are two comparative studies showing the effectiveness of dermoscopy for lateral margin evaluation during MMS. Moreover, these researchers stated that future randomized clinical trials are needed to develop an evidence-based recommendation regarding the use of dermoscopy in MMS.
The authors acknowledged several drawbacks in this systematic review. First, the sample size was limited due to the scarcity of research on this subject in the literature. Only two included studies examined the use of dermoscopy for lateral margin assessment, so these findings should be interpreted with caution. Second, some studies had missing data on outcome measures, leading to their exclusion from the data analysis. Third, the histopathological subtype of BCC, which could act as a confounding factor, was not indicated in all included studies, potentially hindering the interpretation of findings and undermining their accuracy. Fourth, both dermoscopy and MMS are operator-dependent procedures; therefore, controlled, consistent, and reproducible results were not readily attainable.
Janowska et al. (2023) stated that the diagnosis of BCC is based on clinical and dermoscopic features. In uncertain cases, innovative imaging techniques, such as reflectance confocal microscopy (RCM) and optical coherence tomography (OCT), have been employed. The principal drawback of these techniques is their inability to study deep margins. High-frequency ultrasound (HFUS) and the most recent ultra-high-frequency ultrasound (UHFUS) have been used in various applications in dermatology; however, they are not yet routinely used in the diagnosis of BCC. A key point in clinical practice is to find an imaging technique that can aid in reducing post-surgical recurrences through careful pre-surgical assessment of the lesional margins. This technique should demonstrate high sensitivity, specificity, reproducibility, and simplicity of execution. This concept is particularly important for the optimal management of patients who are often elderly and have multiple co-morbidities. These investigators examined the characteristics of current imaging techniques and the studies in the literature on this topic. They independently searched the Medline, PubMed, Embase, Scopus, ScienceDirect, and Cochrane Library databases for studies looking for non-invasive imaging techniques for the pre-surgical margin assessment of BCC. Pre-operative study of the BCC subtype can aid in obtaining a complete excision with free margins. Different non-invasive imaging techniques have been studied for in-vivo evaluation of tumor margins, comparing histologic evaluation with radical surgery. The ability to study both lateral and deep margins would allow for a reduction in recurrences and sparing of healthy tissue.
The authors concluded that non-invasive imaging for pre-surgical evaluation of BCC is constantly evolving and is essential for precise surgery that maintains functional and aesthetic appearance. Moreover, these researchers stated that HFUS and UHFUS represent the most promising non-invasive techniques for the pre-operative study of BCC, facilitating the characterization of vascularization, deep lateral margins, and high-risk subtypes; however, further comparative studies with RCM, OCT, and histological evaluation are needed.
Aoki et al. (2025) noted that MMS offers high cure rates for NMSC but relies on precise margin assessment, traditionally initiated by the naked eye. Dermoscopy has emerged as a potential tool to improve margin delineation. In a prospective, multi-center study, these researchers compared the effectiveness of dermoscopic versus naked eye evaluation in marking initial MMS margins for NMSC. This trial included patients with NMSC undergoing MMS. Subjects were randomized into dermoscopy and naked eye groups; statistical analysis was carried out using statistical package for social sciences. A total of 127 patients were enrolled, with 63 in the naked eye group and 64 in the dermoscopy group. No significant differences in age, sex distribution, or histological subtype were found. The average number of MMS stages and accuracy of initial margins were comparable between the 2 groups. Despite its potential, this trial found no significant reduction in total MMS stages using dermoscopy. Novel imaging modalities or standardized dermoscopic criteria should be examined to enhance margin assessment accuracy and improve outcomes in NMSC treatment. The authors concluded that dermoscopic evaluation of pre-surgical margins did not effectively evaluate lateral/deep margins nor contribute to a reduction in total MMS stages. Improving clinicians’ understanding of pre-surgical margin assessment techniques can result in better treatment outcomes for NMSC.
Dermoscopy for Evaluation of Bacterial, Viral, and Fungal Skin Infections
Chauhan et al. (2023) stated that in the past 30 years, the use of dermoscopy has been extended to inflammatory and infectious dermatoses. Regarding the latter, while the first applications concerned skin parasitoses, there has been a significant increase in the publication trend regarding non-parasitic dermatoses over recent years; however, data on this topic are sparse, and often lack a standardized analytical approach. In a systematic review, these investigators examined available evidence on dermoscopy of bacterial, viral, and fungal dermatoses (dermoscopic findings, used setting, pathological correlation, and level of evidence of studies) and provided a homogeneous terminology of reported dermoscopic features according to a standardized methodology. A total of 152 papers addressing 43 different dermatoses and describing 184 different dermoscopic findings were included in the analysis. The majority of them displayed a level of evidence of V (107 single-case reports, and 40 case-series studies), with only 5 studies showing a level of evidence of IV (case-control studies). Moreover, this analysis also underlined a high variability in the terminology used in published articles (even for the same dermatosis). The authors concluded that this review emphasized that dermoscopy of non-parasitic skin infections has significant potential, as it may allow for the appreciation of sub-clinical findings strictly related to specific histological and/or microbiological features, yet future studies designed according to a systematic and standardized approach are needed for a better characterization of dermoscopy of non-parasitic skin infections.
Dermoscopy for Evaluation of Pigmented Macules on the Head and Neck
Gouda et al. (2023) noted that differentiating early melanoma from other flat pigmented lesions on the head and neck is challenging both clinically and dermoscopically, partly due to the wide differential diagnosis and the lack of specific diagnostic algorithms. In a systematic review, these investigators examined available evidence on the dermoscopic features of pigmented macules on the head and neck. They searched Embase and PubMed (MedLine) database from January 2015 to January 2021 using a 4r-step search. Keywords used were dermoscopy/dermatoscopy or epiluminescence microscopy, lentigo maligna, lentigo maligna melanoma, lichen-planus-like-keratosis, solar lentigo, seborrheic keratosis, pigmented actinic keratosis (PAK), pigmented Bowen disease (pBD), pigmented intraepidermal carcinoma (pIEC), and head and neck. The commonest reported dermoscopic features of facial melanoma were irregular dots, atypical dots/globules, asymmetric pigmented follicular openings, rhomboid gray/black structures, increased vascular network, brown globules/dots and a pattern of circles. Pseudopods, radial streaming, blue white veil, irregular blotches, scar-like depigmentation and atypical pigment network were recorded in low frequencies. For PAK, pBD and pIEC peri-follicular erythema, white/yellow surface scale, linear wavy vessels around hair follicles, hair follicular openings surrounded by a white halo, evident follicles or follicular or keratotic plugs, rosette sign and sharply demarcated borders were the salient features. The authors concluded that further studies are needed to determine the dermoscopic criteria for pigmented melanocytic and non-melanocytic lesions on the head and neck. In addition, there is a gap in the knowledge of site-specific dermoscopic features on specific sites, namely ears, nose, cheeks, scalp, and neck that will also benefit from further studies.
AdvanceAD - Tx
AdvanceAD-Tx (Castle Biosciences) is a 487-gene expression profile test for atopic dermatitis therapy selection. The test uses non-invasive skin scrapings from AD lesions, analyzed by RNA-Seq. An ensemble algorithm comprising 12 neural networks analyzing 487 genes was developed to classify patients by their probability of responding to either JAK inhibitor (JAKi) therapy or Th2-targeted therapy (e.g., dupilumab).
A prospective clinical study evaluated whether a 487‑gene expression profile (GEP) test could guide systemic therapy selection and improve outcomes in patients with atopic dermatitis (AD) by aligning treatment choice with underlying molecular disease drivers (Silverberg et al., 2026). The objective of the study was to develop and validate a molecular diagnostic tool capable of predicting response to different classes of systemic AD therapies, particularly Janus kinase inhibitors (JAKi) versus Th2‑targeted biologics, given that current treatment selection is largely empirical and not biologically informed. The investigators conducted a prospective, multicenter, longitudinal observational trial (IDENTITY) in which skin lesion samples were noninvasively collected and analyzed using RNA sequencing. An ensemble algorithm incorporating 487 genes across multiple inflammatory pathways was trained on treatment response data from patients with AD and psoriasis (n=192 for algorithm development) and independently validated in a cohort of 110 AD patients initiating or switching systemic therapy. Clinical outcomes included Eczema Area and Severity Index (EASI), validated Investigator Global Assessment (vIGA‑AD), itch, flare frequency, and quality of life measures assessed over approximately 3 months. The results demonstrated that the GEP test stratified patients into a JAKi Responder Profile (30.4%) and a Th2 Molecular Profile (69.6%). Among patients identified as JAKi responders, those treated with JAK inhibitors achieved significantly higher rates of EASI‑90 compared with those receiving Th2‑targeted therapy (45.5% vs 8.3%; P=.021), achieved responses 3.8 times faster, and experienced superior patient‑reported outcomes including higher rates of “no itch” (45.5% vs 8.3%) and increased flare‑free status (54.5% vs 16.7%). In contrast, among patients with a Th2 molecular profile, no significant differences in efficacy were observed between JAK inhibitors and Th2‑targeted therapies across clinical or patient‑reported endpoints. Overall, only 25.2% of patients achieved EASI‑90 with standard, non–molecularly guided treatment selection, highlighting the potential benefit of the GEP‑guided approach. The study has several limitations. Validation was restricted to patients aged 12 years and older, limiting generalizability to younger pediatric populations. The distribution of therapies was uneven, with fewer patients receiving JAK inhibitors and limited representation of newer Th2‑targeted agents and emerging therapies. Additionally, psoriasis patient response data were used in the training phase but not fully analyzed in validation, and longer‑term outcomes beyond the short follow‑up window were not comprehensively evaluated.
The current evidence base for AdvanceAD-Tx is limited to a single prospective study with a modest sample size, and the test has not yet been incorporated into any major clinical practice guidelines. Larger, independent validation studies and ideally a prospective randomized trial comparing GEP-guided versus standard therapy selection would strengthen the evidence for clinical adoption.
AURA (Vita Imaging)
The AURA System by Vita Imaging is a non-invasive, AI-supported medical device that utilizes Raman spectroscopy to aid physicians in the rapid detection of skin cancer. This technology is designed to provide real-time results, generating a "molecular fingerprint" of a skin lesion in less than 1.5 seconds. The AURA system was developed in collaboration with the British Columbia Cancer Agency (BCCA) and the University of British Columbia (UBC).
Lui et al. (2012) reported the initial in vivo clinical study on AURA. They noted that Raman spectroscopy is a noninvasive optical technique capable of measuring vibrational modes of biomolecules within viable tissues. The investigators evaluated the application of an integrated real-time system of Raman spectroscopy for in vivo skin cancer diagnosis. A total of 518 benign and malignant skin lesions from 453 patients were measured within 1 second each, including melanomas, basal cell carcinomas, squamous cell carcinomas, actinic keratoses, atypical nevi, melanocytic nevi, blue nevi, and seborrheic keratoses. Lesion classification was made using principal component analysis with general discriminant analysis and partial least-squares in three distinct discrimination tasks: distinguishing skin cancers and precancers from benign skin lesions (receiver operating characteristic (ROC) = 0.879); melanomas from nonmelanoma pigmented lesions (ROC = 0.823); and melanomas from seborrheic keratoses (ROC = 0.898). For sensitivities between 95% and 99%, the specificities ranged between 15% and 54%. The investigators concluded that real-time Raman spectroscopy can be used to distinguish malignant from benign skin lesions with good diagnostic accuracy comparable to clinical examination and other optical-based methods.
Zhao et al. (2019) evaluated whether incorporating patient demographics into Raman spectral analysis could improve diagnostic performance. In vivo Raman spectra of 731 cases were analyzed by dividing the data into two groups: skin cancers/precancers (malignant melanoma, basal cell carcinoma, squamous cell carcinoma, and actinic keratosis, n = 340) and benign lesions (pigmented nevi and seborrheic keratosis, n = 391). Patient age, gender, skin type, and location of the lesion were taken into account in the analysis. Multivariate statistical analysis, including principal component analysis and general discriminant analysis, as well as partial least squares (PLS), were utilized for lesion discrimination. Based on PLS analysis, the area under the receiver operating characteristic curve improved from 0.913 to 0.934 (P < 0.05) after incorporating patient demographics into the algorithm. The specificity increased from 33.5% to 44.5%, 56.0% to 68.5%, and 76.0% to 82.1% for sensitivity levels of 99%, 95%, and 90%, respectively (P < 0.05 for all sensitivity levels).
Vita Imaging is currently conducting a multi-site FDA clinical validation study to support its FDA approval process. This study began in January 2025 in partnership with the VA Boston and VA Tampa healthcare systems and is investigating the device's effectiveness in detecting melanoma and other skin cancers in U.S. veterans. The study aims to supplement the data gathered in Canada, as required by the FDA.
Dermtech Nevome
Dermtech Nevome is a test designed to identify high-risk pigmented lesions by analyzing known mutation risk factors for melanoma. This new test uses tissue samples collected non-invasively with an adhesive patch. When combined with the PLA gene expression analysis, the additional DNA mutation analysis could provide a more complete picture of lesions or moles at high risk for melanoma. Nevome analyzes mutations in BRAF, NRAS and TERT promoter genes, while the PLA analyzes the gene expression of LINC and PRAME. According to DermTech, Nevome can currently be ordered if the PLA test is positive. Nevome and the PLA are intended for use on pigmented skin lesions, clinically suspicious for melanoma. These lesions may meet one or more ABCDE criteria.
However, there is a lack of published evidence regarding the clinical value of Dermtech Nevome.
Computerized Total Body Photography Systems
- naked-eye clinical examination alone,
- clinical examination with the aid of TBP,
- epiluminescence microscopy (ELM),
- digital ELM,
- computer-assisted techniques, and
- teledermatology.
Marchesini et al. (2002) emphasized the critical importance of early detection and prompt excision of cutaneous melanoma to improve patient survival rates. They noted that clinicians should be aware of the clinical features that suggest the presence of a malignant lesion. The clinical diagnosis primarily relies on the observation of the color and shape of a given skin lesion. However, the evaluation of a pigmented lesion is largely subjective and closely tied to the clinician's experience. To address this issue, optical imaging techniques utilizing various instruments (such as color video cameras, epiluminescence microscopy [ELM], and reflectance spectrophotometry [SPT]) along with computer image analysis have been proposed to provide quantitative measurements in an objective and reproducible manner. The different procedures employed for automated diagnosis share a common goal: to mimic the eye and brain of the clinician through image processing and computerized analysis programs. Sensitivity and specificity data in the literature suggest that computer-based melanoma diagnosis does not significantly differ from the diagnostic capabilities of expert clinicians and is independent of the optical acquisition method used to analyze the lesions. Most computer-processed morphometric variables useful in automated diagnosis are not recognizable or objectively evaluable by the human eye, except for lesion dimensions. However, several questions remain regarding the actual usefulness, potential, and limitations of computer-based diagnostic procedures.
In a randomized controlled trial, Walter et al. (2012) investigated whether adding a novel computerized diagnostic tool, the MoleMate system (SIAscopy with a primary care scoring algorithm), to current best practices would result in more appropriate referrals of suspicious pigmented lesions to secondary care and assess its impact on clinicians and patients. The study involved 1,297 adults with pigmented skin lesions that were not immediately diagnosed as benign. Patients were assessed by trained primary care clinicians using best practices (clinical history, naked-eye examination, and a 7-point checklist) either alone (control group) or with the MoleMate system (intervention group). Main outcome measures included the appropriateness of referral, defined as the proportion of referred lesions that were biopsied or monitored. Secondary outcomes related to clinicians (diagnostic performance, confidence, learning effects) and patients (satisfaction, anxiety). Economic evaluation, diagnostic performance of the 7-point checklist, and a 5-year follow-up of melanoma incidence were also secondary outcomes and will be reported later. A total of 1,297 participants with 1,580 lesions were randomized: 643 participants with 788 lesions to the intervention group and 654 participants with 792 lesions to the control group. The appropriateness of referral did not differ significantly between the intervention and control groups: 56.8% (130/229) versus 64.5% (111/172); difference -8.1% (95% CI: -18.0% to 1.8%). The proportion of benign lesions appropriately managed in primary care did not differ (intervention 99.6% versus control 99.2%, p = 0.46), nor did the percentage agreement with an expert decision to biopsy or monitor (intervention 98.5% versus control 95.7%, p = 0.26). However, the percentage agreement with expert assessment that the lesion was benign was significantly lower with MoleMate (intervention 84.4% versus control 90.6%, p < 0.001), and a higher proportion of lesions were referred (intervention 29.8% versus control 22.4%, p = 0.001). A total of 36 histologically confirmed melanomas were diagnosed: 18/18 were appropriately referred in the intervention group and 17/18 in the control group. Clinicians in both groups expressed confidence, and there was no evidence of learning effects or contamination between groups. Patients in the intervention group rated their consultations higher for thoroughness and reassuring care, although anxiety scores were similar between the groups. The authors concluded that there was no evidence that the MoleMate system improved the appropriateness of referral. The systematic application of best practice guidelines alone was more accurate than the MoleMate system, and both performed better than reports of current practice. Therefore, the systematic application of best practice guidelines (including the 7-point checklist) should be the standard for managing suspicious skin lesions in primary care.
- all available CAD data (indirect comparisons), and
- studies providing paired data for both tests (direct comparisons). They tested the contribution of human decision-making to the accuracy of CAD diagnoses in a sensitivity analysis by removing studies that gave CAD results to clinicians to guide diagnostic decision-making.
A total of 42 studies were included in this study, 24 evaluating digital dermoscopy-based CAD systems (Derm-CAD) in 23 study cohorts with 9,602 lesions (1,220 melanomas, at least 83 BCCs, 9 cSCCs), providing 32 datasets for Derm-CAD and 7 for dermoscopy; 18 studies evaluated spectroscopy-based CAD (Spectro-CAD) in 16 study cohorts with 6,336 lesions (934 melanomas, 163 BCC, 49 cSCCs), providing 32 datasets for Spectro-CAD and 6 for dermoscopy. These consisted of 15 studies using multi-spectral imaging (MSI), 2 studies using electrical impedance spectroscopy (EIS) and 1 study using diffuse-reflectance spectroscopy. Studies were incompletely reported and at unclear to high risk of bias across all domains. Included studies inadequately addressed the review question, due to an abundance of low-quality studies, poor reporting, and recruitment of highly selected groups of participants. Across all CAD systems, these researchers found considerable variation in the hardware and software technologies used, the types of classification algorithm employed, methods used to train the algorithms, and which lesion morphological features were extracted and analyzed across all CAD systems, and even between studies evaluating CAD systems. Meta-analysis found CAD systems had high sensitivity for correct identification of cutaneous invasive melanoma and atypical intra-epidermal melanocytic variants in highly selected populations, but with low and very variable specificity, particularly for Spectro-CAD systems. Pooled data from 22 studies estimated the sensitivity of Derm-CAD for the detection of melanoma as 90.1% (95% CI: 84.0% to 94.0%) and specificity as 74.3% (95% CI: 63.6 % to 82.7%). Pooled data from 8 studies estimated the sensitivity of MSI-CAD as 92.9% (95% CI: 83.7% to 97.1%) and specificity as 43.6% (95% CI: 24.8% to 64.5%). When applied to a hypothetical population of 1,000 lesions at the mean observed melanoma prevalence of 20%, Derm-CAD would miss 20 melanomas and would lead to 206 false-positive results for melanoma. MSI-CAD would miss 14 melanomas and would lead to 451 false diagnoses for melanoma. Preliminary findings suggested that CAD systems were at least as sensitive as assessment of dermoscopic images for the diagnosis of invasive melanoma and atypical intra-epidermal melanocytic variants. These investigators were unable to make summary statements regarding the use of CAD in un-referred populations, or its accuracy in detecting keratinocyte cancers, or its use in any setting as a diagnostic aid, because of the paucity of studies. The authors concluded that in highly selected patient populations all CAD types demonstrated high sensitivity, and could prove useful as a back-up for specialist diagnosis to assist in minimizing the risk of missing melanomas. However, the evidence base is currently too poor to understand whether CAD system outputs translate to different clinical decision-making in practice. Insufficient data are available on the use of CAD in community settings, or for the detection of keratinocyte cancers. The evidence base for individual systems is too limited to draw conclusions on which might be preferred for practice. Moreover, they stated that prospective comparative studies are needed to evaluate the use of CAD systems as diagnostic aids, by comparison to face-to-face dermoscopy, and in participant populations that are representative of those in which the test would be used in practice.
Electrical Impedance Spectroscopy
Mohr et al. (2013) stated that previous studies have shown statistically significant differences in electrical impedance between various cutaneous lesions. Electrical impedance spectroscopy (EIS) may therefore aid clinicians in differentiating between benign and malignant skin lesions. These researchers developed a classification algorithm to distinguish between melanoma and benign lesions of the skin with a sensitivity of at least 98% and a specificity approximately 20% higher than the diagnostic accuracy of dermatologists. A total of 1,300 lesions were collected in a multi-center, prospective, non-randomized clinical trial from 19 centers around Europe. All lesions were excised and subsequently evaluated independently by a panel of three expert dermatopathologists. From the data, two classification algorithms were developed and verified. For the first classification algorithm, approximately 40% of the data were used for calibration and 60% for testing. The observed sensitivity for melanoma was 98.1% (101/103), for non-melanoma skin cancer was 100% (25/25), and for dysplastic nevus with severe atypia was 84.2% (32/38). The overall observed specificity was 23.6% (66/280). For the second classification algorithm, approximately 55% of the data were used for calibration. The observed sensitivity for melanoma was 99.4% (161/162), for non-melanoma skin cancer was 98.0% (49/50), and for dysplastic nevus with severe atypia was 93.8% (60/64). The overall observed specificity was 24.5% (116/474). The authors concluded that EIS has the potential to be an adjunct diagnostic tool to help clinicians differentiate between benign and malignant (melanocytic and non-melanocytic) skin lesions. They stated that further studies are needed to confirm the validity of the automatic assessment algorithm.
