Abstract
Background:
There is lack of uniformity in reflectance confocal microscopy (RCM) terminology for non-melanocytic lesions (NMLs).
Objective:
To review published RCM terms for NMLs and identify likely-synonymous terms.
Methods:
Systematic review of original research articles adhering to PRISMA guidelines was conducted until August 19, 2017. Two investigators gathered all published RCM terms used to describe basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and seborrheic keratosis/solar lentigo/lichen planus-like keratosis (SK/SL/LPLK). Synonymous terms were grouped based on similarity in definition and histopathological correlates.
Results:
Thirty-one studies met inclusion criteria. Average frequency of use per term was 1.6 (range 1–8). By grouping synonymous terms, the number of terms could be reduced from 139 to 66 terms (52.5%) in total, from 66 to 18 for BCC, 58 to 36 for SCC, and 23 to 12 for SK/SL/LPLK. The frequency of terms usage stratified by anatomic layer (suprabasal epidermis vs. basal layer/DEJ/Superficial dermis) was 27 (25.7%) vs. 78 (74.2%) for BCC; 60 (64.5%) vs. 33 (34.5%) for SCC, and 15 (45.4%) vs. 18 (54.5%) for SK/SL/LPLK, respectively.
Limitations:
Non-peer reviewed articles were excluded.
Conclusions:
Systematic review of published RCM terms provides the basis for future NMLs terminology consensus.
Keywords: reflectance confocal microscopy, melanoma, non-melanoma skin cancer, basal cell carcinoma, squamous cell carcinoma, seborrheic keratosis, actinic keratosis, lichen planus-like keratosis, diagnosis
Capsule summary:
• Use of reflectance confocal microscopy terminology is inconsistent.
• We built a glossary of reflectance confocal microscopy terms for diagnosis non-melanocytic lesions. We identified terms with similar definition and histopathological correlates and reduced the total number of terms by 52.5%. This systematic review may form the basis for attaining terminology consensus.
INTRODUCTION
Reflectance confocal microscopy (RCM) allows for non-invasive in vivo visualization of the skin at a “quasi-histological” resolution.1 In the 1990s, the histological correlates of RCM attributes of skin were first described.2, 3 Since then, more than two hundred articles have been published showing the added value of RCM in the diagnosis of melanoma4–6 and non-melanoma skin cancer, including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC).7–9 Also, RCM has been used for the diagnosis of nevi and benign non-melanocytic skin lesions (NMLs).10, 11 While the increase in the number of RCM publications suggests a gradual wider adaptation of this technique, there appears to be an inconsistent usage of RCM terminology in the literature. Furthermore, descriptive terms used for diagnosing a particular neoplasm, such as “polarization of nuclei” and “epidermal shadow” for BCC have shown to be associated with low inter-observer agreement.12
The first expert consensus on RCM terminology, published in 2007 by Scope et al. focused solely on melanocytic neoplasms.13 To the best of our knowledge, consensus on terminology related to the diagnosis of malignant and benign NMLs is lacking. Recently, category I Current Procedural Terminology (CPT) reimbursement codes by the Centers for Medicare and Medicaid Services in the United States were allotted to RCM imaging.1, 14 As a result, there is anticipation for increasing assimilation of RCM into routine clinical work-flow and into the dermatology residency curriculum.15 This forthcoming clinical integration necessitates standardization of RCM terminology, so that the terms are clearly defined and reproducible, enable structured reporting of RCM-based diagnosis, and facilitate RCM teaching to novices. Herein, we performed a systematic review of terms used in original papers, from 1995 to 2017, to describe RCM features of common NMLs.
METHODS
The results of this systematic review were obtained according to the guidelines for reporting systematic reviews as published in the PRISMA Statement (available in www.prismastatement.org). All images used for illustrating the terms were acquired at the Dermatology Service of Memorial Sloan Kettering Cancer Center, NY, and Dermatology Associates, Plantation, FL, using commercial RCM systems (Vivascope 1500 or Vivascope 3000, Caliber ID, Rochester, MN) and collected under an approved IRB retrospective protocol (#17–083). The basic principles of RCM image acquisition have been previously described.1
Eligibility criteria
We included all peer-reviewed original articles published to date that contained the diagnosis of common benign and malignant NMLs, including BCC, SCC, actinic keratosis (AK), seborrheic keratosis (SK), solar lentigo (SL), and lichen-planus like keratosis (LPLK). We excluded NMLs that, in our experience, are relatively infrequently subjected to RCM imaging in current practice, such as poroma, clear cell acanthoma, dermatofibroma, atypical fibroxanthoma, and Merkel cell carcinoma, among others. We also excluded articles describing RCM features of NMLs at special anatomic sites, such as genitalia, nails and eyelids.
We excluded literature reviews, single case-reports, conference abstracts, animal studies, and publications lacking full-text. Due to the lack of peer-review process, we also excluded book chapters.
Information sources, search and Study selection
Systematic literature searches were conducted (August 19, 2017) in four databases with no specified date, age, sex, or language restrictions. The databases searched were: (1) MEDLINE (via PubMed); (2) Embase; (3) The Cochrane Library (Cochrane); and (4) Web of Science (WoS). In an effort to be comprehensive and include grey literature publications into the data set of citations, conference proceedings and abstracts were retrieved from Embase and WoS by utilizing broad and inclusive publication-type filters. Search results were combined in a bibliographic management tool (EndNote, Clarivate Analytics) and duplicates were eliminated both electronically and manually to ensure an efficient de-duplication process. The search strategy employed the Medical Subject Headings (MeSH) phrases: “Microscopy, Confocal” AND (“Skin Neoplasms” OR “Dermatology” OR “Carcinoma” OR “keratosis, actinic” AND “in vivo”) AND (“Terminology” OR “Current Procedural Terminology” OR “Terminology as Topic” OR “Dictionaries as Topic” OR “Data Accuracy” OR “Algorithms” OR “Reproducibility of Results” OR “Classification”. For a complete list of keywords and the final search strategy, see Appendix A. Bibliographies within retrieved articles were also reviewed to identify additional studies. For this specific systematic review, we only included RCM terms pertinent for NML and excluded terms related to melanocytic neoplasms (i.e. melanoma and nevus). Two authors (C.N-D. and M.J.) independently screened all relevant titles and abstracts for eligibility. If necessary, full-text articles were screened. Differences in judgment were resolved with a third reviewer (A.S.) until consensus was reached (Figure 1).
Figure 1:
PRISMA diagram.
Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta Analyses: The PRISMA Statement. PLoS Med 6(6): el000097. doi:10.1371/journal.pmed1000097
Data collection and extraction process
Two authors (C.N-D. and M.J.) extracted data from the included studies independently. Disagreements were resolved by consensus; if no agreement could be reach, a third author (A.S.) was consulted. The following information was extracted from each study: RCM terms, definition of the RCM term, diagnosis associated with the term, and when known, the histopathological correlate associated with that term. All extracted RCM terms were recorded as published in the literature, chronologically, in an Excel spreadsheet (Microsoft, Redmond, WA). In addition, to weight the use-frequency of RCM terms, we recorded the number of studies that utilized each term. Lastly, we identified all terms that were likely synonymous, based on being associated with a similar RCM definition and histopathological correlates, such as “cleft’, “clefting”, and “cleft-like space”. Furthermore, terms were grouped by their pertinent anatomic level of skin: (1) “suprabasal epidermis” – including the corneal, granular and spinous layers, and (2) the epidermal basal layer / dermo-epidermal junction (DEJ) / and superficial dermis.
