SKIN January 2021 Volume 5 Issue 1 Copyright 2021 The National Society for Cutaneous Medicine 46 BRIEF ARTICLES Successful Treatment of Multiple Post-Operative Keratoacanthomas with Topical 5-Fluorouracil Nelson C. Ugwu, BS1, Nour Kibbi, MD2 1Department of Dermatology, Yale University School of Medicine, New Haven, CT 2Stanford Dermatologic Surgery, Redwood City, CA Keratoacanthoma (KA) is a rapidly growing, low-grade variant of cutaneous squamous cell carcinoma that often arises as a solitary lesion on sun-exposed skin in adults over age 40. Following a rapid growth phase, KAs may spontaneously regress, but predicting which tumors will do so is challenging. For this reason, KAs are often treated with surgery, however, non-surgical modalities have also been employed, including intralesional 5-FU, intralesional methotrexate, or oral retinoids. Response rates with these non-surgical therapies vary, ranging from 83 to 100%.1 Most KAs arise sporadically, but KAs have also been reported as a reactive phenomenon following traumatic procedures, such as skin surgery,2 skin grafting,3 laser resurfacing,4 and spontaneous injuries such as piercing or scratch injuries.5 Here, we present the case of a very elderly gentleman with multiple post-operative eruptive KAs treated successfully with topical 5-fluorouracil and review the literature on KAs treated with topical 5-fluorouracil. A 94-year-old healthy man presented with a 3-4 week history of five rapidly enlarging, crateriform nodules with central hemorrhagic crust on the right lower leg (Figure 1A). Some of the lesions were painful to the touch. Approximately 6 weeks prior, the patient had undergone Mohs micrographic surgery (MMS) for a well- differentiated squamous cell carcinoma of the lower extremity that was repaired with a linear closure. The patient had a history of multiple non-melanoma skin cancers treated with MMS. He declined further surgical intervention on the new lesions, including ABSTRACT Keratoacanthomas (KAs) are fast-growing tumors and can be difficult to distinguish from squamous cell carcinomas (SCCs). Most KAs are sporadic, but KAs may also arise following traumatic procedures. We report the case of a 94-year-old male who developed multiple KAs following surgical excision of an SCC on the right lower extremity. The patient declined additional procedures including biopsy, surgery, or intralesional therapy. He was started on 5% topical FU using a 2 week on, 2 week off regimen for 16 weeks with resolution of disease. No recurrence was noted at 13 months. Topical 5-FU is a conservative, non-invasive treatment for post-traumatic KAs that is particularly suitable in the elderly, in whom the risks and morbidity from surgical or other non-invasive approaches are worth considering. INTRODUCTION CASE PRESENTATION SKIN January 2021 Volume 5 Issue 1 Copyright 2021 The National Society for Cutaneous Medicine 47 Figure 1. (A) On the right lower leg were five crateriform friable nodules which developed following excision of a well- differentiated squamous cell carcinoma. (B) Following two months of cyclical topical 5% 5-fluorouracil therapy, there was a notable reduction in nodule size, crusting of the lesions, and a moderate irritant reaction of the lower extremity. (C) The lesions resolved after four months of cyclical therapy. biopsy and did not wish to undergo any systemic therapy. He had previously tried tazarotene 0.1% cream without improvement. He elected to initiate 5- fluorouracil 5% cream twice daily on an alternating 2 weeks on then 2 weeks off regimen without occlusion. Two months following initiation of therapy, he was noted to have a significant response with reduction in nodule size and a moderate irritant reaction of the lower extremity (Figure 1B). He declined topical corticosteroids for the irritant reaction and used emollients as needed between the 5-fluorouracil treatments. Four months after presentation, the lesions had resolved (Figure 1C), and the patient was using 5-fluorouracil as needed. The patient was seen in close clinical follow-up until 13 months following initial presentation and was noted to have no recurrence. He had continued to use