10.5826/dpc.1204a162
Introduction: In vivo reflectance confocal microscopy (RCM) is a useful tool for assessing pre-surgical skin tumor margins when performed by a skilled, experienced user. The technique, however, poses significant challenges to novice users, particularly when a handheld RCM (HRCM) device is used.
Objective: To evaluate the performance of an HRCM device operated by a novice user to delineate basal cell carcinoma (BCC) margins before Mohs micrographic surgery (MMS)
Methods: We performed a prospective study of 17 consecutive patients with a BCC in a high-risk facial area (the H zone) in whom tumor margins were assessed by HRCM and dermoscopy before MMS. Predicted surgical defect areas (cm2) were calculated using standardized photographic digital documentation and compared to final defect areas after staged excision.
Results: No significant differences were observed between median HRCM-predicted and observed surgical defect areas (2.95 cm2 [range: 0.83–17.52] vs 2.52 cm2 [range 0.71–14.42]; p=0.586). Dermoscopy, by contrast, produced significantly underestimated values (median area of 1.34 cm2 [0.41-4.64] vs 2.52 cm2 [range 0.71-14.42]; p&lt;0.001). Confounders leading to poor agreement between predicted and observed areas were previous treatment (n=5), a purely infiltrative subtype (n=1), and abundant sebaceous hyperplasia (n=1).
Conclusion: Even in the hands of a novice user, HRCM is more accurate than dermoscopy for delineating lateral BCCs margins in high-risk areas and performs well at predicting final surgical defects.
text/xml
2160-9381
2046
en
Oriol Yélamos
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
margin control
Challenges for new adopters in pre-surgical margin assessment by handheld reflectance confocal microscope of basal cell carcinoma; a prospective single-center study
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2022-10-31
2021-10-25
2022-10-31
2023-06-06
e2022162
Dermatol Pract Concept
Introduction: In vivo reflectance confocal microscopy (RCM) is a useful tool for assessing pre-surgical skin tumor margins when performed by a skilled, experienced user. The technique, however, poses significant challenges to novice users, particularly when a handheld RCM (HRCM) device is used.
Objective: To evaluate the performance of an HRCM device operated by a novice user to delineate basal cell carcinoma (BCC) margins before Mohs micrographic surgery (MMS)
Methods: We performed a prospective study of 17 consecutive patients with a BCC in a high-risk facial area (the H zone) in whom tumor margins were assessed by HRCM and dermoscopy before MMS. Predicted surgical defect areas (cm2) were calculated using standardized photographic digital documentation and compared to final defect areas after staged excision.
Results: No significant differences were observed between median HRCM-predicted and observed surgical defect areas (2.95 cm2 [range: 0.83–17.52] vs 2.52 cm2 [range 0.71–14.42]; p=0.586). Dermoscopy, by contrast, produced significantly underestimated values (median area of 1.34 cm2 [0.41-4.64] vs 2.52 cm2 [range 0.71-14.42]; p&lt;0.001). Confounders leading to poor agreement between predicted and observed areas were previous treatment (n=5), a purely infiltrative subtype (n=1), and abundant sebaceous hyperplasia (n=1).
Conclusion: Even in the hands of a novice user, HRCM is more accurate than dermoscopy for delineating lateral BCCs margins in high-risk areas and performs well at predicting final surgical defects.
Oriol Yélamos
2022/10/31
10.5826/dpc.1204a162
e2022162
Dermatology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain; Dermatology Department, Centro Médico Teknon - Quirónsalud, Barcelona, Spain
2160-9381
margin control
en
e2022162
Challenges for new adopters in pre-surgical margin assessment by handheld reflectance confocal microscope of basal cell carcinoma; a prospective single-center study
https://dpcj.org/index.php/dpc/article/download/2046/1767
        Challenges for New Adopters in Pre-Surgical
        Margin Assessment by Handheld Reflectance
        Confocal Microscope of Basal Cell Carcinoma;
             A Prospective Single-center Study
Nina Anika Richarz1,2,3, Aram Boada 1,2,3, Ane Jaka1,2,3, Julio Bassas1,2,3, Carlos Ferrándiz1,2,3,
                       José Manuel Carrascosa1,2,3, Oriol Yélamos 4,5


1 Dermatology Department, University Hospital Germans Trial i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
2 Institut d’investigació Germans Trias Badalona, Barcelona, Spain.
3 Universitat Autònoma de Barcelona, Barcelona, Spain.
4 Dermatology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain.
5 Dermatology Department, Centro Médico Teknon - Quirónsalud, Barcelona, Spain.



