The use of reflectance confocal microscopy (RCM) and other noninvasive imaging devices can potentially streamline clinical care, leading to more precise and efficient management of skin cancer. This article explores the potential role of RCM in cutaneous oncology, as an adjunct to more established techniques of detecting and monitoring for skin cancer, such as dermoscopy and total body photography. Discussed are current barriers to the adoption of RCM, diagnostic workflows and standards of care in the United States and Europe, and medicolegal issues. The potential role of RCM and other similar technological innovations in the enhancement of dermatologic care is evaluated.
Key points
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A review of the literature shows that the overall sensitivity of RCM for melanoma detection is 91% to 100%, with a specificity ranging from 68% to 98%. The overall RCM sensitivity for BCC is 85% to 97%, with a specificity ranging from 89% to 99%.
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A cost-benefit analysis performed in Europe showed that RCM reduced the number of unnecessary biopsies and led to an overall cost savings in the management of melanoma and nonmelanoma skin cancer.
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Barriers to the adoption of RCM include the image processing time, limited depth of imaging, need for extensive training to master image interpretation, and potential medicolegal risks.
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Proposed methods for overcoming barriers include the continued development of RCM devices to improve speed, diagnostic accuracy, and ease of use; incorporation of RCM training into dermatology residencies and dermatopathology fellowships; and further research studies to justify the use of RCM in dermatology.
Introduction
The incidence rate of melanoma and nonmelanoma skin cancer is increasing in the United States and in most parts of Europe. With this increased burden on the health care system, strides have been made to reduce costs while maintaining a high quality of care. This article examines the complexity of diagnosing skin cancers, discusses the diagnostic workflows and current standards of care in the United States and Europe, and assesses the role of reflectance confocal microscopy (RCM) and other similar technological innovations in the enhancement of dermatologic care.
Introduction
The incidence rate of melanoma and nonmelanoma skin cancer is increasing in the United States and in most parts of Europe. With this increased burden on the health care system, strides have been made to reduce costs while maintaining a high quality of care. This article examines the complexity of diagnosing skin cancers, discusses the diagnostic workflows and current standards of care in the United States and Europe, and assesses the role of reflectance confocal microscopy (RCM) and other similar technological innovations in the enhancement of dermatologic care.
Complexity of diagnosing skin tumors
Skin cancers can sometimes be difficult, even for experienced dermatologists, to recognize and diagnose. Basal cell carcinomas (BCCs) often resemble scars, intradermal nevi, benign lichenoid keratoses, and benign adnexal neoplasms. Squamous cell carcinomas (SCCs) may be difficult to differentiate from hyperplastic actinic keratoses or irritated seborrheic keratoses.
Although some melanomas are diagnosed by gestalt, the diagnosis of many melanocytic lesions is indeterminate without a multidimensional analytical approach that entails assessment of patient history, pattern analysis, comparison with neighboring lesions on the patient, and evaluation of subtle changes over time. Diagnostic algorithms and technological innovations can aid the clinician in developing a clinical impression.
The clinician’s ultimate goal is to diagnose skin cancers at an early stage while maintaining a high enough specificity to differentiate between malignant and benign lesions. The number needed to excise (NNE), also known as the number needed to treat (NNT), is a useful measure of diagnostic accuracy. The NNE expresses the ratio between the number of benign lesions biopsied to rule out skin cancer and the number of actual skin cancers biopsied during the same timeframe. Technological innovations, such as RCM, have made it possible to increase diagnostic accuracy and reduce the NNE, thereby decreasing the number of unnecessary procedures.
United States standard approach to skin cancer
Skin Cancer Screening
Several studies have shown that physician detection of melanoma is associated with thinner tumors at the time of diagnosis. Nevertheless, there is no consensus in the United States about who should be screened or the frequency with which these patients should be screened. In 2009, the US Preventive Services Task Force concluded there is not enough evidence to recommend for or against routine skin cancer screening in the adult general population. Patient populations that should regularly be screened for skin cancer have the following risk factors: fairer skin types, older age, the presence of atypical moles or more than 50 moles, family history of melanoma, personal history, and sunburns. A sentinel study performed in Germany, however, demonstrated that in general skin cancer screening decreased melanoma mortality by 47% to 49% compared with adjacent communities not undergoing screenings.
Dermoscopy and total body photography (TBP) allow the clinician to diagnose skin cancers more effectively than unaided visual inspection, making them relatively mainstream methods for skin cancer screening. One meta-analysis established that dermoscopy could raise the sensitivity of melanoma diagnosis from 74% to 90%, while maintaining the specificity associated with unaided visual inspection. Dermoscopy can also decrease the number of benign lesions biopsied by dermatologists. The use of dermoscopy in the United States is increasing, with a recent survey in 2014 showing that 80.7% of surveyed US dermatologists used dermoscopy, a rate higher than previously reported.