topical 5-fluorouracil for other keratotic lesions on his upper and lower extremities that failed to regress spontaneously. He died two months later of unrelated causes. This case report highlights the phenomenon of multiple post-operative KAs arising in an elderly man. While biopsy and/or additional DISCUSSION A. B. C. SKIN January 2021 Volume 5 Issue 1 Copyright 2021 The National Society for Cutaneous Medicine 48 Table 1. Summary of 43 keratoacanthoma cases treated with topical 5-fluorouracil (5-FU) therapy. Authors Number of patients Mean Age (range) Sex Tumor location Number of tumors Sporadic/Tri ggering event Treatment regimen Adjuvant treatment Patients achieving CR Overall follow-up Additional treatments for patients with incomplete responses Grupper 19708 15 59.9 (38-80) 9M, 6F head (13) and upper extremity (2) solitary lesions 9 sporadic, 6 after initial total excision 5% 5FU ointment 1-2 times daily for 1-2 weeks then 2% 5-FU ointment or 2% 5-FU gel under occlusion for 1-4 weeks None 12/15 at 3- 5 weeks 2-18 months. No recurrence 2/3 patients underwent surgery at 3 weeks (1 PR, 1 no response to 5-FU). 1/3 continued 5- topical FU Goette et al 19829 14 66 (44-80) 6M, 8F head (2), neck (2), upper extremity (5), lower extremity (3), chest (1), shoulder (1) solitary lesions sporadic 20% 5FU ointment, 2-3 times daily for 2-4 weeks, (-) or (+) occlusion None 14/14 at 1- 7 weeks 1-7 weeks none Gray et al 199912 2 74 (68-80) 2M head (2), neck (2), forearm and hand (5), lower leg (3), chest (1), shoulder (1) solitary lesions sporadic 5% 5FU cream daily without occlusion for 4-8 weeks none 1/2 at 8 weeks 8 weeks 1 patient underwent biopsy with electrodessicatio n at 4 weeks after PR Thompson et al 201411 10 74.4 (52-92) 9F, 1M lower extremity (5) and head (5) solitary lesions sporadic short-contact (1 hr) topical 5% 5-fluorouracil cream twice daily until resolution none 9/10 at 4-6 weeks 4-6 weeks 1 patient underwent Mohs surgery after 1 week of 5-FU Silva et al 20197 1 64 F lower extremity 1 photodynamic therapy for porokeratosis of Mibelli 0.5% 5FU + 10% salicylic acid acitretin 0.6- 1 mg/kg/day prior to 5-FU 1/1 at 8 weeks 12 months. No recurrence none Ugwu et al 2020 1 94 M right lower extremity 5 Surgery for SCC on the right lower extremity 5% 5-FU cream daily for 2 weeks followed by 2 weeks without treatment for 4 months none 1/1 at 16 weeks 13 months. No recurrence none CR – complete response; PR – partial response; M – male; F – female; 1 hr – 1 hour; SCC – squamous cell carcinoma SKIN January 2021 Volume 5 Issue 1 Copyright 2021 The National Society for Cutaneous Medicine 49 surgery were among the treatment options discussed with the patient, these approaches carried significant risk. For one, further surgical intervention (biopsy or excision) may have also incited more lesions. Secondly, excision of multiple lesions would have resulted in large wounds on the lower extremity, which may have been further complicated by edema, delayed wound healing, and infection of the lower extremity. Alternative non-surgical treatments also carried significant limitations. Intralesional 5- fluorouracil is painful to administer and requires repeated injections and office visits. Topical 5-fluorouracil with zinc oxide wraps, also known as “chemo wraps," are tedious to apply properly, require repeated applications in the office, and result in significant discomfort 6. Oral retinoids, which have been used alone or in combination of topical agents, carry significant risks, such as hypertriglyceridemia, bony pain, and transaminitis, require repeated laboratory monitoring, and can result in significant xerosis, all of which are significant risks in an elderly patient 2,7. Topical 5-fluorouracil is an ideal medication: since the diseased area is visible to the patient, the medication can easily be applied and adverse events, namely irritant dermatitis, can be readily monitored. We utilized a cyclical application (2 weeks on, 2 weeks off) schedule to allow a period of recovery in between treatment intervals. To the best of our knowledge, this is the first case outlining the successful treatment of multiple, post-operative KAs