Dermatology: Practical and Conceptual Research Letter | Dermatol Pract Concept. 2024;14(3):e2024201 1 Topical Sirolimus 0.1% as Off-Label Treatment of Kaposi’s Sarcoma Vittorio Tancredi1, Gaetano Licata2, Dario Buononato1, Maria Pia Boccellino1, Giuseppe Argenziano1, Caterina Mariarosaria Giorgio1 1 Dermatology Unit, Department of Mental and Physical Health and Preventive Medicine, University of Campania Luigi Vanvitelli, Naples, Italy 2 Dermatology Unit, San Antonio Abate Hospital, Trapani, Italy Key words: Sirolimus, Kaposi, angiogenesis Citation: Tancredi V, Licata G, Buononato D, Boccellino MP, Argenziano G, Giorgio CM. Topical Sirolimus 0.1% as Off Label Treatment of Kaposi’s Sarcoma. Dermatol Pract Concept. 2024;14(3):e2024201. DOI: https://doi.org/10.5826/dpc.1403a201 Accepted: February 19, 2024; Published: July 2024 Copyright: © Tancredi 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: Gaetano Licata, MD, Dermatology Unit, San Antonio Abate Hospital, Via Cosenza 82, 91016, Erice (TP), Italy. Phone: 3276215976, Email: gaetano.licata89@gmail.com Introduction Kaposi’s Sarcoma (KS, now more precisely referred to as Kaposi’s Disease) is a vascular proliferative disorder associ- ated with human herpesvirus 8 (HHV8) infection. Its classi- cal form, Mediterranean Kaposi, is characterized by multiple red-purple macules, patches, and nodules typically involving the lower limbs of elderly subjects. Management of these patients can be challenging. Therapeutic options depend on various factors such as the number and types of lesions, the presence of lymphedema, age, immunosuppression, patients’ compliance, and so on. For skin-limited KS, shaving or cryo- therapy is an option for small macules or nodules, while the treatment of large patches and plaques is more complex. Many topical and systemic approaches have been evaluated, from elastic stocking to beta blockers, intra-lesional chemo- therapeutic agents like vinblastine and bleomycin, electro- chemotherapy, and so on [1]. Case Presentation In our dermatology department, we treated thirteen pa- tients with classical KS, mostly represented by large patches and plaques on the lower limbs, using topical ga- lenic sirolimus (0.1% in Pentravan®) twice daily. The di- agnosis was confirmed by a punch biopsy in all patients. Since June 2023, thirteen patients (eight males and five females, mean age 81.6) have been under treatment. The lesions mainly consisted in large plaques. They were pre- viously treated with elastic compression without signifi- cant benefits. None of them was on beta blockers for other diseases. After three months, the lesions showed a signif- icant reduction in skin infiltration, and after six months, some of the smallest ones had almost disappeared. Only two patient did not show any benefit. The patients are still under treatment, without any significant adverse events (Figure 1). 2 Research Letter | Dermatol Pract Concept. 2024;14(3):e2024201 Conclusion Sirolimus targets a serine threonine kinase known as mTOR (mammalian target Of rapamycin), which plays a crucial role in regulating cell growth, proliferation, and survival. For this reason, several novel anticancer drugs aim to inhibit this enzyme. Growth factors like IGF (insulin-like growth fac- tor), EGF (epidermal growth factor), PDGF (platelet-derived growth factor), and VEGF (vascular endothelial growth fac- tor) bind and activate receptors on the cell surface, initiating a cascade of intracellular pathways mediated by mTOR. Thus, increased activity of mTOR can alter metabolic pathways, in- creasing the risk of tumor development and neo-angiogenesis. HHV-8 genes like ORF-K1 and ORF-K15 are able to increase the levels of pro-inflammatory and pro-angiogenic mediators like VEGF, whose role has been established in KS pathogenesis [2]. Stallone et al. treated with systemic sirolimus 15 kidney- transplanted patients who had developed KS during immuno- suppressive anti-reject treatment with cyclosporine. The au- thors showed that systemic sirolimus was effective in resolving KS without causing kidney rejection [3]. In our clinical prac- tice, KS is mostly encountered in older people often with many comorbidities. Therefore, our proposed approach involves us- ing topical sirolimus 0.1% to be applied morning and evening, exerting an anti-proliferative action on endothelial cells with- out significant immunosuppression. The small cohort patients is the main limitation of this study, but the rationale is well- founded on the literature and clinical practice. More studies need to demonstrate the efficacy and safety of sirolimus 0.1% in the management of Mediterranean KS. References 1. Schneider JW, Dittmer DP. Diagnosis and Treatment of Kaposi Sarcoma. Am J Clin Dermatol. 2017 Aug;18(4):529-539. doi: 10.1007/s40257-017-0270-4. PMID: 28324233; PMCID: PMC 5509489. 2. Kang T, Ye FC, Gao SJ, Wang LD. Angiogenesis, Kaposi’s Sarcoma and Kaposi’s Sarcoma-Associated Herpesvirus. Virol Sin. 2008 Dec 1;23(6):449-458. doi: 10.1007/s12250-008-2998-8. PMID: 19890492; PMCID: PMC2771944. 3. Stallone G, Infante B, Grandaliano G, Schena FP, Gesualdo L. Kaposi’s sarcoma and mTOR: a crossroad between viral infec- tion neoangiogenesis and immunosuppression. Transpl Int. 2008 Sep;21(9):825-32. doi: 10.1111/j.1432-2277.2008.00697.x. Epub 2008 May 22. PMID: 18498314. Figure 1. 79-year-old female patient’s left foot. (A) panel shows a large red-purplish infiltrated plaque, confirmed as KS by an incisional biopsy. (B) panel shows the same foot after six month of sirolimus 0.1% in Pentravan® applied morning and evening. At clinical examination, the infiltration has almost disappeared, while hyperpigmentation persists.