Key words: reflectance confocal microscopy, basal cell carcinoma, micrographic Mohs surgery, margin control
Citation: Richarz NA, Boada A, Jaka A, et al. Challenges for New Adopters in Pre-Surgical Margin Assessment by Handheld Reflectance
Confocal Microscope of Basal Cell Carcinoma; A Prospective Single-center Study. Dermatol Pract Concept. 2022;12(4):e2022162. DOI:
https://doi.org/10.5826/dpc.1204a162
Accepted: February 9, 2022; Published: October 2022
Copyright: ©2022 Richarz et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-
NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use,
distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing interests: None.
Authorship: All authors have contributed significantly to this publication.




  ABSTRACT             Introduction: In vivo reflectance confocal microscopy (RCM) is a useful tool for assessing pre-­surgical
                       skin tumor margins when performed by a skilled, experienced user. The technique, however, poses
                       significant challenges to novice users, particularly when a handheld RCM (HRCM) device is used.
                       Objectives: To evaluate the performance of an HRCM device operated by a novice user to delineate
                       basal cell carcinoma (BCC) margins before Mohs micrographic surgery (MMS).
                       Methods: Prospective study of 17 consecutive patients with a BCC in a high-risk facial area (the H zone)
                       in whom tumor margins were assessed by HRCM and dermoscopy before MMS. ­Predicted surgical
                       ­defect areas (cm2) were calculated using standardized photographic digital documentation and com-
                        pared to final defect areas after staged excision.
                       Results: No significant differences were observed between median HRCM-predicted and observed
                       surgical defect areas (2.95 cm2 [range: 0.83–17.52] versus 2.52 cm2 [range 0.71–14.42]; P = 0.586).
                       Dermoscopy, by contrast, produced significantly underestimated values (median area of 1.34 cm2




Review | Dermatol Pract Concept. 2022;12(4):e2022162                                                                                  1
                      [0.41-4.64] versus 2.52 cm2 [range 0.71-14.42]; P < 0.001). Confounders leading to poor agreement
                      between predicted and observed areas were previous treatment (N = 5), a purely infiltrative subtype
                      (N = 1), and abundant sebaceous hyperplasia (N = 1).
                      Conclusions: Even in the hands of a novice user, HRCM is more accurate than dermoscopy for delin-
                      eating lateral BCCs margins in high-risk areas and performs well at predicting final surgical defects.




Corresponding author: Nina A. Richarz, MD, Department of
Dermatology University Hospital Germans Trias i Pujol. Address:
                                                                    Objectives
Carretera de Canyet s/n, 08916 Badalona, Barcelona, Spain. Phone:
+34 934651200, E-mail: richarznina@gmail.com                        The aim of this study was to investigate the performance of a
                                                                    handheld RCM (HRCM) device operated by a user with 1-year
                                                                    experience in this technique for lateral margin a­ ssessment in
Introduction                                                        BCCs in high-risk locations in a real-life ­clinical setting.