Rocha et al. (2017) noted that electrical impedance spectroscopy (EIS) is a non-invasive diagnostic technique that measures tissue impedance. These investigators examined the effect of adding an EIS measurement at baseline to suspicious melanocytic lesions undergoing routine short-term sequential digital dermoscopy imaging (SDDI). Participants included patients who presented with suspicious melanocytic lesions that were eligible for short-term SDDI (with no clear features of melanoma on dermoscopy). EIS measurement was performed at the first visit following dermoscopic photography. Normally, an EIS score of 4 or higher is considered positive; however, this protocol examined a higher cut-off in combination with SDDI. When the EIS score was 7 or greater, the lesion was excised immediately owing to the high risk of melanoma. Lesions with a score of less than 7 were monitored with standard SDDI over a 3-month period. From a total of 160 lesions analyzed, 128 of 154 benign lesions received an EIS score of 0 to 6, giving a specificity of the EIS method for the diagnosis of melanoma of 83.1% (95% CI: 76.3 to 88.7); 5 of the 6 melanomas found in this study had an EIS score of 7 or higher, with a sensitivity for melanoma diagnosis of 83.3% (95% CI: 35.9 to 99.6). When EIS 0 to 6 lesions were subsequently followed up with SDDI, 1 additional melanoma was detected (EIS = 6), giving a sensitivity for the diagnosis of melanoma overall of 100% (95% CI: 54.1 to 100; 6 of 6 malignant melanomas excised) and a specificity of 69.5% (95% CI: 61.5 to 76.6; 107 of 154 benign lesions not excised). The authors concluded that if utilizing a protocol where an EIS score of 3 or less required no SDDI and 7 or higher required immediate excision, it reduced the need for SDDI by 46.9% (n = 75/160; 95% CI: 39.0 to 54.9). Moreover, these researchers stated that further investigations in other centers with larger sample sizes are needed to confirm the role of EIS in examining suspicious melanocytic lesions using this protocol.
The authors stated that a possible drawback of this trial was that 3-month unchanged lesions were not followed up beyond that time period to confirm their benign nature. However, in the authors’ hands, when following up 3-month unchanged lesions beyond that time period, 99.2% were benign. Indeed, of the 0.8% that were subsequently found to be melanoma, it was impossible to know whether they had transformed from previously benign naevi or were melanoma at baseline. Another drawback of this trial was that these researchers did not randomize lesions to the combined protocol (EIS and SDDI) with SDDI alone, which would have allowed a precise comparison of the number of lesions needed to be excised to find a melanoma between both of these groups. In addition, the clinician was not strictly blinded to the baseline EIS score when assessing SDDI change, which was a potential source of bias, and an independent panel of histopathologists did not review the cases. Finally, this study was not powered for sensitivity, indicated by the wide CIs in the sensitivity results. However, the sensitivity of both the EIS device and SDDI has been previously reported in studies with larger samples.
Braun et al. (2017) stated that EIS is a non-invasive method that aims to help diagnose skin cancer. The EIS device consists of a hand-held probe with a disposable electrode that is applied directly to the skin and uses electrical impedance differences to differentiate between normal and abnormal skin lesions. The EIS algorithm is best used on lesions that are deemed clinically or dermoscopically suspicious and has a high sensitivity in detecting malignant melanoma. The greatest usefulness of EIS is achieved in conjunction with a physician who has experience with this modality and excellent training in the clinical detection of suspicious lesions. These investigators stated that although further investigation is needed to determine the ability of EIS to correctly classify other lesions such as lentigines and seborrheic keratosis as benign, in the present study, the seborrheic keratoses were inaccurately classified as malignant by EIS. This observation underscored the importance that EIS should be performed by clinicians trained to correctly recognize seborrheic keratosis, thereby preventing them from being evaluated via EIS. Moreover, these researchers stated that although the sensitivity for the diagnosis of non-melanoma skin cancer was 100%, more research is needed to determine the effectiveness of EIS in diagnosing different subtypes and stages of non-melanoma skin cancers.
Svoboda et al. (2019) examined the impact of EIS results on clinicians' diagnostic accuracy and biopsy decisions. A total of 164 dermatology trainees completed an online survey presenting clinical images of 45 pigmented lesions (28 benign, 17 melanoma). For each image, respondents were asked if they would recommend biopsy based on morphologic assessment alone, and then asked again once presented with the corresponding EIS score (along with positive and negative predictive values [PPV and NPV]). The proportion of clinical decisions for which the addition of the EIS score altered the decision to biopsy was calculated. Furthermore, the sensitivity, specificity, and proportion of missed melanomas and benign biopsies were determined for morphologic assessment alone and for morphologic assessment plus EIS score. Significance testing was carried out using the McNemar test for categorical variables and paired t-tests for continuous variables. A total of 7,380 clinical decisions (164 respondents × 45 lesions) were made based on morphology alone and 7,380 were made based on morphology plus EIS score. The decision to biopsy was made in 4,527 of 7,380 cases based on morphology alone and 4,553 of 7,380 cases based on morphology plus EIS. The EIS results altered the individual biopsy decision in 24.3% of cases. The addition of the EIS score resulted in 402 fewer missed melanomas and a net decrease of 376 benign biopsies (p < 0.001). When including the EIS score, the mean sensitivity of respondents for ruling out melanoma increased from 80.7% to 95.2% (p < 0.001) and mean specificity from 50.4% to 58.6% (p < 0.001). These investigators stated that a diagnostic device is only useful if it affects clinical management and improves accuracy. In this study, the EIS score resulted in a change in the decision to biopsy in approximately 25% of cases and improved diagnostic accuracy, resulting in fewer biopsies of benign lesions and more biopsies of melanomas, without significantly changing the total number of biopsies. A higher specificity was observed in this study compared with the EIS pivotal trial (58.6% versus 34.4%), which measured the specificity of the device alone. This suggested that respondents used the EIS information synergistically with the clinical image, rather than basing decisions solely on the EIS results. The authors stated that a limitation of this study was that additional clinical data, such as patient history, risk factors, and dermoscopic images, were unavailable to participants. Furthermore, as this study only included trainees, the results might not extrapolate to more experienced clinicians.
Litchman et al. (2020) stated that the number-needed-to-biopsy (NNB) metric measures the efficiency of a clinician’s ability to accurately diagnose and recommend pigmented skin lesions (PSLs) for biopsy for suspected melanomas. EIS is a non-invasive technique that measures differences in resistance between healthy and cancerous skin cells, intended as an aid to enhance diagnostic accuracy. Dermatology clinicians from three distinct groups (residents, physician assistants/nurse practitioners, and practicing dermatologists) were evaluated on their ability to accurately recommend suspect PSLs for biopsy before and after the integration of EIS data. All three groups had a reduction in NNB after the inclusion of EIS. Instances of missed biopsies for malignant melanoma were significantly reduced, with simultaneous significant reductions in unnecessary biopsies for benign lesions. There was a material improvement in biopsy selection for PSLs having clinically challenging features. EIS also greatly improved the diagnostic acumen of clinicians whose assessments were less accurate than their peers before EIS incorporation. The authors concluded that the integration of EIS technology into the PSL biopsy decision was shown to be effective in significantly enhancing clinician NNB and more accurate PSL biopsy selection. Moreover, these researchers stated that a material positive impact on PSL biopsy selection occurred in the most clinically challenging lesions, suggesting that this technology may be especially helpful in this spectrum of PSLs.
The authors stated that a drawback of this study was that decisions were made based on clinical images alone versus in-vivo examination. Dermoscopic images were also not included to remove any possible confounding effects of dermoscopy, allowing for assessment of the independent impact of EIS technology. Furthermore, despite its growing use as a biopsy efficacy metric, NNB may not be ideal due to a lack of standardization and under-reporting. For these reasons, a lower NNB may not necessarily result in more efficient outcomes.
Pathiraja et al. (2020) noted that electrical impedance technology has been well-established for the past two decades. Recently, research has begun to emerge into its potential uses in the detection and diagnosis of pre-malignant and malignant conditions. In a systematic review, these investigators examined the clinical use of electrical impedance technology in the detection of malignant neoplasms. They searched Embase Classic, Embase, and Medline databases from 1980 to February 22, 2018, to identify studies reporting on the use of bioimpedance technology in the detection of pre-malignant and malignant conditions. The ability to distinguish between tissue types was defined as the primary endpoint, and other points of interest were also reported. A total of 731 articles were identified, of which 51 reported sufficient data for analysis. These studies covered 16 different cancer subtypes in a total of 7,035 patients. As the studies took various formats, a qualitative analysis of each cancer subtype’s data was undertaken. All the studies were able to show differences in electrical impedance and/or related metrics between malignant and normal tissue. The authors concluded that electrical impedance technology provided a novel method for the detection of malignant tissue, with large studies of cervical, prostate, skin, and breast cancers showing encouraging results. Moreover, these researchers stated that while these studies provided promising insights into the potential of this technology as an adjunct in screening, diagnosis, and intra-operative margin assessment, customized development as well as multi-center clinical trials are needed before it can be reliably used in the clinical detection of malignant tissue.
The authors stated that one major drawback that should be noted in this review was that several of the studies (25/51) included in this systematic review used ex-vivo specimens; only the cervical, cutaneous, and oral lesion studies exclusively examined electrical impedance in pre-malignant and normal tissue. One of the breast studies included a comparison between in-vivo and ex-vivo measurements of specimens and showed that various EIS metrics (conductivity and permittivity) clearly decreased as measurements were taken ex-vivo. It is known that as soon as tissue is resected and loses its blood supply, the fluid status of the tissue changes, which in turn would affect the electrical conductivity and impedance properties of the tissue. However, it is understandable that in these initial proof-of-concept (POC) studies, where novel technology and techniques are being used for the first time, ex-vivo studies preceded more realistic in-vivo studies; thus, further research examining the electrical impedance of these tissue types in-vivo is needed before an assessment of the effectiveness of this technology could be made. Another drawback to consider was that many of the studies included had a small sample size and had each reported on different outcomes, which therefore could not be statistically analyzed as a whole. This heterogeneity was increased by the studies having multiple variables, such as frequency ranges used by the studies’ tools, the specific impedance tool used, as well as unreported ischemic times. For the cancer types that had many studies reporting findings, the studies had often been carried out at the same institution using the same methodology but had not reported quantitative statistics that could be pooled for analysis. Consequently, more meaningful statistical analysis of the results could not be reported at this early stage. Nevertheless, qualitative analysis of the results was still possible, from which significant conclusions and further work can be planned.
Sarac et al. (2020) noted that EIS is a non-invasive method that can aid in diagnosing malignant skin tumors. Depending on the cellular irregularity of the lesion, EIS can reveal changes in the structure and form of the cells, using a harmless electrical current applied to the skin. A score between 0 and 10 is generated by the electrical impedance spectrometer, where 0 is considered benign, and 10 is malignant. This prospective study was carried out in 101 patients with a total of 200 skin lesions: 62 benign and 138 malignant. There was a significant difference between the electrical impedance of malignant and benign lesions (p < 0.001). The sensitivity, specificity, PPV, and NPV of EIS for non-melanoma skin cancer were 94.2%, 41.9%, 78.3%, and 76.5%, respectively, when the cut-off for the EIS score was set at between 5 and 6. The area under the curve in receiver operating characteristics (AUROC) analyses was 0.758. The authors concluded that EIS exhibited good discriminative power to distinguish NMSC from benign cutaneous lesions. These investigators stated that although EIS could not replace the gold standard, histopathology, it may guide and support clinicians in the early diagnosis of NMSC, as in melanoma. They noted that due to the ease of use and no requirement for dermatology expertise training, the EIS device appeared to be most appropriate for use in primary healthcare offices as a screening tool for triage of the lesions for referral to specialists for further evaluation. Moreover, these researchers stated that further prospective studies with larger numbers of tumors are needed to test the sensitivity and specificity of this method and to confirm or reject the findings of this trial.
The authors stated that this study had several drawbacks. Firstly, this was a single-center study, which may be biased by the specific patient collective being treated at this center. Second, thick SCC and BCC tumors may be over-represented in the dermato-surgery division of the university hospital, whereas thinner lesions are often operated on in private dermatology offices and outpatient clinics. Third, this study analyzed a rather limited number of cases, especially for the benign lesions, which limited the statistical power of the study. Since the EIS score is affected by cellular features, it would be optimal to evaluate tumors derived from different tissues in separate studies and to make the comparison in malignant and benign tumors of similar origin. In this study, there were only 3 connective tissue-derived benign lesions, which were fibrous papule of the nose (n = 1) and solar elastosis (n = 2). Although the mean EIS score of these 3 lesions was lower than the sarcoma group’s score, the sample size was not adequate to make a significant comparison.
Litchman et al. (2021) stated that novel non-invasive technologies augment information available to a clinician to enhance diagnosis; EIS is a highly sensitive technology used before biopsy to differentiate equivocal lesions via differences in electrical resistance of benign versus malignant cells. A recent study of an EIS device supported this device's impact on clinical management among dermatology residents. The device provides an EIS score, which increases with a greater likelihood of malignancy. These investigators examined if the addition of an EIS score would improve uniformity and diagnostic accuracy of pigmented lesions. This study was a post-hoc analysis of previously collected data from a survey of 164 dermatology residents. Residents were asked to determine whether they would biopsy a lesion based on clinical morphology alone versus clinical morphology with an EIS score. A total of 45 lesions were assessed (including 17 malignant and 28 benign lesions). Participants were grouped by percent correct pre-EIS score biopsy decisions and divided into quartiles. With clinical assessment alone, the mean correct decisions to biopsy were 59.9%. With the addition of the EIS score, the mean increased to 71.0%. All quartiles significantly increased their correct biopsy decisions with EIS (p < 0.001); however, the lowest scoring quartiles improved more than the highest scoring quartiles. The authors concluded that the data from the EIS device were designed to be integrated into the biopsy decision as an additional piece of information in the diagnostic pathway. The study findings were consistent with this objective. In addition to clinical judgment, the use of the EIS score most increased the lowest-scoring residents, but all were improved after integrating the EIS score. EIS information improved the homogeneity of ability and diagnostic accuracy. These researchers stated that this technology has the potential to aid in the management of pigmented lesions and may be especially useful to clinicians with less experience by enhancing the accuracy of their biopsy decisions.
The authors stated that a drawback of this study was that decisions were made based on clinical images alone, whereas, in actual practice, a physician would have the option to integrate clinical history and potentially dermoscopy information. In this study, these researchers specifically chose to measure the effect of EIS independent of the effect of dermoscopy to remove any possible confounding effects on enhancing the clinical diagnosis. Furthermore, only the diagnostic skills of medical residents were evaluated. Residents were chosen for this analysis because they were more likely to have varying levels of diagnostic skills; however, the results may not extrapolate to other clinicians with differing levels of experience and expertise.
In a “Letter to the Editor,” Litchman et al. (2021) discussed whether integrating EIS (independent of dermoscopy) would improve PSL biopsy selection and NNB. A total of 267 practicing dermatologists were each tested on their clinical biopsy decisions for 43 PSLs (total biopsy decisions, n = 11,481); 43 randomly selected clinically suspicious PSLs (16 melanomas and 27 benign lesions) from a previously published prospective, blinded trial of 2,416 lesions were evaluated. Benign lesions ranged from ordinary melanocytic nevi to mild/moderate dysplastic nevi. All diagnoses were histologically confirmed, with clinical diagnostic difficulty assessed by using the ABCD characteristics (A, asymmetry; B, border irregularity; C, color variegation; D, diameter of 6 mm or larger). Participants were asked to determine whether biopsy was indicated based on clinical morphology alone and then again on the same images when given the corresponding EIS data. The impact of EIS on decision-making was analyzed. Significance was calculated using McNemar and Richardson proportion comparison tests. Incorporating EIS scores into dermatologists' clinical decision-making process significantly improved NNB from 6.3 to 5.3 (p < 0.001), sensitivity from 84% to 98% (p < 0.001), and specificity from 34% to 44% (p < 0.001). The integration of EIS data significantly appropriately affected biopsy decisions, with an additional 581 melanomas correctly selected for biopsy and 782 unnecessary biopsies avoided. Furthermore, the greatest impact of EIS score integration was noted on the more clinically challenging cases. There was a significantly greater increase in biopsies for the melanomas with the fewest (1 or 2) ABCD characteristics and a similar significantly greater decrease in biopsies for those benign lesions with the greatest number (3 or 4) of ABCD characteristics, further demonstrating the positive impact of EIS on challenging PSLs. The authors concluded that the findings of this study suggested that integrating EIS data into dermatologists' biopsy decisions improved their NNB, sensitivity, and specificity, resulting in significant improvement in correct biopsy assessment, with the greatest impact occurring in clinically challenging lesions. With healthcare costs and melanoma incidence increasing, adjunctive technologies such as EIS have the potential to play an increasingly important role in enhancing PSL biopsy efficiency.
The authors stated that a drawback of this study was that biopsy decisions were made based on clinical images alone versus in-vivo examination, so the cost of an additional biopsy or a missed melanoma was less than in an actual clinical setting. Furthermore, these researchers specifically chose to measure the effect of EIS independent of dermoscopy to remove possible confounding effects, although analyzing how each of these techniques augments each other would be an interesting future study.
Kolla et al. (2022) stated that Nevisense is a non-invasive device that measures EIS of individual skin lesions to aid in the diagnosis of melanoma. While EIS has demonstrated high sensitivity in diagnosing melanoma, its impact on a clinician’s diagnostic confidence remains unknown. In a pilot study, these researchers examined if clinician diagnostic confidence, sensitivity, specificity, and accuracy could be improved by adding EIS measurement scores to clinical and dermoscopic images of lesions clinically suspicious for melanoma. A total of three pigmented lesion specialists and three 4th-year medical students completed an online survey to examine 34 melanocytic lesions suspicious for melanoma. For each lesion, participants provided their diagnosis, biopsy recommendation, and confidence in diagnosing a lesion as benign or malignant based on history and clinical and dermoscopic images, and again after receiving an EIS score. The addition of EIS scores increased mean biopsy sensitivity for melanoma/severely dysplastic nevi from 70% to 84% (p = 0.014) and mean diagnostic accuracy from 74% to 86% (p = 0.005). Mean diagnostic confidence increased for all histopathologic categories for both students and dermatologists (all p < 0.05). The authors concluded that in this pilot study, EIS increased novice and expert diagnosticians’ confidence regarding dermoscopically equivocal melanocytic lesions. Moreover, these researchers stated that additional larger studies in real-world clinical settings are needed to examine how EIS could aid clinicians in reassuring patients regarding the management of clinically dysplastic melanocytic nevi.
The authors stated that there were several drawbacks to this pilot study. Most importantly, these researchers recognized the small sample size of participants (3 specialists and 3 medical students) in this study. The number of participants was intentionally kept small since the Nevisense device is not available in the authors’ center at this time for routine clinical use, and these investigators did not want to inadvertently promote its use among trainees and other faculty members. Another important consideration was that in clinical settings, many diagnostically equivocal pigmented lesions may be non-melanocytic (e.g., atypical solar lentigines). These lesions are known to have elevated EIS scores; thus, applying EIS measurement to a clinically suspicious yet non-melanocytic lesion has a high chance of a false-positive test result. Therefore, clinicians have to make the additional decision of whether or not it would be appropriate to employ EIS on a particular lesion, a step that was not included in this study. Moreover, the stakes of deciding whether or not to biopsy a lesion are higher in a clinical setting than in the context of a survey study. Additional drawbacks included the small number of lesions included and the potential for selection bias in the choice of lesions provided by SciBase. As noted above, the specificity of Nevisense for the diagnosis of melanoma/severely dysplastic nevus was higher than that reported in the pivotal clinical trial.
Owji et al. (2022) noted that EIS is a non-invasive diagnostic device that measures the electrical impedance of skin lesions to aid in detecting melanoma. While this tool has been shown to have a high sensitivity for melanoma diagnosis, data on its impact on clinical decision-making for PSLs compared to other diagnostic tools is lacking. In a pilot study, these researchers examined how this technology – specifically, the effect it has on clinical decision-making for PSLs – compares to traditional dermoscopy. Dermatologists, dermatology residents, and medical students completed an online survey eliciting their biopsy decisions for 24 PSLs of varying histopathological diagnoses; 50% of the lesions from each diagnosis group were presented as a clinical image with an associated dermoscopic image, and the other 50% as a clinical image with the corresponding EIS score. Decisions made with EIS demonstrated a mean sensitivity of 75% for melanomas/severely dysplastic nevi versus 66% for decisions made with dermoscopy (p = 0.008). While dermatologists biopsied with similar sensitivities when using EIS or dermoscopy (81% versus 81%), residents and medical students biopsied with significantly greater sensitivity when using EIS. Respondents who reported rarely using dermoscopy showed the greatest improvement in sensitivity and specificity when using EIS compared to dermoscopy. The authors concluded that given that not all providers were trained in dermoscopy, and these findings that EIS particularly benefited those who infrequently use dermoscopy, EIS may complement dermoscopy by helping a broader range of providers make improved PSL diagnostic decisions.
