Version May 2024
INTRODUCTION — Keratoacanthoma (KA) is a cutaneous squamoproliferative tumor that usually presents as a 1 to 2 cm dome-shaped or crateriform nodule with central hyperkeratosis (picture 1A-E). A common and distinctive feature of KA is a clinical course characterized by phases of rapid growth, lesion stability, and spontaneous involution.
The approach to the management of KA is debatable since lesions can resolve without treatment. However, the well-accepted difficulty in distinguishing KA from cutaneous squamous cell carcinoma, a common tumor associated with a risk for metastasis, leads many clinicians (including ourselves) to recommend treatment of these lesions.
The treatment and prognosis of KA will be discussed here. The epidemiology, risk factors, and diagnosis of KA are reviewed separately. (See "Keratoacanthoma: Epidemiology, risk factors, and diagnosis".)
GENERAL CONSIDERATIONS — A longstanding debate over the classification of KA as a benign, spontaneously resolving tumor versus a variant of cutaneous squamous cell carcinoma with a rare potential for metastasis has contributed to a lack of definitive guidelines on the treatment of these lesions. Although most authors, including ourselves, advocate for treatment of KA [1-7], observation until spontaneous resolution has also been used for management of these lesions [4,8].
We opt to treat KA based upon the following considerations [2]:
●No clinical or pathologic features can reliably differentiate KA and cutaneous squamous cell carcinoma.
●Treatment accelerates lesion resolution.
●Treatment is usually straightforward and efficient, with relatively minor risk.
●Early treatment may improve cosmetic outcomes by limiting damage to the skin and underlying structures, such as the nose, eyelids, or lips.
Surgical excision is the first-line treatment for patients with the most common clinical presentation of KA, a solitary lesion. Other therapeutic options for solitary KA include electrodesiccation and curettage (ED&C), intralesional injections, radiation, and topical therapy.
We defer therapeutic intervention and proceed with observation only in patients who refuse to proceed with treatment. (See 'Deferring therapy' below.)
The management of patients with numerous KAs or very large KAs is more challenging than the treatment of solitary KA since the methods typically used to treat individual lesions are often impractical in these settings. Systemic pharmacologic therapy is an additional treatment option for patients with large or numerous KAs. Oral retinoids, such as acitretin and isotretinoin, are the systemic agents most commonly prescribed for this indication. (See "Keratoacanthoma: Epidemiology, risk factors, and diagnosis", section on 'Clinical variants' and "Keratoacanthoma: Epidemiology, risk factors, and diagnosis", section on 'Multiple keratoacanthomas'.)
SOLITARY KERATOACANTHOMA
First-line therapy — Conventional surgical excision is the treatment of choice for solitary KA since it allows for both the assessment of histopathologic features to aid in diagnosis and pathologic confirmation of the removal of the tumor. Mohs surgery, a more complex and more expensive method of surgical excision, is usually reserved for patients in whom a tissue-sparing procedure is desired. In a single institution, retrospective study, both surgical excision and Mohs surgery were associated with a recurrence rate of <1 percent [9]. (See "Mohs surgery" and "Keratoacanthoma: Epidemiology, risk factors, and diagnosis", section on 'Diagnosis'.)
Conventional surgical excision — Although the efficacy of conventional surgical excision for the treatment of KA has not been formally studied, this procedure is considered a first-line therapy for KA due to the fact that it is simple, well tolerated, and as noted above, provides histopathologic confirmation of tumor removal [2,7,9,10].
The technique utilized to perform surgical excision is important to ensure adequate treatment. The excision should include a periphery of normal skin and should extend into the subcutaneous fat. Due to the well-accepted difficulty in distinguishing KA from cutaneous squamous cell carcinoma, we typically excise these lesions with the recommended surgical margins for squamous cell carcinoma (at least 4 mm) [10]. (See "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma (cSCC)".)
Mohs surgery — Mohs surgery is a tissue-sparing surgical technique that also allows for the intraoperative assessment of 100 percent of the tissue margins, unlike conventional surgical excision, in which only representative sections of the tumor margin are examined [11]. Mohs surgery requires greater time to perform than conventional surgical excision and is a more costly and less widely available procedure. (See "Mohs surgery".)
Cure rates for Mohs surgery for cutaneous squamous cell carcinoma are high, but data on the efficacy of Mohs surgery for KA are limited. In a large series of 95 patients with 119 KAs treated with Mohs surgery, one recurrence (0.8 percent) occurred three months after the initial treatment; a similar recurrence rate (0.9 percent) was observed among 100 patients with 112 KAs treated with conventional surgical excision [9].