Basal cell carcinoma (BCC) is the most common skin can-
cer and its incidence is rising worldwide due to chronic UV         Methods
exposure and aging [1]. While the vast majority of BCCs at
                                                                    We prospectively included consecutive patients with
sites such as the trunk and extremities can be removed by
                                                                    non-pigmented, ill-defined, biopsy-proven BCCs located in
simple excision or local destructive therapies, tumors located
                                                                    high-risk areas of the face treated with MMS at our der-
in high-risk areas such as the H zone (central area of the
                                                                    matology department between August 2020 and September
face, around the eyes, nose, lips, and ears) are at greater risk
                                                                    2021. The study was approved by the hospital ethics com-
of destructive local spread and recurrence. Effective surgical
                                                                    mittee, and informed written consent was obtained from all
treatment is essential for guaranteeing tumor-free margins
                                                                    participants prior to enrolment. The study was conducted
and maximal functional and cosmetic outcomes in BCCs
                                                                    according to the principles of the Declaration of Helsinki.
that are clinically ill defined and those in high-risk areas,
                                                                        The target lesions were imaged using the Vivascope 3000
with an aggressive histologic subtype (micronodular, mor-
                                                                    HRCM device (MAVIG/Caliber ID), which has a horizon-
pheaform, basosquamous, infiltrative), or a history of in-
                                                                    tal resolution of ~1 μm, optical sectioning of ~3 μm, and a
complete excision.
                                                                    field of view of 0.75 × 0.75 mm. The images were captured
    Mohs micrographic surgery (MMS) with rapid intraop-
                                                                    in vivo before surgery by an investigator (NR) with 1-year
erative histologic confirmation of full tumor margins offers
                                                                    experience who had attended an RCM course and received
the highest success rates in the excision of facial BCCs [2].
                                                                    2 months practical training at a reference unit.
MMS, however, requires advanced surgical and histopatho-
                                                                        The clinical margins were first determined by dermos-
logic skills and support from histotechnicians with expe-
                                                                    copy and marked on the skin using a silver paint marker
rience in this procedure. There may also be financial and
                                                                    (Edding 780 creative 0.8 mm, Edding International. These
resource-related obstacles. Reflectance confocal microscopy
                                                                    markings facilitated RCM navigation and margin calculation
(RCM) might facilitate BCC margin mapping prior to MMS
                                                                    since ­silver ink can be visualized by RCM [6]. The margins
as it can be used to delineate lateral tumor margins that can-
                                                                    were then determined using HRCM and the original silver
not be determined clinically or by dermoscopy [3,4]. Studies
                                                                    markings readjusted to the distance of one field of view (0.75
of the use of RCM in this setting, however, have involved
                                                                    x 0.75) between the last inside tumor island to the internal
users with more than 5-years experience in image navigation
                                                                    side of the silverpen delineation. Using a method previously
and interpretation [3,5-9]. In addition, most of the lesions
                                                                    described by a member of our team (OY) [12], we produced
investigated were located on flat, even surfaces on the face
                                                                    standardized photographic documentation containing digi-
or trunk, where natural skin folds and bony prominences,
                                                                    tal images of the lesions before and after dermoscopy, before
such as those found in the H zone, do not interfere with nav-
                                                                    and after RCM, and during and after MMS. These images
igation. With the recent approval of new Current Procedural
                                                                    were then calibrated in ImageJ (NIH, available from http://
Terminology (CPT) codes for RCM imaging and evaluation
                                                                    imagej.nih.gov/ij/) using anthropometric measurements and
in the United States and the advent of lower-cost RCM de-
                                                                    a surgical ruler placed in the image field. The same soft-
vices, the number of users is expected to increase [10,11].
                                                                    ware was used to calculate surgical defect areas predicted
                                                                    by dermoscopy and HRCM. A 3-mm margin was added to