Summary measures and statistical analysis
Descriptive statistics were used to detail the number of RCM terms by diagnosis and by anatomic layer. ‘Use frequency’ describes the number of papers describing each RCM term. ‘Weighted use frequency’ describes the relative use frequency for RCM terms per diagnosis – it is the proportion between ‘use frequency’ for RCM terms (as individual terms or as subgroups of synonymous terms) divided by the total ‘use frequency’ for all terms describing that diagnosis.
RESULTS
Thirty-one studies met the inclusion criteria (Figure 1). We identified a total of 139 RCM terms for NMLs described in the literature, including 58 terms for diagnosis of BCC,6–8, 16–27 58 terms for SCC and AK,6, 9, 28–37 and 23 terms for SK/SL/LPLK.10, 31, 38–42
The use-frequency of each RCM term and of subgroups of likely-synonymous RCM terms are shown by diagnosis (Tables 1–3). The overall average use frequency of RCM terms was 1.6 (range 1–8). When stratified by specific diagnosis, the average use frequency of RCM terms was 1.8 (range 1–8), 1.6 (range 1–7), and 1.4 (range 1–3) times for the diagnosis of BCC, SCC/AK, and SK/SL/LPLK, respectively. For example, commonly utilized RCM terms included ‘increased vascularity’ – used 8 times among BCC-related papers, and ‘atypical honeycomb pattern’ – used 7 times across SCC-related articles. In contrast, the terms ‘prominent nucleoli’ and ‘fibrillar polarized pattern around tumor’ were used only once among BCC-related papers, and the term ‘multinucleated keratinocytes’ was used only once across SCC-related articles.
TABLE 1.
BASAL CELL CARCINOMA: RCM TERMS, FREQUENCY OF LITERATURE USE, SUGGESTED GROUPING BASED ON SIMILARITY IN DEFINITIONS AND HISTOPTAHOLOGICAL CORRELATES
| RCM terms | Frequency of use of an individual RCM term | Definition | Histopathological correlates |
|---|---|---|---|
| SUPRABASAL EPIDERMIS TERMS (N=13; 22.4%) | |||
| Actinic changes in honeycomb7,8,19* | 3 | Keratinocytic atypia with varying size of nuclei, pleomorphism, architectural disarray, parakeratotic nuclei | Keratinocytic atypia within the epidermis |
| Architectural disorder of overlying epidermis18 | 1 | ||
| Mild keratinocyte atypia21 | 1 | ||
| Atypical honeycomb pattern6 | 0 | ||
| Subtotal (weight**) | 5 (4.7%) | ||
| Elongated nuclei in the epidermis7,8,19 | 3 | Elongated monomorphic basaloid nuclei both in the epidermis aligned in the same axis and underlying tumor nests | No known histopathologic correlate. Probably the en face view of the uppermost part of a tumor nest or cord with palisading |
| Streaming of the epidermis21–26 | 6 | ||
| Polarization19, 27 | 2 | ||
| Polarized in the honeycomb6 | 1 | ||
| Polarization of nuclei of the epidermis7,8,19 | 3 | ||
| Subtotal (weight) | 15 (14.2%) | ||
| Prominent nucleoli7 | 1 | Visible nucleoli inside the nucleus of a BCC elongated cell | Prominent nucleoli in the nucleus of keratinocytes |
| Subtotal (weight) | 1 (0.9%) | ||
| Epidermal shadow6,27 | 2 | Large featureless area with blurred border disrupting the normal epidermis and corresponding to the horizontal clefting | Not known, probably an optical effect of the en face view of a tumor nest |
| Subtotal (weight) | 2 (1.9%) | ||
| Ulceration23,26 | 2 | Disruption in the bright skin surface and in the underlying layers of the epidermis, seen as a dark area with or without bright amorphous or fibrillar debris12 | Ulceration of the epidermis |
| Subtotal (weight) | 2 (1.9%) | ||
| Onion-like structures23,26 | 2 | Round black spaces centered by brightly refractile material, corresponding to milia-like cysts | Epidermal cysts |
| Subtotal (weight) | 2 (1.9%) | ||
| Total for Suprabasal Epidermis (weight) | 27 (25.7%) | ||
| BASAL LAYER/DEJ/SUPERFICIAL DERMIS TERMS (N=45; 77.6%) | |||
| Pigmented nests of basal cells16 | 1 | Highly packed cells corresponding to islands of basaloid tumor cells with high refractivity | Nests of basaloid cells in the DEJ or superficial dermis. Mostly associated to the nodular subtype |
| Tumor nodules18,19 | 2 | ||
| Nests of basaloid cells21 | 1 | ||
| Tumor island22,25,26 | 3 | ||
| Bright tumor islands24 | 1 | ||
| ∘ Small tumor islands23 | 1 | Tumor islands <300 um diameter | |
| ∘ Big tumor islands23 | 1 | Tumor islands >300 um diameter | |
| Subtotal (weight) | 10 (9.5%) | ||
| Basaloid cells17 | 1 | Cells with elongated nuclei and a palisading in the periphery of the tumor parenchyma | Organization of the basaloid cells at the periphery of the tumor nests |
| Palisading18,22 | 2 | ||
| Peripheral palisading21,23–26 | 5 | ||
| Subtotal (weight) | 8 (7.6%) | ||
| Peritumoral dark space18 | 1 | Cleft-like hyporeflective spaces surrounding tumor nests | Clear spaces between the tumor parenchyma and the surrounding stroma. Most probably correspond to mucin. |
| Cleft-like spaces20 | 1 | ||
| Clefting6,23,27 | 3 | ||
| Clefts44 | 1 | ||
| Peripheral clefting26 | 1 | ||
| Dark peritumoral cleft24,25 | 2 | ||
| Subtotal (weight) | 9 (8.6%) | ||
| Cord-like structures18,26 | 2 | Tightly packed tumor cells forming trabeculae | Nests of basaloid cells connected to the DEJ. Highly associated to the superficial subtype |
| Basaloid cords and nodules6,27 | 2 | ||
| Cord23 | 1 | ||
| Subtotal (weight) | 5 (4.7%) | ||
| Dendritic structures19 | 1 | Bright thin or coarse dendritic-like structures within tumor islands frequently associated to a clearly visible nucleated cell | When within the tumor nest, mostly they correspond to melanocytes (Melan-A stain) and few are Langerhans cell (CD 1a) |
| Dendritic-like features6 | 1 | ||
| Nucleated cell within tumor island6 | 1 | ||
| Bright dendritic structures19,24 | 1 | ||
| Dendritic cells26*** | 1 | ||
| Bright round cells24 | 1 | ||
| Subtotal (weight) | 6 (5.7%) | ||
| Dark silhouettes22–26 | 5 | Low reflectance tumor islands / Longo:23 Hyporeflective areas outlined by bright collagen bundles in the surrounding dermis that correspond to basaloid islands | Nests of basaloid cells in the superficial dermis or deeper, not visible due to the lack of resolution after 150 – 200 μm. Associated to the infiltrative subtype |
| Dark nodules26,27*** | 1 | ||
| Subtotal (weight) | 6 (5.7%) | ||
| Solar elastosis21 | 2 | Peppelman et al:21 bright irregular bundles and lacelike structures | Degeneration of the elastic fibers of the chronically sun-exposed skin |
| Subtotal (weight) | 2 (1.9%) | ||
| Melanophages16,18 | 2 | Irregularly shaped bright cells with ill-defined borders and usually no visible nucleus distributed within and outside tumor islands | Melanin-laded macrophages in the superficial dermis |
| Plump bright cells19,21,22 | 3 | ||
| Subtotal (weight) | 5 (4.7%) | ||
| Collagen bundles17 | 1 | Increased number of fibers bundles orientated parallel, surrounding tumor | Collagen reaction to the tumor in the surrounding stroma |
| Fibrosis surrounding tumor nests21 | 1 | ||
| Stromal reaction26*** | 1 | ||
| Thickened collagen bundles24,25 | 2 | ||
| Subtotal (weight) | 5 (4.7%) | ||
| Increased vascularity7,8,18,19,21–23,26 | 8 | Increased number of dilated (10 – 105 μm) blood vessels with occasional rolling of leukocytes (starting at 35 – 50 μm below epidermal surface); these vessels are often horizontal (parallel) | Dilated blood vessels running parallel to the epidermal surface |
| Enlarged blood vessels17 | 1 | ||
| Prominent vasculature19 | 1 | ||
| Linear telangiectasia-like horizontal vessels6 | 1 | ||
| Linear or convoluted dilated blood vessels25,26 | 2 | ||
| Linear blood vessels24 | 1 | ||
| Subtotal (weight) | 14 (13.3%) | ||
| Fibrillar polarized pattern around tumor6 | 1 | Fibrillary polarized features drawing a reticulation pattern around tumor island | N/A |
| Subtotal (weight) | 1 (0.9%) | ||
| Inflammatory infiltrate | 1 | Bright, highly refractile round or scattered cells representing leukocytes and neutrophils, respectively | Infiltrate of lymphocytes and leukocytes in the tumor parenchyma and stroma |
| Prominent inflammatory infiltrate7, 8, 19 | 3 | ||
| Inflammatory particles26 | 1 | ||
| Inflammation23 | 1 | ||
| Subtotal (weight) | 6 (5.7%) | ||
| Total for basal layer/DEJ/superficial dermis (weight) | 78 (74.2%) | ||
| TOTAL TERMS FOR BCC (N=58; 100%) | 105 (100%) | ||
Superscripted numbers denote reference numbers.
