10.5826/dpc.1204a207
Background： Patients with multifocal superficial basal cell carcinomas (sBCC) require a non-invasive treatment and follow-up with a non-invasive technique. Imiquimod 5% cream is a new non-invasive therapy for BCC. Reflectance confocal microscopy (RCM) is a non-invasive, real-time imaging technique.
Methods：The efficacy of imiquimod 5% cream for the treatment of multifocal sBCC was evaluated, as well as the potential of RCM for assessing therapeutic effects. We reported four patients with 34 sBCC lesions were treated with imiquimod 5% cream. RCM was performed in the baseline and at 12 weeks, 24 weeks and 52 weeks after starting treatment.
Results： Of 34 lesions treated with imiquimod 5%, 32 responded to the treatment and showed complete clinical clearing. Two subclinical BCC lesions were identified by RCM. The complete tumor clearance&nbsp;rate&nbsp;was 88.2%, and the efficiency rate was 97.1%. No lesion recurred at 24-month follow-up. RCM identified previously described confocal features of BCC and was more sensitive than clinical examination. Local skin reactions were relieved&nbsp;after&nbsp;expectant&nbsp;treatment.
Conclusions： Imiquimod 5% cream may be useful for the treatment of multifocal sBCC, and its side effects are easy to manage. RCM can be used for non-invasive monitoring of treatment response and improved the tumor clearance&nbsp;rate.
&nbsp;
text/xml
2160-9381
2442
en
 Rushan  Xia
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
superficial basal cell carcinoma; imiquimod 5% cream; reflectance confocal microscopy；multifocal
Reflectance confocal microscopy follow-up of multifocal superficial basal cell carcinomas treated with imiquimod 5% cream
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2022-10-31
2022-03-06
2022-10-31
2022-12-05
e2022207
Dermatol Pract Concept
Background： Patients with multifocal superficial basal cell carcinomas (sBCC) require a non-invasive treatment and follow-up with a non-invasive technique. Imiquimod 5% cream is a new non-invasive therapy for BCC. Reflectance confocal microscopy (RCM) is a non-invasive, real-time imaging technique.
Methods：The efficacy of imiquimod 5% cream for the treatment of multifocal sBCC was evaluated, as well as the potential of RCM for assessing therapeutic effects. We reported four patients with 34 sBCC lesions were treated with imiquimod 5% cream. RCM was performed in the baseline and at 12 weeks, 24 weeks and 52 weeks after starting treatment.
Results： Of 34 lesions treated with imiquimod 5%, 32 responded to the treatment and showed complete clinical clearing. Two subclinical BCC lesions were identified by RCM. The complete tumor clearance&nbsp;rate&nbsp;was 88.2%, and the efficiency rate was 97.1%. No lesion recurred at 24-month follow-up. RCM identified previously described confocal features of BCC and was more sensitive than clinical examination. Local skin reactions were relieved&nbsp;after&nbsp;expectant&nbsp;treatment.
Conclusions： Imiquimod 5% cream may be useful for the treatment of multifocal sBCC, and its side effects are easy to manage. RCM can be used for non-invasive monitoring of treatment response and improved the tumor clearance&nbsp;rate.
&nbsp;
 Rushan  Xia
2022/10/31
10.5826/dpc.1204a207
e2022207
Department of Dermatology, Wuxi Second Affiliated Hospital of Nanjing Medical University, Wuxi, Jiangsu Province, China
2160-9381
superficial basal cell carcinoma; imiquimod 5% cream; reflectance confocal microscopy；multifocal
en
e2022207
Geisse JK, Rich P, Pandya A, etal. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: a double-blind, randomized, vehicle-controlled study. J Am Acad Dermatol. 2002 Sep;47(3):390-8. doi: 10.1067/mjd.2002.126215. PMID: 12196749.
Reflectance confocal microscopy follow-up of multifocal superficial basal cell carcinomas treated with imiquimod 5% cream
https://dpcj.org/index.php/dpc/article/download/2442/1788
       Reflectance Confocal Microscopy Follow-up of
        Multifocal Superficial Basal Cell Carcinomas
             Treated With Imiquimod 5% Cream
                                     Yunmin Zou1, Xiaohong Zhu1, Rushan Xia1


1 Department of Dermatology, The Affiliated Wuxi No.2 People’s Hospital of Nanjing Medical University Wuxi, Jiangsu Province, China



