Successful Treatment of Multiple Post-Operative Keratoacanthomas with Topical 5-Fluorouracil

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%.

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 welldifferentiated 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 biopsy and did not wish to undergo any systemic therapy. He had previously tried tazarotene 0.1% cream without improvement. He elected to initiate 5fluorouracil 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  No recurrence none CRcomplete response; PRpartial response; Mmale; Ffemale; 1 hr -1 hour; SCCsquamous cell carcinoma 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 5fluorouracil 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 5fluorouracil. 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 5fluorouracil 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.