Mohs surgery, when available, is the preferred treatment for KAs in areas such as the central face, ear, nose, and periocular and perioral skin since tissue sparing is desired in these sites. Mohs surgery may also be used for lesions greater than 2 cm in diameter (giant KA) since it allows for confirmation of tumor removal prior to wound closure and may minimize the size of the surgical defect [10]. Intralesional pharmacologic therapy is an additional treatment option for such lesions. (See 'Intralesional therapy' below.)
Alternative therapies — Examples of other therapies that have been used for the management of KA include electrodesiccation and curettage (ED&C), intralesional pharmacologic therapy, ionizing radiation, and topical agents. Compared with surgical excision, the major disadvantage of these alternative procedures is the lack of histopathologic confirmation of the removal of the tumor. ED&C is the most commonly used alternative therapy [3].
Electrodesiccation and curettage — ED&C is a quick surgical procedure that is often used to treat KA after a shave biopsy [3]. The procedure involves three cycles in which curettage is followed by electrodesiccation of the lesion site. Only a few minutes are required to administer this therapy. (See "Minor dermatologic procedures", section on 'Curettage and electrodesiccation'.)
Data on the efficacy of ED&C are limited. In a retrospective study of 111 KAs followed for 3 to 26 months, recurrence was detected in four lesions (4 percent) [12]. An overall recurrence rate of 8 percent was documented in a separate retrospective study in which 75 out of 78 patients received this treatment [3].
Although ED&C is well tolerated, the round, hypopigmented scar that is typically left after healing makes this a less favorable option for some patients. The potential for this result is of particular concern when a KA is located in a cosmetically sensitive area.
Intralesional therapy — Intralesional therapy is infrequently utilized for the treatment of KA. Most of the reported cases involve the use of fluorouracil or methotrexate [13-16]. Compared with fluorouracil, intralesional methotrexate is a less expensive therapy.
●Fluorouracil – Intralesional fluorouracil is typically administered undiluted in a concentration of 50 mg/mL on a weekly basis for three to eight treatment sessions. The efficacy of fluorouracil is supported by case reports and case series [17,18]. In the largest series, which consisted of 41 lesions, a complete response rate of 98 percent was achieved with a dose of 40 to 75 mg per lesion [19]. In another series of 30 patients with eruptive KA (also called eruptive squamous atypia), 20 patients (67 percent) achieved complete resolution with intralesional fluorouracil at a dose of up to 50 mg per lesion [18].
●Methotrexate – Resolution of KA after treatment with intralesional methotrexate has been reported in case reports and case series [14,17,20,21]. In a series of 54 patients with 73 KAs treated with intralesional methotrexate (dose range 0.075 to 1 mL of a 12.5 mg/mL solution), 64 (88 percent) resolved with one to four injections [20]. In addition, in a randomized trial of 25 patients, intralesional methotrexate administered prior to surgical excision reduced lesion size by 50 to 80 percent [22].
A standard dose for the treatment of KA is the injection of 1 mL of methotrexate in a concentration of 12.5 or 25 mg/mL. Injection is performed every two to three weeks for one to four treatment sessions. One or two treatments are usually sufficient for resolution.
Data on the use of bleomycin [23-26] and interferon alfa-2a and alfa-2b [27,28] are limited to case reports and case series with fewer than 10 patients [17]. These agents also appear to be effective.
A common technique used to perform intralesional injection of a KA is the delivery of a total of five injections per lesion: a single injection into the center and one injection into each quadrant. The goal is to blanch the entire rim of the lesion [14,15]. Due to discomfort associated with the injection of fluorouracil and bleomycin, local anesthesia is frequently given prior to these injections. In contrast, anesthesia is not usually necessary for the administration of methotrexate and interferon [17]. In all cases, surgical excision with histopathologic evaluation is recommended if lesions fail to respond as expected to intralesional therapy.
The potential adverse effects common to these treatments include local pain, erythema, necrosis, ulceration, and crusting. The possibility that side effects associated with the systemic administration of these agents may occur must also be considered [17]. Pancytopenia has occurred in two hemodialysis-dependent patients with renal failure after treatment with 25 mg of intralesional MTX [29,30]. Thus, some authors have suggested obtaining a complete blood count before treatment and one week after injection of methotrexate [14].
Radiation — Although the efficacy of radiation therapy for KA is supported by case series and case reports [31-35], this treatment is infrequently employed due to the multiple visits required and the potential long term consequences of radiation therapy. Radiation therapy is usually reserved for older adult patients for whom surgical treatment is not an option. (See "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma (cSCC)", section on 'Drawbacks and contraindications'.)
Guidelines for the administration of radiation therapy for KA have not been established. Of note, radiation therapy was associated with the induction of numerous new lesions in a patient with multiple self-healing squamous epithelioma (Ferguson-Smith disease), a genetic disorder characterized by the development of multiple KAs [36]. (See "Keratoacanthoma: Epidemiology, risk factors, and diagnosis", section on 'Multiple keratoacanthomas'.)