Weight calculates the relative frequency of use for each subgroup of terms; the denominator is the total times BCC terms were used in the literature (n=78).
These terms had no definition in the cited articles and thus grouping under each likely-synonymous term was done by the authors of this paper.
TABLE 3.
SEBORRHEIC KERATOSIS, SOLAR LENTIGO AND LICHEN PLANUS-LIKE KERATOSIS: RCM TERMS, FREQUENCY OF LITERATURE USE, SUGGESTED GROUPING BASED ON SIMILARITY IN DEFINITIONS AND HISTOPTAHOLOGICAL CORRELATES
| RCM Terms | Frequency of use of an individual RCM term | Definition | Histopathological correlates |
|---|---|---|---|
| SUPRABASAL EPIDERMIS TERMS (N=9; 39.1%) | |||
| Milia-like cysts31 | 1 | Homogeneous and bright areas without sharply demarcated borders surrounded by a dark halo within the epidermis | Intraepidermal keratin cysts |
| Corneal pseudo cysts10,39,41 | 3 | ||
| Subtotal (weight*) | 4 (12.1%) | ||
| Keratin-filled invaginations10,41 | 2 | Round to longitudinal invaginations of the lesion surface, harboring structureless amorphous material of variable brightness on RCM | Keratin-filled papillomatous epidermis |
| Surface holes and fissures39 | 1 | ||
| Subtotal (weight*) | 3 (9.1%) | ||
| Cerebriform appearance38 | 1 | Round to linear structures, darker than the surrounding epidermis, resembling the surface of a brain (gyri and sulci) | Papillomatous epidermis |
| Subtotal (weight*) | 1 (3.03%) | ||
| Typical honeycomb pattern39 | 1 | Honeycomb pattern with regular thickness of lines and sizes of holes | Regular epidermis |
| Regular honeycomb pattern10,41,42 | 3 | ||
| Subtotal (weight*) | 4 (12.1%) | ||
| Epidermal projections10,41 | 2 | Projections of the epidermal surface of the lesion | Projections of rete ridges |
| Subtotal (weight*) | 2 (6.1%) | ||
| Small bright homogeneous cells31** | 1 | Small bright homogeneous cells present on basal layers, corresponding to pigmented keratinocytes | Pigmented keratinocytes in the basal layer |
| Subtotal (weight*) | 1 (3.03%) | ||
| Total for Suprabasal Epidermis (weight) | 15 (45.4%) | ||
| BASAL LAYER/DEJ/SUPERFICIAL DERMIS TERMS (N=14; 60.8%) | |||
| Polycyclic shapes of dermal papillae38 | 1 | At the DEJ level, densely packed round to polymorphous dermal papillae, usually with pigmented keratinocytes. | Elongated and bridging rete ridges with pigmented keratinocytes |
| Densely packed round to polymorphous dermal papillae10 | 1 | ||
| Packed dermal papillae41 | 1 | ||
| Polycyclic papillary contours40 | 1 | ||
| Subtotal (weight*) | 4 (12.1%) | ||
| Edged papillae42 | 1 | Dark round to oval structures surrounded by a rim of bright monomorphic cells | Pigmented keratinocytes at the DEJ |
| Subtotal (weight*) | 1 (3.03%) | ||
| Cords*** and bulbous projections10,41 | 2 | Elongated bright tubular structures (cords***) with bulbous projections at the DEJ | Elongated and bridging rete ridges with pigmented keratinocytes |
| Cord-like*** rete ridges42 | 1 | ||
| Elongated cords39*** | 1 | ||
| Anastomosing epithelial cords31*** | 1 | ||
| Bulbous projections39 | 1 | ||
| Subtotal (weight*) | 7 (21.2%) | ||
| Mixed vascular pattern10,41 | 2 | A prominent vascular pattern with dilated round and linear blood vessels (running perpendicular and parallel, respectively) | Neovascularization |
| Subtotal (weight*) | 2 (6.1%) | ||
| Plump bright cells10,31,39† | 3 | Irregularly shaped bright cells with ill-defined borders and no visible nucleus, corresponding to melanophages | Melanophages in the dermis |
| Melanophages10† | 1 | ||
| Subtotal (weight*) | 4 (12.1%) | ||
| Bright stellate spots39†† | 1 | Small bright round structures (<20 um) without visible nucleus corresponding to leukocytes | Inflammatory cells: lymphocytes and neutrophils |
| Subtotal (weight*) | 1 (3.03%) | ||
| Total for basal layer/DEJ/superficial dermis | 18 (54.5%) | ||
| TOTAL TERMS FOR SL/SK/LPLK (N=23; 100%) | 33 (100%) | ||
Superscripted numbers refer to the publication.
Weight calculates the relative frequency of use for each subgroup of terms; the denominator is the total times SL/SK/LPLK terms were used in the literature (n=30).
Despite not defined for this group of lesions, we recommend using the standard term “cobblestone pattern” to avoid confusion.
We do not recommend using the term ‘cords’ to avoid confusion with ‘cord-like’ structures of Basal cell carcinoma.
These criteria have been associated mostly to lichen planus-like keratosis.
The term “Inflammatory infiltrate” was not used in the literature in reference to SL/SK/LPLK; for consistency with the literature, we recommend using “bright stellate spots”.
By grouping of individual RCM terms based on likely-synonymous definition and histopathological correlates, the total number of RCM terms could be reduced to 66 (52.5% reduction), including 18 terms (68.9% reduction) for BCC (Table 1), 36 terms (37.9% reduction) for SCC/AK (Table 2), and 12 terms (47.8% reduction) for SK/SL/LPLK (Table 3).
TABLE 2.