The authors stated that this study had several limitations. One limitation was that respondents’ biopsy decisions were made on the basis of clinical images in an online survey rather than in-vivo examination. As such, the true consequences of a missed melanoma or an unnecessary biopsy were likely diminished compared to lesions examined in a real clinical setting. Furthermore, this survey also did not include non-melanocytic lesions such as seborrheic keratoses, which could alter the accuracy of EIS-based biopsy decisions. Lastly, inherent to survey-based studies was the potential for participation bias.
Chavez-Bourgeois et al. (2022) noted that EIS has clinical relevance in diagnosing malignancy in melanocytic lesions. A total of 68 lesions with changes during digital follow-up of patients at very high risk of developing melanoma were prospectively included in this study from February to December 2016. Reflectance confocal microscopy and EIS were carried out to examine their performance in this subset of difficult lesions; 46 lesions were considered suspicious on reflectance confocal microscopy and were excised; of these, 19 were diagnosed as melanoma. A total of 15 melanomas were detected by EIS, while 4 received a score lower than 4, which suggested no malignancy. The authors concluded that the addition of reflectance confocal microscopy improved accuracy while maintaining the same sensitivity. In the case of EIS scores of less than 4, lesions exhibiting changes in follow-up may need short-term monitoring or excision if dermoscopy showed criteria for melanoma. Moreover, these investigators stated that results of EIS in this subset of very early lesions should be carefully considered due to the risk of false negatives.
Anushree et al. (2022) stated that skin cancer is among the fastest-growing cancers with an excellent prognosis if detected early. However, the current method of diagnosis by visual inspection has several disadvantages, such as overlapping tumor characteristics, subjectivity, low sensitivity, and specificity. Hence, several adjunctive diagnostic techniques such as thermal imaging, optical imaging, ultrasonography, tape stripping methods, and EIS are employed along with visual inspection to improve the diagnosis. Electrical impedance-based skin cancer detection depends upon the variations in electrical impedance characteristics of the transformed cells. The information provided by this technique is fundamentally different from other adjunctive techniques; therefore, it has good prospects. Depending on the stage, type, and location of skin cancer, various impedance-based devices have been developed. These devices, when used as an adjunct to visual methods, have increased the sensitivity and specificity of skin cancer detection up to 100% and 87%, respectively; thus, demonstrating their potential to minimize unnecessary biopsies.
Jutzi et al. (2023) noted that the incidence of malignant melanoma is increasing globally. If detected early, melanoma is highly treatable, so early detection is crucial. Skin cancer early detection has improved significantly in recent decades, for example, by the introduction of screening in 2008 and dermoscopy. Nevertheless, visual detection of early melanomas remains challenging because they show many morphological overlaps with nevi. Thus, there continues to be a high medical need to further develop methods for early skin cancer detection to reliably diagnose melanomas at a very early stage. Routine diagnostics for melanoma detection include visual whole-body inspection, often supplemented by dermoscopy, which can significantly increase the diagnostic accuracy of experienced dermatologists. A procedure that is additionally offered in some practices and clinics is whole-body photography combined with digital dermoscopy for the early detection of malignant melanoma, especially for monitoring high-risk patients. In recent years, many non-invasive adjunctive diagnostic techniques were developed for the examination of suspicious pigmented moles that may have the potential to allow improved and, in some cases, automated evaluation of these lesions. First, confocal laser microscopy should be mentioned here, as well as EIS, multi-photon laser tomography, multi-spectral analysis, Raman spectroscopy, or OCT. These diagnostic techniques usually focus on high sensitivity to avoid malignant melanoma being overlooked; however, this usually implies lower specificity, which may result in unnecessary excision of benign lesions in screening. Furthermore, some of the procedures are time-consuming and costly, which also limits their applicability in skin cancer screening. In the near future, the use of AI might change skin cancer diagnostics in many ways. The most promising approach may be the analysis of routine macroscopic and dermoscopic images by AI. For the classification of pigmented skin lesions based on macroscopic and dermoscopic images, AI, especially in the form of neural networks, has achieved comparable diagnostic accuracies to dermatologists under experimental conditions in numerous studies. In particular, it achieved high accuracies in the binary melanoma/nevus classification task, but it also performed comparably well to dermatologists in multi-class differentiation of various skin diseases. However, proof of the basic applicability and utility of such systems in clinical practice is still pending. Prerequisites that remain to be established to enable the translation of such diagnostic systems into dermatological routine are means that allow users to comprehend the system's decisions as well as a uniformly high performance of the algorithms on image data from other hospitals and practices. At present, hints are accumulating that CAD systems could provide their greatest benefit as assistance systems, since studies indicated that a combination of human and machine achieved the best results. Diagnostic systems based on AI are capable of detecting morphological characteristics quickly, quantitatively, objectively, and reproducibly, and thus could provide a more objective analytical basis in addition to medical experience.
Kashani-Sabet et al. (2023) stated that therapy for advanced melanoma has transformed during the last 10 years; however, early detection and prognostic assessment of cutaneous melanoma (CM) remain key objectives. Best practices for screening and the use of pigmented lesion evaluation tools and gene expression profile (GEP) testing in CM remain to be defined. These investigators provided consensus recommendations on optimal screening practices and pre-biopsy diagnostic, post-biopsy diagnostic, and prognostic assessment of CM. Case scenarios were interrogated using a modified Delphi consensus method. Melanoma panelists (n = 60) were invited to vote on hypothetical scenarios via an emailed survey (n = 42), which was followed up by a consensus conference (n = 51) that reviewed the literature and the rationale for survey answers. Panelists participated in a follow-up survey for final recommendations on the scenarios (n = 45). The panelists reached consensus (70% or higher agreement) in supporting a risk-stratified approach to melanoma screening in clinical settings and public screening events, screening personnel recommendations (self/partner, primary care provider, general dermatologist, and pigmented lesion expert), screening intervals, and acceptable appointment wait times. Participants also reached consensus that visual and dermoscopic examination are sufficient for evaluation and follow-up of melanocytic skin lesions deemed innocuous. The panelists reached consensus on interpreting reflectance confocal microscopy and some but not all results from epidermal tape stripping; however, they did not reach consensus on the use of certain pigmented lesion evaluation tools, such as EIS. Regarding GEP scores, the panelists reached consensus that a low-risk prognostic GEP score should not outweigh concerning histologic features when selecting patients to undergo sentinel lymph node biopsy (SLNB) but did not reach consensus on imaging recommendations in the setting of a high-risk prognostic GEP score and low-risk histology and/or negative nodal status. The authors concluded that for this consensus statement, panelists reached consensus on aspects of a risk-stratified approach to melanoma screening and follow-up, as well as the use of visual examination and dermoscopy. These findings supported a practical approach to diagnosing and evaluating CM. Panelists did not reach consensus on a clearly defined role for GEP testing in clinical decision-making, citing the need for additional studies to establish the clinical use of existing GEP assays.
Zakria et al. (2023) examined if EIS technology can further improve correct biopsy choices beyond clinical and dermoscopic evaluation for melanoma (MM), severe dysplastic nevi (SDN), and benign pigmented skin lesions (PSLs). Images of 49 MMs, SDNs, and benign PSLs were randomly selected from a previous study and were provided in a reader-type survey study to dermatologists to evaluate for biopsy. A total of 33,957 biopsy decisions were analyzed. Respondents significantly improved on the correct biopsy choice with the addition of dermoscopy versus clinical image alone for melanoma and severely dysplastic nevi. Respondents also showed a statistically significant improvement in correct biopsy choice beyond their dermoscopic evaluation when integrating the EIS score versus dermoscopy with clinical images for MM, SDN, and benign lesions. Respondents also made fewer incorrect biopsy choices with the addition of the EIS score versus dermoscopy and clinical image for MM and benign lesions. Sub-analyses of biopsy choices were also conducted based on experience and practice type. The authors concluded that the findings from this study showed that the integration of EIS technology into PSL biopsy decisions has the potential to significantly improve the accuracy of lesion selection for biopsy beyond clinical and dermoscopic evaluation alone.
The authors stated that drawbacks of their study included not evaluating the lesions in-vivo and the fact that actual biopsy behavior could be different in the clinical setting. Another drawback was the small sample size in some of the subset analyses. As a result, some did not show a significant change in incorrect biopsy choice with the addition of dermoscopy or EIS. However, the overall findings from this study showed that the integration of EIS technology into PSL biopsy decisions has the potential to significantly improve the accuracy of lesion selection for biopsy beyond clinical and dermoscopic evaluation alone.
Emerging Diagnostic Techniques
The recent advent of digital imaging systems for acquiring and archiving total body skin images has resulted in greater dissemination of this technique. Although computer-based systems purportedly provide sophisticated functionalities for automated feature extraction and lesion assessment for quantitative analysis, there is a need to better standardize computerized TBP systems if they are to be used more extensively.
In a review on skin imaging, Rallan and Harland (2004) noted that mole scanners are increasingly available on a commercial basis, even though computer diagnosis of pigmented lesions is currently no better than diagnosis by human experts. They also mentioned that other imaging techniques, such as high-resolution ultrasonography, spectroscopy, and optical coherence tomography, may yet find a role in diagnosis and disease monitoring.
Glud et al. (2009) stated that spectrophotometric intra-cutaneous analysis (SIAscopy) is a new, commercially available method for analyzing pigmented skin lesions non-invasively. The diagnosis is based on objective features such as the presence of dermal pigment, vascularity of the lesion, and the integrity of collagen. The objective of this study was to examine the usefulness of SIAscopy for the clinical diagnosis of malignant melanoma in a prospective, unbiased manner. These investigators enrolled 65 patients with 83 lesions, where the diagnosis of melanoma could not be ruled out based on clinical evaluation by a non-dermatologist. All lesions were investigated by dermoscopy and SIAscopy and subsequently excised. Histopathologically, 12 lesions were diagnosed as malignant melanoma. Both dermoscopy and SIAscopy overestimated the proportion of possible malignant lesions (n = 24 and 41, respectively) and had sensitivities of 92% and 100%, respectively. The specificity of dermoscopy in this study was 81% compared to 59% for SIAscopy. These findings showed that dermoscopy remains the best diagnostic tool for the pre-operative diagnosis of pigmented skin lesions. However, as the SIAscope, in addition to the SIAgraph images, produces dermoscopic images, it holds advantages in training and archiving.
Ascierto et al. (2010) stated that spectrophotometric analysis (SPT) could represent a promising technique for the diagnosis of cutaneous melanoma (CM) at earlier stages of the disease. These investigators evaluated the role of SPT in CM early detection. During a health campaign for malignant melanoma at the National Cancer Institute of Naples, these researchers identified a subset of 54 lesions to be addressed for surgical excision and histological examination. Before surgery, all patients were investigated by clinical and epiluminescence microscopy (ELM) screenings; selected lesions underwent SPT analysis. For SPT, these investigators used a video SPT imaging system (Spectroshade MHT S.p.A., Verona, Italy). Among the 54 patients harboring cutaneous pigmented lesions, these researchers compared results from the SPT screening with histological diagnoses and evaluated both sensitivity and specificity in detecting CM using either SPT or conventional approaches. For all pigmented lesions, agreement between histology and SPT classification was 57.4%. The sensitivity and specificity of SPT in detecting melanoma were 66.6% and 76.2%, respectively. The authors concluded that although SPT is still considered a valuable diagnostic tool for CM, its low accuracy, sensitivity, and specificity represent the main barriers to the introduction of such a methodology in clinical practice. Dermoscopy remains the best diagnostic tool for the pre-operative diagnosis of pigmented skin lesions.
The American Academy of Dermatology (AAD)’s "Guidelines of care for the management of primary cutaneous melanoma" (Swetter et al., 2019) states that "In review of the currently available highest-level evidence, the expert WG acknowledges that although much is known about the management of primary CM, much has yet to be learned. Bedside diagnosis will continue to improve with further investigation of existing, noninvasive imaging/electrical data acquisition and evaluation tools (e.g., RCM, electrical impedance spectroscopy combined with digital dermoscopy, optical coherence tomography, cross-polarized light and fluorescence photography, and high-frequency ultrasound, some of which are already FDA approved) and novel software technologies (e.g., artificial intelligence-based deep learning algorithms) that can inform and target those lesions most concerning for malignancy. Noninvasive genomic methods (e.g., adhesive patch ‘‘biopsy’’) are being investigated to further classify melanocytic lesions as either benign or malignant to guide the need for further biopsy. The uptake of 1 or more of these technologies will eventually depend on cumulative evidence regarding their effectiveness, clinical utility, cost versus benefit, and competing strategies".
Hand-Held Fluorescent Molecular Imaging (The Orlucent System) for Evaluation of a Mole’s Transition to Atypia
Orlucent, Inc. has developed the first hand-held molecular-based imaging system to provide physicians with greater certainty in the evaluation of suspicious moles. The in-office system employs a novel fluorescent biotag, which is topically applied to detect non-invasively a biomarker of early tissue changes that occur during a mole’s transition from benign to atypia; atypical nevi have the potential to become melanoma. Orlucent is performing clinical trials to identify transition thresholds in early tissue remodeling and to document the clinical impact of point-of-care, non-invasive biological information in the management of moles.
Currently, there is a lack of evidence regarding the effectiveness of fluorescent molecular imaging (the Orlucent system) for the evaluation of a mole’s transition to atypia.
Chin and Finger (2009) described the autofluorescence characteristics of 30 suspicious choroidal nevi. Fundus autofluorescence (FAF) images were reviewed retrospectively on 30 consecutive cases of suspicious choroidal nevi. Autofluorescence imaging was achieved using a fundus camera-based system with a barrier filter of 695 nm and excitation of 580 nm. All nevi exhibited one or more of the following characteristics: tumor thickness, basal dimension greater than 5 mm, subretinal fluid, posterior location, ophthalmic symptoms, or lipofuscin (orange pigment). Suspicious choroidal nevi were found to have specific FAF features. Orange pigment was noted in 67% of the nevi and appeared as very bright hyperfluorescent areas. Overlying retinal pigment epithelium hypertrophy and atrophy were noted in 50% and appeared darkly hypofluorescent. Subretinal fluid (17%) and drusen (17%) both appeared mildly hyperfluorescent. The authors concluded that orange pigment was the most hyperfluorescent FAF finding. Because the presence of orange pigment is a known risk factor for malignant transformation, the use of camera-based FAF imaging may improve the ability to identify those choroidal nevi that would transform into malignant melanoma. Moreover, these researchers stated that further long-term follow-up studies are needed to determine the exact prognostic value of these findings.
March and colleagues (2015) noted that confirming a diagnosis of cutaneous melanoma requires obtaining a skin biopsy specimen; however, obtaining numerous biopsy specimens, which often happens in patients with increased melanoma risk, is associated with significant cost and morbidity. While some melanomas are easily recognized by the naked eye, many can be difficult to distinguish from nevi; thus, there is a need to develop new technologies that can facilitate clinical examination and melanoma diagnosis. These investigators reviewed the practical applications of emerging technologies for non-invasive melanoma diagnosis, including mobile (smartphone) applications, multi-spectral imaging (i.e., MoleMate and MelaFind), and electrical impedance spectroscopy (Nevisense). Fluorescent molecular imaging (the Orlucent system) was not mentioned in this study, which is a reference cited on the Orlucent webpage.
In an observer accuracy and reproducibility study, Elmore and associates (2017) quantified the accuracy and reproducibility of pathologists' diagnoses of melanocytic skin lesions. Skin biopsy cases (n = 240) were grouped into sets of 36 or 48. Pathologists from 10 U.S. states were randomized to independently interpret the same set on two occasions (phases 1 and 2), at least 8 months apart. Pathologists' interpretations were condensed into five classes: I (e.g., nevus or mild atypia); II (e.g., moderate atypia); III (e.g., severe atypia or melanoma in situ); IV (e.g., pathologic stage T1a (pT1a) early invasive melanoma); and V (e.g., ≥pT1b invasive melanoma). Reproducibility was evaluated by intra-observer and inter-observer concordance rates, and accuracy by concordance with three reference diagnoses. In phase 1, 187 pathologists completed 8,976 independent case interpretations, resulting in an average of 10 (SD 4) different diagnostic terms applied to each case. Among pathologists interpreting the same cases in both phases, when pathologists diagnosed a case as class I or class V during phase 1, they gave the same diagnosis in phase 2 for the majority of cases (class I 76.7%; class V 82.6%). However, the intra-observer reproducibility was lower for cases interpreted as class II (35.2%), class III (59.5%), and class IV (63.2%). Average inter-observer concordance rates were lower, but with similar trends. Accuracy using a consensus diagnosis of experienced pathologists as reference varied by class: I, 92% (95% CI: 90% to 94%); II, 25% (22% to 28%); III, 40% (37% to 44%); IV, 43% (39% to 46%); and V, 72% (69% to 75%). It is estimated that at a population level, 82.8% (81.0% to 84.5%) of melanocytic skin biopsy diagnoses would have their diagnosis verified if reviewed by a consensus reference panel of experienced pathologists, with 8.0% (6.2% to 9.9%) of cases over-interpreted by the initial pathologist and 9.2% (8.8% to 9.6%) under-interpreted. The authors concluded that diagnoses spanning moderately dysplastic nevi to early-stage invasive melanoma were neither reproducible nor accurate in this large study of pathologists in the U.S. These researchers stated that reliable and objective techniques need to be developed and validated to support pathologists’ visual assessments of melanocytic lesions. They hoped that future systems using digital whole slide imaging platforms to obtain second opinions or molecular analysis of skin biopsies can be developed, which may lead to more definitive classification of melanocytic lesions. Again, fluorescent molecular imaging (the Orlucent system) was not mentioned in this study, which is a reference cited on the Orlucent webpage.
High-Frequency Ultrasonography
Starritt et al. (2005) stated that the value of targeted high-resolution ultrasound (US) examination in detecting sentinel lymph node (SLN) metastases in patients with newly diagnosed primary cutaneous melanomas has not yet been fully evaluated. These investigators examined the threshold size of metastatic melanoma deposits in SLNs that can be detected by targeted US examination before initial melanoma surgery (n = 304). Metastatic disease was present in SLNs from 33 node fields in 31 patients. The US results in 7 of these cases were suggestive of metastatic disease, while 26 node fields contained positive nodes that were not detected by US. The undetected deposits had diameters of less than 4.5 mm. The researchers concluded that the findings suggest that a targeted US examination of SLNs can detect metastatic melanoma deposits down to approximately 4.5 mm in diameter. However, they further noted that most metastatic melanoma deposits in SLNs are considerably smaller than this at the time of initial staging, thus targeted high-resolution ultrasound cannot be considered cost-effective in this setting.
- determine the minimum cross-sectional area (CSA) of an SLN metastasis detectable by US, and
- establish whether targeted, high-resolution US of SLNs identified by lymphoscintigraphy before initial melanoma surgery can be used as a substitute for excisional SLN biopsy.
High-resolution US was performed on SLNs identified in 871 lymph node fields in 716 patients; SLN biopsy was performed within 24 hours of lymphoscintigraphy and US examination. The CSA of each SLN metastatic deposit was determined sonographically and histologically. The sensitivity of targeted US in the detection of positive SLNs was 24.3% (95% confidence interval [CI]: 19.5% to 28.7%), and the specificity was 96.8% (95% CI: 95.9% to 97.7%). The sensitivity was highest for neck SLNs (45.8%) and improved with greater Breslow thickness. The median histologic CSA of the SLN metastatic deposits was 0.39 mm(2) (12.75 mm(2) for US true-positive results and 0.22 mm(2) for US false-negative results). True-positive, US-detected SLNs had significantly greater CSAs (t-test p < 0.001) than undetected SLN metastases and were more likely to be spherical in cross-section. More than 2 sonographic descriptors of SLN metastases or rounding of the node alone were factors highly suggestive of a melanoma deposit. The authors concluded that high-resolution US is not an appropriate substitute for SLN biopsy, but it is of value in pre-operative SLN assessment and post-operative monitoring. These findings are in agreement with those of Kunte et al. (2009) who reported that high resolution B-mode US can not replace SLN biopsy, especially in the detection of micro-metastases, but it remains the most important method to assess the lymph node status for macrometastases pre-surgically.
In a Cochrane review, Dinnes and colleagues (2018a) evaluated the diagnostic accuracy of high-frequency ultrasound (HFUS) to assist in the diagnosis of (a) cutaneous invasive melanoma and atypical intra-epidermal melanocytic variants, (b) cSCC, and (c) BCC in adults. These researchers 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. They studied reference lists as well as published systematic review articles. Studies evaluating HFUS (20 MHz or more) in adults with lesions suspicious for melanoma, cSCC, or BCC versus a reference standard of histological confirmation or clinical follow-up were selected for analysis. Two review authors independently extracted all data using a standardized data extraction and quality assessment form (based on QUADAS-2). Due to the scarcity of data and the poor quality of studies, these investigators did not undertake a meta-analysis for this review. For illustrative purposes, they plotted estimates of sensitivity and specificity on coupled forest plots. The authors included six studies, providing 29 datasets: 20 for the diagnosis of melanoma (1,125 lesions and 242 melanomas) and nine for the diagnosis of BCC (993 lesions and 119 BCCs). They did not identify any data relating to the diagnosis of cSCC. Studies were generally poorly reported, limiting judgments of methodological quality; 50% of the 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 regarding the 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 lack of visualization in 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, homogeneous, and well-defined) demonstrated 100% sensitivity in two studies (lower limits of the 95% CIs were 94% and 82%), with variable corresponding specificities of 33% (95% CI: 20% to 48%) and 73% (95% CI: 57% to 85%), 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. The authors concluded that 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, these researchers cannot draw any implications for practice. The main value of the preliminary studies may be in providing guidance on the possible components of new diagnostic rules for the diagnosis of melanoma or BCC using HFUS that will require future evaluation. They stated that a prospective evaluation of HFUS added to visual inspection and dermoscopy alone in a standard healthcare setting, with a clearly defined and representative population of participants, would be needed for a full and proper evaluation of accuracy.