Topical therapy — Resolution of KA following topical application of fluorouracil has been documented in case reports and case series [37]. A 5% formulation of fluorouracil is typically applied daily, and resolution usually occurs within eight weeks [38,39]. The application of imiquimod 5% cream has also been associated with lesion resolution within 4 to 11 weeks in case reports [40]. Treatment is usually applied three to four times per week. Significant local inflammation commonly occurs during topical therapy.
Other — Other therapies that have been reported to be effective in small numbers of patients with KA include treatment with curettage alone, cryotherapy, an argon laser [41], an erbium-doped yttrium aluminum garnet (Er:YAG) laser in combination with topical fluorouracil [42], and photodynamic therapy [43]. Of note, KA has been reported to occur as a consequence of trauma related to treatment with a fractional laser [44], a carbon dioxide (CO2) laser [45], and cryotherapy [46,47]. Worsening of a KA lesion has also been documented after photodynamic therapy [48].
Deferring therapy — Given the possibility for spontaneous resolution of solitary KA, occasional patients elect to defer therapy. When this approach is taken, close patient follow-up is recommended. Several guidelines have been proposed for the management of these patients [8].
●Follow-up from presentation through resolution should be performed by a single clinician experienced in the natural history of these lesions.
●The course of the lesion should be documented with photographs every two to three weeks until lesion resolution.
●The patients must be informed that resolution may take six months or longer.
●Patients should be informed of the option for surgical excision and other treatments.
We also inform patients who are considering deferring therapy of the possibility of aggressive lesion behavior and the chance for misdiagnosis of squamous cell carcinoma as KA. If, during the course of observation, the lesion develops an atypical appearance, growth fails to cease, or the tumor fails to regress as expected, surgical excision with histopathologic examination of the lesion is indicated [4]. (See "Keratoacanthoma: Epidemiology, risk factors, and diagnosis", section on 'Solitary keratoacanthoma'.)
SPECIAL CASES
Multiple and large keratoacanthomas — The treatment of numerous KAs, such as those seen in the rare multiple KA syndromes, and the extremely large lesions that characterize keratoacanthoma centrifugum marginatum presents unique challenges. Although surgical intervention and the other local therapies, including intralesional fluorouracil (described above) [18], remain options for treatment, such therapies are usually impractical in patients with hundreds or thousands of lesions. (See "Keratoacanthoma: Epidemiology, risk factors, and diagnosis", section on 'Multiple keratoacanthomas'.)
Systemic agents are an additional option for these patients. These include:
●Systemic retinoids [36,49]
●Methotrexate plus prednisone [50]
●Intravenous fluorouracil [52]
Multiple case reports have documented the efficacy of oral retinoids in patients with multiple self-healing squamous epithelioma (MSSE) or generalized eruptive keratoacanthoma of Grzybowski [36,49,53-64]. Acitretin (25 to 60 mg per day) and isotretinoin (20 mg per day to 1.5 mg/kg per day) have been used for therapy. Between two and several months of treatment is usually required to achieve a satisfactory response. A more rapid response to oral retinoid therapy has been reported in a patient who developed multiple KAs secondary to vemurafenib therapy [65].
Although long-term maintenance therapy may be required [53,58,62,64], persistent remission after the discontinuation of therapy has been reported in individual patients with MSSE, eruptive keratoacanthomas of Grzybowski, and keratoacanthoma centrifugum marginatum [54-56]. Atrophic scars may remain at the sites of healed lesions.
Multiple adverse effects are associated with systemic retinoid therapy, including cheilitis, xerosis, visual changes, transaminitis, hyperlipidemia, and teratogenicity. Pregnancy should be avoided for one month after isotretinoin therapy and for three years after the discontinuation of acitretin. Thus, treatment with acitretin is usually avoided in women of child-bearing age. In the United States, prescribing and receipt of isotretinoin requires participation in the iPLEDGE program. The iPLEDGE program provides detailed guidelines for pregnancy prevention counseling, pregnancy screening, and contraceptive use during treatment. (See "Oral isotretinoin therapy for acne vulgaris", section on 'iPLEDGE program'.)
Subungual keratoacanthoma — Although spontaneous resolution of subungual KA has been reported [66,67], these lesions typically persist [5]. Surgical excision is the preferred therapeutic intervention. Curettage with or without electrodesiccation and systemic methotrexate have also been utilized [67,68]. Digital amputation is reserved for lesions that fail to respond to other therapies [67,68].
Muir-Torre syndrome — The Muir-Torre variant of Lynch syndrome may present with sebaceous tumors, visceral malignancies, and KA. The management of patients with this syndrome is reviewed separately. (See "Muir-Torre syndrome".)