SQUAMOUS CELL CARCINOMA: RCM TERMS, FREQUENCY OF LITERATURE USE, SUGGESTED GROUPING BASED ON SIMILARITY IN DEFINITIONS AND HISTOPTAHOLOGICAL CORRELATES
| RCM Term | Frequency of use of individual RCM terms | Definition | Histopathological correlates |
|---|---|---|---|
| SUPRABASAL EPIDERMIS TERMS (N=37; 63.7%) | |||
| Hyperkeratosis32,35,37 | 3 | Thickening of the stratum corneum >15um | Hyperkeratosis |
| Subtotal (weight***) | 3 (3.2%) | ||
| Parakeratosis32,34–37 | 5 | Nucleated cells appearing as dark nuclei surrounded by a bright outline centrally stratum corneum corneocytes | Parakeratosis |
| Subtotal (weight***) | 5 (5.3%) | ||
| Detached corneocytes32 | 1 | White, highly refractive polygonal structure of approximately 30–40 um in diameter in the stratum corneum | Detached corneocytes |
| Polygonal nucleated cells at the stratum corneum9 | 1 | ||
| Disruption/individual cells36 | 1 | ||
| Individual corneocytes37 | 1 | ||
| Superficial epidermal disruption33 | 1 | ||
| Subtotal (weight***) | 5 (5.3%) | ||
| Stratum corneum disruption | 1 | Alteration of the smooth contour of the stratum corneum observed in mosaic images | N/A |
| Subtotal (weight***) | 1 (1.1%) | ||
| Orthokeratosis32 | 1 | Hyperkeratosis without parakeratosis | Orthokeratosis |
| Subtotal (weight***) | 1 (1.1%) | ||
| Scale9,34,36 | 3 | Variably refractile, amorphous material in stratum corneum | Hyperkeratosis |
| Subtotal (weight***) | 3 (3.2%) | ||
| Atypical honeycomb pattern6,9,31–33,35,36* | 7 | Irregularly shaped cells deviating from the normal honeycomb pattern | Variation in cellular and nuclear shape and size of epidermal keratinocytes |
| Diamond shaped honeycomb6 | 1 | ||
| Irregular honeycomb pattern29,34 | 2 | ||
| Subtotal (weight***) | 10 (10.7%) | ||
| Architectural disarray28,32 | 2 | Severe disarranged epidermal pattern in which the honeycomb pattern is no longer visible | Severe variation in cellular and nuclear shape and size of epidermal keratinocytes |
| Honeycomb atypical and disarrayed6 | 1 | ||
| Loss of regular stratification of epidermal layers29 | 1 | ||
| Disarranged epidermal pattern9,31,36 | 3 | ||
| Architectural disarrangement35,37 | 2 | ||
| Subtotal (weight***) | 9 (9.6%) | ||
| Cellular and nuclear pleomorphism (of the epidermis)32 | 1 | Variation in cellular and nuclear shape and size | Variation in cellular and nuclear shape and size |
| Different size and shape of the nuclei of keratinocytes29 | 1 | ||
| Keratinocyte pleomorphism37 | 1 | ||
| Pleomorphic nuclei of keratinocytes28 | 1 | ||
| Subtotal (weight***) | 4 (4.3%) | ||
| Irregular borders of keratinocytes29 | 1 | Irregular borders of keratinocytes | N/A |
| Subtotal (weight***) | 1 (1.1%) | ||
| Irregular intercellular keratinocyte connections29 | 1 | Irregular intercellular keratinocyte connections | N/A |
| Subtotal (weight***) | 1 (1.1%) | ||
| Targetoid cells32,33,35,36† | 4 | Two cell types have been described: Large cell with a bright center and a dark peripheral halo (denoted as ′Targetoid cells 1′);32,33 Large cell with a dark center and a bright rim surrounded by a dark halo (denoted as ′Targetoid cells 2′)32,33 |
Dyskeratotic keratinocytes within the epidermis |
| Dyskeratotic areas29 | 1 | ||
| Round nucleated cells at spinous-granular layer9 | 1 | ||
| Dyskeratotic cell28 | 1 | ||
| Subtotal (weight***) | 7 (7.5%) | ||
| Multinucleated keratinocytes32 | 1 | Large cells with tight aggregates of bright nuclei | Multinucleated keratinocytes |
| Large cells with aggregated nuclei in the epidermis33 | 1 | ||
| Subtotal (weight***) | 2 (2.1%) | ||
| Spongiosis32,35 | 2 | Enlargement of the bright intercellular spaces due to fluid accumulation between keratinocytes | Spongiosis |
| Subtotal (weight***) | 2 (2.1%) | ||
| Exocytosis32 | 1 | Inflammatory cells appearing as highly refractive structures in the epidermis | Exocytosis |
| Subtotal (weight***) | 1 (1.1%) | ||
| Spindle-shaped cells with dendritic branches infiltrating the epidermis34 | 1 | Bright cells with elongated branching structures extending from fusiform cell body; seen at the spinous and granular layers of the epidermis (corresponding to Langerhans cells of pigmented SCC or pigmented AK) | Langerhans cells infiltrating the epidermis |
| Dendritic cells in the epidermis35,36¶ | 2 | ||
| Subtotal (weight***) | 2 (2.1%) | ||
| Erosion/ulceration35 | 1 | Dark areas, with sharp borders and irregular contours, filled with amorphous material, cellular debris and small particles | Ulceration of the epidermis |
| Subtotal (weight***) | 1 (1.1%) | ||
| Corneal pseudocysts36 | 1 | Well circumscribed large, round, highly refractile intraepidermal structures | Intraepidermal cysts |
| Subtotal (weight***) | 1 (1.1%) | ||
| Speckled nucleated cells in the epidermis | 1 | Roundish-to-polygonal cells with speckled appearance and dark nucleus in the epidermis. Size is slightly larger than surrounding keratinocytes. They are larger than lymphocytes and have polygonal shape that differentiate them from dendritic cells | N/A |
| Subtotal (weight***) | 1 (1.1%) | ||
| Total for Suprabasal Epidermis (weight) | 60 (64.5%) | ||
| BASAL LAYER/DEJ/SUPERFICIAL DERMIS TERMS (N=21; 36.2%) | |||
| Elongated dermal papillae28 | 1 | Elongated dermal papillae | N/A |
| Subtotal (weight***) | 1 (1.1%) | ||
| Edged papillae34 | 1 | Multiple scattered dermal papillae demarcated by a rim of bright cells. In pigmented SCC, the edged papillae are mostly peripheral in location with widened interpapillary spaces | Atypical pigmented keratinocytes |
| Subtotal (weight***) | 1 (1.1%) | ||
| Mottled pigmentation36¶ | 1 | Corresponds to presence of clustered bright keratinocytes detectable in context of honeycombed pattern | Basilar pigmented keratinocytes |
| Subtotal (weight***) | 1 (1.1%) | ||
| Keratin pearl32,35 | 2 | Whorl-shaped accumulation of keratin appearing as highly refractive, speckled structure in the dermis†† | Keratinization |
| Subtotal (weight***) | 2 (2.1%) | ||
| Convoluted glomerular vessel6 | 1 | Coiled canalicular vessels | Aberrant vessels |
| Subtotal (weight***) | 1 (1.1%) | ||
| Linear vessels36 | 1 | Vessels oriented parallel to the imaging plane | Aberrant vessels |
| Subtotal (weight***) | 1 (1.1%) | ||
| Round blood vessels traversing the dermal papilla9,36 | 2 | Dilated blood vessels within the dermal papillae that run perpendicular to the horizontal RCM plane of imaging / Dilated blood vessels within the dermal papillae looping perpendicular to the horizontal plane of RCM imaging. The presence of multiple looping vessels renders the dermal papillae a Button-hole like appearance | Aberrant and neo formed vessels |
| Round-to-oval vessels33 | 1 | ||
| Buttonhole vessels35,36 | 2 | ||
| Dilated looping blood vessels withinpapillae34,35 | 2 | ||
| Subtotal (weight***) | 7 (7.5%) | ||
| Increased number of blood vessels32,37 | 2 | > 5 blood vessels per 0.5 × 0.5 mm | Neovascularization |
| Subtotal (weight***) | 2 (%) | ||
| Increased blood vessel dilatation32,37 | 2 | Blood vessels of diameter >5 um | Aberrant vessels |