MelaFind
In a prospective, multi-center, blinded study, Monheit et al. (2011) examined the safety and effectiveness of MelaFind, a non-invasive and objective computer-vision system designed to aid in the detection of early pigmented cutaneous melanoma. The diagnostic performance of MelaFind and study clinicians was evaluated using the histologic reference standard. Standard images and patient information for a subset of 50 randomly selected lesions (25 melanomas) were used in a reader study involving 39 independent dermatologists to estimate clinicians' biopsy sensitivity to melanoma. A total of 1,383 patients with 1,831 lesions were enrolled from January 2007 to July 2008; 1,632 lesions (including 127 melanomas—45% in situ—with a median Breslow thickness of invasive lesions of 0.36 mm) were eligible and evaluable for the study endpoints. Main outcome measures included the sensitivity of MelaFind, specificities and biopsy ratios for MelaFind and the study investigators, and biopsy sensitivities of independent dermatologists in the reader study. The measured sensitivity of MelaFind was 98.4% (125 of 127 melanomas) with a 95% lower confidence bound at 95.6% and a biopsy ratio of 10.8:1; the average biopsy sensitivity of dermatologists was 78% in the reader study. Including borderline lesions (high-grade dysplastic nevi, atypical melanocytic proliferations, or hyperplasias), MelaFind's sensitivity was 98.3% (172 of 175), with a biopsy ratio of 7.6:1. On lesions biopsied mostly to rule out melanoma, MelaFind's average specificity (9.9%) was superior to that of clinicians (3.7%) (p = 0.02). The authors concluded that MelaFind is a safe and effective tool to assist in the evaluation of pigmented skin lesions. However, it is unclear if an instrument with such low specificity is clinically useful.
MoleSafe
According to its website, MoleSafe is a comprehensive skin documentation system designed to expose layers of skin lesions not typically viewed during a regular examination by dermatologists. The MoleSafe system produces high-resolution diagnostic images and creates a profile for a person’s skin that is monitored for any changes in lesions. The MoleSafe process involves 6 important steps:
- Meeting with a melanographer to discuss medical history and address skin concerns
- Total body photography – A series of 25 pictures is taken of 96 %of the body’s surface
- Total body dermoscopy – A visual exam is performed and any abnormal lesion is examined with a dermatoscope
- Digital melanogram – Images from the exam are compiled into a digital record of the skin, along with other information, including lesion coding and history
- Dermoscopist report is created – Dermoscopist report of suspicious legions included with recommendations for treatment and ongoing surveillance
- Patient education – Educating patients on skin cancer risk factors and tips for protecting skin against UV radiation
Multi-Photon Laser Microscopy
An Agency for Healthcare Research and Quality Technical Brief on "Noninvasive Diagnostic Techniques for the Detection of Skin Cancers" (Parsons et al., 2011) stated that multi-photon laser scanning microscopy (also known as multi-photon fluorescence microscopy or multi-photon excitation microscopy) uses more than one photon excitation to illuminate endogenous fluorophores in skin tissues, which emit a fluorescence signal captured by a detector. Similar to confocal laser scanning microscopy (CLSM), multi-photon laser scanning microscopy uses a laser beam and allows imaging of tissues beyond the superficial epidermis. Unlike CLSM, this technique does not use a confocal pinhole filter. Evidence of the current application of this modality is sparse. A systematic literature search identified three narrative reviews and two diagnostic studies of multi-photon microscopy or tomography. These investigators identified two registered cross-sectional studies assessing the use of this technology for skin lesion evaluation. Both studies are based in Taiwan and are currently recruiting participants. The only commercially available device for multi-photon tomography is DermaInspect, manufactured by JenLab in Germany. The authors could not determine the FDA clearance status for this device in the FDA CDRH database and listed multi-photon laser scanning microscopy as one of the investigational devices for the detection of skin cancers.
Non-Invasive Gene Expression "Patch Biopsy" (e.g., DermTech Pigmented Lesion Assay [PLA])
According to DermTech, the Pigmented Lesion Assay (PLA; DermTech) involves non-invasive gene expression tests designed to assist in the clinical diagnosis of skin cancer and other skin conditions. This assay was developed to provide physicians with a non-invasive alternative for biopsying clinically atypical pigmented lesions using an adhesive patch instead of a scalpel. The PLA is specifically utilized for detecting melanoma in atypical skin lesions or moles and employs a sample collected with the Adhesive Patch Skin Biopsy Kit. It provides a ribonucleic acid (RNA) gene expression score for two genes (CMIP and LINC00518). The PLA can help reduce unnecessary surgical biopsy procedures by ruling out false positives based on visual assessments before surgical removal. Additionally, it may offer immediate information on lesions that require follow-up for changes over 6 to 12 months. This non-invasive biopsy approach is particularly beneficial for patient populations that are anticoagulated, at increased risk for infection and scarring, or at risk for wound complications, as well as for lesions located in cosmetically sensitive areas.
Gerami et al. (2014) developed a non-invasive genomic method using messenger RNA (mRNA) to classify pigmented skin lesions as either benign or malignant. An adhesive patch method was employed to collect cells from the surface of melanocytic lesions; mRNA was extracted, and a genomic signature was formulated in a training set of benign and malignant melanocytic neoplasms, which was subsequently tested in a validation set. A two-gene signature assessing the expression levels of CMIP and LINC00518 was able to differentiate melanomas from nevi in an independent validation set of 42 melanomas and 22 nevi, achieving a sensitivity of 97.6% and specificity of 72.7%. The authors concluded that these findings suggest that mRNA molecular signatures can serve as a highly useful non-invasive method for differentiating melanoma from nevi, thereby decreasing the number of unnecessary biopsies. They also noted the need for larger and more diverse sets of melanomas and nevi for further validation of the molecular expression profiling across various subsets of melanocytic neoplasms.
Clarke and associates (2015) identified a gene expression signature that reliably differentiates benign and malignant melanocytic lesions and evaluated its potential clinical applicability. These investigators described the development of a gene expression signature and its clinical validation using multiple independent cohorts of melanocytic lesions representing a broad spectrum of histopathologic subtypes. By employing quantitative reverse-transcription polymerase chain reaction (RT-PCR) on a selected set of 23 differentially expressed genes and applying a threshold value and weighting algorithm, they developed a gene expression signature that produced a score differentiating benign nevi from malignant melanomas. The gene expression signature classified melanocytic lesions as benign or malignant with a sensitivity of 89% and specificity of 93% in a training cohort of 464 samples. The signature was validated in an independent clinical cohort of 437 samples, achieving a sensitivity of 90% and specificity of 91%. The authors concluded that the performance, objectivity, reliability, and minimal tissue requirements of this test suggest it could have clinical applications as an adjunct to histopathology in diagnosing melanocytic neoplasms.
Yao et al. (2016) previously reported on the clinical performance of a novel non-invasive and quantitative PCR (qPCR)-based molecular diagnostic assay (the PLA) that differentiates primary cutaneous melanoma from benign pigmented skin lesions through two target gene signatures, LINC00518 (LINC) and preferentially expressed antigen in melanoma (PRAME). This study focused on the analytical characterization of the PLA, including qPCR specificity and sensitivity, optimization of RNA input in qPCR to achieve desired diagnostic sensitivity and specificity, and analytical performance (repeatability and reproducibility) of this two-gene PLA. All target qPCRs demonstrated good specificity (100%) and sensitivity (with a limit of detection of 1-2 copies), allowing reliable detection of gene expression changes of LINC and PRAME between melanomas and non-melanomas. By normalizing RNA input in qPCR, these researchers converted traditional gene expression analyses to a binomial detection of gene transcripts (i.e., detected or not detected). By combining the binomial qPCR results of the two genes, improved diagnostic sensitivity (increased from 52% to 65% to 71% at 1 pg of total RNA input, and to 91% at 3 pg of total RNA input) was achieved. The authors concluded that this two-gene PLA demonstrated high repeatability and reproducibility (coefficient of variation less than 3%) and met all required analytical performance characteristics for the commercial processing of clinical samples.
Gerami et al. (2017) noted that clinical and histopathologic assessment of pigmented skin lesions remains challenging even for experts, and there is a high demand for differentiated and accurate non-invasive diagnostic modalities. These researchers aimed to provide clinicians with such a tool. A two-gene classification method based on LINC00518 and PRAME gene expression was evaluated and validated in 555 pigmented lesions (157 training and 398 validation samples) obtained non-invasively via adhesive patch biopsy. Results were compared with standard histopathologic assessments in lesions with a consensus diagnosis among three experienced dermatopathologists. In 398 validation samples (87 melanomas and 311 non-melanomas), LINC00518 and/or PRAME detection appropriately differentiated melanoma from non-melanoma samples with a sensitivity of 91% and specificity of 69%. These investigators established LINC00518 and PRAME in both adhesive patch melanoma samples and underlying formalin-fixed paraffin-embedded (FFPE) samples of surgically excised primary melanomas and in melanoma lymph node metastases. The authors concluded that this non-invasive two-gene pigmented lesion assay classified pigmented lesions into melanoma and non-melanoma groups and may serve as a tool to assist with diagnostic challenges that may be inherently linked to the visual image and pattern recognition approach. The main drawback is that this technology cannot be used on mucous membranes, palms of hands, and soles of feet.
Yao and associates (2017) noted that many diagnoses in clinical dermatology are currently confirmed histopathologically, and this image recognition-based confirmation generally requires surgical biopsies. The increasing ability of molecular pathology to corroborate or correct a clinical diagnosis based on objective gene expression, mutation analysis, or molecular microbiome data is on the horizon and would be further supported by a tool or procedure to collect samples non-invasively. This study characterized such a tool in the form of a "bladeless" adhesive patch-based skin biopsy device. The performance of this device was evaluated through various complementary technologies, including assessment of sample biomass, electron microscopy demonstrating the harvesting of layers of epidermal tissue, and isolation of RNA and DNA from epidermal skin samples. Samples were obtained by applying adhesive patches to the anatomical area of interest. Biomass assessment demonstrated the collection of approximately 0.3 mg of skin tissue per adhesive patch, and electron microscopy confirmed the nature of the harvested epidermal skin tissue. The obtained tissue samples were stored stably on adhesive patches over a wide range of temperatures (-80°C to +60°C) and for extended periods (7 days or more). Total human RNA, human genomic DNA, and microbiome DNA yields were 23.35 ± 15.75 ng, 27.72 ± 20.71 ng, and 576.2 ± 376.8 pg, respectively, in skin samples obtained from combining four full patches collected non-invasively from the forehead of healthy volunteers. The authors concluded that the adhesive patch skin sampling procedure was well-tolerated and provided a robust means to obtain skin tissue, RNA, DNA, and microbiome samples without involving surgical biopsies. The non-invasively obtained skin samples can be shipped cost-effectively at ambient temperature by mail or standard courier service and were suitable for a variety of molecular analyses of the skin microbiome as well as keratinocytes, T cells, dendritic cells, melanocytes, and other skin cells involved in the pathology of various skin conditions where the skin can serve as a surrogate target organ.
In a secure web-based, multiple-reader-multiple-case study, Ferris and colleagues (2017) determined the utility of the PLA for LINC00518/PRAME expression in decisions to biopsy a series of pigmented skin lesions. Board-certified dermatologists evaluated 60 clinical and dermoscopic images of clinically atypical pigmented lesions, first without and then with PLA gene expression information, and were asked whether the lesions should be biopsied. Data were collected from March 24, 2014, through November 13, 2015. Participants received a report for each lesion, which included the results of an assay for expression of LINC00518/PRAME and a PLA score with data on the predictive values of the information provided. Main outcome measures were biopsy sensitivity and specificity with versus without PLA data. A total of 45 dermatologists (29 men and 16 women) performed the evaluation. After incorporating the PLA into their decision-making regarding whether to biopsy a pigmented lesion suggestive of melanoma, dermatologists improved their mean biopsy sensitivity from 95.0% to 98.6% (p = 0.01); specificity increased from 32.1% to 56.9% (p < 0.001) with PLA data. The authors concluded that the non-invasive PLA enabled dermatologists to significantly improve biopsy specificity while maintaining or improving sensitivity. They stated that this finding may increase the number of early melanomas biopsied and reduce the number of benign lesions biopsied, thereby improving patient outcomes and reducing healthcare costs.
Ferris et al. (2018) stated that approximately 3 million surgical pigmented skin lesion biopsies are performed every year in the U.S. to diagnose fewer than 200,000 new cases of invasive melanoma and melanoma in situ using the current standard of care, which includes visual assessment and histopathology. A recently described non-invasive adhesive patch-based gene expression rule-out test (Pigmented Lesion Assay, PLA) may be helpful in identifying high-risk pigmented skin lesions to aid with surgical biopsy decisions. These researchers determined the real-world clinical performance of PLA use and examined how the PLA changes physician behavior in an observational cohort analysis of 381 patients assessed with the PLA. All (100%) of the 51 PLA(+) test results were clinically managed with surgical biopsy. Of these, 19 (37%) were melanomas, corresponding to a number needed to biopsy of 2.7 and a biopsy ratio of 1.7. All melanomas were histopathologically classified as melanoma in situ or stage 1. Nearly all (99%) of the 330 PLA(-) test results were clinically managed with surveillance. None of the three follow-up biopsies performed in the following 3 to 6 months were diagnosed as melanoma histopathologically. The estimated sensitivity and specificity of the PLA from these data sets are 95% and 91%, respectively. Overall, 93% of PLA results positive for both LINC00518 and PRAME were diagnosed histopathologically as melanoma. PRAME-only and LINC00518-only lesions were melanomas histopathologically in 50% and 7%, respectively. The authors concluded that the PLA changed the clinical management of pigmented lesions and demonstrated high clinical performance. The likelihood of a positive histopathologic diagnosis of melanoma was higher in PLA results that were positive for both LINC00518 and PRAME.
The authors stated that an inherent key limitation of this study was the assumption that PLA(-) lesions not biopsied at 3 to 6 months were true negatives. In underlying validation studies, all lesions examined by PLA were also surgically biopsied so that consensus histopathology diagnoses could be established and correlated with PLA results. In this study, the objective was to examine if clinicians follow the biopsy guidance the PLA offers. Other than subjecting all PLA(-) patients to the very surgical biopsy this technology helps minimize, there is no other good way to estimate true negatives. Studies using dermoscopy to follow suspicious melanoma lesions indicated that melanomas will undergo observable changes within 3 to 6 months, while changes in early melanoma in situ may be more difficult to evaluate. A study to examine findings with up to 2 years of follow-up has been initiated recently. Nonetheless, these researchers could not rule out that some PLA(-) lesions may not have been adequately re-assessed in the follow-up period, and they certainly recommended erring on the side of caution and surgically biopsying a lesion in question if additional risk factors, further clinical suspicion, or patient concern mandate such a step. These researchers did not recommend the use of the PLA if a frank melanoma is suspected. Another perceived limitation was that the validation study by Gerami et al. (2017) and this real-world utility study reported different specificity numbers (69% versus 91%). Potential reasons for the noted difference included study objectives and design, physician environment and bias (validation studies were performed by academic investigators who directed pigmented lesion clinics and routinely used tools such as total body photography and dermoscopy that may not be used routinely by all dermatologists in clinical practice), required assumptions, and possibly, most importantly, a lower prevalence of melanoma in biopsied real-world lesions (5%, 19 of 381 cases) in line with reports from other comparable studies and settings. It should be noted that L.K.F., P.G., G.P., and D.M.S. are scientific advisors to DermTech.
Ferris et al. (2019a) noted that tools that help reduce the number of surgical biopsies performed on benign lesions have the potential to improve patient care. The PLA is a non-invasive tool validated against histopathology that helps rule out melanoma and the need for surgical biopsies of atypical pigmented skin lesions. Genetic information is collected using adhesive patches, and the expression of two genes, LINC00518 and PRAME, is measured. Using genetic material collected non-invasively and to further validate the PLA, somatic hotspot mutations in genes known to be drivers of early melanoma development (BRAF other than V600E, NRAS, and the TERT promoter) can also be identified. The frequency of these hotspot mutations in samples of early melanoma was 77%, which is higher than the 14% found in non-melanoma samples (p < 0.0001). TERT promoter mutations were the most prevalent mutation type in PLA-positive melanomas; 82% of PLA-negative lesions had no mutations, and 97% of histopathologically confirmed melanomas were PLA and/or mutation positive (cohort 1, n = 103). Mutation frequencies were similar in prospectively collected real-world PLA samples (cohort 2, n = 519), in which 88% of PLA-negative samples had no mutations. The authors concluded that combining gene expression and mutation analyses enhanced the ability to non-invasively detect early cutaneous melanoma. Moreover, these researchers stated that not all TERT promoter mutations, the mutation type observed in 79% of melanomas confirmed by histopathologic consensus diagnosis, may be created equal. Borah et al. (2015) found TERT promoter mutations at position -124 in most of their urothelial cancer cell lines studied, and this mutation may confer tumor aggressiveness and facilitate the establishment of cell lines. Although further studies are needed to examine the roles that different TERT promoter mutations may play in the progression of melanocytic lesions, it is of interest to note that -124 mutations were the mutation type most often observed in melanomas positive for both LINC and PRAME.
Ferris and colleagues (2019b) stated that the Pigmented Lesion Assay (PLA, sensitivity of 91% to 95%, specificity of 69% to 91%, negative predictive value [NPV] of greater than 99%) is a commercially available, non-invasive gene expression test that helps dermatologists guide pigmented lesion management decisions and rule out melanoma. Earlier studies have demonstrated high clinical utility and no missed melanomas in a 3 to 6 months follow-up period. These researchers provided 12-month follow-up data on PLA(-) tests to further confirm utility. They carried out a 12-month chart review follow-up of 734 pigmented lesions that had negative PLA results from five U.S. dermatology centers; 13 of these lesions (1.8%) were biopsied in the follow-up period and submitted for histopathologic review. None of the lesions biopsied had a histopathologic diagnosis of melanoma. The test's utility was studied further in a registry (n = 1,575, 40 U.S. dermatology offices, 62 participating providers), which demonstrated that 99.9% of PLA(-) lesions were clinically monitored, thereby avoiding a surgical procedure, and 96.5% of all PLA(+) lesions were appropriately biopsied, most commonly with a tangential shave. The authors concluded that this long-term follow-up study confirmed the PLA's high NPV and high utility in helping guide the management of pigmented lesions to avoid unnecessary surgical procedures.
The authors stated that inherent limitations of the data presented included the assumption that lesions of patients not returning to follow-up visits at the site of PLA testing within a 12-month follow-up period were true negatives. Furthermore, these investigators could not rule out that some PLA(-) lesions may not have been adequately re-assessed within the 12-month follow-up period, and they recommended erring on the side of caution and performing a surgical biopsy of a lesion in question if additional risk factors and further clinical suspicion or patient concern mandated such a step. Further limitations inherent to studies designed to evaluate melanoma rule-out tests and platforms in real-world settings included the low prevalence of melanoma compared to how common benign lesions of clinically similar appearance are in given target populations. However, it was comforting to consider that the non-invasive gene expression platform used here lends itself to validation study comparisons that can exceed the quality level of randomized control groups. With this platform, it is possible to obtain non-invasive gene expression information and histopathology reads from the same lesion.
In a discussion of "emerging" diagnostic technologies, guidelines on cutaneous melanoma from the American Academy of Dermatology (Swetter et al., 2019) state that "Noninvasive genomic methods (e.g., adhesive patch 'biopsy') are being investigated to further classify melanocytic lesions as either benign or malignant to guide the need for further biopsy."
Robinson and Jansen (2020) noted that physician appointments for non-essential care ceased during COVID-19. These researchers pilot-tested a telehealth solution for patients to rule out melanomas and the need for surgical biopsies based on genomic analyses of pigmented lesion samples obtained via adhesive patches. Surveys examined skin self-examination (SSE) anxiety. Under remote clinician guidance, patients or partners obtained samples using adhesive patches (DermTech, La Jolla, CA). SSE anxiety increased. Guided self-sampling led to molecular risk factor analyses in 7 of 7 (100%) of cases compared to 9 of 10 (90%) randomly selected physician-sampled control cases. The authors concluded that adhesive patch (DermTech) self-sampling under remote physician guidance is a viable specimen collection option. This was a proof-of-concept (pilot) study with a small sample size (n = 7 for the DermTech group); its findings need to be validated by well-designed studies.