2                                                                               Review | Dermatol Pract Concept. 2022;12(4):e2022162
the predicted values as the MMS protocol at our hospital            (patient #12), another had a purely infiltrative component
requires histologic clearance of at least 3 mm. Images of the       (patient #14), and another had prominent sebaceous hyper-
final surgical defect were obtained before surgical recon-          plasia mistaken for tumor islands by the confocalist (patient
struction and the area was re-measured to compare it with           #3). Of the 4 patients with underestimated defect areas, 1 had
the dermoscopy- and HRCM-predicted areas.                           been treated with conventional surgery (patient #11), 1 with
   The surgeons who performed MMS (AJ, JB, GC) were                 curettage (patient #16), 1 with radiotherapy (patient #9), and
blinded to the dermoscopy and HRCM calculations, and,               1 with imiquimod (patient #5). These treatments had resulted
as per protocol, extended the dermoscopic margin by 3 mm            in scarring at different levels of the epidermis and/or dermis.
during the first excision stage. The excised specimen was fro-
zen and sectioned for microscopic examination of lateral and
                                                                    Conclusions
deep margins and, where necessary, the process was r­ epeated
until achievement of full histologic clearance.                     The main limitation of this study is its small sample size
                                                                    (17 consecutive patients), which was partly due to the
Statistical Analysis                                                COVID-19 pandemic, as fewer operations were performed
Descriptive statistics were used to describe the characteristics    and fewer patients agreed to participate in the study due to
of the cohort, lesion size, and predicted and observed surgi-       fear of infection by severe acute respiratory syndrome coro-
cal defect areas. Normal distribution was checked using the         navirus 2. Another notable limitation is the decreased resolu-
Kolmogorov-Smirnoff test. Since most of the variables were          tion offered by RCM at depths of greater than 200-250 μm.
non-normally distributed, non-parametric tests were used. The       Deep margin assessment with this technique is thus subopti-
Wilcoxon test was used to compare the final surgical defect         mal, particularly for purely infiltrative tumors, deep tumors,
area and the areas predicted by dermoscopy and HRCM. All            and tumors located under scar tissue [13]. Finally, since this
analyses were performed in SPSS version 22 (IBM corporation).       was a real-life bedside study involving live imaging, we were
                                                                    unable to assess the difficulty of each case and compare the
Results                                                             performance of the novice confocalist with that of an expert.
                                                                    Another limitation is that there is yet no follow-up of the
Seventeen consecutive patients (9 men and 8 women) agreed           cases available.
to participate in the study and underwent complete BCC ex-             The use of in vivo RCM imaging for the bedside diagnosis
cision by MMS (Table 1). The median age at the time of              and histologic subtyping of BCC and other skin cancers has
HRCM examination was 70 years (range: 46–86 years).                 gained popularity in the past decade [13-15]. Its usefulness
Thirteen tumors were located on the nose, 2 on the temple,          in the assessment of lateral margins has been demonstrated
and 1 each on the ear and inner canthus of the eye ­(Figure 1).     in nodular and superficial BCCs located on flat surfaces such
Four patients had previously undergone conventional sur-            as the cheek, forehead, and trunk [3,5,6]. Candidates for
gery at the same site and had had positive margins or ex-           MMS, however, usually have lesions in high-risk areas of the
perienced recurrence. Another 4 patients had been treated           face, where performance of wide-probe RCM is complicated
with cryotherapy, curettage, or topical imiquimod and 2 had         by skin elasticity and the presence of concave and convex
undergone radiotherapy. Salvage MMS was performed in                surfaces. HRCM, by contrast, offers advantages in uneven
one patient in whom oral vismodegib had been discontin-             locations, as it allows for free-form navigation. It also pres-
ued after 4 months due to adverse effects. Fourteen patients        ents challenges, however, especially for new users working
(82.3%) had an infiltrative BCC component on histology, 2           in real-life settings, as unlike wide-probe RCM, it does not
had a nodular/superficial subtype, and 1 had a superficial,         have mosaicking capabilities. Image acquisition is therefore
undetermined subtype (Table 1).                                     heavily user dependent.
   A median of 2 MMS stages (range: 1–4) were needed to                This prospective study analyzed the use of HRCM in the
achieve tumor-free margins after margin delineation with der-       assessment of BCC margins prior to MMS in clinical prac-
moscopy (Table 1). Dermoscopy underestimated the f­inal sur-        tice at a single institution. Our results suggest that, even in
gical defect area by a median of 1.18 cm2 (1.34 cm2 [range:         the hands of novice operators and in challenging locations
0.41–4.64] versus 2.52 cm2 [range: 0.71–14.42]; P < 0.001).         such as the nose, HRCM outperforms dermoscopy. In more
There were no statistical differences between the HRCM-pre-         complex cases, however, such as tumors previously treated
dicted area and the final area (2.95 cm2 [range: 0.83–17.52]        with radiotherapy, surgery, or imiquimod, it may produce
versus 2.52 cm2 [range: 0.71–14.42]; P = 0.586). HRCM,              less accurate results due to the presence of scar tissue im-
however, overestimated defect size in three cases and underesti-    peding visualization of tumor structures. Other difficulties
mated it in four (Figure 2). Of the 3 patients with overestimated   include recognition of infiltrative BCC components or BCC
defect areas, 1 had been previously treated by radiotherapy