| Subtotal (weight***) | 2 (2.1%) | ||
| S-shaped vessels33 | 1 | Round-to-oval vessels with increased tortuosity at the center of the dermal papillae, S-shaped at lower papillary dermis | N/A |
| Subtotal (weight***) | 1 (1.1%) | ||
| Solar elastosis32,37 | 2 | Network of thick, highly refractile collagen bundles intermixed with moderately refractive, lace-like elastic fibers | Solar elastosis |
| Curled fibers36 | 1 | ||
| Subtotal (weight***) | 3 (3.2%) | ||
| Huddled collagen bundles36 | 1 | Large hyporefractive blotches of amorphous and hyporeflective material; individual collagen fibers are no longer visible | N/A |
| Subtotal (weight***) | 1 (1.1%) | ||
| Coarse collagen bundles36 | 1 | Bright fibrillar structures that appear finely reticulated, forming a web-like | N/A |
| Subtotal (weight***) | 1 (1.1%) | ||
| Nest-like structures32,35 | 2 | Round, demarcated structures in the dermis that are often surrounded by fibrosis | N/A |
| Subtotal (weight***) | 2 (2.1%) | ||
| Plump cells34–36 | 3 | Melanophages | Melanin-laden macrophages in dermis |
| Subtotal (weight***) | 3 (3.2%) | ||
| Speckled nucleated cells in the dermis35 | 1 | Roundish to polygonal cells with speckled appearance and dark nucleus within the dermis. They are larger than the usual size of lymphocytes and have a polygonal shape that differentiate them from plump bright cells | N/A |
| Subtotal (weight***) | 1 (1.1%) | ||
| Inflammatory cells32,33,37 | 3 | Highly refractile structures of 8–10 um in diameter located in the epidermis or dermis | Inflammatory cells: lymphocytes and neutrophils |
| Subtotal (weight***) | 3 (3.2%) | ||
| Total for basal layer/DEJ/superficial dermis | 33 (35.4%) | ||
| TOTAL TERMS FOR SCC (N=58) | 93 (100%) | ||
Most studies recommend stating partial thickness or full thickness atypia to differentiate between actinic keratosis and squamous cell carcinoma.
Superscripted numbers denote reference numbers.
Weight calculates the relative frequency of use for each subgroup of terms; the denominator is the total times SCC terms were used in the literature (n=71).
This term has been mainly described in association with Bowen’s disease.
Features of pigmented actinic keratosis
This feature can be also seen at the level of the epidermis.
To weighed use-frequency for each subgroup of likely-synonymous RCM terms was analyzed by diagnosis. The most commonly used term-subgroups for BCC (Table 1) were “streaming / polarization of nuclei” (n=15, 14.2%), “increased vascularity / prominent vascularity” (n=14, 13.3%), and “tumor nodules / bright tumor islands” (n=10, 9.5%). The most commonly used term-subgroups for SCC/AK (Table 2) were “atypical honeycomb pattern” (n=10, 10.7%), “architectural disarray” (n=9, 9.6%), and “dyskeratotic cells” and “buttonhole vessels” (n=7 for each term; 7.5% each). The most commonly used term-subgroups for SK/SL/LPLK (Table 2) were “bulbous projections” (n=7, 21.2%), “milia-like cysts” (n=4, 13.3%), “typical honeycomb pattern” (n=4; 12.1%), “presence of plump cells/melanophages” (n=4; 12.1%), and “polycyclic dermal papillae” (n=4; 12.1%).
We also stratified RCM terms by their anatomical level in the skin described, stratified by suprabasal epidermis vs. basal layer/DEJ/superficial dermis.
For BCC, 13 (22.4%) individual RCM terms (in 6 synonymous-term subgroups, 33.3%) were categorized to suprabasal epidermal, while 45 (75%) individual RCM terms (in 12 synonymous-term subgroups, 66.6%) were categorized to basal layer/DEJ/superficial dermis. The weighted use frequency for basal layer/DEJ/superficial dermis terms was higher than suprabasal epidermis terms (n=78 [74.2%] vs. n=27 [25.7%], respectively).
For SCC/AK, 37 (63.7%) individual RCM terms (in 19 synonymous-term subgroups, 51.3%) were categorized to suprabasal epidermal, while 21 (36.2%) individual RCM terms (in 18 synonymous-term subgroups, 48.6%) were categorized to basal layer/DEJ/superficial dermis. The weighted use frequency for suprabasal epidermis terms was higher than basal layer/DEJ/superficial dermis terms (n=60 [64.5%] vs. n=33 [35.4%], respectively).
For SK/SL/LPLK, 9 (39.1%) individual RCM terms (in 6 synonymous-term subgroups, 50%) were categorized to suprabasal epidermal, while 14 (60.8%) individual RCM terms (in 6 synonymous-term subgroups, 50%) were categorized to basal layer/DEJ/superficial dermis. The weighted use frequency for suprabasal epidermis terms was similar to that of basal layer/DEJ/superficial dermis terms (n=15 (45.4%) vs. n=18 (54.5%), respectively).
DISCUSSION
RCM is a non-invasive imaging technique that has demonstrated good clinical utility in the diagnosis, margin assessment, and treatment monitoring of skin neoplasms.1, 43 However, learning to read RCM images may be perceived, at present, as a daunting task that should be left in the hands of dedicated experts. The inconsistent use of RCM terminology in the literature and in scientific meetings, may pose a barrier to the adaptation of RCM by novices. As RCM terminology is still evolving, a systematic review of the terms is warranted at this juncture. Toward improving the consistency of RCM terminology use, we conducted a systematic review of terms for the diagnosis of common benign and malignant NMLs. The goal was to create a more concise and unified glossary of RCM terms for NMLs. First, we gathered all RCM terms described in pertinent original peer-reviewed papers, and then, identified likely-synonymy across terms with similar definition and histopathology correlates. We found a total of 139 RCM terms used to describe features of common NMLs in the literature—an overwhelming number for a novice to comprehend. By grouping based on ‘likely-synonymy’ in the associated definition or histopathological correlation, the list of terms could be reduced by at least half. Furthermore, we assigned a relative weighted score for each RCM term based on its frequency of usage in the literature. We found an average use of 1.6 times for a given term across the 31 studies, highlighting the inconsistent usage of the RCM terms.
Another observation is that the frequency of use of terms was highest at the anatomical level in which the neoplasms is expected to proliferate based on the histopathological correlation. For instance, most of the RCM terms (~75%) for BCC are described at the level of DEJ/superficial dermis level, where BCC aggregates proliferate. Likewise, roughly two-thirds (64.5%) of the RCM terms for SCC/AK were located at epidermal levels, corresponding to pertinent anatomic level of histopathological diagnostic criteria for this the neoplasms. This finding confirms at a larger scale (systematic review) the good correlation between histopathology and RCM. Interestingly, Farnetani et al. found a higher interobserver reproducibility for epidermal than dermal RCM terms;12 they conjectured that the degrading RCM optical resolution and image quality with increasing imaging depth accounts for this observation.12 Larger studies are needed to confirm this observation.
