Dermatology: Practical and Conceptual Research Letter | Dermatol Pract Concept. 2025;15(4):5586 1 Combination of Fractional CO2 Laser and Imiquimod in Pigmented Basal Cell Carcinoma: Preliminary Clinical Observations Luca Ambrosio1,2, Giovanni Di Lella1, Caterina Longo3, Giovanni Pellacani2, Iris Zalaudek4, Claudio Conforti1,5 1 IDI-IRCCS, Dermatological Research Hospital, Rome, Italy 2 Dermatology Unit, Department of Medical and Cardiovascular Sciences, "Sapienza" University of Rome, Rome, Italy 3 Dermatology Department, University of Modena and Reggio Emilia, Modena, Italy 4 Department of Dermatology, Maggiore Hospital, University of Trieste, Trieste, Italy 5 Link University of Rome, Italy, Department of Life Science, Health, and Health Professions Key words: Pigmented Basal Cell Carcinoma, Fractional CO2 Laser, Imiquimod, Combination Therapy, Preliminary Clinical Outcomes Citation: Ambrosio L, Di Lella G, Longo C, Pellacani G, Zalaudek I, Conforti C. Combination of Fractional CO2 Laser and Imiquimod in Pigmented Basal Cell Carcinoma: Preliminary Clinical Observations. Dermatol Pract Concept. 2025;15(4):5586. DOI: https://doi. org/10.5826/dpc.1504a5586 Accepted: March 15, 2025; Published: October 2025 Copyright: ©2025 Ambrosio 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. Corresponding Author: Luca Ambrosio, MD, Via dei Monti di Creta, 104, 00167 Roma RM 1 IDI-IRCCS, Dermatological Research Hospital, 00167 Rome, Italy. ORCID: 0000-0002-6312-7709. E-mail: luca.ambrosio@uniroma1.it Introduction Basal cell carcinoma (BCC) is the most common cutaneous malignancy, with rising incidence rates. Typically presenting as a solitary or multiple lesions, surgical excision remains the gold standard treatment; however, non-surgical options are gaining traction, particularly for patients unable or unwill- ing to undergo surgery. Systemic immunotherapy, reserved for advanced BCC, often has limited use due to significant side effects. Among non-surgical treatments, imiquimod, a topical immunotherapeutic agent approved for superfi- cial BCC, has demonstrated efficacy. Acting as an agonist of toll-like receptors 7 and 8, imiquimod stimulates in- nate immune cells, promoting adaptive immune responses through cytokine and chemokine production [1]. Physical modalities like cryotherapy are also approved for superfi- cial BCC, but the use of conventional CO2 lasers has been studied less, with few reports. Over the past decade, frac- tional CO2 laser therapy has emerged as a novel technique to enhance topical drug absorption through laser-assisted drug delivery (LADD). This combination approach is particularly useful for deeper subtypes, such as pigmented and nodular BCC, where imiquimod’s dermal penetration is insufficient. Beyond its facilitative role, laser therapy itself has demon- strated immunomodulatory properties, including local im- mune activation, tumor mass reduction, and the induction of resistance to tumor reinoculation [2]. Despite these ad- vances, non-surgical therapies yield lower complete response rates than surgery, necessitating rigorous post-treatment monitoring. Dermoscopy is widely used for follow-up but 2 Research Letter | Dermatol Pract Concept. 2025;15(4):5586 may present limitations, such as overlapping features with other lesions, and the presence of features like fine telan- giectatic vessels or whitish areas may not definitively indi- cate tumor persistence [3]. Reflectance confocal microscopy (RCM), offering superior sensitivity and specificity, is more effective for detecting tumor persistence and recurrence in BCC and other non-melanoma skin cancers (NMSC) [4,5]. Case Presentation We report the case of an 83-year-old female with a pig- mented lesion on her left back diagnosed as pigmented BCC (pBCC) via dermoscopy and RCM. The patient refused surgery due to cosmetic concerns and accepted an off-label combination