These articles have been accepted for publication in the British Journal of Dermatology and are currently being edited and typeset. Readers should note that articles published below have been fully refereed, but have not been through the copy-editing and proof correction process. Wiley-Blackwell and the British Association of Dermatologists cannot be held responsible for errors or consequences arising from the use of information contained in these articles; nor do the views and opinions expressed necessarily reflect those of Wiley-Blackwell or the British Association of Dermatologists This article is protected by copyright. All rights reserved. Accepted Date : 08-Feb-2015 Article type

: Correspondence

Successful treatment of classic Kaposi sarcoma with topical timolol: report of two cases C. Meseguer-Yebraa , M.E. Cardeñoso-Álvareza, M.T. Bordel-Gómeza, M. del Carmen Fraile-Alonsob, M.E. Pérez-Losadac , J. Sánchez-Estellaa. a

Sección de Dermatología. Hospital Virgen de la Concha. Complejo asistencial de Zamora,

Spain. b

c

Servicio de Dermatología. Hospital Clínico Universitario de Valladolid, Spain.

Servicio de Cuidados Intensivos, Complejo Asistencial de Salamanca, Spain.

Corresponding autor: Carmen Meseguer-Yebra. Address: Avenida Requejo, 35 49022 Zamora, Spain. E-mail: [email protected] Telephone: 0034 980548200 ext: 48557/48563

This article is protected by copyright. All rights reserved. Key words: Kaposi sarcoma, timolol, cutaneous, beta-adrenergic receptor antagonist, betablocker.

Acknowledgements: To Dr. Miguel Marcos for his generous help and support. Financial disclosure: • Relationships relevant to this manuscript: None • All other relationships: None Funding/Support: We declare to have no funding sources. Role of the Sponsors: The sponsors had no role in the design and conduct of the study; in the collection, analysis, and interpretation of data; or in the preparation, review, or approval of the manuscript. Financial Disclosure: None reported. We have no financial interests.

Dear Editor, Kaposi sarcoma (KS) is a low-grade angioproliferative tumour associated to human herpes virus 8 (HHV-8). Classic Kaposi sarcoma (CKS) usually affects the lower extremities of Mediterranean and Eastern European middle age or elderly patients and shows an indolent chronic course. Occasionally, cutaneous lesions cause morbidity that seriously impairs quality of life as recurrent bleeding, ulceration, pain, scarring and/or psychological stress.

This article is protected by copyright. All rights reserved. superficial IHs5,6: twice daily, 1 or 2 drops per lesion with a gently massage and without occlusion. Follow-up visits were at 0, 2, 6, 12 weeks and the treatment was stopped after 12 weeks. Blood pressure, capillary glucose and pulse were checked in each visit which also included image compilation. Both patients signed a written consent form and the protocol was approved by the Ethics Committee Board of our hospital.

CASE 1 A 78-years-old male, with no remarkable medical history presented with an erosive papule on the medial aspect of the first metatarsophalangeal joint of his right foot. In the first follow-up visit the lesion showed prominent changes and presented as a necrotic crusty papule and afterwards it appeared as a smaller erythematous macule (Fig. 1A). At 12 weeks the lesion was completely excised for histological examination. The first and blinded histological examination resulted in the description of a scar (Fig.2A). The HHV-8 immunohistochemical stain confirmed no evidence of KS in the sample (Fig.2B). No recurrence has been detected after 22 months of follow-up.

CASE 2 A 94-years-old female diagnosed with CKS in 2003 presented with several papules on his right leg. Initially we treated two lesions marked in the basal image as 1 and 2. In the 2-week visit we observed the growth of an adjacent lesion which we also treated since then. Similarly to case 1, two of the lesions showed partial regression with the appearance of a crust on its

This article is protected by copyright. All rights reserved. superficial IHs5,6: twice daily, 1 or 2 drops per lesion with a gently massage and without occlusion. Follow-up visits were at 0, 2, 6, 12 weeks and the treatment was stopped after 12 weeks. Blood pressure, capillary glucose and pulse were checked in each visit which also included image compilation. Both patients signed a written consent form and the protocol was approved by the Ethics Committee Board of our hospital.

CASE 1 A 78-years-old male, with no remarkable medical history presented with an erosive papule on the medial aspect of the first metatarsophalangeal joint of his right foot. In the first follow-up visit the lesion showed prominent changes and presented as a necrotic crusty papule and afterwards it appeared as a smaller erythematous macule (Fig. 1A). At 12 weeks the lesion was completely excised for histological examination. The first and blinded histological examination resulted in the description of a scar (Fig.2A). The HHV-8 immunohistochemical stain confirmed no evidence of KS in the sample (Fig.2B). No recurrence has been detected after 22 months of follow-up.