Towards generating a shortlist of most pertinent RCM terms, we propose several steps. First, “redundant terms” need to be unified, as suggested herein. Second, omission of most infrequently used terms (e.g., ‘prominent nucleoli’ and ‘onion-like’ for BCC7, 23) should be considered. Third, unified terms that have a been assigned diagnostic value in studies (e.g. tumor islands for BCC) should be ranked higher than descriptive/supportive terms (e.g., presence of ‘plump cells’ in the dermis and ‘button-hole sign’ for SCC) without clear diagnostic utility. Finally, for select RCM terms with clear-cut histopathological correlates and future new terms, the histopathological term could be preferred (e.g., “dyskeratotic cells” instead of “targetoid cells”), facilitating communication between clinicians and dermatopathologists.
Our study has limitations. First, while the initial tier of our search did not impose any language restrictions, we only included full-text articles in English. This was done to allow direct comparisons of terms without biases due to translation. However, distinct RCM terms in non-English language papers may have been missed. Second, for standardization, all non-peer reviewed articles such as book chapters, conference papers, and case reports were excluded; we may have missed some up-to-date terms, coined by the experts, especially in book chapters. Third, the weightage given to the RCM terms in this review may be influenced by frequency of publications by a specific researcher or a group.
Conclusion:
Through systematic review, we presented a glossary of RCM terms for the diagnosis of NMLs. By grouping the terms, based on likely-synonymy in the associated definition and histopathological correlation, the number of RCM terms published in the literature could be reduced by 50%. This systematic review may form the basis for an expert Delphi consensus process on NML terminology. A concise reproducible glossary of RCM terms can facilitate learning and clinical application of RCM by dermatologists.
Supplementary Material
Supplementary Figure 1: Basal cell carcinoma (BCC). A. RCM mosaic (1.7 × 1.5 mm), at the superficial dermis level, of a nodular BCC showing tumor islands (yellow asterisks) with palisading (yellow arrows) and clefting (white arrows). The surrounding stroma displays bright collagen bundles (green arrows). In addition, there are dilated vessels (red arrows) coursing parallel to the en face imaging plane. B. Corresponding histopathological section (Hematoxylin and Eosin, 10×) showing basaloid neoplastic aggregates (yellow asterisks), with peripheral palisading and adjacent mucin-filled clefts (white arrows). There is fibroplasia (green arrows) and prominent vascularity (red arrows) in the surrounding stroma. C. RCM image (0.75 × 0.75 mm) of a nodular BCC showing cord-like tumor structures (red arrows) with palisading (yellow arrows) and clefting (blue arrows). There are also tumor islands (yellow asterisks). D. Corresponding histopathological section showing anastomosing neoplastic aggregates (red arrow) which emanate from the undersurface of an atrophic epidermis. The neoplastic aggregates are immersed in a mucinous stroma (blue arrows) (Hematoxylin and Eosin, 10X).
Supplementary Figure 2: Squamous cell carcinoma in situ. A. RCM mosaic (3.0 × 2.0 mm) image at the spinous-granular/dermoepidermal junction layer showing atypical honeycomb pattern (yellow asterisks), dilated vessels looping the dermal papillae (so called “buttonhole vessels”; red arrows), and bright dyskeratotic cells (yellow arrows). The insert is showing a regular honeycomb pattern of normal skin to compare. B. Corresponding histopathological section (Hematoxylin and Eosin, 10X) showing a full-thickness epidermal atypia with crowding, pleomorphism and disarray of nuclei and with dyskeratotic cells (yellow arrows). In addition, there are tortuous looping blood vessels traversing the dermal papillae (red arrows). C. RCM image (0.75 × 0.75 mm) at the spinous-granular layer showing disarranged honeycomb pattern (yellow asterisks) and bright dyskeratotic cells (yellow arrows). The insert is showing a regular honeycomb pattern of normal skin to compare. D. Corresponding histopathological section showing full thickness epidermal atypia with nuclear pleomorphism (asterisk) and dyskeratotic cells (yellow arrows) (Hematoxylin and Eosin, 20X).
Supplementary Figure 3: Solar lentigo / lichen planus-like keratosis (LPLK) / seborrheic keratosis. A. RCM mosaic (2.5 × 2.5 mm), at the dermoepidermal-junction, showing polycyclic dermal papillae (red arrows) and bulbous projections (green arrows) of a solar lentigo on the left-side of the image and inflammatory infiltrate composed of plump bright cells (blue arrows) and small bright cells (yellow arrows) of a LPLK on the right-side of the image (white dashed square area). B. Corresponding histopathological section (from the dashed square on panel A on RCM) shows the area of lichen planus-like keratosis with inflammatory infiltrate composed of melanophages (blue arrows) and lymphocytes (yellow arrows) (Hematoxylin and Eosin, 20X). C. RCM mosaic (3.0 × 3.5 mm), at the suprabasal epidermis layer, of a seborrheic keratosis showing keratin plugs and crypts (yellow arrows), C- and S-shaped vessels (green arrows), and inflammatory infiltrate (white arrows). D. Corresponding histopathological section (from the dashed square on panel C on RCM) shows an inflamed seborrheic keratosis with keratin plugs (yellow arrows), dilated vessels (green arrows), and lymphocytes (white arrows) (Hematoxylin and Eosin, 20X).
Founding source:
This research is funded in part by a grant from the National Cancer Institute / National Institutes of Health (P30-CA008748) made to the Memorial Sloan Kettering Cancer Center. Alon Scope’s RCM research is funded by the Israel Science Foundation (ISF-1546–16).
Footnotes
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Conflict of interest: Allan Halpern, Margaret Oliviero, and Harold Rabinovitz has conflicts of interest to declare. See attached COI forms.
Consent for publication: The authors consent the publication of this submission (manuscript and figures).