PROGNOSIS
Recurrence — Incomplete removal of KA may result in lesion recurrence. As a group, the rate of recurrence after excision or ED&C is estimated to be between 3 and 8 percent [8]. Recurrence rates of <1 percent have been reported with Mohs surgery [9].
Involution — Although it is generally well accepted that solitary KAs usually spontaneously regress, detailed documentation of lesions followed through to regression is limited [8,69]. In a retrospective review of 19 patients followed with serial photographs by a single clinician, four out of five patients who had the lesions surgically removed during observation did so due to concern about the clinical behavior of the lesion [8]. Among the 14 patients followed to lesion involution, the mean time to resolution was 27 weeks. No recurrences were observed during patient follow-up, which ranged from nine months to eight years.
The type of KA influences the likelihood for spontaneous resolution. Unlike solitary KA and individual lesions in multiple self-healing squamous epithelioma (Ferguson-Smith disease) and generalized eruptive keratoacanthoma of Grzybowski, involution is unlikely to occur in mucosal KA, subungual KA, and keratoacanthoma centrifugum marginatum. (See "Keratoacanthoma: Epidemiology, risk factors, and diagnosis", section on 'Clinical variants'.)
Metastasis — Although cases of metastatic KA have been reported [70-72], the incidence of this appears to be exceedingly low and there is some question as to whether some or all of the few cases reported as metastatic KA actually represent the misdiagnosis of squamous cell carcinoma [1,73,74].
The relevance of the histopathologic detection of perineural invasion in 1 to 4 percent of KAs, a finding associated with an increased risk for local recurrence and metastasis in cutaneous squamous cell carcinoma, is uncertain [75-77]. Perineural invasion in KA has generally been considered an incidental finding with little impact on prognosis [76,78]. In the largest series documenting cases of KA with perineural invasion, 1 out of 40 lesions recurred and no metastases were noted [75]. However, aggressive local behavior of a KA with histopathologic evidence for perineural invasion has also been reported [76].
FOLLOW-UP — Patients should be instructed to return for reevaluation if signs of lesion regrowth occur after treatment. The appropriate interval for routine clinical follow-up is not standardized. We typically see patients with small, uncomplicated, solitary KAs six months after treatment for reevaluation of the treatment site and a full skin examination. We then follow these patients once yearly.
Certain clinical scenarios may demand more frequent follow-up. Earlier and more frequent follow-up is appropriate for patients with large, aggressive, or multiple lesions.
PREVENTION — Since ultraviolet light exposure likely contributes to the development of KA, daily sun protective measures (application of sunscreen, use of sun-protective clothing, and midday sun avoidance) are recommended as a preventive measure. As noted above, patients with multiple KA syndromes may benefit from long term systemic retinoid therapy to reduce the development of new lesions.
SUMMARY AND RECOMMENDATIONS
●General considerations – Although keratoacanthoma (KA) is a cutaneous squamoproliferative tumor with the potential for spontaneous resolution, treatment is recommended in most cases. Among the available treatment options, surgical excision is preferred for solitary lesions as it allows for the histopathologic confirmation of tumor removal. (See 'General considerations' above.)
●Solitary keratoacanthoma
•Surgery – We suggest surgical excision rather than destructive therapies as the first-line treatment for KA (Grade 2C). Conventional surgical excision may be performed on most lesions. Lesions in areas where tissue sparing is desired, such as the central face, can be treated with Mohs surgery. (See 'First-line therapy' above.)
•Other therapies – Other effective options for the treatment of KA include electrodesiccation and curettage (ED&C), intralesional pharmacologic therapy, radiation therapy, and topical therapy. Disadvantages of these interventions compared with surgical excision include the lack of histopathologic confirmation of tumor removal, longer healing times, and worse cosmetic outcomes. (See 'Alternative therapies' above.)
•Deferring therapy – For patients who elect to defer therapy and prefer to wait for lesion spontaneous resolution, close clinical follow-up should be implemented. Spontaneous resolution may take several months or longer. If lesions deviate from the expected clinical course, surgical excision to confirm the diagnosis is indicated. (See 'Deferring therapy' above.)
●Multiple keratoacanthomas – For patients with numerous KAs, such as those seen in the rare multiple KA syndromes, we suggest treatment with oral retinoids (Grade 2C). Acitretin 25 to 60 mg per day or isotretinoin 20 mg per day up to 1.5 mg/kg per day are given for several months to achieve a satisfactory response. (See 'Multiple and large keratoacanthomas' above.)
●Prognosis – Incomplete removal of KA may result in lesion recurrence. Metastasis is exceedingly rare. (See 'Prognosis' above.)
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