Brouha et al. (2020) stated that the Pigmented Lesion Assay (PLA) is a non-invasive gene expression test that aids clinicians in ruling out melanoma via a genomics approach, which elevates pigmented lesion management beyond what the eye can see. It improves care with a negative predictive value (NPV) of greater than 99% while reducing biopsies by 90% and costs. This registry study described in this study (53 U.S. dermatology offices, 90 providers, median patient age of 48 years, 60.80% female and 39.20% male patients) assesses real-world utility to determine if the PLA changes clinical practice. Of 3,418 pigmented skin lesions clinically suspicious for melanoma and assessed by PLA, 324 lesions (9.48%) were PLA(+) and 3,094 (90.52%) were negative. A PLA test result was positive if LINC, PRAME, or both target genes are detected; these molecular pathology findings are known to correspond with histopathology findings of in situ or invasive primary melanoma in 7%, 50%, and 93%, respectively. The 9.48% PLA(+) cases consisted of 5.15% LINC only, 1.93% PRAME only, and 2.40% LINC and PRAME double-positive cases. Notably, PLA(+) lesions were surgically biopsied 97.53%, while PLA(-) cases were clinically monitored and not biopsied in 99.94% of the cases. The authors concluded that these findings demonstrated that community-based clinicians who employ the PLA to improve pigmented lesion management used the test’s results to guide how they practice. Pigmented lesions with PLA(+) test results were subjected to surgical biopsies, whereas PLA(-) lesions were followed clinically and not biopsied. It should be noted that this study was partially supported by DermTech, Inc.; and BB, LF, MS, RM, and GP are advisors to, and BJ and ZY are employees of, DermTech.
Brouha et al. (2021) noted that melanoma is diagnosed in approximately 200,000 individuals within the U.S. each year and is responsible for more than 6,850 deaths. Currently, clinical suspicion guides biopsy decisions, and melanoma is confirmed in approximately 4% of biopsied lesions. A non-invasive two-gene expression test (2-GEP) was demonstrated to enhance the physical examination by examining genomic atypia to guide biopsy decisions. These researchers examined the corresponding histopathology of real-world 2-GEP-positive cases. Cutaneous lesions suspicious for melanoma (n = 3,418) were 2-GEP tested by 90 licensed clinicians in real-world practice. 2-GEP-positive lesions (genomically atypical as indicated by the detection of LINC and/or PRAME) were biopsied in 316 out of 324 (97.5%) cases, and 313 pathology reports were available for analysis. Biopsied 2-GEP-positive lesions were separated into diagnostic subgroups based on corresponding pathology reports. The prevalence of melanoma in biopsies of 2-GEP-positive lesions was 18.7%. Gene expression of both LINC and PRAME was present in ever-increasing percentages of melanocytic lesions as pathology reports demonstrated increasing levels of atypia. Notably, 47.5% of the histopathologically confirmed melanomas demonstrated this double-positive genomic signature, while 23.7% were single-positive for LINC and 28.8% were single-positive for PRAME. The authors concluded that these findings showed that biopsied 2-GEP-positive lesions were enriched almost five-fold for advanced histopathologic features compared to those biopsied based solely on visual assessment criteria. The close correlation between genomic atypia and atypical pathology should be considered when planning treatment of a 2-GEP-positive lesion. Consideration of genomic atypia may be a superior approach to guide biopsy decisions and manage pigmented lesions.
There is an ongoing clinical trial on "Targeted Melanoma Detection with Skin Self-Examination During COVID-19 Restricted Physician Access (TMD)" (ClinicalTrials.gov ID NCT04420273). This trial entails physician-supervised non-invasive adhesive patch-based home sample collection of a concerning mole for genomic analysis (last updated September 4, 2020).
An Ontario Health technology assessment on “Pigmented Lesion Assay for Suspected Melanoma Lesions” (2021) noted that early detection of melanoma is key, as survival rates are substantially better when the cancer is detected in its early stages. To date, the standard of care (SOC) is to biopsy any lesion suspected of melanoma for diagnostic confirmation by histopathology. As a result, most individuals who undergo biopsy receive negative melanoma results. If effective, a non-invasive alternative, such as PLA, could minimize the number of unnecessary biopsies carried out. These researchers performed a health technology assessment of PLA for individuals with suspected melanoma lesions, which included an evaluation of diagnostic accuracy, clinical utility, the budget impact of publicly funding PLA, and the preferences and values of individuals who have undergone biopsy for suspected melanoma. These investigators carried out a systematic literature search of the clinical evidence. They examined the risk of bias of each included study using the Quality Assessment of Diagnostic Accuracy Studies–2 (QUADAS-2) and the Risk of Bias Assessment Tool for Non-randomized Studies (RoBANS). These researchers evaluated the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. They conducted a systematic literature search of the economic evidence and also analyzed the budget impact of publicly funding PLA in adults with suspected melanoma in Ontario. To contextualize the potential value of PLA, the authors spoke with individuals who had undergone skin biopsy for melanoma. They also employed qualitative research synthesis from a report by the Canadian Agency for Drugs and Technologies in Health (CADTH) to provide context for the preferences and values of those with suspected melanoma. These researchers included seven studies in the clinical evidence review. The Pigmented Lesion Assay has a sensitivity of 79% (95% CI: 58% to 93%) and a specificity of 80% (95% CI: 73% to 85%; GRADE: Low). They found one published cost-effectiveness study with potentially serious limitations; thus, the cost-effectiveness of PLA compared with the SOC pathway is currently uncertain. Assuming a very low uptake, these investigators estimated that the budget impact of publicly funding PLA in Ontario over the next five years is about $3.44 million if the test is used exclusively by primary care providers, or about $2.56 million if it is used exclusively by specialists. The individuals with whom the authors spoke who had experienced biopsy for suspected melanoma responded positively to the potential benefits of PLA, emphasizing its ease of use, potential increase in early detection of melanoma, and reduction in the physical and emotional burden of unnecessary biopsies. Participants also felt that the accuracy of this tool was essential to ensure minimal false negatives. The authors concluded that there is uncertainty because of the low-quality evidence for the diagnostic accuracy of PLA. The cost-effectiveness of PLA compared with SOC is also uncertain. These investigators estimated that publicly funding PLA in Ontario over the next five years would result in additional costs of $3.44 million (if used exclusively by primary care providers) or $2.56 million (if used exclusively by specialists). For individuals who had experienced biopsy for suspected melanoma, it was felt that PLA could represent an effective tool to increase early detection and avoid unnecessary biopsies if the tool was accurate.
The authors stated that this analysis had several drawbacks. First, these investigators relied on data from the Ontario Health Insurance Plan (OHIP) claims database; however, those data were collected for billing and administrative purposes, not for research. One limitation of the administrative data is the possibility of inaccurate coding; thus, these researchers carried out extensive sensitivity analyses using different OHIP codes and diagnosis codes. Second, all accuracy studies of PLA were performed in dermatology clinics. Due to a lack of data, these investigators assumed the diagnostic accuracy of PLA in primary care would be similar. Third, since PLA is less invasive and easier to perform than biopsy, physicians may choose to use the test on more individuals if it was available. Therefore, there is the possibility that physicians may overuse PLA on inappropriate patients (e.g., giving the test just to reassure patients).
Skelsey et al. (2021) stated that management of pigmented lesions currently relies on visual assessment with surgical biopsy and histopathologic examination for those lesions suspicious for melanoma. A non-invasive genomic assay that detects two melanoma-associated biomarkers (PLA, 2-GEP) has recently been validated as an adjunct to visual assessment for distinguishing high-risk pigmented lesions appropriate for biopsy from those that could be safely monitored via clinical surveillance. In a retrospective study, these researchers determined real-world NPV by following a cohort of 1,233 PLA-negative pigmented lesions for evidence of malignancy for up to 36 months and by re-testing a separate prospective cohort of 302 PLA-negative lesions up to 2 years after initial testing. Real-world positive predictive value (PPV) was determined by identifying melanoma diagnoses among PLA-positive lesions within a U.S.-based registry of 3,418 PLA-tested cases. A total of 10 early-stage melanomas (4 in situ and 6 pT1a) were identified among 1,233 PLA-negative lesions (0.8%), corresponding to a real-world NPV of 99.2% (95% CI: 98.5% to 99.6%). Of 302 initially PLA-negative lesions subjected to repeat testing an average of 15 months later, 34 were PLA-positive. Biopsy revealed three melanomas (all in situ), further confirming an NPV of greater than 99%. Among 316 PLA-positive cases, 59 were diagnosed as melanoma by histopathology, corresponding to a PPV of 18.7%. Of all PLA-positive lesions, 30.5% had histopathologic diagnoses corresponding to high-risk MPATH-Dx categories (Classes III to V). The authors concluded that the PLA had an NPV of greater than 99% within the real-world intended use population. The PLA had a PPV of 18.7% for melanoma and also detected high-risk lesions such as dysplastic nevi with severe/high-grade atypia that are generally targeted for complete excision.
The authors stated that an important drawback of this trial was that follow-up visits were not documented for 548 of the 1,781 PLA-negative patients; therefore, it could not be confirmed that none of these 548 patients developed a melanoma that remained undetected or was identified and treated elsewhere. For this reason, the most definitive NPV calculation was that derived from the subset of 1,233 patients with documented follow-up visits within the indicated period. Furthermore, retrospective medical chart review could erroneously assess a lesion not tested with the PLA. While real-world data from lesion cohort studies are the most relevant to actual clinical practice, the strategies chosen did not allow for comparisons based on consensus histopathology reads that may reduce variability in histopathologically determined diagnoses. Finally, PLA-negative lesions that were negative on repeat testing and by clinical evaluation were considered true negatives for purposes of these analyses, and the possibility that some lesions were, in fact, melanomas that were negative on both the initial and repeat tests and also by clinical follow-up could not be entirely excluded.
Skudalski et al. (2022) stated that in response to rising rates of melanoma worldwide, novel non-invasive melanoma detection techniques are emerging to facilitate the early detection of melanoma and decrease unnecessary biopsies of benign pigmented lesions. Because they often report similar study findings, it may be difficult to determine how best to incorporate these technologies into clinical practice based on their supporting studies alone. The authors concluded that as the incidence of melanoma continues to rise, numerous technological advances have entered the field of dermatology in recent years to aid in the identification, surveillance, and diagnosis of these potentially invasive lesions. Although not indicated for every patient or feasible in every practice, total body photography (TBP), sequential digital dermoscopic imaging (SDDI), PLA, reflectance confocal microscopy (RCM), dynamic optical coherence tomography (OCT), and tele-dermatology have the potential to transform the way in which melanoma is diagnosed daily; thus, it is imperative for dermatologists and other practitioners to be educated on these novel technologies and which, if any, are appropriate for use within the infrastructure of their current practice.
The National Comprehensive Cancer Network’s clinical practice guideline on “Melanoma: Cutaneous” (Version 1.2023) states that “For melanocytic neoplasms that are clinically/dermoscopically suspicious for melanoma, pre-diagnostic noninvasive patch testing may also be helpful to guide biopsy decisions."
Peck et al. (2024) noted that many melanoma-specific dermoscopic features have been described in invasive melanomas, while fewer features are found in melanoma in situ (MIS) and atypical nevi (ATN). Consensus regarding which features are critical for the differentiation of MIS from ATN has not been reached. In a single-center study, these researchers examined if there are dermoscopic features that differentiate early MIS from ATN, and if non-invasive assessment of genomic biomarkers (LINC00518 and PRAME) can aid in patient management. From 2018 to 2023, a total of 56 melanomas were evaluated for five clinical and 13 dermoscopic features and melanoma-associated genomic biomarkers. Two groups of ATN with positive and negative genomic biomarkers were randomly selected for comparison. All melanomas in this study expressed one or both melanoma-associated genomic markers. MIS had an average of 3.90 (range of 2-7) of the 13 dermoscopic features, while invasive melanomas had an average of 4.44 (range of 3-6); 16 of 40 (40%) MIS and 3 of 16 (18.8%) invasive melanomas had three or fewer dermoscopic features. These findings were comparable to those observed in both ATN groups. The most common dermoscopic features were absent or diminished pigment network, regression structures, and granularity. This combination of features was most helpful in identifying lesions for genomic testing. The authors concluded that clinical and dermoscopic features alone could not differentiate MIS from ATN. Non-invasive genomic testing helped differentiate lower from higher-risk lesions and aid in clinical management decisions. Genomic testing was especially helpful in patients with large numbers of lesions, with several being considered for biopsy based on clinical and dermoscopic examination. The authors stated that drawbacks of this study included small cohort size, subjectivity of the clinical and dermoscopic assessment of the melanocytic lesions, and the study’s single-center setting. (It should be noted that some of the authors are/were associated with DermTech—GLP and MKS are clinical investigators and consultants for DermTech; BJ and LEC are employees of DermTech. SWM is a former employee of DermTech. Also, this study was partially funded by DermTech.)
Kaufmann et al. (2024) stated that non-invasive adjuncts to visual assessment of pigmented lesions may reduce biopsies of benign lesions without compromising melanoma detection. A non-invasive genomic melanoma rule-out assay analyzes RNA extracted from stratum corneum cells for PRAME and LINC00518—two genes often expressed in melanomas but less often in benign lesions. These researchers examined the performance of this test in a large patient cohort tested in the real-world clinical setting. The test was applied to suspicious pigmented skin lesions at 63 U.S. dermatology and primary care practices. Test results (positive/negative) were compared to pathology diagnoses (melanoma/not melanoma) for lesions that were biopsied and to follow-up visual examination for those that were monitored. Of 19,653 total lesions evaluated, 17,858 (90.87%) tested negative. Biopsy results and/or follow-up examinations were available for 5,096 lesions, with median and mean follow-up durations of 352 and 341 days, respectively. For melanoma, sensitivity was 95.8% and specificity was 69.4%. Positive predictive value (PPV) was 13.4%, and NPV was 99.7%. For melanoma and “borderline” lesions combined, sensitivity was 94.2%, specificity was 71.2%, PPV was 20.8%, and NPV was 99.3%. The authors concluded that the results suggested that this non-invasive test could facilitate the distinction of melanoma from its benign simulators, increasing the proportion of pigmented lesions that can be safely managed with surveillance rather than biopsy and/or excision. The authors stated that drawbacks of this study included a cohort comprised of individuals evaluated primarily by dermatologists, which may not represent the general population, and comparison to histopathologic diagnosis in biopsied lesions, which has lower accuracy for early-stage melanocytic neoplasms. (MDK, MKS, LKF, and MW are consultants and/or investigators of DermTech; AR, BJ, and LEC are employees of DermTech. Also, this study was funded by DermTech.)
Van Sambeek et al. (2024) stated that being one of the largest dermatology groups in the country with an in-house pathology laboratory, these investigators have observed a marked increase in the number of adhesive-based pigmented lesion assays (ABPLAs) in addition to biopsies and excisions following a moderate-risk or high-risk result with this test. They reported their clinical experience and independently confirmed that their results with this ABPLA (Pigmented Lesion Assay, DermTech, San Diego, CA) are consistent with the results of the validation studies completed by the test manufacturer. These researchers carried out a retrospective review of their electronic medical records for results of ABPLAs; corresponding histopathologic results and available clinical follow-up, along with their statistical analysis, were completed. After reviewing their electronic medical records, they found that 893 ABPLAs for pigmented lesions concerning for melanoma were obtained in a period of 14 months. Of the 893 ABPLAs completed, 161 biopsies and excisions were performed after the initial results of these assays. Additional clinical follow-up data were recorded and used for the statistical analysis of the performance and accuracy of this test. The authors concluded that in their experience, this ABPLA has a sensitivity of 92.0%, a specificity of 79.5%, a PPV of 16.9%, and a NPV of 99.5% for the detection of melanoma.
These researchers stated that drawbacks of this trial included the small number of lesions reported as low risk for melanoma with corresponding histopathologic results, which limited the evaluation of the performance of this test. Furthermore, there may have been some melanomas that were not identified because the duration of the clinical follow-up was insufficient or because some patients were lost to follow-up.
In a “Letter to the Editor,” Skelsey et al. (2025) stated that many studies suggested that melanoma in individuals with higher Fitzpatrick skin types (FST) is more likely to present at an advanced stage and result in higher mortality. A non-invasive genomic rule-out test examining gene expression of LINC00518 and PRAME has been introduced to aid in augmenting the detection of melanoma at an early stage while reducing the number of biopsies carried out for benign pigmented lesions that simulate melanoma. Clinical validation using histopathologic consensus diagnoses as a reference standard showed the test has a 99% or higher NPV, indicating that a lesion that tests negative is unlikely to be a melanoma. Although patients of all skin types were eligible for inclusion in the validation study, the cohorts consisted mostly of samples from individuals with FST I, II, or III. These investigators examined the performance of this non-invasive rule-out melanoma test across all FST, with a particular focus on NPV in FST IV to VI patients. Test performance metrics for patients with FST I to III (n = 4,152) and IV to VI (n = 130) across 73 U.S. clinical practice sites were compared using biopsy results and follow-up information compiled via the DermTech Melanoma Test Registry Protocol (WCG IRB waiver obtained March 3, 2021). Performance metrics were also calculated for a cohort limited to lesions with at least 6 months of follow-up or biopsy results. In the full cohort (n = 4,282), sensitivity was 0.9429 (66/70), specificity was 0.9086 (3,709/4,082), PPV was 0.1503 (66/439), and NPV was 0.9989 (3,709/3,713) for FST I to III. For FST IV to VI, sensitivity was 1.0 (3/3), specificity was 0.9449 (120/127), PPV was 0.3 (3/10), and NPV was 1.0 (120/120). Three of three melanomas (0.55 mm, 0.40 mm, and melanoma in situ in non–sun-exposed areas on the trunk) in the IV to VI group diagnosed by histopathology were correctly identified as positive with the test. The 95% CIs for the differences in sensitivity, specificity, NPV, and PPV between the two groups included 0, indicating no significant difference in any of the performance metrics. Additional analyses limited to subjects with either a biopsy result or at least 6 months (182 days or longer) of follow-up after testing (n = 2,266) confirmed the results observed in the full cohort for sensitivity, specificity, PPV, and NPV, and no statistically significant differences between groups were observed. The authors concluded that the findings of this study showed that the performance of the non-invasive test in FST IV to VI patients did not differ from that in FST I to III patients. These researchers stated that these findings support the test's utility in guiding biopsy decisions for ambiguous pigmented skin lesions of all skin types without a need to limit access for patients with FST IV to VI. It should be noted that Drs. Skelsey, Loftis, Kaufmann, Siegel, Bhatia, Wangia, and Walker are investigators and/or consultants of DermTech; Drs. Rigby, Whitaker, Stone, Moccia, O'Brien, Jansen, and Clarke are employees of DermTech.
Non-Melanocytic Skin Cancer
According to DermTech, the Pigmented Lesion Assay (PLA; DermTech) entails non-invasive gene expression tests to aid the clinical diagnosis of skin cancer and other skin conditions. It was developed to provide physicians with a non-invasive option for the biopsy of clinically atypical pigmented lesions using an adhesive patch rather than a scalpel. The PLA is used for the detection of melanoma in atypical skin lesions or moles and utilizes a sample collected with the Adhesive Patch Skin Biopsy Kit. It provides ribonucleic acid (RNA) gene expression scores for two genes (CMIP and LINC00518). The PLA can reduce unnecessary surgical biopsy procedures by ruling out false positives based on visual assessment prior to performing surgical removal. It may also provide immediate information on lesions that require 6 to 12 months of follow-up for change. This non-invasive biopsy approach has additional utility in patient populations that are anticoagulated, at increased risk for infection and scarring, or at risk for wound complications, and for lesions in cosmetically sensitive areas.
Gerami et al. (2014) developed a non-invasive genomic method using messenger RNA (mRNA) to classify pigmented skin lesions as either benign or malignant. An adhesive patch method was used to obtain cells from the surface of melanocytic lesions; mRNA was extracted, and a genomic signature was formulated in a training set of benign and malignant melanocytic neoplasms and subsequently tested in a validation set. A two-gene signature assessing the expression levels of CMIP and LINC00518 was able to differentiate melanomas from nevi in an independent validation set of 42 melanomas and 22 nevi, with a sensitivity of 97.6% and specificity of 72.7%. The authors concluded that these findings suggested that mRNA molecular signatures can serve as a highly useful non-invasive method of differentiating melanoma from nevi and decrease the number of unnecessary biopsies. Moreover, they stated that larger and more diverse sets of melanomas and nevi are needed for additional validation of the molecular expression profiling in various subsets of melanocytic neoplasms.
Clarke and associates (2015) identified a gene expression signature that reliably differentiated benign and malignant melanocytic lesions and evaluated its potential clinical applicability. These investigators described the development of a gene expression signature and its clinical validation using multiple independent cohorts of melanocytic lesions representing a broad spectrum of histopathologic subtypes. Using quantitative reverse-transcription polymerase chain reaction (RT-PCR) on a selected set of 23 differentially expressed genes, and by applying a threshold value and weighting algorithm, these researchers developed a gene expression signature that produced a score differentiating benign nevi from malignant melanomas. The gene expression signature classified melanocytic lesions as benign or malignant with a sensitivity of 89% and a specificity of 93% in a training cohort of 464 samples. The signature was validated in an independent clinical cohort of 437 samples, with a sensitivity of 90% and specificity of 91%. The authors concluded that the performance, objectivity, reliability, and minimal tissue requirements of this test suggested that it could have clinical application as an adjunct to histopathology in the diagnosis of melanocytic neoplasms.