TBP is also used by 67% of US dermatologists, especially in patients with several risk factors for melanoma. TBP involves taking a series of photographs covering the full body surface area and monitoring for the development of new melanocytic nevi or any change in existing nevi. When used as an adjunct to dermoscopy in high-risk patients, TBP can help detect de novo melanomas and leads to the diagnosis of thinner melanomas.
Melanoma
The American Academy of Dermatology has published a set of guidelines for the management of primary cutaneous melanoma. For a lesion clinically suspicious for melanoma, the ideal biopsy is a narrow excisional biopsy with 1- to 3-mm margins. For very large lesions and for lesions on the face or acral sites, an incisional biopsy of the most atypical portion is acceptable. If this initial biopsy is inadequate to make a diagnosis or to stage the lesion, a repeat biopsy is indicated.
Surgical excision is the standard of care for the treatment of melanoma, with recommended margins based on prospective randomized controlled trials or consensus opinion ; follow-up and diagnosis of eventual regional or distant metastases are outlined by the National Comprehensive Cancer Network.
Nonmelanoma Skin Cancer
In 2015, the American Society for Dermatologic Surgery published its consensus statement on the treatment of BCC and SCC. Although the American Society for Dermatologic Surgery guidelines do not specify the follow-up interval for BCCs, patients with a history of BCC are typically followed every 6 months for the first few years, with the interval extended to 9 to 12 months, and then yearly.
European approach to skin cancer and guidelines
Guidelines for the management of melanoma in Europe have been set forth by the European Association of Dermato-Oncology. Briefly, the European Association of Dermato-Oncology recommends the excision of cutaneous melanoma with 1- to 2-cm margins and advocates for sentinel lymph node dissection for patients with tumors more than 1 mm in thickness.
There have been numerous skin cancer prevention campaigns and screenings organized throughout Europe, such as the Euromelanoma initiative, all with the intent of promoting primary and secondary skin cancer screening. European dermatologists are more likely to report the use of dermoscopy than US dermatologists and were pioneers in the adoption and implementation of dermoscopy as a diagnostic tool.
Why reflectance confocal microscopy represents an innovation and how it can change the standards
Recently there has been a surge of RCM research in the dermatologic literature. Researchers have investigated the application of RCM in dermato-oncology for the following purposes: improving diagnosis of skin tumors, monitoring of melanocytic nevi over time, monitoring after treatment with nonsurgical approaches, selection of biopsy sites, and surgical margin delineation.
RCM can be used as an adjunct to dermoscopy to determine whether a biopsy is indicated. It can potentially reduce the number of unnecessary biopsies. A study by Alarcon and colleagues showed that use of RCM could lower the hypothetical NNT. The authors included a set of lesions showing dermoscopic patterns suggestive of melanoma. Analysis of lesions with dermoscopy alone resulted in an NNT of 3.73, the combination of dermoscopy and RCM resulted in a lower NNT of 2.87, and RCM alone reduced NNT even more to 1.12. There was no significant difference between the specificities of dermoscopy and RCM versus RCM alone.
However, a prospective interventional study on a cohort of approximately 1000 patients referred to a skin cancer unit showed that the number of unnecessary excisions of benign nevi could be reduced by more than 50% using RCM. This reduces the NNE from a potential 14.6 without RCM to an actual NNE of 6.8 with the systematic use of RCM on equivocal lesions.
In cases where an incisional or partial biopsy of a large melanoma is warranted, RCM can help to indicate which site is best to biopsy to establish the diagnosis. In the setting of dermatologic surgery, RCM can potentially be used to indicate surgical margins before Mohs micrographic surgery. For lesions that are treated with nonsurgical approaches, RCM can be used to monitor the clearance of tumor with topical chemotherapy agents.
How the confocal microscope works
The confocal microscope uses near-infrared light at 830 nm and focuses the light through a gating pinhole before it enters the detector. The gating pinhole effectively filters out the extraneous light, thus improving the resolution. Images obtained are horizontal and parallel to the surface of the skin. Images can be viewed in stack mode, which enables the viewing of each consecutive level from the epidermis to the dermoepidermal junction down to the papillary dermis (up to a depth of 200 μm). They can also be viewed in mosaic mode, where optical sections are stitched together into a larger image.
Several confocal microscopy models are currently in use. The wide-probe RCM (VivaScope 1500; CaliberID, Rochester, NY) can piece together optical sections into an 8 × 8 mm mosaic image. The handheld RCM (VivaScope 3000; Caliber ID), a newer device, is more ideal for imaging lesions on concave surfaces but has a limited field of view of 1 × 1 mm. Other confocal microscopes use fluorescence, which has been especially useful in ex vivo examination of specimens during Mohs micrographic surgery.