Prior presentation: none; IRB status: N/A;
REFERENCES
- 1.Rajadhyaksha M, Marghoob A, Rossi A, Halpern AC, Nehal KS. Reflectance confocal microscopy of skin in vivo: From bench to bedside. Lasers Surg Med 2017;49:7–19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Rajadhyaksha M, Grossman M, Esterowitz D, Webb RH, Anderson RR. In vivo confocal scanning laser microscopy of human skin: melanin provides strong contrast. J Invest Dermatol 1995;104:946–52. [DOI] [PubMed] [Google Scholar]
- 3.Rajadhyaksha M, Gonzalez S, Zavislan JM, Anderson RR, Webb RH. In vivo confocal scanning laser microscopy of human skin II: advances in instrumentation and comparison with histology. J Invest Dermatol 1999;113:293–303. [DOI] [PubMed] [Google Scholar]
- 4.Guitera P, Pellacani G, Crotty KA, Scolyer RA, Li LX, Bassoli S et al. The impact of in vivo reflectance confocal microscopy on the diagnostic accuracy of lentigo maligna and equivocal pigmented and nonpigmented macules of the face. J Invest Dermatol 2010;130:2080–91. [DOI] [PubMed] [Google Scholar]
- 5.Pellacani G, De Pace B, Reggiani C, Cesinaro AM, Argenziano G, Zalaudek I et al. Distinct melanoma types based on reflectance confocal microscopy. Exp Dermatol 2014;23:414–8. [DOI] [PubMed] [Google Scholar]
- 6.Guitera P, Menzies SW, Longo C, Cesinaro AM, Scolyer RA, Pellacani G. In vivo confocal microscopy for diagnosis of melanoma and basal cell carcinoma using a two-step method: analysis of 710 consecutive clinically equivocal cases. J Invest Dermatol 2012;132:2386–94. [DOI] [PubMed] [Google Scholar]
- 7.Gonzalez S, Tannous Z. Real-time, in vivo confocal reflectance microscopy of basal cell carcinoma. J Am Acad Dermatol 2002;47:869–74. [DOI] [PubMed] [Google Scholar]
- 8.Nori S, Rius-Diaz F, Cuevas J, Goldgeier M, Jaen P, Torres A et al. Sensitivity and specificity of reflectance-mode confocal microscopy for in vivo diagnosis of basal cell carcinoma: a multicenter study. J Am Acad Dermatol 2004;51:923–30. [DOI] [PubMed] [Google Scholar]
- 9.Rishpon A, Kim N, Scope A, Porges L, Oliviero MC, Braun RP et al. Reflectance confocal microscopy criteria for squamous cell carcinomas and actinic keratoses. Arch Dermatol 2009;145:766–72. [DOI] [PubMed] [Google Scholar]
- 10.Ahlgrimm-Siess V, Cao T, Oliviero M, Laimer M, Hofmann-Wellenhof R, Rabinovitz HS et al. Seborrheic keratosis: reflectance confocal microscopy features and correlation with dermoscopy. J Am Acad Dermatol 2013;69:120–6. [DOI] [PubMed] [Google Scholar]
- 11.Pellacani G, Vinceti M, Bassoli S, Braun R, Gonzalez S, Guitera P et al. Reflectance confocal microscopy and features of melanocytic lesions: an internet-based study of the reproducibility of terminology. Arch Dermatol 2009;145:1137–43. [DOI] [PubMed] [Google Scholar]
- 12.Farnetani F, Scope A, Braun RP, Gonzalez S, Guitera P, Malvehy J et al. Skin Cancer Diagnosis With Reflectance Confocal Microscopy: Reproducibility of Feature Recognition and Accuracy of Diagnosis. JAMA Dermatol 2015;151:1075–80. [DOI] [PubMed] [Google Scholar]
- 13.Scope A, Benvenuto-Andrade C, Agero AL, Malvehy J, Puig S, Rajadhyaksha M et al. In vivo reflectance confocal microscopy imaging of melanocytic skin lesions: consensus terminology glossary and illustrative images. J Am Acad Dermatol 2007;57:644–58. [DOI] [PubMed] [Google Scholar]
- 14.Current Procedural Terminology, Professional Edition. Chicago IL: American Medical Association; 2016. [Google Scholar]
- 15.Jain M, Pulijal SV, Rajadhyaksha M, Halpern AC, Gonzalez S. Evaluation of Bedside Diagnostic Accuracy, Learning Curve, and Challenges for a Novice Reflectance Confocal Microscopy Reader for Skin Cancer Detection In Vivo. JAMA Dermatol 2018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Charles CA, Marghoob AA, Busam KJ, Clark-Loeser L, Halpern AC. Melanoma or pigmented basal cell carcinoma: a clinical-pathologic correlation with dermoscopy, in vivo confocal scanning laser microscopy, and routine histology. Skin Res Technol 2002;8:282–7. [DOI] [PubMed] [Google Scholar]
- 17.Sauermann K, Gambichler T, Wilmert M, Rotterdam S, Stucker M, Altmeyer P et al. Investigation of basal cell carcinoma [correction of carcionoma] by confocal laser scanning microscopy in vivo. Skin Res Technol 2002;8:141–7. [DOI] [PubMed] [Google Scholar]
- 18.Agero AL, Busam KJ, Benvenuto-Andrade C, Scope A, Gill M, Marghoob AA et al. Reflectance confocal microscopy of pigmented basal cell carcinoma. J Am Acad Dermatol 2006;54:638–43. [DOI] [PubMed] [Google Scholar]
- 19.Segura S, Puig S, Carrera C, Palou J, Malvehy J. Development of a two-step method for the diagnosis of melanoma by reflectance confocal microscopy. J Am Acad Dermatol 2009;61:216–29. [DOI] [PubMed] [Google Scholar]
- 20.Ulrich M, Roewert-Huber J, Gonzalez S, Rius-Diaz F, Stockfleth E, Kanitakis J. Peritumoral clefting in basal cell carcinoma: correlation of in vivo reflectance confocal microscopy and routine histology. J Cutan Pathol 2011;38:190–5. [DOI] [PubMed] [Google Scholar]
- 21.Peppelman M, Wolberink EA, Blokx WA, van de Kerkhof PC, van Erp PE, Gerritsen MJ. In vivo diagnosis of basal cell carcinoma subtype by reflectance confocal microscopy. Dermatology 2013;227:255–62. [DOI] [PubMed] [Google Scholar]
- 22.Manfredini M, Arginelli F, Dunsby C, French P, Talbot C, Konig K et al. High-resolution imaging of basal cell carcinoma: a comparison between multiphoton microscopy with fluorescence lifetime imaging and reflectance confocal microscopy. Skin Res Technol 2013;19:e433–43. [DOI] [PubMed] [Google Scholar]
- 23.Longo C, Lallas A, Kyrgidis A, Rabinovitz H, Moscarella E, Ciardo S et al. Classifying distinct basal cell carcinoma subtype by means of dermatoscopy and reflectance confocal microscopy. J Am Acad Dermatol 2014;71:716–24 e1. [DOI] [PubMed] [Google Scholar]
- 24.Castro RP, Stephens A, Fraga-Braghiroli NA, Oliviero MC, Rezze GG, Rabinovitz H et al. Accuracy of in vivo confocal microscopy for diagnosis of basal cell carcinoma: a comparative study between handheld and wide-probe confocal imaging. J Eur Acad Dermatol Venereol 2015;29:1164–9. [DOI] [PubMed] [Google Scholar]
- 25.Cinotti E, Jaffelin C, Charriere V, Bajard P, Labeille B, Witkowski A et al. Sensitivity of handheld reflectance confocal microscopy for the diagnosis of basal cell carcinoma: A series of 344 histologically proven lesions. J Am Acad Dermatol 2015;73:319–20. [DOI] [PubMed] [Google Scholar]
- 26.Ruini C, Hartmann D, Saral S, Krammer S, Ruzicka T, von Braunmuhl T. The invisible basal cell carcinoma: how reflectance confocal microscopy improves the diagnostic accuracy of clinically unclear facial macules and papules. Lasers Med Sci 2016;31:1727–32. [DOI] [PubMed] [Google Scholar]
- 27.Guitera P, Menzies SW, Argenziano G, Longo C, Losi A, Drummond M et al. Dermoscopy and in vivo confocal microscopy are complementary techniques for diagnosis of difficult amelanotic and light-coloured skin lesions. Br J Dermatol 2016;175:1311–9. [DOI] [PubMed] [Google Scholar]
- 28.Aghassi D, Anderson RR, Gonzalez S. Confocal laser microscopic imaging of actinic keratoses in vivo: a preliminary report. J Am Acad Dermatol 2000;43:42–8. [DOI] [PubMed] [Google Scholar]
- 29.Horn M, Gerger A, Ahlgrimm-Siess V, Weger W, Koller S, Kerl H et al. Discrimination of actinic keratoses from normal skin with reflectance mode confocal microscopy. Dermatol Surg 2008;34:620–5. [DOI] [PubMed] [Google Scholar]