Key words: superficial basal cell carcinoma, imiquimod 5% cream, reflectance confocal microscopy, multifocal
Citation: Zou Y, Zhu X, Xia R. Reflectance confocal microscopy follow-up of multifocal superficial basal cell carcinomas treated with
imiquimod 5% cream. Dermatol Pract Concept. 2022;12(4):e2022207. DOI: https://doi.org/10.5826/dpc.1204a207
Accepted: March 28, 2022; Published: October 2022
Copyright: ©2022 Zou 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: Scientific Research Project of Wuxi Municipal Health Commission. (Q202141)
Competing interests: None.
Authorship: All authors have contributed significantly to this publication.
Corresponding author: Rushan Xia, Department of Dermatology, The Affiliated Wuxi No.2 People’s Hospital of Nanjing Medical
University, 68 Zhongshan Road, Wuxi, 214002, Jiangsu Province, China E-mail: wxeyxrs@163.com




  ABSTRACT             Introduction: Patients with multifocal superficial basal cell carcinomas (sBCC) require a non-in-
                       vasive treatment and follow-up with a non-invasive technique. Imiquimod 5% cream is a new
                       non-invasive therapy for BCC. Reflectance confocal microscopy (RCM) is a non-invasive, real-time
                       imaging technique.
                       Objectives: To evaluate and describe the feasibility and efficacy of imiquimod 5% cream for the treat-
                       ment of multifocal sBCC using RCM.
                       Methods: The efficacy of imiquimod 5% cream for the treatment of multifocal sBCC was evaluat-
                       ed, as well as the potential of RCM for assessing therapeutic effects. We reported four patients with
                       34 sBCC lesions were treated with imiquimod 5% cream. RCM was performed in the baseline and at
                       12 weeks, 24 weeks and 52 weeks after starting treatment.
                       Results: Of 34 lesions treated with imiquimod 5%, 32 responded to the treatment and showed com-
                       plete clinical clearing. Two subclinical BCC lesions were identified by RCM. The complete tumor clear-
                       ance rate was 88.2%, and the efficiency rate was 97.1%. No lesion recurred at 24-month follow-up.
                       RCM identified previously described confocal features of BCC and was more sensitive than clinical
                       examination. Local skin reactions were relieved after expectant treatment.
                       Conclusions: Imiquimod 5% cream may be useful for the treatment of multifocal sBCC, and its side
                       effects are easy to manage. RCM can be used for non-invasive monitoring of treatment response and
                       improved the tumor clearance rate.




Original Article | Dermatol Pract Concept. 2022;12(4):e2022207                                                                          1
Introduction                                                         histologically (Figure 1B). Each lesion was treated with 5%
                                                                     imiquimod cream (Aldara®; 3M Pharmaceuticals).
Basal cell carcinoma (BCC) is the most common skin cancer               Imiquimod 5% cream was applied once daily for 5 days/
worldwide. Although surgical treatment of BCC is the gold            week for 12 weeks. Treatment visit was performed once ev-
standard, patients may be reluctant to accept invasive treat-        ery two weeks. Treatment ended when there was no clini-
ment by reason of multifocal BCC-lesions. In recent years,           cal or RCM evidence. If there is no response or insufficient
non-invasive therapies have been widely used for the treatment       response, treatment was continued and reevaluated every
of superﬁcial (s)BCC [1,2]. Imiquimod is a new local treatment       2 weeks, until complete clinical response was obtained. The
that can remove tumor tissues without injuring the surround-         imiquimod cream was applied before going to bed and re-
ing normal tissues. However, histological evidence of tumor          moved with soap and water approximately 8 hours later. The
clearance is difficult to obtain. In vivo reflectance confocal mi-   treatment area was not covered except in cases of bleeding
croscopy (RCM) is a non-invasive, real-time imaging technique        or excessive discharge from the wound. Each treatment field
that provides near histologic level resolution cross-sectional       encompassed the lesion and 1.0 cm margins surrounding the
images of superficial layers of the skin. RCM can be used to         visible BCC lesion.
diagnose and monitor treatment effectiveness in BCC [3-5].              Each lesion was followed up by RCM (Vivascope 1500,
                                                                     Lucid Technologies) at 12 weeks, 24 weeks and 52 weeks af-
                                                                     ter the start of imiquimod treatment. Baseline and follow-up
Objectives
                                                                     images were collected. The RCM images were evaluated by
The aim of this study was to evaluate and describe the feasi-        two experienced physicians. If there was discordance between
bility and efficacy of imiquimod 5% cream for the treatment          the two evaluators, a consistent interpretation was obtained
of multifocal sBCC using RCM.                                        from a third reviewed. Therapeutic effects were determined
                                                                     by tumor size combined with RCM imaging features.