of fractional CO2 laser and imiquimod cream. Dermoscopy revealed structureless gray-blue areas, arboriz- ing vessels, and gray nests, while RCM identified basaloid islands in the deep dermis, peripheral clefting, palisading of nuclei, bright dendritic cells, and tortuous vessels (Figure 1). Fractional CO2 laser was performed biweekly to create epi- dermal channels, facilitating imiquimod penetration into the dermis where BCC nests were located. Imiquimod was applied five days weekly for six weeks. At the 8-week fol- low-up, RCM revealed no residual BCC feature, demonstrat- ing collagen fiber remodeling and the absence of basaloid islands. Excellent cosmetic results were achieved, with no scarring or discoloration. Follow-ups at 12, 24 weeks, and one year confirmed sustained remission, with no evidence of recurrence on RCM. Conclusion This case highlights the potential of laser immunotherapy as an effective, minimally invasive treatment for pBCC, offering robust clinical responses and excellent cosmetic outcomes [2]. Advanced imaging modalities like RCM are invaluable for monitoring, enabling early detection of recur- rence. These findings underscore the need for further clinical Figure 1. (A) Pigmented macular lesion on the right scapular region pre-treatment. (B) Right scapular area post-treatment with fractional CO2 laser. (C) Local inflammatory re- action in the right scapular area after imiquimod cream application. (D) Complete lesion resolution with minimal dyspigmentation 12 weeks after initiating laser-immunotherapy. (E) Pre-treatment dermoscopy showing a structureless area with gray-blue nests and arborizing telangiectatic vessels, consistent with BCC. (F) Dermoscopy at 12-week follow-up showing absence of BCC features. (G) Pre-treatment confocal microscopy (RCM) showing basaloid islands with peripheral clefting, palisading of nuclei, bright dendritic cells, and tortuous vessels. (H) RCM at 12-week follow-up showing significant collagen remodeling and absence of basaloid island. Research Letter | Dermatol Pract Concept. 2025;15(4):5586 3 trials to validate combined non-surgical therapies for BCC and NMSC, paving the way for personalized treatments that prioritize both efficacy and patient quality of life. Ethical Approval: The study was a retrospective evaluation conducted in accordance with the principles of the Decla- ration of Helsinki and the International Council for Har- monization and Good Clinical Practice guidelines. Written informed consent was obtained from the patient to publish this paper. References 1. Peris K, Fargnoli MC, Kaufmann R, et al. European consen- sus-based interdisciplinary guideline for diagnosis and treat- ment of basal cell carcinoma-update 2023. Eur J Cancer. 2023 Oct;192:113254. DOI: 10.1016/j.ejca.2023.113254. PMID:  37604067. 2. Omland SH, Wenande EC, Svane IM, Tam J, Olesen UH, Hædersdal M. Laser immunotherapy: A potential treat- ment modality for keratinocyte carcinoma. Vol. 13, Can- cers. 2021; 13(21):5405. DOI: 10.3390/cancers13215405. PMID: 34771568. 3. Apalla Z, Lallas A, Tzellos T, et al. Applicability of dermos- copy for evaluation of patients’ response to nonablative thera- pies for the treatment of superficial basal cell carcinoma. Br J Dermatol. 2014 Apr;170(4):809–15. DOI: 10.1111/bjd.12749. PMID: 24283541. 4. Alma A, Pongetti L, Clementi A, et al. Combined Carbon Diox- ide Laser with Photodynamic Therapy for Nodular Basal Cell Carcinoma Monitored by Reflectance Confocal Microscopy. Medicina (Lithuania). 2024 Jan 1;60(1). DOI: 10.3390/me- dicina60010030. PMID: 38256291. 5. Navarrete-Dechent C, Cordova M, Aleissa S, et al. Reflectance confocal microscopy confirms residual basal cell carcinoma on clinically negative biopsy sites before Mohs micrographic sur- gery: A prospective study. J Am Acad Dermatol. 2019 Aug;81(2): 417–26. DOI: 10.1016/j.jaad.2019.02.049. PMID: 31227277.