Yao et al. (2016) previously reported the clinical performance of a novel non-invasive and quantitative PCR (qPCR)-based molecular diagnostic assay (the PLA) that differentiates primary cutaneous melanoma from benign pigmented skin lesions through two target gene signatures, LINC00518 (LINC) and preferentially expressed antigen in melanoma (PRAME). This study focused on the analytical characterization of this PLA, including qPCR specificity and sensitivity, optimization of RNA input in qPCR to achieve desired diagnostic sensitivity and specificity, and analytical performance (repeatability and reproducibility) of this two-gene PLA. All target qPCRs demonstrated good specificity (100%) and sensitivity (with a limit of detection of 1-2 copies), allowing reliable detection of gene expression changes of LINC and PRAME between melanomas and non-melanomas. By normalizing RNA input in qPCR, these researchers converted traditional gene expression analyses to a binomial detection of gene transcripts (i.e., detected or not detected). By combining the binomial qPCR results of the two genes, improved diagnostic sensitivity (raised from 52% to 65% to 71% at 1 pg of total RNA input, and to 91% at 3 pg of total RNA input) was achieved. The authors concluded that this two-gene PLA demonstrated high repeatability and reproducibility (coefficient of variation less than 3%) and all required analytical performance characteristics for the commercial processing of clinical samples.
Gerami et al. (2017) noted that clinical and histopathologic assessment of pigmented skin lesions remains challenging even for experts. Differentiated and accurate non-invasive diagnostic modalities are highly desirable. These researchers sought to provide clinicians with such a tool. A two-gene classification method based on LINC00518 and PRAME gene expression was evaluated and validated in 555 pigmented lesions (157 training and 398 validation samples) obtained non-invasively via adhesive patch biopsy. Results were compared with standard histopathologic assessment in lesions with a consensus diagnosis among three experienced dermatopathologists. In 398 validation samples (87 melanomas and 311 non-melanomas), LINC00518 and/or PRAME detection appropriately differentiated melanoma from non-melanoma samples with a sensitivity of 91% and a specificity of 69%. These investigators established LINC00518 and PRAME in both adhesive patch melanoma samples and underlying formalin-fixed paraffin-embedded (FFPE) samples of surgically excised primary melanomas and in melanoma lymph node metastases. The authors concluded that this non-invasive two-gene pigmented lesion assay classified pigmented lesions into melanoma and non-melanoma groups and may serve as a tool to help with diagnostic challenges that may be inherently linked to the visual image and pattern recognition approach. The main drawback is that this technology cannot be used on mucous membranes, palms of hands, and soles of feet.
Yao and associates (2017) noted that a number of diagnoses in clinical dermatology are currently histopathologically confirmed, and this image recognition-based confirmation generally requires surgical biopsies. The increasing ability of molecular pathology to corroborate or correct a clinical diagnosis based on objective gene expression, mutation analysis, or molecular microbiome data is on the horizon and would be further supported by a tool or procedure to collect samples non-invasively. This study characterized such a tool in the form of a "bladeless" adhesive patch-based skin biopsy device. The performance of this device was evaluated through a variety of complementary technologies, including assessment of sample biomass, electron microscopy demonstrating the harvesting of layers of epidermal tissue, and isolation of RNA and DNA from epidermal skin samples. Samples were obtained by applying adhesive patches to the anatomical area of interest. Biomass assessment demonstrated the collection of approximately 0.3 mg of skin tissue per adhesive patch, and electron microscopy confirmed the nature of the harvested epidermal skin tissue. The obtained tissue samples were stored in a stable fashion on adhesive patches over a wide range of temperatures (-80°C to +60°C) and for extended periods (7 days or more). Total human RNA, human genomic DNA, and microbiome DNA yields were 23.35 ± 15.75 ng, 27.72 ± 20.71 ng, and 576.2 ± 376.8 pg, respectively, in skin samples obtained from combining four full patches collected non-invasively from the forehead of healthy volunteers. The authors concluded that the adhesive patch skin sampling procedure was well-tolerated and provided a robust means to obtain skin tissue, RNA, DNA, and microbiome samples without involving surgical biopsies. The non-invasively obtained skin samples can be shipped cost-effectively at ambient temperature by mail or standard courier service and were suitable for a variety of molecular analyses of the skin microbiome as well as keratinocytes, T cells, dendritic cells, melanocytes, and other skin cells involved in the pathology of various skin conditions where the skin can serve as a surrogate target organ.
In a secure web-based, multiple-reader-multiple-case study, Ferris and colleagues (2017) determined the utility of the PLA for LINC00518/PRAME expression in decisions to biopsy a series of pigmented skin lesions. Board-certified dermatologists each evaluated 60 clinical and dermoscopic images of clinically atypical pigmented lesions, first without and then with PLA gene expression information, and were asked whether the lesions should be biopsied. Data were collected from March 24, 2014, through November 13, 2015. Participants were given a report for each lesion, which included the results of an assay for expression of LINC00518/PRAME and a PLA score with data on the predictive values of the information provided. Main outcome measures were biopsy sensitivity and specificity with versus without PLA data. A total of 45 dermatologists (29 men and 16 women) performed the evaluation. After incorporating the PLA into their decision as to whether to biopsy a pigmented lesion suggestive of melanoma, dermatologists improved their mean biopsy sensitivity from 95.0% to 98.6% (p = 0.01); specificity increased from 32.1% to 56.9% (p < 0.001) with PLA data. The authors concluded that the non-invasive PLA enabled dermatologists to significantly improve biopsy specificity while maintaining or improving sensitivity. They stated that this finding may increase the number of early melanomas biopsied and reduce the number of benign lesions biopsied, thereby improving patient outcomes and reducing healthcare costs.
Ferris et al. (2018) stated that approximately 3 million surgical pigmented skin lesion biopsies are carried out every year in the U.S. alone to diagnose fewer than 200,000 new cases of invasive melanoma and melanoma in situ using the current standard of care, which includes visual assessment and histopathology. A recently described non-invasive adhesive patch-based gene expression rule-out test (Pigmented Lesion Assay, PLA) may be helpful in identifying high-risk pigmented skin lesions to aid with surgical biopsy decisions. These researchers determined the real-world clinical performance of PLA use and examined how the PLA changes physician behavior in an observational cohort analysis of 381 patients assessed with the PLA. All (100%) of the 51 PLA(+) test results were clinically managed with surgical biopsy. Of these, 19 (37%) were melanomas, corresponding to a number needed to biopsy of 2.7 and a biopsy ratio of 1.7. All melanomas were histopathologically classified as melanoma in situ or stage 1. Nearly all (99%) of the 330 PLA(-) test results were clinically managed with surveillance. None of the three follow-up biopsies performed in the following 3 to 6 months were diagnosed as melanoma histopathologically. The estimated sensitivity and specificity of the PLA from these data sets are 95% and 91%, respectively. Overall, 93% of PLA results positive for both LINC00518 and PRAME were diagnosed histopathologically as melanoma. PRAME-only and LINC00518-only lesions were melanomas histopathologically in 50% and 7%, respectively. The authors concluded that the PLA changed the clinical management of pigmented lesions and demonstrated high clinical performance. The likelihood of a positive histopathologic diagnosis of melanoma was higher in PLA results that were positive for both LINC00518 and PRAME.
The authors stated that an inherent key limitation of this study was the assumption that PLA(-) lesions not biopsied at 3 to 6 months were true negatives. In underlying validation studies, all lesions examined by PLA were also surgically biopsied so that consensus histopathology diagnoses could be established and correlated with PLA results. In this study, the objective was to examine if clinicians follow the biopsy guidance the PLA offers. Other than subjecting all PLA(-) patients to the very surgical biopsy this technology helps minimize, there is no other good way to estimate true negatives. Studies using dermoscopy to follow suspicious melanoma lesions indicated that melanomas will undergo observable changes within 3 to 6 months, while changes in early melanoma in situ may be more difficult to evaluate. A study to examine findings with up to 2 years of follow-up has been initiated recently. Nonetheless, these researchers could not rule out that some PLA(-) lesions may not have been adequately re-assessed in the follow-up period, and they certainly recommended erring on the side of caution and surgically biopsying a lesion in question if additional risk factors, further clinical suspicion, or patient concern mandate such a step. These researchers did not recommend the use of the PLA if a frank melanoma is suspected. Another perceived limitation was that the validation study by Gerami et al. (2017) and this real-world utility study reported different specificity numbers (69% versus 91%). Potential reasons for the noted difference included study objectives and design, physician environment and bias (validation studies were performed by academic investigators who directed pigmented lesion clinics and routinely used tools such as total body photography and dermoscopy that may not be used routinely by all dermatologists in clinical practice), required assumptions, and possibly, most importantly, a lower prevalence of melanoma in biopsied real-world lesions (5%, 19 of 381 cases) in line with reports from other comparable studies and settings. It should be noted that L.K.F., P.G., G.P., and D.M.S. are scientific advisors to DermTech.
Ferris et al. (2019a) noted that tools that help reduce the number of surgical biopsies performed on benign lesions have the potential to improve patient care. The PLA is a non-invasive tool validated against histopathology that helps rule out melanoma and the need for surgical biopsies of atypical pigmented skin lesions. Genetic information is collected using adhesive patches, and the expression of two genes, LINC00518 and PRAME, is measured. Using genetic material collected non-invasively and to further validate the PLA, somatic hotspot mutations in genes known to be drivers of early melanoma development (BRAF other than V600E, NRAS, and the TERT promoter) can also be identified. The frequency of these hotspot mutations in samples of early melanoma was 77%, which is higher than the 14% found in non-melanoma samples (p < 0.0001). TERT promoter mutations were the most prevalent mutation type in PLA-positive melanomas; 82% of PLA-negative lesions had no mutations, and 97% of histopathologically confirmed melanomas were PLA and/or mutation positive (cohort 1, n = 103). Mutation frequencies were similar in prospectively collected real-world PLA samples (cohort 2, n = 519), in which 88% of PLA-negative samples had no mutations. The authors concluded that combining gene expression and mutation analyses enhanced the ability to non-invasively detect early cutaneous melanoma. Moreover, these researchers stated that not all TERT promoter mutations, the mutation type observed in 79% of melanomas confirmed by histopathologic consensus diagnosis, may be created equal. Borah et al. (2015) found TERT promoter mutations at position -124 in most of their urothelial cancer cell lines studied, and this mutation may confer tumor aggressiveness and facilitate the establishment of cell lines. Although further studies are needed to examine the roles that different TERT promoter mutations may play in the progression of melanocytic lesions, it is of interest to note that -124 mutations were the mutation type most often observed in melanomas positive for both LINC and PRAME.
Ferris et al. (2019b) stated that the Pigmented Lesion Assay (PLA, sensitivity of 91% to 95%, specificity of 69% to 91%, negative predictive value [NPV] of greater than 99%) is a commercially available, non-invasive gene expression test that helps dermatologists guide pigmented lesion management decisions and rule out melanoma. Earlier studies have demonstrated high clinical utility and no missed melanomas in a 3 to 6 months follow-up period. These researchers provided 12-month follow-up data on PLA(-) tests to further confirm utility. They carried out a 12-month chart review follow-up of 734 pigmented lesions that had negative PLA results from five U.S. dermatology centers; 13 of these lesions (1.8%) were biopsied in the follow-up period and submitted for histopathologic review. None of the lesions biopsied had a histopathologic diagnosis of melanoma. The test's utility was studied further in a registry (n = 1,575, 40 U.S. dermatology offices, 62 participating providers), which demonstrated that 99.9% of PLA(-) lesions were clinically monitored, thereby avoiding a surgical procedure, and 96.5% of all PLA(+) lesions were appropriately biopsied, most commonly with a tangential shave. The authors concluded that this long-term follow-up study confirmed the PLA's high NPV and high utility in helping guide the management of pigmented lesions to avoid unnecessary surgical procedures.
The authors stated that inherent limitations of the data presented included the assumption that lesions of patients not returning to follow-up visits at the site of PLA testing within a 12-month follow-up period were true negatives. Furthermore, these investigators could not rule out that some PLA(-) lesions may not have been adequately re-assessed within the 12-month follow-up period, and they recommended erring on the side of caution and performing a surgical biopsy of a lesion in question if additional risk factors and further clinical suspicion or patient concern mandated such a step. Further limitations inherent to studies designed to evaluate melanoma rule-out tests and platforms in real-world settings included the low prevalence of melanoma compared to how common benign lesions of clinically similar appearance are in given target populations. However, it was comforting to consider that the non-invasive gene expression platform used here lends itself to validation study comparisons that can exceed the quality level of randomized control groups. With this platform, it is possible to obtain non-invasive gene expression information and histopathology reads from the same lesion.
In a discussion of "emerging" diagnostic technologies, guidelines on cutaneous melanoma from the American Academy of Dermatology (Swetter et al., 2019) state that "Noninvasive genomic methods (e.g., adhesive patch 'biopsy') are being investigated to further classify melanocytic lesions as either benign or malignant to guide the need for further biopsy."
Robinson and Jansen (2020) noted that physician appointments for non-essential care ceased during COVID-19. These researchers pilot-tested a telehealth solution for patients to rule out melanomas and the need for surgical biopsies based on genomic analyses of pigmented lesion samples obtained via adhesive patches. Surveys examined skin self-examination (SSE) anxiety. Under remote clinician guidance, patients or partners obtained samples using adhesive patches (DermTech, La Jolla, CA). SSE anxiety increased. Guided self-sampling led to molecular risk factor analyses in 7 of 7 (100%) of cases compared to 9 of 10 (90%) randomly selected physician-sampled control cases. The authors concluded that adhesive patch (DermTech) self-sampling under remote physician guidance is a viable specimen collection option. This was a proof-of-concept (pilot) study with a small sample size (n = 7 for the DermTech group); its findings need to be validated by well-designed studies.
Brouha et al. (2020) stated that the Pigmented Lesion Assay (PLA) is a non-invasive gene expression test that aids clinicians in ruling out melanoma via a genomics approach, which elevates pigmented lesion management beyond what the eye can see. It improves care with a negative predictive value (NPV) of greater than 99% while reducing biopsies by 90% and costs. This registry study described in this study (53 U.S. dermatology offices, 90 providers, median patient age of 48 years, 60.80% female and 39.20% male patients) assesses real-world utility to determine if the PLA changes clinical practice. Of 3,418 pigmented skin lesions clinically suspicious for melanoma and assessed by PLA, 324 lesions (9.48%) were PLA(+) and 3,094 (90.52%) were negative. A PLA test result was positive if LINC, PRAME, or both target genes are detected; these molecular pathology findings are known to correspond with histopathology findings of in situ or invasive primary melanoma in 7%, 50%, and 93%, respectively. The 9.48% PLA(+) cases consisted of 5.15% LINC only, 1.93% PRAME only, and 2.40% LINC and PRAME double-positive cases. Notably, PLA(+) lesions were surgically biopsied 97.53%, while PLA(-) cases were clinically monitored and not biopsied in 99.94% of the cases. The authors concluded that these findings demonstrated that community-based clinicians who employ the PLA to improve pigmented lesion management used the test’s results to guide how they practice. Pigmented lesions with PLA(+) test results were subjected to surgical biopsies, whereas PLA(-) lesions were followed clinically and not biopsied. It should be noted that this study was partially supported by DermTech, Inc.; and BB, LF, MS, RM, and GP are advisors to, and BJ and ZY are employees of, DermTech.
Brouha et al. (2021) noted that melanoma is diagnosed in approximately 200,000 individuals within the U.S. each year and is responsible for more than 6,850 deaths. Currently, clinical suspicion guides biopsy decisions, and melanoma is confirmed in approximately 4% of biopsied lesions. A non-invasive two-gene expression test (2-GEP) was demonstrated to enhance the physical examination by examining genomic atypia to guide biopsy decisions. These researchers examined the corresponding histopathology of real-world 2-GEP-positive cases. Cutaneous lesions suspicious for melanoma (n = 3,418) were 2-GEP tested by 90 licensed clinicians in real-world practice. 2-GEP-positive lesions (genomically atypical as indicated by the detection of LINC and/or PRAME) were biopsied in 316 out of 324 (97.5%) cases, and 313 pathology reports were available for analysis. Biopsied 2-GEP-positive lesions were separated into diagnostic subgroups based on corresponding pathology reports. The prevalence of melanoma in biopsies of 2-GEP-positive lesions was 18.7%. Gene expression of both LINC and PRAME was present in ever-increasing percentages of melanocytic lesions as pathology reports demonstrated increasing levels of atypia. Notably, 47.5% of the histopathologically confirmed melanomas demonstrated this double-positive genomic signature, while 23.7% were single-positive for LINC and 28.8% were single-positive for PRAME. The authors concluded that these findings showed that biopsied 2-GEP-positive lesions were enriched almost five-fold for advanced histopathologic features compared to those biopsied based solely on visual assessment criteria. The close correlation between genomic atypia and atypical pathology should be considered when planning treatment of a 2-GEP-positive lesion. Consideration of genomic atypia may be a superior approach to guide biopsy decisions and manage pigmented lesions.
There is an ongoing clinical trial on "Targeted Melanoma Detection with Skin Self-Examination During COVID-19 Restricted Physician Access (TMD)" (ClinicalTrials.gov ID NCT04420273). This trial entails physician-supervised non-invasive adhesive patch-based home sample collection of a concerning mole for genomic analysis (last updated September 4, 2020).
An Ontario Health technology assessment on “Pigmented Lesion Assay for Suspected Melanoma Lesions” (2021) noted that early detection of melanoma is key, as survival rates are substantially better when the cancer is detected in its early stages. To date, the standard of care (SOC) is to biopsy any lesion suspected of melanoma for diagnostic confirmation by histopathology. As a result, most individuals who undergo biopsy receive negative melanoma results. If effective, a non-invasive alternative, such as PLA, could minimize the number of unnecessary biopsies carried out. These researchers performed a health technology assessment of PLA for individuals with suspected melanoma lesions, which included an evaluation of diagnostic accuracy, clinical utility, the budget impact of publicly funding PLA, and the preferences and values of individuals who have undergone biopsy for suspected melanoma. These investigators carried out a systematic literature search of the clinical evidence. They examined the risk of bias of each included study using the Quality Assessment of Diagnostic Accuracy Studies–2 (QUADAS-2) and the Risk of Bias Assessment Tool for Non-randomized Studies (RoBANS). These researchers evaluated the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. They conducted a systematic literature search of the economic evidence and also analyzed the budget impact of publicly funding PLA in adults with suspected melanoma in Ontario. To contextualize the potential value of PLA, the authors spoke with individuals who had undergone skin biopsy for melanoma. They also employed qualitative research synthesis from a report by the Canadian Agency for Drugs and Technologies in Health (CADTH) to provide context for the preferences and values of those with suspected melanoma. These researchers included seven studies in the clinical evidence review. The Pigmented Lesion Assay has a sensitivity of 79% (95% CI: 58% to 93%) and a specificity of 80% (95% CI: 73% to 85%; GRADE: Low). They found one published cost-effectiveness study with potentially serious limitations; thus, the cost-effectiveness of PLA compared with the SOC pathway is currently uncertain. Assuming a very low uptake, these investigators estimated that the budget impact of publicly funding PLA in Ontario over the next five years is about $3.44 million if the test is used exclusively by primary care providers, or about $2.56 million if it is used exclusively by specialists. The individuals with whom the authors spoke who had experienced biopsy for suspected melanoma responded positively to the potential benefits of PLA, emphasizing its ease of use, potential increase in early detection of melanoma, and reduction in the physical and emotional burden of unnecessary biopsies. Participants also felt that the accuracy of this tool was essential to ensure minimal false negatives. The authors concluded that there is uncertainty because of the low-quality evidence for the diagnostic accuracy of PLA. The cost-effectiveness of PLA compared with SOC is also uncertain. These investigators estimated that publicly funding PLA in Ontario over the next five years would result in additional costs of $3.44 million (if used exclusively by primary care providers) or $2.56 million (if used exclusively by specialists). For individuals who had experienced biopsy for suspected melanoma, it was felt that PLA could represent an effective tool to increase early detection and avoid unnecessary biopsies if the tool was accurate.
The authors stated that this analysis had several drawbacks. First, these investigators relied on data from the Ontario Health Insurance Plan (OHIP) claims database; however, those data were collected for billing and administrative purposes, not for research. One limitation of the administrative data is the possibility of inaccurate coding; thus, these researchers carried out extensive sensitivity analyses using different OHIP codes and diagnosis codes. Second, all accuracy studies of PLA were performed in dermatology clinics. Due to a lack of data, these investigators assumed the diagnostic accuracy of PLA in primary care would be similar. Third, since PLA is less invasive and easier to perform than biopsy, physicians may choose to use the test on more individuals if it was available. Therefore, there is the possibility that physicians may overuse PLA on inappropriate patients (e.g., giving the test just to reassure patients).
Skelsey et al. (2021) stated that management of pigmented lesions currently relies on visual assessment with surgical biopsy and histopathologic examination for those lesions suspicious for melanoma. A non-invasive genomic assay that detects two melanoma-associated biomarkers (PLA, 2-GEP) has recently been validated as an adjunct to visual assessment for distinguishing high-risk pigmented lesions appropriate for biopsy from those that could be safely monitored via clinical surveillance. In a retrospective study, these researchers determined real-world NPV by following a cohort of 1,233 PLA-negative pigmented lesions for evidence of malignancy for up to 36 months and by re-testing a separate prospective cohort of 302 PLA-negative lesions up to 2 years after initial testing. Real-world positive predictive value (PPV) was determined by identifying melanoma diagnoses among PLA-positive lesions within a U.S.-based registry of 3,418 PLA-tested cases. A total of 10 early-stage melanomas (4 in situ and 6 pT1a) were identified among 1,233 PLA-negative lesions (0.8%), corresponding to a real-world NPV of 99.2% (95% CI: 98.5% to 99.6%). Of 302 initially PLA-negative lesions subjected to repeat testing an average of 15 months later, 34 were PLA-positive. Biopsy revealed three melanomas (all in situ), further confirming an NPV of greater than 99%. Among 316 PLA-positive cases, 59 were diagnosed as melanoma by histopathology, corresponding to a PPV of 18.7%. Of all PLA-positive lesions, 30.5% had histopathologic diagnoses corresponding to high-risk MPATH-Dx categories (Classes III to V). The authors concluded that the PLA had an NPV of greater than 99% within the real-world intended use population. The PLA had a PPV of 18.7% for melanoma and also detected high-risk lesions such as dysplastic nevi with severe/high-grade atypia that are generally targeted for complete excision.