Methods
                                                                     Results
Four patients (3 females and 1 male) with diagnoses of
sBCC, with 2 or more lesions, and aged from 27 to 76 years           A total of 34 BCC lesions were included in the analysis. The
(mean 56 years) were included in the study.                          tumor size ranged from 0.5 to 3 cm in the maximum diam-
    The patients presented with 34 sBCC appearing as mild            eter (mean, 1.4 cm). Lesions were located in the neck area
reddish-brown patches and pigmented patches (Figure 1A).             (N = 3), scalp (N = 2), chest (N = 8), abdomen (N = 5), back
The patients were overall healthy and had no other symp-             (N = 5), lower extremities (N = 6), and upper extremities
toms associated with Gorlin Syndrome. All lesions were di-           (N = 5). The durations of the drug application period var-
agnosed clinically, and BCC features were confirmed under            ied from 8 weeks to 28 weeks, with an average of 18.6 ±
RCM. All the lesions were confirmed as superﬁcial (s)BCC             6.9 weeks.




Figure 1. (A) Multifocal BCCs in the chest area before treatment. (B) Histopathology showed the basaloid cords and basaloid island
­connected to the epidermis (H&E, magnification 40×).




2                                                                        Original Article | Dermatol Pract Concept. 2022;12(4):e2022207
Reflectance Confocal Microscopy Analysis                                residual BCC was detected by RCM in 4 of 34 sites (11.8%),
RCM imaging details are provided in Table 1. RCM crite-                 and there was no clinical manifestation in two lesions. The
ria previously described were used for the diagnosis of BCC             area of three lesions was obviously reduced, but no effect
[6-8]. The RCM criteria for the diagnosis of BCC include                was observed in one lesion. The complete tumor clear-
principal criteria (≧ 2 principal criteria present): tumor is-          ance rate was 88.2%, and the efficiency rate was 97.1%.
lands, elongated and polarized nuclei, peripheral palisading;           In the residual lesion, treatment with imiquimod 5% cream
and secondary criterion (≧ 3 secondary criterion present):              was discontinued, and surgical treatment was performed. No
keratinocyte atypia, cords connected to the epidermis, bright           lesion recurred at 24-month follow-up.
particles, peri-tumoral clefting, increased vascularization,
and dendritic cells inside tumor islands (Figure 2). At the             Local Skin Reactions
12-week, 24-week and 52-week follow-up evaluations,                     The patient is still under clinical and RCM monitoring. All
there was no RCM evidence in 22 lesions, 26 lesions, and                lesions had good cosmetic outcomes except hypopigmen-
30 lesions, respectively (Figure 3). At the 52-week follow-up,          tation in eight lesions (23.5%). Local skin reactions (LSR)


  Table 1. Reflectance confocal microscopy characteristics of basal cell carcinomas before (baseline)
                treatment with imiquimod and at 12, 24 and 52 weeks after treatment.
       Reflectance confocal                 Baseline,       12-week follow-up,          24-week follow-up, 52-week follow-up,
            microscopy                       % (No.)             % (No.)                     % (No.)            % (No.)
 Tumor islands                             82.4 (28)                23.5 (8)                   17.6 (6)                     2.9 (1)
 Elongated and polarized nuclei            79.4 (27)                23.5 (8)                   14.7 (5)                     2.9 (1)
 Peripheral palisading                     52.9 (18)                20.6 (7)                    8.8 (3)                       0 (0)
 Keratinocyte atypia                        100 (34)                35.3 (12)                  23.5 (8)                   11.8 (4)
 Peri-tumoral clefting                       17.6 (6)                5.9 (2)                      0 (0)                       0 (0)
 Dendritic cells inside                    97.1 (33)                35.3 (12)                  20.6 (7)                     8.8 (3)
 tumor islands
 Cords connected to the epidermis          94.1 (32)                32.4 (11)                  17.7 (6)                     5.9 (2)
 Increased vascularization                 82.4 (28)                26.5 (9)                    5.9 (2)                       0 (0)
 Bright particles                          70.6 (24)                35.3 (12)                  23.5 (8)                     5.9 (2)




Figure 2. Reflectance confocal microscopy (RCM) image of basal cell carcinoma (BCC). (A) Keratinocyte atypia (blue arrowheads).
(B) Increased vascularization (blue arrowheads). (C) Peri-tumoral clefting (blue arrowheads). (D)Tumor islands (blue arrowheads) and bright
particles (red arrowheads). (E) Elongated and polarized nuclei (red arrowheads). (F) Dendritic cells inside tumor islands (blue arrowheads).
(G) Cords connected to the epidermis (blue arrowheads). (H) Peripheral palisading (blue arrowheads).