CASE 2 A 94-years-old female diagnosed with CKS in 2003 presented with several papules on his right leg. Initially we treated two lesions marked in the basal image as 1 and 2. In the 2-week visit we observed the growth of an adjacent lesion which we also treated since then. Similarly to case 1, two of the lesions showed partial regression with the appearance of a crust on its

This article is protected by copyright. All rights reserved. surface in the first weeks of treatment. After 12 weeks only three erythematous macules remained (Fig. 1B).

After 20 months of follow-up there is no evidence of recurrence. A significant response was seen in both cases with no adverse effects associated. Reports of spontaneous resolution have been published although it is an extremely rare phenomenon. We think that the similar evolution of our cases (parallel timing of response, the crusty appearance before involution…) support a potential therapeutic effect of timolol. In our experience high compliance and excellent tolerability were constant. Patients suffering from CKS usually are elderly and topical β-ARAs can be administered by the patient easily at home. In previous studies, even in ulcerated IHs7,8, timolol has not produced any systemic adverse reaction, but its pharmacokinetics has not been studied in detail so monitoring is recommended. Topical β-blockers timolol and propranolol also can cause allergic contact dermatitis but importantly they do not show cross-reactivity9. Local treatment of cutaneous CKS with topical timolol may be an effective, painless, simple and inexpensive alternative for symptomatic CKS lesions compared with the treatments currently available. To our knowledge this is the first report of the treatment of KS with a βARA and our results are promising. Further studies are needed to validate these preliminary observations.

This article is protected by copyright. All rights reserved. REFERENCES

1.- Léauté-Labrèze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taïeb A. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008 Jun 12;358(24):264951. 2.- Chambers CB, Katowitz WR, Katowitz JA, Binenbaum G. A controlled study of topical 0.25% timolol maleate gel for the treatment of cutaneous infantile capillary hemangiomas. Ophthal Plast Reconstr Surg. 2012 Mar-Apr;28(2):103-6. 3.- Storch CH, Hoeger PH. Propranolol for infantile haemangiomas: insights into the molecular mechanisms of action. Br J Dermatol. 2010 Aug;163(2):269-74. 4.- Chisholm KM, Chang KW, Truong MT, Kwok S, West RB, Heerema-McKenney. βAdrenergic receptor expression in vascular tumors. Mod Pathol. 2012 Nov;25(11):1446-51. 5.- Chakkittakandiyil A, Phillips R, Frieden IJ, Siegfried E, Lara-Corrales I, Lam J, Bergmann J, Bekhor P, Poorsattar S, Pope E. Timolol maleate 0.5% or 0.1% gel-forming solution for infantile hemangiomas: a retrospective, multicenter, cohort study.Pediatr Dermatol. 2012 Jan-Feb;29(1):28-31. 6.- Calvo M, Garcia-Millán C, Villegas C, Fueyo-Casado A, Burón I. Topical timolol for infantile hemangioma of the eyelid. Int J Dermatol. 2013 May;52(5):603-4. 7.- Tlougan BE, Gonzalez ME, Orlow SJ. Abortive segmental perineal hemangioma. Dermatol Online J. 2011 Oct 15;17(10):8. 8.- Cante V, Pham-Ledard A, Imbert E, Ezzedine K, Léauté-Labrèze C.First report of topical timolol treatment in primarily ulcerated perineal haemangioma. Arch Dis Child Fetal Neonatal Ed. 2012 Mar;97(2):F155-6.

This article is protected by copyright. All rights reserved. 9.- Bonifazi E, Milano A, Foti C.Allergic contact dermatitis caused by topical propranolol in a 5-month-old baby. Contact Dermatitis. 2014 Oct;71(4):250-1.

FIGURE LEGENDS

Figure 1: A. Case 1: after 2 weeks of treatment the previous papular lesion appeared flattened and covered with a crust. From the third visit (6 weeks of treatment) the lesion presented as a residual erythematous macule. B. Case 2: all lesions presented a significant reduction in size along the protocol, and as in case 1, they presented a crusty appearance within the first weeks of treatment. In the last visit (12 weeks) all lesions showed a residual macular appearance.

Figure 2. Biopsy case 1 after treatment: A: it showed a proliferation of fusiform fibroblastic cells in superficial dermis disposed between collagen bounds parallel to the epidermis, with no evidence of spindle cells remaining (Hematoxiline-eosine, 10x). B: negative (HHV-8 staining, 10x).

This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.