The authors stated that an important drawback of this trial was that follow-up visits were not documented for 548 of the 1,781 PLA-negative patients; therefore, it could not be confirmed that none of these 548 patients developed a melanoma that remained undetected or was identified and treated elsewhere. For this reason, the most definitive NPV calculation was that derived from the subset of 1,233 patients with documented follow-up visits within the indicated period. Furthermore, retrospective medical chart review could erroneously assess a lesion not tested with the PLA. While real-world data from lesion cohort studies are the most relevant to actual clinical practice, the strategies chosen did not allow for comparisons based on consensus histopathology reads that may reduce variability in histopathologically determined diagnoses. Finally, PLA-negative lesions that were negative on repeat testing and by clinical evaluation were considered true negatives for purposes of these analyses, and the possibility that some lesions were, in fact, melanomas that were negative on both the initial and repeat tests and also by clinical follow-up could not be entirely excluded.
Skudalski et al. (2022) stated that in response to rising rates of melanoma worldwide, novel non-invasive melanoma detection techniques are emerging to facilitate the early detection of melanoma and decrease unnecessary biopsies of benign pigmented lesions. Because they often report similar study findings, it may be difficult to determine how best to incorporate these technologies into clinical practice based on their supporting studies alone. The authors concluded that as the incidence of melanoma continues to rise, numerous technological advances have entered the field of dermatology in recent years to aid in the identification, surveillance, and diagnosis of these potentially invasive lesions. Although not indicated for every patient or feasible in every practice, total body photography (TBP), sequential digital dermoscopic imaging (SDDI), PLA, reflectance confocal microscopy (RCM), dynamic optical coherence tomography (OCT), and tele-dermatology have the potential to transform the way in which melanoma is diagnosed daily; thus, it is imperative for dermatologists and other practitioners to be educated on these novel technologies and which, if any, are appropriate for use within the infrastructure of their current practice.
Peck et al. (2024) noted that many melanoma-specific dermoscopic features have been described in invasive melanomas, while fewer features are found in melanoma in situ (MIS) and atypical nevi (ATN). Consensus regarding which features are critical for the differentiation of MIS from ATN has not been reached. In a single-center study, these researchers examined if there are dermoscopic features that differentiate early MIS from ATN, and if non-invasive assessment of genomic biomarkers (LINC00518 and PRAME) can aid in patient management. From 2018 to 2023, a total of 56 melanomas were evaluated for five clinical and 13 dermoscopic features and melanoma-associated genomic biomarkers. Two groups of ATN with positive and negative genomic biomarkers were randomly selected for comparison. All melanomas in this study expressed one or both melanoma-associated genomic markers. MIS had an average of 3.90 (range of 2-7) of the 13 dermoscopic features, while invasive melanomas had an average of 4.44 (range of 3-6); 16 of 40 (40%) MIS and 3 of 16 (18.8%) invasive melanomas had three or fewer dermoscopic features. These findings were comparable to those observed in both ATN groups. The most common dermoscopic features were absent or diminished pigment network, regression structures, and granularity. This combination of features was most helpful in identifying lesions for genomic testing. The authors concluded that clinical and dermoscopic features alone could not differentiate MIS from ATN. Non-invasive genomic testing helped differentiate lower from higher-risk lesions and aid in clinical management decisions. Genomic testing was especially helpful in patients with large numbers of lesions, with several being considered for biopsy based on clinical and dermoscopic examination. The authors stated that drawbacks of this study included small cohort size, subjectivity of the clinical and dermoscopic assessment of the melanocytic lesions, and the study’s single-center setting. (It should be noted that some of the authors are/were associated with DermTech—GLP and MKS are clinical investigators and consultants for DermTech; BJ and LEC are employees of DermTech. SWM is a former employee of DermTech. Also, this study was partially funded by DermTech.)
Kaufmann et al. (2024) stated that non-invasive adjuncts to visual assessment of pigmented lesions may reduce biopsies of benign lesions without compromising melanoma detection. A non-invasive genomic melanoma rule-out assay analyzes RNA extracted from stratum corneum cells for PRAME and LINC00518—two genes often expressed in melanomas but less often in benign lesions. These researchers examined the performance of this test in a large patient cohort tested in the real-world clinical setting. The test was applied to suspicious pigmented skin lesions at 63 U.S. dermatology and primary care practices. Test results (positive/negative) were compared to pathology diagnoses (melanoma/not melanoma) for lesions that were biopsied and to follow-up visual examination for those that were monitored. Of 19,653 total lesions evaluated, 17,858 (90.87%) tested negative. Biopsy results and/or follow-up examinations were available for 5,096 lesions, with median and mean follow-up durations of 352 and 341 days, respectively. For melanoma, sensitivity was 95.8% and specificity was 69.4%. Positive predictive value (PPV) was 13.4%, and NPV was 99.7%. For melanoma and “borderline” lesions combined, sensitivity was 94.2%, specificity was 71.2%, PPV was 20.8%, and NPV was 99.3%. The authors concluded that the results suggested that this non-invasive test could facilitate the distinction of melanoma from its benign simulators, increasing the proportion of pigmented lesions that can be safely managed with surveillance rather than biopsy and/or excision. The authors stated that drawbacks of this study included a cohort comprised of individuals evaluated primarily by dermatologists, which may not represent the general population, and comparison to histopathologic diagnosis in biopsied lesions, which has lower accuracy for early-stage melanocytic neoplasms. (MDK, MKS, LKF, and MW are consultants and/or investigators of DermTech; AR, BJ, and LEC are employees of DermTech. Also, this study was funded by DermTech.)
Van Sambeek et al. (2024) stated that being one of the largest dermatology groups in the country with an in-house pathology laboratory, these investigators have observed a marked increase in the number of adhesive-based pigmented lesion assays (ABPLAs) in addition to biopsies and excisions following a moderate-risk or high-risk result with this test. They reported their clinical experience and independently confirmed that their results with this ABPLA (Pigmented Lesion Assay, DermTech, San Diego, CA) are consistent with the results of the validation studies completed by the test manufacturer. These researchers carried out a retrospective review of their electronic medical records for results of ABPLAs; corresponding histopathologic results and available clinical follow-up, along with their statistical analysis, were completed. After reviewing their electronic medical records, they found that 893 ABPLAs for pigmented lesions concerning for melanoma were obtained in a period of 14 months. Of the 893 ABPLAs completed, 161 biopsies and excisions were performed after the initial results of these assays. Additional clinical follow-up data were recorded and used for the statistical analysis of the performance and accuracy of this test. The authors concluded that in their experience, this ABPLA has a sensitivity of 92.0%, a specificity of 79.5%, a PPV of 16.9%, and a NPV of 99.5% for the detection of melanoma.
These researchers stated that drawbacks of this trial included the small number of lesions reported as low risk for melanoma with corresponding histopathologic results, which limited the evaluation of the performance of this test. Furthermore, there may have been some melanomas that were not identified because the duration of the clinical follow-up was insufficient or because some patients were lost to follow-up.
In a “Letter to the Editor,” Skelsey et al. (2025) stated that many studies suggested that melanoma in individuals with higher Fitzpatrick skin types (FST) is more likely to present at an advanced stage and result in higher mortality. A non-invasive genomic rule-out test examining gene expression of LINC00518 and PRAME has been introduced to aid in augmenting the detection of melanoma at an early stage while reducing the number of biopsies carried out for benign pigmented lesions that simulate melanoma. Clinical validation using histopathologic consensus diagnoses as a reference standard showed the test has a 99% or higher NPV, indicating that a lesion that tests negative is unlikely to be a melanoma. Although patients of all skin types were eligible for inclusion in the validation study, the cohorts consisted mostly of samples from individuals with FST I, II, or III. These investigators examined the performance of this non-invasive rule-out melanoma test across all FST, with a particular focus on NPV in FST IV to VI patients. Test performance metrics for patients with FST I to III (n = 4,152) and IV to VI (n = 130) across 73 U.S. clinical practice sites were compared using biopsy results and follow-up information compiled via the DermTech Melanoma Test Registry Protocol (WCG IRB waiver obtained March 3, 2021). Performance metrics were also calculated for a cohort limited to lesions with at least 6 months of follow-up or biopsy results. In the full cohort (n = 4,282), sensitivity was 0.9429 (66/70), specificity was 0.9086 (3,709/4,082), PPV was 0.1503 (66/439), and NPV was 0.9989 (3,709/3,713) for FST I to III. For FST IV to VI, sensitivity was 1.0 (3/3), specificity was 0.9449 (120/127), PPV was 0.3 (3/10), and NPV was 1.0 (120/120). Three of three melanomas (0.55 mm, 0.40 mm, and melanoma in situ in non–sun-exposed areas on the trunk) in the IV to VI group diagnosed by histopathology were correctly identified as positive with the test. The 95% CIs for the differences in sensitivity, specificity, NPV, and PPV between the two groups included 0, indicating no significant difference in any of the performance metrics. Additional analyses limited to subjects with either a biopsy result or at least 6 months (182 days or longer) of follow-up after testing (n = 2,266) confirmed the results observed in the full cohort for sensitivity, specificity, PPV, and NPV, and no statistically significant differences between groups were observed. The authors concluded that the findings of this study showed that the performance of the non-invasive test in FST IV to VI patients did not differ from that in FST I to III patients. These researchers stated that these findings support the test's utility in guiding biopsy decisions for ambiguous pigmented skin lesions of all skin types without a need to limit access for patients with FST IV to VI. It should be noted that Drs. Skelsey, Loftis, Kaufmann, Siegel, Bhatia, Wangia, and Walker are investigators and/or consultants of DermTech; Drs. Rigby, Whitaker, Stone, Moccia, O'Brien, Jansen, and Clarke are employees of DermTech.
Optical Coherence Tomography
Reggiani et al. (2015) stated that non-melanoma skin cancer (NMSC) is the most common malignancy in fair-skinned populations. Dermoscopy, reflectance confocal microscopy (RCM), and optical coherence tomography (OCT) are non-invasive imaging techniques that play an important role in the diagnosis of skin tumors. These investigators provided new insights into the role of non-invasive techniques in the diagnosis of NMSCs, concentrating especially on dermoscopy, RCM, and OCT. They performed a PubMed search concerning the role of dermoscopy, RCM, and OCT in the diagnosis of NMSC. Duplicated studies, single-case reports, and papers in languages other than English were excluded from analysis. New and old literature about the early diagnosis of NMSC through non-invasive imaging techniques was analyzed. The role and diagnostic accuracy of dermoscopy, RCM, and OCT for the diagnosis of NMSC were reported. The authors concluded that the development of non-invasive diagnostic devices (especially dermoscopy, RCM, and OCT) allows for in-vivo tissue imaging, contributing to a more accurate diagnosis of skin cancer, thereby saving time for the patient and costs for the public health system.
In a Cochrane review, Ferrante di Ruffano and colleagues (2018b) determined the diagnostic accuracy of OCT for the detection of cutaneous invasive melanoma and atypical intra-epidermal melanocytic variants, BCC, or cSCC in adults. These researchers 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. They studied reference lists and published systematic review articles. These investigators included studies of any design evaluating OCT in adults with lesions suspicious for invasive melanoma and atypical intra-epidermal melanocytic variants, BCC, or cSCC, compared with a reference standard of histological confirmation or clinical follow-up. Two review authors independently extracted data using a standardized data extraction and quality assessment form (based on QUADAS-2); the unit of analysis was lesions. Where possible, these researchers estimated summary sensitivities and specificities using the bi-variate hierarchical model. They included five studies with 529 cutaneous lesions (282 malignant lesions), providing nine datasets for OCT, two for visual inspection alone, and two for visual inspection plus dermoscopy. Studies were of moderate-to-unclear quality, using data-driven thresholds for test positivity and providing poor accounts of reference standard interpretation and blinding. Studies may not have been representative of populations eligible for OCT in practice, for example, due to high disease prevalence in study populations, and may not have reflected how OCT is used in practice, for example, by using previously acquired OCT images. It was not possible to make summary statements regarding the accuracy of detection of melanoma or cSCC because of the paucity of studies, small sample sizes, and differences in the OCT technologies used (high-definition versus conventional resolution OCT), as well as differences in the degree of testing performed prior to OCT (i.e., visual inspection alone or visual inspection plus dermoscopy). Pooled data from two studies using conventional swept-source OCT alongside visual inspection and dermoscopy for the detection of BCC estimated the sensitivity of OCT as 95% (95% CI: 91% to 97%) and specificity of 77% (95% CI: 69% to 83%). When applied to a hypothetical population of 1,000 lesions at the mean observed BCC prevalence of 60%, OCT would miss 31 BCCs (91 fewer than would be missed by visual inspection alone and 53 fewer than would be missed by visual inspection plus dermoscopy), and OCT would lead to 93 false-positive results for BCC (a reduction in unnecessary excisions of 159 compared to using visual inspection alone and of 87 compared to visual inspection plus dermoscopy). The authors concluded that insufficient data are available on the use of OCT for the detection of melanoma or cSCC. Initial data suggested that conventional OCT may have a role in the diagnosis of BCC in clinically challenging lesions, with this meta-analysis showing a higher sensitivity and higher specificity when compared to visual inspection plus dermoscopy. However, the small number of studies and varying methodological quality meant that implications to guide practice cannot currently be drawn. These investigators stated that appropriately designed prospective comparative studies are needed, given the paucity of data comparing OCT with dermoscopy and other similar diagnostic aids such as reflectance confocal microscopy.
Precision Medicine Test for Psoriasis
Mindera Health (San Diego, CA) has developed Mind.Px as a precision medicine test that may have predictive value by utilizing biomarkers as a potential guide for the optimal selection of biologic therapy in the treatment of psoriasis. With the use of the Mindera platform, Mind.Px is FDA registered and is described as "a proprietary minimally invasive dermal biomarker patch (DBP)" that extracts mRNA from the epidermis and dermis of the patient's skin (Wu et al., 2021). Each test sample then undergoes next-generation sequencing (NGS), which evaluates more than 7,000 biomarkers. Furthermore, this transcriptomic data is processed by algorithms gathered through machine learning, which then generates a report that provides information to healthcare providers regarding potential patient response to drug class (Strober et al., 2021). Currently, there are no published data in clinical practice and no net health benefit outcome studies available for the use of this precision medicine test.
Strober et al. (2021) surveyed 43 community dermatologists to understand the factors influencing the selection of biologic treatments for psoriasis. Key findings included the significant influence of insurance formularies on first-line biologic drug utilization, with 77% of dermatologists considering it a moderate-to-major influence, although only 14% found the formulary compatible with their first-line choice most of the time. Non-response at 12 to 16 weeks was used to determine switching therapy, aligning with AAD/NPF guidelines. The Mind.Px diagnostic test, a dermal biomarker patch, was highlighted for its potential to predict therapeutic response to biologics, with 98% of respondents willing to use it. Factors influencing biologic selection included perceived response rates, adverse events (AEs), co-morbidities, patient preference, dermatologist familiarity, ease of use, and cost. Over 75% of patients were treated with biologics, with dermatologists using multiple biologics. The use of Mind.Px was seen as beneficial for improving patient outcomes and streamlining the prior authorization process, with 93% of physicians willing to follow its recommendations. The authors concluded that, overall, the study underscored the impact of insurance formularies and highlighted the potential benefits of predictive diagnostic tools like Mind.Px in improving treatment outcomes and clinical workflows. Moreover, these researchers stated that potential biases included reliance on self-reported data and the proprietary nature of the data.
Bagel et al. (2021) developed and validated Mind.Px, a machine learning (ML)-based algorithm to predict patient responses to the most common biologic drug classes used in managing psoriasis: IL-23i, IL-17i, and TNFαi. Patients were enrolled in observational STAMP studies where dermal biomarker patches (DBPs) were applied at baseline, followed by clinical evaluations at 12 weeks. Transcriptomes from DBPs were sequenced to derive predictive classifiers for each biologic class. This trial included 242 psoriasis patients, with classifiers developed and validated using both STAMP study data and publicly available datasets. The IL-23i classifier was developed from early enrollees and validated with later patients, while IL-17i and TNFαi classifiers were trained using public data and validated with STAMP study patients. The classifiers showed high positive predictive values (PPVs), and nearly all patients were predicted to respond to at least one biologic class. The authors stated that this study highlighted the potential for personalized medicine in psoriasis treatment, aiming to improve patient outcomes and reduce healthcare costs by predicting the most effective biologic treatment for individual patients. Moreover, these researchers stated that drawbacks of this study included the smaller sample sizes for IL-17i and TNFαi classifiers, necessitating the use of public datasets for training, which differed in sample collection and RNA preparation methods from the test sets.
Strober et al. (2025) aimed to assess the clinical utility of a machine learning-based tool, Mind.Px, which predicts patient response to biologic drug classes used in the management of psoriasis. This randomized, prospective study, known as MATCH, included 210 patients who were either biologic naïve or approaching a medication change due to nonresponse. Of the 310 patients initially selected for the study, 210 completed it, with both baseline and week 12 PASI scores recorded. The remaining 100 patients either failed screening, were lost to follow-up, or withdrew their consent during the study. The study involved applying a dermal biomarker patch to lesional skin and providing Mind.Px test results to physicians for patients in the informed arm before biologic selection. Patients were evaluated at weeks 4 and 12 using the Psoriasis Area and Severity Index (PASI). The study demonstrated a significant alteration in physician prescribing behavior when Mind.Px test results were available. Concordance between physician choice and Mind.Px results was significantly higher in the informed arm (93.1%) compared to the uninformed arm (65.4%). Patients whose treatment aligned with Mind.Px test results showed better clinical outcomes. A higher percentage of patients in the informed arm reached the clinical endpoint (PASI75) at 12 weeks compared to the uninformed arm (81.6% vs. 53.7%). Additionally, more patients in the informed arm reached PASI75 by week 4 (77.4% vs. 53.3%). However, of the 210 patients who completed the study, only 143 had complete patient outcome data sets. The study suggests that using Mind.Px can potentially translate into cost savings for healthcare systems by minimizing the trial-and-error approach to psoriasis treatment. Limitations of the study noted by the authors include the short follow-up period. The study had a 12-week follow-up period, which does not allow for the assessment of long-term durability and limits the interpretation of longer-term patient outcomes. The study used PASI75 as the primary endpoint. The authors suggested that future research could include other endpoints such as PASI90, PASI100, or patient-reported outcomes like the Dermatology Life Quality Index (DLQI) to gain a more comprehensive understanding of the clinical benefits. Validation of these findings in independent patient cohorts will be valuable to confirm the generalizability of the results across varying populations and clinical settings. Physicians who assessed patient outcomes were not blinded to assignment. In addition, there was no protocol for the uninformed arm to ensure that their choice and dose of biologic coincided with the best guideline-supported standard of care. The authors noted that further research is needed to validate these findings over a longer period and across different patient populations.
Reflectance Confocal Microscopy
Confocal laser scanning microscopy is similar to dermoscopy; however, it uses a low-power laser beam projected through a lens onto a specific point on the skin and then detects the light reflected from the focal point through a filter. The reflected light is transformed into an electrical signal, which is recorded as an image by a computer. This technology claims to be capable of producing images of skin lesions at various depths below the skin’s surface. One example of such technology is the VivaScope.
Gerger et al. (2005) stated that in vivo confocal laser scanning microscopy (CLSM) represents a novel imaging tool that allows the examination of skin morphology in real time at a resolution equal to that of conventional microscopes. These researchers tested the applicability of CLSM to the diagnostic discrimination of benign nevi and melanoma. Five independent observers without previous experience in CLSM received standardized instruction about diagnostic CLSM features. Subsequently, 117 melanocytic skin tumors (90 benign nevi and 27 melanoma), imaged using a commercially available, near-infrared, reflectance confocal laser scanning microscope, were evaluated by each observer. Overall, a sensitivity of 88.2% and specificity of 97.6% was achieved by the five observers. Logistic regression analysis revealed that mainly cytomorphology, architecture, and keratinocyte cell borders should be taken into account for diagnostic decisions. Remarkably, using the presence or absence of monomorphic melanocytes as a single diagnostic criterion, the classification results with a sensitivity of 98.2% and a specificity of 98.9% were superior to the intuitive, integrative judgment of the observers. These investigators concluded that this first sensitivity and specificity study with CLSM has yielded promising results. Furthermore, Marghoob and Halpern (2005) stated that the future of CLSM looks bright; however, much work is needed before the application of this technology in routine clinical practice.
Gerger et al. (2006) noted that in vivo confocal laser scanning microscopy (CLSM) examination appeared to be a promising method for the non-invasive assessment of melanoma and non-melanoma skin tumors. This observation aligns with Menzies (2006), who stated that the use of automated instruments for the diagnosis of cutaneous melanoma is still in an experimental phase, and its utility depends on the evidence that such instruments provide a clinically useful expert second opinion. Currently, other non-invasive diagnostic techniques, such as in vivo CLSM, are reserved for clinical research settings.