Original Article | Dermatol Pract Concept. 2022;12(4):e2022207                                                                            3
Figure 3. Clinical and confocal images before treatment and during follow-up on the second lesion. (A) reddish-brown and pigmented
patches before treatment. (B) At the 12-week follow-up, the lesion presents with erythema and crusting induced by treatment. (C) At the
24-week follow-up, the lesion presents as a small residual tumor on the border. (D) At the 52-week follow-up, complete clearance, with
no sign of recurrence. (E)Before treatment, RCM shows tumor islands with peripheral palisading. (F) The12-week RCM follow-up shows
increased high-refractive particles inside the tumor. (G) The 24-week RCM follow-up shows irregular tumor islands and increased dendritic
cells inside tumor islands. (H) At the 52-week RCM follow-up, RCM showed regularly spaced cells composing a regular honeycomb pattern.



including erythema, edema, dryness, crusting, and erosion             bright particles in the epidermis (Figure 3F) after 12 weeks
were present in nine lesions (26.5%). They were relieved af-          of imiquimod application indicate that imiquimod 5% has
ter expectant treatment with moisturizer. Treatment was in-           initiated an immune response and is a reliable biomarker for
terrupted for 1 week or 2 weeks for recovery in serious cases.        predicting treatment response.
                                                                          Surgery is the gold standard for treatment of BCC. How-

Conclusions                                                           ever, in some cases such as elderly patients who are too frail to
                                                                      withstand excisional surgery, or patients with multifocal
RCM provides a useful, noninvasive tool for the diagno-               BCC-lesions, non-invasive therapies are needed. Studies eval-
sis of BCC. The presence of two or more RCM criteria is               uating BCCs of the trunk or extremities suggest that imiqui-
100% sensitive for the diagnosis of BCC, and with 4 or                mod is as effective as surgical treatment regarding clinical
more RCM criteria present the specificity was 95.7% [9].              cure rates and it achieves good to excellent cosmetic out-
In this study, 5 criteria or more present could be diagnosed          comes [10-11]. In this study, we also confirmed that imiqui-
as BCC, by which diagnostic coincidence rate was 100%                 mod 5% is effective for the treatment of multiple sBCCs.
comparing with pathological outcome. Our study confirmed              The complete tumor clearance rate was 88.2%, higher than
that imiquimod 5% cream is highly effective for the treat-            those of documents reported [1,2,12], which may be credited
ment of multifocal sBCC. Notably, RCM features were not               to RCM surveillance. The therapeutic regimens were differ-
present after treatment with imiquimod 5% cream in 30 of              ent in the previous studies [12-15]. Consistent with previous
34 lesions. Before treatment, the RCM criteria for the di-            studies [16-17], the imiquimod dosing regimen of 5 times per
agnosis of BCC were detected as described in Table 1. At              week for 12 weeks is an effective treatment for sBCC.
12 weeks after treatment, these RCM parameters were re-                   In this study, the most common side effects were ery-
duced by approximately 64.7 % of the initial values. At the           thema and hypopigmentation, and recovery was gradual.
52-week follow-up, clinical evaluation showed that 94.1%              The erythema may be a sign of an immune response in the
(32 of 34 lesions) achieved complete clearance, whereas               epidermis. LSRs mainly occurred during the first 3 months
RCM showed that 88.2% (30 of 34 lesions) of lesions had               of therapy.
lost BCC features. Residual BCC was identified upon RCM                   The present study had some limitations. This was an
examination in two lesions that did not present clinical man-         open study with no control group and it included only four
ifestation. RCM improved the tumor clearance rate during              patients. Larger clinical studies with longer follow-up peri-
follow-up. The presence of increased dendritic structures and         ods are necessary. In conclusion, we confirmed the efficacy



4                                                                          Original Article | Dermatol Pract Concept. 2022;12(4):e2022207
of imiquimod 5% for the treatment of multiple sBCC and                          Evaluation with Reflectance Confocal Microscopy. Dermatol-
showed that RCM is a valuable tool for non-invasive moni-                       ogy. 2019;235(1):35-44. DOI: 10.1159/000493727. PMID:
                                                                                30404078.
toring of treatment response.
                                                                           9.   Nori S, Rius-Díaz F, Cuevas J, et al. Sensitivity and specificity of
                                                                                reflectance-mode confocal microscopy for in vivo diagnosis of
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Original Article | Dermatol Pract Concept. 2022;12(4):e2022207                                                                                   5
6   Original Article | Dermatol Pract Concept. 2022;12(4):e2022207