Review | Dermatol Pract Concept. 2022;12(4):e2022162                                                                                  3
4
                                                       Table 1. Summary of demographic and BCC characteristics and comparison of surgical defect areas predicted by HRCM and dermoscopy and observed
                                                                                                                       after MMS.
                                                                                                                                                                               Dermoscopy-                                Final
                                                                                                                                                                                predicted         HRCM-predicted        surgical     No. of
                                                                                                                                                                              surgical defect   surgical defect area   defect area    MMS
                                                          Case        Sex     Age (y)        BCC location                BCC subtype             Treatment before RCM           area (cm2 )            (cm2)              (cm2)      stages
                                                            1         M          83      Nasal tip               Nodular /infiltrative           Surgery in 2012,                   4.727              4.687              4.364        1
                                                                                                                                                 vismodegib for 4
                                                                                                                                                 months in 2017
                                                            2         M          42      Nasal ala               Nodular/adenoid/                Surgery with positive              1.082              0.803              0.818        2
                                                                                                                 micronodular                    margins in 2019
                                                            3         M          86      Nose                    Superficial multifocal/                                            2.114              4.148              2            1
                                                                                                                 nodular/infiltrative
                                                            4         M          76      Nose                    Superficial/nodular                                                2.191              3.326              3.468        3
                                                            5         M          68      Tip/dorsum of nose      Superficial multifocal/         Imiquimod                          3.614              2.718              3.968        2
                                                                                                                 nodular
                                                            6          F         68      Nasal ala               Infiltrative/micronodular                                          2.725              2.947              2.874        1
                                                            7         M          84      Ear                     Nodular/infiltrative            Cryotherapy                        2.149              2.249              2.125        2
                                                            8          F         71      Nose                    Infiltrative                                                       1.72               1.87               1.794        1
                                                            9         M          70      Nasal ala               Infiltrative/micronodular       Radiotherapy                       2.612              3.261              7.647        4
                                                           10          F         46      Temple                  Infiltrative/superficial        Surgery in 2015                    6.351              8.426              8.423        2
                                                                                                                                                 cryotherapy, imiquimod
                                                           11         M          82      Nose                    Infiltrative/superficial/       Curettage +                        6.559              5.379              7.124        1
                                                                                                                 nodular                         electro-coagulation
                                                           12          F         52      Nasal tip               Superficial/undefined           Radiotherapy                       0.977              6.83               0.71         1
                                                           13          F         68      Nasal ala               Micronodular                                                       2.509              2.505              2.357        3
                                                           14          F         73      Temple                  Micronodular/infiltrative                                          5.13              17.519            14.416         4
                                                           15          F         78      Nasal tip               Infiltrative/micronodular                                          1.044              1.06               1.105        3
                                                           16         M          60      Inner canthus of eye Infiltrative                       Surgery in 2020                    1.753              1.832              2.52         1
                                                           17          F         53      Nasal ala               Infiltrative                                                       1.106              1.115              1.03         1
                                                       BCC = basal cell carcinoma; F = female; HRCM = handheld reflectance confocal microscopy; M = male; MMS = micrographic Mohs surgery.




Review | Dermatol Pract Concept. 2022;12(4):e2022162
                                                                        mimickers, such as sebaceous hyperplasia, hair follicles, and
                                                                        eccrine glands (Table 2). Novice users need to be familiar
                                                                        with normal skin structures and aware of the limitations
                                                                        of HCRM. We believe that image-reading challenges can
                                                                        be overcome by ensuring that training programs, in addi-
                                                                        tion to focusing on pathologic characteristics of tumors,
                                                                        include content on normal skin structures, mimickers, and
                                                                        RCM limitations. This knowledge should shorten the learn-
                                                                        ing curve. Rapid feedback from experienced confocalists via
                                                                        image-sharing platforms in cases of doubt could also be very
                                                                        valuable. Scouting biopsies are useful in complex cases as
                                                                        they can help differentiate tumors from benign structures
                                                                        or scar tissue, especially when working at depths of greater
                                                                        than 200-250 µm. A summary of the above challenges and
                                                                        proposed solutions is given in Table 2.
                                                                            Although HRCM has cellular resolution, it presents some
                                                                        technical challenges. Navigation in the horizontal plane, for
                                                                        example, can be problematic due to loss of reference points
                                                                        and the impossibility of building an overall mosaic of the
                                                                        lesion. Visualization thus is restricted to a small field of vi-
                                                                        sion (0.75 × 0.75 mm or 1 × 1 mm depending on the gener-
    Figure 1. Locations of basal cell carcinomas (red circles)
                                                                        ation of microscope). Patient breathing and movement can
    included in the study. High-risk areas are shown in orange.