Gerger and colleagues (2009) stated that in vivo confocal microscopy represents a novel imaging tool that allows the non-invasive examination of skin cancer morphology in real time at a "quasi-histopathological" resolution, viewing micro-anatomical structures and individual cells. Numerous morphological confocal features of melanocytic skin tumors have been described, and histopathological correlates of confocal structures have been previously elucidated. Recently, several studies have evaluated the diagnostic accuracy of in vivo confocal microscopy for melanocytic skin tumors, investigating approximately 50,000 tumor images. Remarkably, this imaging modality achieved sensitivity superior to the diagnostic accuracy obtained with dermoscopy. These studies represent a significant contribution to the body of research necessary for the evaluation and implementation of in vivo confocal microscopy in clinical practice, potentially avoiding many currently unnecessary biopsies. In vivo confocal microscopy may herald a significant change in the evaluation of melanocytic skin tumors in the future and will ultimately bring the art of histological diagnosis closer to the bedside.
Psaty and Halpern (2009) noted that diagnostic aids such as TBP and dermoscopy improve clinicians' ability to diagnose melanoma beyond unaided visual inspection and are considered mainstream methods for early detection. Emerging technologies such as in vivo reflectance confocal microscopy are currently being investigated to determine their utility for the non-invasive diagnosis of melanoma.
Longo et al. (2013) stated that reflectance confocal microscopy (RCM) is a novel technique that allows visualization of the skin at nearly histological resolution, although limited laser depth penetration hampers visualization of the deep dermis. These researchers examined if the diagnostic accuracy of RCM was comparable to histopathology for the diagnosis of nodular lesions and identified possible limitations of this technique. They retrospectively evaluated 140 nodules by means of RCM while blinded to the histopathological diagnosis. At the end of the study, the patient codes were broken, and the evaluations were matched with histopathological diagnosis before performing statistical analysis. The study consisted of 140 nodular lesions (23 "pure" nodular melanomas, 9 melanoma metastases, 28 basal cell carcinomas (BCCs), 6 invasive squamous cell carcinomas (SCCs), 32 naevi, 14 seborrheic keratoses, 17 dermatofibromas, 5 vascular lesions, and 6 other lesions). Reflectance confocal microscopy correctly diagnosed 121 of 140 lesions (86.4%); 8 of 140 (5.7%) lesions revealed discordance between histopathology and confocal microscopy. Eight of the 140 (5.7%) cases were not evaluable by means of RCM due to the presence of ulceration or hyperkeratosis, and 3 cases showed a non-specific pattern. Interestingly, confocal microscopy reached a 96.5% sensitivity and 94.1% specificity (area under curve 0.970) (95% CI: 0.924 to 1.015) (p < 0.001) for the diagnosis of melanoma. The authors concluded that this study was retrospective and that lesions were not included on the basis of their diagnostic difficulty. They noted that despite the limited laser depth penetration of RCM, this imaging tool represents an effective instrument in diagnosing nodular lesions; however, for fully ulcerated lesions or when marked hyperkeratosis is present, biopsy should always be performed. They stated that prospective studies on difficult-to-diagnose nodules should be performed to further analyze the pros and cons of RCM in skin cancer diagnosis.
In a Cochrane review, Dinnes and colleagues (2018b) determined the diagnostic accuracy of RCM for the detection of cutaneous invasive melanoma and atypical intra-epidermal melanocytic variants in adults with any lesion suspicious for melanoma and lesions that are difficult to diagnose, and compared its accuracy with that of dermoscopy. These researchers undertook a comprehensive search of the following databases from inception up to August 2016: Cochrane Central Register of Controlled Trials; Medline; Embase; and seven other databases. They studied reference lists and published systematic review articles. Studies of any design that evaluated RCM alone, or RCM in comparison to dermoscopy, in adults with lesions suspicious for melanoma or atypical intra-epidermal melanocytic variants, compared with a reference standard of either histological confirmation or clinical follow-up, were selected for analysis. Two review authors independently extracted all data using a standardized data extraction and quality assessment form (based on QUADAS-2). They contacted authors of included studies where information related to the target condition or diagnostic threshold was missing. They estimated summary sensitivities and specificities per algorithm and threshold using the bi-variate hierarchical model. To compare RCM with dermoscopy, these investigators grouped studies by population (defined by the difficulty of lesion diagnosis) and combined data using hierarchical summary receiver operating characteristic (SROC) methods. Analysis of studies allowing direct comparison between tests was undertaken. To facilitate interpretation of results, the authors computed values of specificity at the point on the SROC curve with 90% sensitivity, as this value lies within the estimates for the majority of analyses. They examined the impact of using a purposely developed RCM algorithm and in-person test interpretation. The search identified 18 publications reporting on 19 study cohorts with 2,838 lesions (including 658 with melanoma), which provided 67 datasets for RCM and 7 for dermoscopy. Studies were generally at high or unclear risk of bias across almost all domains and of high or unclear concern regarding the applicability of the evidence. Selective participant recruitment, lack of blinding of the reference test to the RCM result, and differential verification were particularly problematic. Studies may not be representative of populations eligible for RCM, and test interpretation was often undertaken remotely from the patient and blinded to clinical information. Meta-analysis found RCM to be more accurate than dermoscopy in studies of participants with any lesion suspicious for melanoma and in participants with lesions that were more difficult to diagnose (equivocal lesion populations). Assuming a fixed sensitivity of 90% for both tests, specificities were 82% for RCM and 42% for dermoscopy for any lesion suspicious for melanoma (9 RCM datasets; 1,452 lesions and 370 melanomas). For a hypothetical population of 1,000 lesions at the median observed melanoma prevalence of 30%, this equated to a reduction in unnecessary excisions with RCM of 280 compared to dermoscopy, with 30 melanomas missed by both tests. For studies in equivocal lesions, specificities of 86% would be observed for RCM and 49% for dermoscopy (7 RCM datasets; 1,177 lesions and 180 melanomas). At the median observed melanoma prevalence of 20%, this reduced unnecessary excisions by 296 with RCM compared with dermoscopy, with 20 melanomas missed by both tests. Across all populations, algorithms, and thresholds assessed, the sensitivity and specificity of the Pellacani RCM score at a threshold of 3 or greater were estimated at 92% (95% CI: 87 to 95) for RCM and 72% (95% CI: 62 to 81) for dermoscopy. The authors concluded that RCM may have a potential role in clinical practice, particularly for the assessment of lesions that are difficult to diagnose using visual inspection and dermoscopy alone, where the evidence suggested that RCM may be both more sensitive and specific in comparison to dermoscopy. Moreover, these researchers stated that given the paucity of data to allow comparison with dermoscopy, the results presented require further confirmation in prospective studies comparing RCM with dermoscopy in a real-world setting in a representative population.
In a Cochrane review, Dinnes and colleagues (2018c) determined the diagnostic accuracy of RCM for the detection of BCC, cSCC, or any skin cancer in adults with any suspicious lesion and lesions that are difficult to diagnose (equivocal); and compared its accuracy with that of usual practice (visual inspection or dermoscopy, or both). These researchers 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. They studied reference lists and published systematic review articles. 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, were selected for analysis. Two review authors independently extracted data using a standardized data extraction and quality assessment form (based on QUADAS-2). These investigators contacted authors of included studies where information related to the target condition or diagnostic threshold was missing. They estimated summary sensitivities and specificities using the bi-variate hierarchical model. For computation of likely numbers of true-positive, false-positive, false-negative, and true-negative findings in the "Summary of findings" tables, they applied summary sensitivity and specificity estimates to lower quartile, median, and upper quartiles of the prevalence observed in the study groups. They also examined the impact of observer experience. The review included 10 studies reporting on 11 study cohorts. All 11 cohorts reported data for the detection of BCC, including 2,037 lesions (464 with BCC); and 4 cohorts reported data for the detection of cSCC, including 834 lesions (71 with cSCC). Only 1 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 the 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 was unclear whether studies were representative of populations eligible for testing with RCM, and test interpretation was often undertaken using images, remotely from the participant, and the interpreter was 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%; 3 studies) compared to studies that included any suspicious lesion (sensitivity 76%, 95% CI: 45% to 92%; specificity 95%, 95% CI: 66% to 99%; 4 studies), although CIs 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 1,000 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 1,000 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 the paucity of data. The authors concluded that 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. These investigators stated that the potential for, and consequences of, misclassification of other skin cancers such as melanoma as BCCs requires further research; and more importantly, data are lacking that compare RCM to standard clinical practice (with or without dermoscopy).
Guo et al. (2018) stated that seborrheic keratosis (SK) is one of the most common skin tumors seen by dermatologists. It should be differentiated from many diseases, especially skin tumors. Reflectance confocal microscopy (RCM) has been used for the evaluation of SK. There are a few studies that describe the RCM of SK. The aim of the study was to find the challenges of diagnosing SK with RCM. A total of 390 patients with a clinically suspicious diagnosis of SK were enrolled in this study, and lesions from each patient were imaged with RCM; 37 of these patients had a biopsy performed in order to obtain a histological diagnosis. These investigators retrospectively analyzed the outcomes of RCM diagnosis and histological diagnosis, and then identified the RCM characteristics of biopsy-proven lesions. According to RCM images, 258 of 390 (66.2%) patients were diagnosed with SK, while 97 of 390 (24.9%) patients could not be diagnosed by the dermatologist according to RCM. Of all 37 biopsied lesions, 23 were SK, 6 were actinic keratosis (AK), 2 were basal cell carcinoma (BCC), and 2 were squamous cell carcinoma (SCC). The authors concluded that it was a challenge to diagnose SK with RCM; this may be due to the variable clinical and RCM appearances of SK and the limited depth of RCM.
Pezzini et al. (2018) noted that SKs with atypical dermoscopy presentations are increasingly reported. These lesions do not exhibit the typical dermoscopy features of SK and sometimes mimic melanoma, thereby complicating the differential diagnosis. RCM is a non-invasive tool that allows for in-vivo imaging of the skin. In a retrospective study, these researchers examined the agreement between RCM classification and histological diagnoses, as well as the reliability of well-known RCM criteria for SK in the identification of SK with atypical dermoscopy presentations. They analyzed RCM excised lesions presenting in dermoscopy with a score of 1 or higher on the revisited 7-point checklist. The study population consisted of cases showing no melanocytic RCM findings. Lesions were examined for distinct non-melanocytic RCM features, blinded to histopathology diagnoses. Histopathology matching was then performed before statistical analysis. The study consisted of 117 cases, classified at RCM as SK (71 cases), dermatofibroma (18 cases), BCC (13 cases), SCC (2 cases), and "non-specific" (13 cases). Overall, the K strength of agreement at histopathology matching proved to be 0.76. Of the 71 cases classified at RCM as SK, agreement was achieved in 97%. The authors concluded that RCM classification exhibited a high agreement with histopathological diagnoses for SK with atypical dermoscopy presentations. RCM features for the selected lesions were similar to those observed in typical SK. These investigators stated that these findings suggested that RCM is an optimal non-invasive examination for the early differential diagnosis of SK with atypical dermoscopy presentations; thus, RCM may be able to assist in differential diagnosis and avoid unnecessary excisions.
The authors stated that the key drawback of this trial was the sample size. Only lesions with atypical dermoscopy presentations and RCM imaging, excised and sent for histopathological analysis, were selected and included. In addition, as RCM was installed as a non-invasive analysis tool at the authors’ center, many SKs with atypical dermoscopy presentations were assessed with RCM only and were not always sent for histopathological analysis.
Navarrete-Dechent et al. (2019) noted that there is a lack of uniformity in RCM terminology for non-melanocytic lesions (NMLs). In a systematic review, these investigators examined published RCM terms for NMLs and identified likely synonymous terms. They carried out a systematic review of original research studies published up to August 19, 2017, adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Two investigators gathered all published RCM terms used to describe BCC, SCC, and SK/solar lentigo/lichen planus-like keratosis (SK/SL/LPLK). Synonymous terms were grouped based on similarity in definition and histopathologic correlates. The inclusion criteria were met by 31 studies. The average frequency of use per term was 1.6 (range of 1 to 8). By grouping synonymous terms, the number of terms could be reduced from 58 to 18 for BCC, from 58 to 36 for SCC, from 23 to 12 for SK/SL/LPLK, and from 139 to 66 terms (52.5% reduction) in total. The frequency of term usage stratified by anatomic layer (supra-basal epidermis versus epidermal basal layer, dermo-epidermal junction, and superficial dermis) was 27 (25.7%) versus 78 (74.2%) for BCC; 60 (64.5%) versus 33 (34.5%) for SCC; and 15 (45.4%) versus 18 (54.5%) for SK/SL/LPLK, respectively. The authors concluded that the systematic review of published RCM terms provided the basis for future NML terminology consensus.
Hanlon et al. (2019) stated that SK has a number of varying clinical and histopathologic features and can be challenging to diagnose with RCM. Although streaming of epidermal keratinocytes has been a recognized feature of BCCs, it is important to keep in mind that this process can be seen in several other lesions, including seborrheic keratoses.
The American Academy of Dermatology (AAD)’s guideline on "Care for the management of primary cutaneous melanoma" (Swetter et al., 2019) lists RCM as one of the "emerging" diagnostic technologies. The guideline states that "Currently, there are limited data to support the use of in vivo imaging technologies for intraoperative surgical margin assessment of melanoma in situ (MIS), lentigo maligna (LM) type. Some preliminary data suggest that in vivo RCM can be helpful in identifying the tumor’s peripheral margin and therefore guide surgical removal, and this approach remains an active area of investigation."
Moscarella et al. (2021) noted that SKs are exceedingly common in the elderly and usually are easy to diagnose and do not require treatment. However, given their great variety of clinical presentations, they may give rise to false-positive cases, meaning that they may at times mimic melanoma, SCC, and BCC. On the other hand, melanoma may mimic SK, leading to incorrect patient management. With this review, these investigators summarized the current knowledge regarding the epidemiology, clinical, dermoscopic, as well as RCM imaging of this common entity, and the authors also summarized the currently available therapeutic options. These researchers stated that the limits of RCM diagnosis of SKs have been highlighted in a study on 390 cases. In this study (Guo et al., 2018), over 390 patients were included with a clinical diagnosis of SK; of these, 258 (66.2%) patients were diagnosed with SK, while 97 of 390 (24.9%) patients could not be diagnosed by the dermatologist according to RCM. Of all 37 biopsied lesions, 23 were SK, 6 were AK, 2 were BCC, and 2 were SCC. The authors concluded that this could be due to the limit in depth penetration of RCM.
Spyridonos et al. (2021) stated that non-invasive optical methods, such as RCM and OCT, can be used to improve accuracy in melanoma diagnosis; however, in SK-like MMs, the use of RCM has been limited due to frequent clinical and dermoscopic misdiagnosis.
Sequencing Monitoring with Digital Dermoscopy and Total Body Photography for the Detection of Amelanotic/Hypomelanotic Melanoma
Borroni et al. (2023) stated that sequential digital dermoscopy (SDD) enables the diagnosis of a subgroup of slow-growing melanomas that lack suspicious features at baseline examination but exhibit detectable change on follow-up. The combined use of total body photography (TBP) and SDD is recommended in high-risk subjects by current guidelines. To establish the usefulness of SDD for low-risk individuals, these investigators conducted a retrospective study using electronic medical records of low-risk patients with a histopathological diagnosis of cutaneous melanoma between January 1, 2016, and December 31, 2019, who had been referred and monitored for long-term follow-up of clinically suspicious melanocytic nevi. They compared the distribution of "early" cutaneous melanoma, defined as melanoma in situ and pT1a melanoma, between SDD and periodic hand-held dermoscopy in low-risk patients. A total of 621 melanomas were diagnosed over a 4-year period; 471 melanomas were diagnosed by hand-held dermoscopy, and 150 by SDD. Breslow tumor thickness was significantly higher for melanomas diagnosed by hand-held dermoscopy compared to SDD (0.56 ± 1.53 versus 0.26 ± 0.84, p = 0.030), with a significantly different distribution of pT stages between the two dermoscopic techniques. However, no significant difference was found regarding the distribution of pT stages, mean Breslow tumor thickness, ulceration, and prevalence of associated melanocytic nevus in tumors diagnosed on periodic hand-held dermoscopy compared to SDD. The authors concluded that these findings confirmed that periodic dermoscopic examination enabled the diagnosis of cutaneous melanoma at an earlier stage compared to first-time examination, as this was associated with better prognostic features. However, in the long-term monitoring of low-risk subjects, Breslow tumor thickness and pT stage distribution did not differ between hand-held periodic dermoscopy and SDD. Moreover, these researchers stated that additional studies with larger cohorts of patients and possibly with a prospective design are needed to further validate the usefulness of long-term SDD in the general population.
Toncic et al. (2024) noted that the prognosis, outcome, and overall survival (OS) of melanoma patients improve with early diagnosis, which has been facilitated in the past few decades with the introduction of dermoscopy. Further advancements in dermoscopic research, coupled with skilled, educated dermatologists in dermoscopy, have contributed to timely diagnoses. However, detecting amelanotic/hypomelanotic melanoma (AHM) remains a challenge even for the most skilled experts because these melanomas can mimic inflammatory diseases, numerous benign lesions, and non-melanoma skin cancers. The list of possible differential diagnoses can be extensive. Melanoma prediction without pigment relies solely on vascular criteria, and all classic dermoscopic algorithms have failed to meet expectations. In fact, the diagnosis of AHM is very challenging, which is why every tool in detecting these lesions is significant. These researchers examined the available evidence on the possibility of detecting AHM using sequential monitoring with digital dermoscopy (DD) and skin TBP. They noted that with more additional information and more images of these lesions for datasets, deep learning (DL) systems may become better at detecting AHM. The data so far showed that DL systems are not refined enough to make highly reliable diagnoses of melanoma, especially of any melanoma subtypes, including AHM, without a dermatologist’s input. However, surveillance of high-risk patients with DD/skin TBP and DL systems would aid in diagnosing melanomas at an early stage, which improves prognosis and survival rates, enhances overall quality of life (QOL), and reduces long-term healthcare costs associated with advanced disease management. Nevertheless, in the detection of AHM, future studies and meta-analyses are needed to determine the potential and effectiveness of sequential monitoring with DD and skin TBP to justify the cost-effectiveness of this method.
Teledermatology / Teledermoscopy
In a Cochrane review, Chuchu and colleagues (2018) determined the diagnostic accuracy of teledermatology for the detection of any skin cancer (melanoma, BCC, or cSCC) in adults and compared its accuracy with that of in-person diagnosis. These researchers 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. They studied reference lists and published systematic review articles. 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, clinical follow-up, and expert opinion were selected for analysis. They also included studies evaluating the referral accuracy of teledermatology compared with a reference standard of face-to-face diagnosis by a specialist clinician. Two review authors independently extracted all data using a standardized data extraction and quality assessment form (based on QUADAS-2). They contacted authors of included studies where information related to the target condition of any skin cancer was missing. Data permitting, these investigators estimated summary sensitivities and specificities using the bi-variate hierarchical model. Due to the scarcity of data, these researchers undertook no co-variate investigations for this review. For illustrative purposes, they plotted estimates of sensitivity and specificity on coupled forest plots for the diagnostic threshold and target condition under consideration. The review included 22 studies reporting diagnostic accuracy data for 4,057 lesions and 879 malignant cases (16 studies) and referral accuracy data for 1,449 lesions and 270 "positive" cases as determined by the reference standard face-to-face decision (6 studies). Methodological quality was variable, with poor reporting hindering assessment. The overall risk of bias was high or unclear for participant selection, reference standard, and participant flow and timing in at least 50% of all studies; the majority were at low risk of bias for the index test. The applicability of study findings was of high or unclear concern for most studies in all domains assessed due to the recruitment of participants from secondary care settings or specialist clinics rather than from primary or community-based settings in which teledermatology was 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 (1,588 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 was 84.3% (95% CI: 48.5% to 96.8%) (from 4 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 intra-epidermal melanocytic variants, both sensitivities and specificities were more variable. Sensitivities ranged from 59% (95% CI: 42% to 74%) to 100% (95% CI: 48% 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," and 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 lesions 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 to recommend excision, referral, or follow-up compared to in-person decisions. The authors concluded that 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, these findings suggested that teledermatology could 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. These investigators stated that 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.
Bruce and associates (2018) noted that the use of teledermoscopy in the diagnostic management of pre-cancerous and cancerous skin lesions involves digital dermoscopic images transmitted over telecommunication networks via email or web applications. Teledermoscopy may improve the accuracy of clinical diagnoses of melanoma skin cancer if integrated into electronic medical records and made available to rural communities, potentially leading to decreased morbidity and mortality. These investigators presented a systematic review of evidence on the use of teledermoscopy to improve the accuracy of skin lesion identification in adult populations. The PRISMA method guided the development of this systematic review. A total of seven databases were searched for articles published between the years of 2000 and 2015. All studies were critically appraised using the Rosswurm and Larrabee critique worksheet, placed in a matrix for comparison evaluating internal and external validity, and inspected for homogeneity of findings. A total of 16 articles met inclusion criteria for this review. A majority of the studies were cross-sectional and non-experimental; 10 of the 16 focused on inter-observer concordance and diagnostic agreement between teledermoscopy and another comparator. Instrumentation in conducting the studies showed inconsistency with reported results. The authors concluded that higher-level evidence is needed to support the clinical application of teledermoscopy for the accuracy of diagnostic measurement in the treatment of pre-cancerous and cancerous skin lesions in adults. They stated that future research is needed to develop a standardized, reliable, and valid measurement tool for implementation in clinical practice.
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