- 30.Ulrich M, Maltusch A, Rowert-Huber J, Gonzalez S, Sterry W, Stockfleth E et al. Actinic keratoses: non-invasive diagnosis for field cancerisation. Br J Dermatol 2007;156 Suppl 3:13–7. [DOI] [PubMed] [Google Scholar]
- 31.Wurm EM, Curchin CE, Lambie D, Longo C, Pellacani G, Soyer HP. Confocal features of equivocal facial lesions on severely sun-damaged skin: four case studies with dermatoscopic, confocal, and histopathologic correlation. J Am Acad Dermatol 2012;66:463–73. [DOI] [PubMed] [Google Scholar]
- 32.Peppelman M, Nguyen KP, Hoogedoorn L, van Erp PE, Gerritsen MJ. Reflectance confocal microscopy: non-invasive distinction between actinic keratosis and squamous cell carcinoma. J Eur Acad Dermatol Venereol 2015;29:1302–9. [DOI] [PubMed] [Google Scholar]
- 33.Ulrich M, Kanitakis J, Gonzalez S, Lange-Asschenfeldt S, Stockfleth E, Roewert-Huber J. Evaluation of Bowen disease by in vivo reflectance confocal microscopy. Br J Dermatol 2012;166:451–3. [DOI] [PubMed] [Google Scholar]
- 34.Shahriari N, Grant-Kels JM, Rabinovitz HS, Oliviero M, Scope A. Reflectance Confocal Microscopy Criteria of Pigmented Squamous Cell Carcinoma In Situ. Am J Dermatopathol 2018;40:173–9. [DOI] [PubMed] [Google Scholar]
- 35.Manfredini M, Longo C, Ferrari B, Piana S, Benati E, Casari A et al. Dermoscopic and reflectance confocal microscopy features of cutaneous squamous cell carcinoma. J Eur Acad Dermatol Venereol 2017;31:1828–33. [DOI] [PubMed] [Google Scholar]
- 36.Moscarella E, Rabinovitz H, Zalaudek I, Piana S, Stanganelli I, Oliviero MC et al. Dermoscopy and reflectance confocal microscopy of pigmented actinic keratoses: a morphological study. J Eur Acad Dermatol Venereol 2015;29:307–14. [DOI] [PubMed] [Google Scholar]
- 37.Tan JM, Lambie D, Sinnya S, Sahebian A, Soyer HP, Prow TW et al. Histopathology and reflectance confocal microscopy features of photodamaged skin and actinic keratosis. J Eur Acad Dermatol Venereol 2016;30:1901–11. [DOI] [PubMed] [Google Scholar]
- 38.Langley RG, Burton E, Walsh N, Propperova I, Murray SJ. In vivo confocal scanning laser microscopy of benign lentigines: comparison to conventional histology and in vivo characteristics of lentigo maligna. J Am Acad Dermatol 2006;55:88–97. [DOI] [PubMed] [Google Scholar]
- 39.Bassoli S, Rabinovitz HS, Pellacani G, Porges L, Oliviero MC, Braun RP et al. Reflectance confocal microscopy criteria of lichen planus-like keratosis. J Eur Acad Dermatol Venereol 2012;26:578–90. [DOI] [PubMed] [Google Scholar]
- 40.de Carvalho N, Farnetani F, Ciardo S, Ruini C, Witkowski AM, Longo C et al. Reflectance confocal microscopy correlates of dermoscopic patterns of facial lesions help to discriminate lentigo maligna from pigmented nonmelanocytic macules. Br J Dermatol 2015;173:128–33. [DOI] [PubMed] [Google Scholar]
- 41.Pezzini C, Mandel VD, Persechino F, Ciardo S, Kaleci S, Chester J et al. Seborrheic keratoses mimicking melanoma unveiled by in vivo reflectance confocal microscopy. Skin Res Technol 2018. [DOI] [PubMed] [Google Scholar]
- 42.Richtig E, Hofmann-Wellenhof R, Kopera D, El-Shabrawi-Caelen L, Ahlgrimm-Siess V. In vivo analysis of solar lentigines by reflectance confocal microscopy before and after Q-switched ruby laser treatment. Acta Derm Venereol 2011;91:164–8. [DOI] [PubMed] [Google Scholar]
- 43.Yelamos O, Cordova M, Blank N, Kose K, Dusza SW, Lee E et al. Correlation of Handheld Reflectance Confocal Microscopy With Radial Video Mosaicing for Margin Mapping of Lentigo Maligna and Lentigo Maligna Melanoma. JAMA Dermatol 2017;153:1278–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Peppelman M, Wolberink EA, Koopman RJ, van Erp PE, Gerritsen MJ. In vivo Reflectance Confocal Microscopy: A Useful Tool to Select the Location of a Punch Biopsy in a Large, Clinically Indistinctive Lesion. Case Rep Dermatol 2013;5:129–32. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Figure 1: Basal cell carcinoma (BCC). A. RCM mosaic (1.7 × 1.5 mm), at the superficial dermis level, of a nodular BCC showing tumor islands (yellow asterisks) with palisading (yellow arrows) and clefting (white arrows). The surrounding stroma displays bright collagen bundles (green arrows). In addition, there are dilated vessels (red arrows) coursing parallel to the en face imaging plane. B. Corresponding histopathological section (Hematoxylin and Eosin, 10×) showing basaloid neoplastic aggregates (yellow asterisks), with peripheral palisading and adjacent mucin-filled clefts (white arrows). There is fibroplasia (green arrows) and prominent vascularity (red arrows) in the surrounding stroma. C. RCM image (0.75 × 0.75 mm) of a nodular BCC showing cord-like tumor structures (red arrows) with palisading (yellow arrows) and clefting (blue arrows). There are also tumor islands (yellow asterisks). D. Corresponding histopathological section showing anastomosing neoplastic aggregates (red arrow) which emanate from the undersurface of an atrophic epidermis. The neoplastic aggregates are immersed in a mucinous stroma (blue arrows) (Hematoxylin and Eosin, 10X).
Supplementary Figure 2: Squamous cell carcinoma in situ. A. RCM mosaic (3.0 × 2.0 mm) image at the spinous-granular/dermoepidermal junction layer showing atypical honeycomb pattern (yellow asterisks), dilated vessels looping the dermal papillae (so called “buttonhole vessels”; red arrows), and bright dyskeratotic cells (yellow arrows). The insert is showing a regular honeycomb pattern of normal skin to compare. B. Corresponding histopathological section (Hematoxylin and Eosin, 10X) showing a full-thickness epidermal atypia with crowding, pleomorphism and disarray of nuclei and with dyskeratotic cells (yellow arrows). In addition, there are tortuous looping blood vessels traversing the dermal papillae (red arrows). C. RCM image (0.75 × 0.75 mm) at the spinous-granular layer showing disarranged honeycomb pattern (yellow asterisks) and bright dyskeratotic cells (yellow arrows). The insert is showing a regular honeycomb pattern of normal skin to compare. D. Corresponding histopathological section showing full thickness epidermal atypia with nuclear pleomorphism (asterisk) and dyskeratotic cells (yellow arrows) (Hematoxylin and Eosin, 20X).
Supplementary Figure 3: Solar lentigo / lichen planus-like keratosis (LPLK) / seborrheic keratosis. A. RCM mosaic (2.5 × 2.5 mm), at the dermoepidermal-junction, showing polycyclic dermal papillae (red arrows) and bulbous projections (green arrows) of a solar lentigo on the left-side of the image and inflammatory infiltrate composed of plump bright cells (blue arrows) and small bright cells (yellow arrows) of a LPLK on the right-side of the image (white dashed square area). B. Corresponding histopathological section (from the dashed square on panel A on RCM) shows the area of lichen planus-like keratosis with inflammatory infiltrate composed of melanophages (blue arrows) and lymphocytes (yellow arrows) (Hematoxylin and Eosin, 20X). C. RCM mosaic (3.0 × 3.5 mm), at the suprabasal epidermis layer, of a seborrheic keratosis showing keratin plugs and crypts (yellow arrows), C- and S-shaped vessels (green arrows), and inflammatory infiltrate (white arrows). D. Corresponding histopathological section (from the dashed square on panel C on RCM) shows an inflamed seborrheic keratosis with keratin plugs (yellow arrows), dilated vessels (green arrows), and lymphocytes (white arrows) (Hematoxylin and Eosin, 20X).