Figure 2. Representative cases of basal cell carcinoma (BCC) showing good agreement between surgical defect areas predicted by handheld
reflectance confocal microscopy (HRCM) and the defect areas after Mohs micrographic surgery (MMS) (A-D), overestimated defect areas
(E-H), and underestimated defect areas (I-L). (A) Similarity between the HRCM-predicted surgical defect area (blue line) and the final area
(B) in a BCC with evident tumor islands seen by RCM (C) and a nodular subtype identified in the intraoperative frozen section (D). (E)
HRCM-predicted surgical defect area in a BCC previously treated with radiotherapy that was significantly larger than the final defect area
after MMS (F). HRCM images of radiation-induced dermal fibrosis (G) were mistaken for collagen surrounding deep tumor islands, but
these were ruled out by histology (H). The HRCM–predicted surgical defect area in (I) was significantly smaller than the final area (J) in a
superficial, infiltrative BCC visible by HRCM (K) and histology (L).



Review | Dermatol Pract Concept. 2022;12(4):e2022162                                                                                      5
    Table 2. Basal cell carcinoma margin delineation by HRCM: limitations, challenges for new users,
                                        and proposed solutions.
                Image-reading challenges/limitations                                          Proposed solutions
 Infiltrative subtypes (no clear tumor islands or clefting but dark          Training in image reading
 silhouettes that appear as imprints embedded in bright collagen)            Scouting biopsies
                                                                             Combined use of OCT
                                                                             Platforms for consulting with RCM experts
 Limited penetration depth for delineating deep margins                      Combined use of OCT to explore vertical planes
 Prominent sebaceous hyperplasia, hair follicles, and eccrine glands         Training in image reading
 that can be mistaken for tumor islands in facial BCC                        Scouting biopsies
                                                                             Platforms for consulting with RCM experts
 Tissue distortion due to previous biopsies and treatments                   Training in image reading
                                                                             Scouting biopsies
 Technical challenges associated with horizontal plane navigation            Proposed solutions
 Loss of reference points due to small field of vision (0.75 × 0.75 mm       Integration of videomosaicking algorithm into
 or 1 × 1 mm) and lack of automated mosaicking capabilities                  native HRCM software
                                                                             Use of in vivo wide-field imaging to guide HRCM
                                                                             navigation
                                                                             Use of a robotic arm
 Image distortion due to patient breathing and movement                      Use of a a robotic arm
                                                                             Artificial intelligence image modeling to restore
                                                                             image aberrations
 Loss of direct contact with HRCM device over natural skin folds             Smaller-diameter HRCM lens to facilitate direct
 and bony prominences                                                        contact with the skin
                                                                             Use of a robotic arm
FOV = field of view; HRCM = handheld reflectance confocal microscopy; OCT = optical coherence tomography; RCM = reflectance confocal
microscopy.