Short literature overview and the accuracy of reflectance confocal microscopy
A review of the literature reveals high sensitivity and specificity for the diagnosis of melanoma and BCC using RCM ( Table 1 ). The overall sensitivity of RCM for melanoma detection is 87% to 100%, with a specificity ranging from 68% to 98%. The overall RCM sensitivity for BCC is 85% to 97%, with a specificity ranging from 89% to 99%.
| First Author, Year | Country of Study | Study Type | Number of Lesions | Number of Tumors (MM-NMSC) | Accuracy | Tumor Type |
|---|---|---|---|---|---|---|
| Witkowski et al, 2016 | Italy | Retrospective | 260 | 114 BCC; 12 MM; 13 SCC; 1 other | Sn: 85.1% Sp: 93.8% | BCC |
| Kadouch et al, 2015 | Netherlands | Meta-analysis of 6 studies | 6 studies | — | Sn: 97% Sp: 93% | BCC |
| Farnetani et al, 2015 | Italy, United States, Australia, Spain, Switzerland | Retrospective World Wide Web–based study | 100 | 55 melanocytic nevi; 20 MM; 15 BCC; 7 solar lentigines or SK; 3 AK | Sn: 88.9% Sp: 79.3% | Melanoma, BCC |
| Lovatto et al, 2015 | Spain | Retrospective | 64 | 8 MM; 5 invasive MM; 51 melanocytic nevi | Sn: 100% Sp: 69% | Melanoma |
| Cinotti et al, 2014 | France | Prospective, noninterventional | 47 | 5 MM; 9 melanocytic nevi; 14 BCC; 3 SCC | Sn: 100% Sp: 69.20% | Melanoma, SCC, BCC (eyelid margin tumors) |
| Bennassar et al, 2014 | Spain | Prospective, noninterventional, detection of residual tumor in Mohs sections | 80 | 80 BCC | Sn: 88% Sp: 99% | BCC |
| Larson et al, 2013 | United States | Retrospective | 17 | 17 BCC | Sn: 94% Sp: 94% | BCC |
| Longo et al, 2013 | Italy | Retrospective | 140 | 23 nodular MM; 9 MM mets; 28 BCC; 6 SCC; 32 nevi; 14 SK; 17 dermatofibromas; 5 vascular lesions; 6 other |
| Melanoma data (overall study about nodular lesions) |
| Gareau et al, 2009 | United States | Retrospective, Mohs excisions | 45 confocal mosaics | BCC | Sn: 96.6% Sp: 89.2% | BCC |
| Guitera et al, 2009 | Australia | Prospective, noninterventional | 326 | 203 melanocytic nevi; 123 MM | Sn: 91% Sp: 68% | Melanoma, nevi |
| Horn et al, 2007 | Austria | Retrospective | 120 | — | Sn: 95% Sp: 96.25% | SCC |
| Langley et al, 2007 | Canada | Prospective, noninterventional | 125 | 88 melanocytic nevi; 37 MM | Sn: 97.3% Sp: 83% | Melanoma, nevi |
| Gerger et al, 2005 | Austria | Retrospective | 117 | 90 melanocytic nevi; 27 MM | Sn: 98.15% Sp: 98.89% | Melanoma, nevi |
| Guitera et al, 2010 | Australia | Retrospective | 284 | 81 MM; 203 benign macules | Sn: 93% Sp: 82% | Lentigo maligna |
| Witkowski et al, 2016 | Italy, United States, Poland | Retrospective, combined dermoscopy-RCM evaluation | 260 | 144 BCC; 12 MM; 13 SCC; 1 other | Sn: 77.2% Sp: 96.6% | Pink cutaneous lesions, melanoma, SCC, BCC |
| Guitera et al, 2012 | Australia | Prospective noninterventional | 710 | 216 MM; 266 melanocytic nevi; 119 BCC; 67 pigmented facial macules; 42 other |
| Melanoma/BCC |
| Pellacani et al, 2005 | Italy | Retrospective | 102 | 37 MM; 49 acquired nevi; 16 Spitz/Reed nevi | Sn: 97% Sp: 72% | Melanoma/nevi |
| Pellacani et al, 2007 | Italy | Retrospective | 351 | 136 MM; 215 melanocytic nevi | Sn: 92% Sp: 69% | Melanoma/nevi |
| Segura et al, 2009 | Spain | Retrospective | 154 | 36 MM; 64 melanocytic nevi; 27 BCC; 8 SK; 5 solar lentigines; 4 BLK; 4 vascular lesions; 3 AKs; 2 dermatofibromas; 1 sebaceous hyperplasia |
| Melanocytic and BCC |
| Ferrari et al, 2015 | Italy | Retrospective | 322 | 70 MM; 252 melanocytic nevi | Sn: 96% Sp: 70% | Melanoma/nevi |
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