with topical 5- fluorouracil. There are 43 published cases of KAs treated with topical 5-fluorouracil (Table 1) 7-12. The average age among the cohort was 68.8 years with a female to male ratio of 1.3. The most common tumor locations in patients were the head (51.1%), lower extremities (23.3%) and upper extremities (16.2%). The majority of reported lesions were solitary (98%). Only 11.6% of patients developed KAs following a surgical procedure. The most commonly used 5- fluorouracil formulations were the 5% ointment (35%), 20% ointment (33%) and 5% cream (30%). One patient received acitretin for 1 month prior to initiating 5-fluorouracil treatment. The overall response rate was 95.3% (41/43 patients) with 90.7% (39/43) achieving complete response between 2 and 8 weeks of therapy. Lesions with partial or no response to 5-fluorouracil were treated with surgical excision (2) or shave biopsy with electrodessication and curettage (1). One patient opted for Mohs surgery after one week of 5-fluorouracil therapy. Over the follow-up period which ranged from 2 to 18 months, there were no reported recurrences. This case highlights the successful and cyclical use of topical 5-fluorouracil in the treatment of post-operative eruptive KAs. This conservative, non-invasive treatment is particularly suited for the very elderly and for post-traumatic KAs. Patient selection is critical, and close follow-up is recommended to refine the treatment schedule and interval between treatment courses. Further systematic study into this phenomenon is needed to better outline treatment parameters and resolve the question of whether, under certain circumstances, eruptive KAs may regress spontaneously. Conflict of Interest Disclosures: None Funding: None Corresponding Author: Nour Kibbi, MD Stanford Dermatologic Surgery 450 Broadway 4th floor Redwood City, CA 94063 Phone: 650-725-5272 email: kibbi@stanford.edu SKIN January 2021 Volume 5 Issue 1 Copyright 2021 The National Society for Cutaneous Medicine 50 References: 1. Chitwood K, Etzkorn J, Cohen G. Topical and intralesional treatment of nonmelanoma skin cancer: efficacy and cost comparisons. Dermatol Surg. 2013;39(9):1306-1316. 2. Goldberg LH, Silapunt S, Beyrau KK, Peterson SR, Friedman PM, Alam M. Keratoacanthoma as a postoperative complication of skin cancer excision. J Am Acad Dermatol. 2004;50(5):753- 758. 3. Clark MA, Guitart J, Gerami P, Marks BR, Amin S, Yoo SS. Eruptive keratoacanthomatous atypical squamous proliferations (KASPs) arising in skin graft sites. JAAD Case Rep. 2015;1(5):274-276. 4. Gewirtzman A, Meirson DH, Rabinovitz H. Eruptive keratoacanthomas following carbon dioxide laser resurfacing. Dermatol Surg. 1999;25(8):666-668. 5. Pattee SF, Silvis NG. Keratoacanthoma developing in sites of previous trauma: a report of two cases and review of the literature. J Am Acad Dermatol. 2003;48(2 Suppl):S35-38. 6. Manalo IF, Lowe MC, Nelson KC, Chen SC. Triple therapy with intralesional 5-fluorouracil, chemowraps, and acitretin: A well-tolerated option for treatment of widespread cutaneous squamous cell carcinomas on the legs. JAAD Case Rep. 2019;5(12):1051-1054. 7. Silva E, Estebanez A, Martin JM, Monteagudo C, Montesinos E. Keratoacanthoma centrifugum marginatum after photodynamic therapy with good response to oral retinoids and topical 5- fluorouracil. Dermatol Ther. 2019;32(4):e12988. 8. Grupper C. Treatment of keratoacanthomas by local applications of the 5-fluorouracil (5-FU) ointment. Dermatologica. 1970;140:Suppl 1:127+. 9. Goette DK, Odom RB, Arrott JW, Diakon NC, Horn RT, Jr. Treatment of keratoacanthoma with topical application of fluorouracil. Arch Dermatol. 1982;118(5):309-311. 10. Singal A, Mohanty S, Bhattacharya SN, Baruah MC, Singh N. Unusual multiple keratoacanthoma in a child successfully treated with 5-fluorouracil. J Dermatol. 1997;24(8):546-548. 11. Thompson BJ, Ravits M, Silvers DN. Clinical efficacy of short contact topical 5-Fluorouracil in the treatment of keratoacanthomas: a retrospective analysis. J Clin Aesthet Dermatol. 2014;7(11):35-37. 12. Gray RJ, Meland NB. Topical 5-fluorouracil as primary therapy for keratoacanthoma. Ann Plast Surg. 2000;44(1):82-85.