also result in abrupt motion changes that can distort im-           well in the presurgical assessment of BCC margins. We have
ages. Distortion can also occur when navigating skin folds          also offered some suggestions on how performance can be
or bony prominences where it is impossible to establish a           further improved. RCM users often receive limited training
flat contact (Table 2). Newer multimodal systems such as            in image acquisition and interpretation. They typically learn
combined RCM and optical coherence tomography (OCT)                 by experience and feedback (based on pathology reports, for
and line-field confocal OCT allow for deeper tissue imaging         example). While this also has positive effects, the learning
and improved accuracy in the delineation of lateral and deep        curve could be shortened by designing certificate training
tumor margins [10,17]. The problem of reference point loss          courses and mentoring programs, establishing image-sharing
could be overcome by using in vivo wide-field imaging to            platforms for consultations between novice and experienced
guide the horizontally moving device over the skin surface          users, and integrating novel technical advances, such as mul-
(Table 2) [18]. HRCM video-mosaicking can also be used to           timodal imaging and artificial intelligence. Nevertheless, our
create static images from dynamic videos, enabling improved         findings show that, even in difficult conditions, HCRM op-
navigation and interpretation and facilitating comparisons          erated by a single, novice user, performed well in the delin-
between confocalists [8,12,19]. A subsequent image process-         eation of BCC margins and provided very useful data for
ing step is necessary, however, as in vivo video-mosaicking is      application in everyday clinical practice.
not currently available in native HRCM software. Other op-
tions for more precise imaging over uneven surfaces include         References
the use of robotics or HRCM devices with a smaller optical
                                                                     1. Lomas A, Leonardi-Bee J, Bath-Hextall F. A systematic r­eview of
lens for improved skin contact.
                                                                        worldwide incidence of nonmelanoma skin cancer. Br J Derma-
     Although the number of RCM users is growing world-                 tol. 2012;166(5):1069–1080. DOI: 10.1111/j.1365-2133.2012.​
wide and will continue to grow following the recent approval            10830.x. PMID: 22251204.
of RCM CPT codes in the United States, expert users are still        2. Van Loo E, Mosterd K, Krekels GAM, et al. Surgical excision versus
limited in number. We have shown that an HRCM device op-                Mohs’ micrographic surgery for basal cell carcinoma of the face:
                                                                        A randomised clinical trial with 10 year follow-up. Eur J Cancer.
erated by a novice user in real-life clinical practice performs



6                                                                               Review | Dermatol Pract Concept. 2022;12(4):e2022162
      2014;50(17):3011–3020. DOI: 10.1016/j.ejca.2014.08.018.                       contrast enhancer. Dermatologic Surg. 2003;29(8):839–846.
      PMID: 25262378.                                                               DOI: 10.1046/j.1524-4725.2003.29219.x. PMID: 12859385.
 3.   Pan ZY, Lin JR, Cheng TT, Wu JQ, Wu WY. In vivo reflectance con-        10.   Rajadhyaksha M, Marghoob A, Rossi A, Halpern AC NK.
      focal microscopy of basal cell carcinoma: Feasibility of preoperative         ­Reflectance Confocal Microscopy of skin in vivo: From bench
      mapping of cancer margins. Dermatologic Surg. 2012;38(12):­1945–               to bedside. Lasers Surg Med. 2017;49(1):7–19. DOI: 10.1002/
      1950. DOI: 10.1111/j.1524-4725.2012.02587.x. PMID: 23039159.                   lsm.22600. PMID: 27785781. PMCID: PMC5575825.
      PMCID: PMC3546396.                                                      11.    Freeman EE, Semeere A, Osman H, et al. Smartphone confocal
 4.   Iftimia N, Yélamos O, Chen C-SJ, et al. Handheld optical ­coherence            microscopy for imaging cellular structures in human skin in vivo.
      tomography–reflectance confocal microscopy probe for detection                 Biomed Opt Express. 2018;9(4):1906-1915. DOI: 10.1364/
      of basal cell carcinoma and delineation of ­margins. J Biomed Opt.             BOE.9.001906. PMID: 29675328. PMCID: PMC5905933.
      2017;22(7):076006. DOI: 10.1117/1.JBO.22.7.076006. PMID:                12.    Yélamos O, Cordova M, Blank N, et al. Margin ­mapping of Lentigo
      28697233. PMCID: PMC5995139.                                                   maligna and Lentigo maligna melanoma ­using handheld reflectance
 5.   Venturini M, Gualdi G, Zanca A, Lorenzi L, Pellacani G,                        confocal microscopy with radial videomosaicking: a prospective
      Calzavara-Pinton PG. A new approach for presurgical margin                     concordance study. JAMA Dermatol. 2017;153(12):1278–1284.
      assessment by reflectance confocal microscopy of basal cell car-               DOI: 10.1001/jamadermatol.2017.3114. PMID: 29049429.
      cinoma. Br J Dermatol. 2016;174(2):380–385. DOI: 10.1111/                      ­PMCID: PMC5730495.
      bjd.14244. PMID: 26498991.                                              13.     Longo C, Borsari S, Pampena R, et al. Basal cell carcinoma: the
 6.   Aleissa S, Navarrete-Dechent C, Banzhaf CA, et al. Using a me-                  utility of in vivo and ex vivo confocal microscopy. J Eur Acad
      tallic ink pen to assist in the demarcation of skin lesions un-                 Dermatology Venereol. 2018;32(12):2090–2096. DOI: 10.1111/
      der reflectance confocal microscopy. J Am Acad Dermatol.                        jdv.14984. PMID: 29633358.
      2019;81(6):e173–e174. DOI: 10.1016/j.jaad.2019.04.062. PMID:            14.     Nori S, Rius-Díaz F, Cuevas J, et al. Sensitivity and specificity of
      31078611.                                                                       reflectance-mode confocal microscopy for in vivo diagnosis of
 7.   Gualdi G, Venturini M, Zanca A, Calzavara-Pinton PG,                            basal cell carcinoma: A multicenter study. J Am Acad Dermatol.
    Pellacani G. Pre-surgical basal cell carcinoma margin                         2004;51(6):923–930. DOI: 10.1016/j.jaad.2004.06.028. PMID:
    definition: The SMART approach. J Eur Acad Dermatology Ve-                    15583584.
    nereol. 2016;30(3):474–476. DOI: 10.1111/jdv.12858. PMID:                 15. Longo C, Lallas A, Kyrgidis A, et al. Classifying distinct basal cell
    25413728.                                                                     carcinoma subtype by means of dermatoscopy and reflectance
 8. Flores E, Yélamos O, Cordova M, et al. Peri-operative delinea-                confocal microscopy. J Am Acad Dermatol. 2014;71(4):716-724.
    tion of non-melanoma skin cancer margins in vivo with hand-                   e1. DOI: 10.1016/j.jaad.2014.04.067. PMID: 24928707.
    held ­reflectance confocal microscopy and video-mosaicking. J             16. Sahu A, Yélamos O, Iftimia N, et al. Evaluation of a Combined
    Eur Acad Dermatology Venereol. 2019;33(6):1084–1091. DOI:                     Reflectance Confocal Microscopy-Optical Coherence Tomogra-
    10.1111/jdv.15491. PMID: 30811707. PMCID: PMC6534461.                         phy Device for Detection and Depth Assessment of Basal Cell
 9. Tannous Z, Torres A, González S. In vivo real-time confocal                   Carcinoma. JAMA Dermatol. 2018;154(10):1175–1183. DOI:
    reflectance microscopy: A noninvasive guide for Mohs micro-                   10.1001/jamadermatol.2018.2446. PMID: 30140851. PMCID:
    graphic surgery facilitated by aluminum chloride, an excellent                PMC6179925.




Review | Dermatol Pract Concept. 2022;12(4):e2022162                                                                                                   7
17. Suppa M, Fontaine M, Dejonckheere G, et al. Line-field confocal
    optical coherence tomography of basal cell carcinoma: a descrip-
    tive study. J Eur Acad Dermatology Venereol. 2021;35(5):­1099-
    1110. DOI: 10.1111/jdv.17078. PMID: 33398911.
18. Dickensheets DL, Kreitinger S, Peterson G, Heger M, Rajad-
    hyaksha M. Wide-field imaging combined with confocal micros-
    copy using a miniature f/5camera integrated within a high NA
    ­objective lens. Opt Lett. 2017;42(7):1241–1244. DOI: 10.1364/
     OL.42.001241. PMID: 28362739. PMCID: PMC5597432.
19. Kose K, Gou M, Yélamos O, et al. Automated video-mosaicking
     approach for confocal microscopic imaging in vivo: An approach
     to address challenges in imaging living tissue and extend field
     of view. Sci Rep. 2017;7(1):10759. DOI: 10.1038/s41598-017-
     11072-9. PMID: 28883434. PMCID: PMC5589933.




8                                                                      Review | Dermatol Pract Concept. 2022;12(4):e2022162
