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Keratoacanthomas (KAs) are a variant of squamous cell carcinomas. Some KAs have shown aggressive behaviour, leading to metastasis and death. Surgical excision is the treatment of choice for most KA patients. Intralesional methotrexate (MTX) may also be a potential treatment option for KAs.
To evaluate intralesional MTX as a treatment modality for KA.
A retrospective chart review of nine patients with KAs treated with intralesional MTX was performed. Each patient had biopsy-proven KA. The lesion was initially debulked, and MTX was injected at the base. Patients were seen weekly in the office, and reinjected with intralesional MTX depending on the response of the lesion. Each patient was evaluated for their response to the intralesional MTX injections, the number of injections required and complications.
Patients required approximately two to four intralesional injections (12.5 mg to 25 mg per injection) before KA resolution. Eight of nine (88.9%) patients experienced complete resolution of their tumours. One patient experienced treatment failure, and underwent surgical excision of the KA. The average follow-up period was 2.8 years, and there were no recurrences.
The results from the present retrospective study show that intralesional MTX injection is an effective treatment option for KAs. The authors propose that intralesional MTX injection with initial debulking of the KA should be used as a first line of treatment when KAs present on the extremities, in cosmetically sensitive areas and in elderly patients with multiple comorbities.
Les kératoacanthomes (KA) sont une variante des carcinomes spinocellulaires. Certains KA sont agressifs et entraînent des métastases et la mort. L’excision chirurgicale constitue le traitement de choix chez la plupart des patients. Le méthotrexate (MTX) intralésionnel pourrait aussi représenter une option thérapeutique des KA.
Évaluer le MTX intralésionnel comme modalité thérapeutique du KA.
Les chercheurs ont procédé à une étude rétrospective des dossiers de neuf patients ayant un KA traité à l’aide de MTX intralésionnel. Chaque patient avait un KA démontré par biopsie. Les patients ont d’abord subi une chirurgie de réduction tumorale, puis se sont fait injecter du MTX à la base de la lésion. Ils ont été vus toutes les semaines en cabinet et se sont fait réinjecter du MTX intralésionnel selon la réponse de la lésion. Les chercheurs ont évalué la réponse de chaque patient aux injections de MTX intralésionnel, le nombre d’injections requises et les complications.
Les patients ont eu besoin d’environ deux à quatre injections intralésionnelles (12,5 mg à 25 mg par injection) avant la résolution du KA. Huit des neuf patients (88,9 %) ont profité d’une résolution totale de leur tumeur. Un patient a présenté un échec du traitement et subi une excision chirurgicale du KA. La période de suivi moyenne était de 2,8 ans, et aucune récurrence n’a été observée.
Les résultats de la présente étude rétrospective démontrent que l’injection de MTX intralésionnel est une option thérapeutique efficace des KA. Les auteurs postulent que l’injection de MTX intralésionnel précédée d’une chirurgie initiale de réduction tumorale du KA devrait constituer le traitement de première ligne en cas de KA aux membres, dans les régions esthétiquement sensibles et chez les patients âgés ayant des comorbidités multiples.
In 1889, Jonathan Hutchinson first described keratoacanthomas (KAs) as crater-shaped ulcers on the face (1). KAs are rapidly growing tumours that present more commonly in the elderly, in fair-skinned individuals and on sun-exposed areas. They have been associated with ultraviolet radiation exposure and other conditions such as stasis dermatitis, lichen planus and thermal burn injuries (2).
KAs exhibit three clinical stages: proliferative, maturation and involution. During the proliferative stage, the lesion grows rapidly over two to three months. During the maturation stage, a dome-shaped nodule with a central keratinous core forms. Within a few months, the lesion involutes, resulting in a depressed, hypopigmented scar (3).
KAs were once believed to be benign. However, KAs are a variant of squamous cell carcinomas and some have shown aggressive behaviour, leading to metastasis and death (4,5). Therefore, some form of treatment is warranted. Several options exist for the treatment of KA. Surgical excision is the treatment of choice for most KA patients. However, complete excision of a large KA may require extensive reconstruction. In addition, surgical treatment may lead to hospitalization in patients with multiple comorbidities or those taking anticoagulation medications (6).
Other treatment modalities for KA include the following: Moh’s excision, systemic retinoids, radiotherapy, curettage and electrodissection, intralesional 5-fluorouracil and intralesional methotrexate (MTX) (7). MTX is a folic acid analogue that irreversibly binds to dihydrofolate reductase, thereby blocking the formation of tetrahydrofolate and, subsequently, preventing the synthesis of the purine nucleotide thymidine (8), leading to a halt in DNA synthesis (9).
After systemic MTX, KAs may improve or resolve. A potential mechanism for the involution of the KA after MTX treatment is the decrease in DNA synthesis in the rapidly dividing tumour (10). Certain patients, however, are unable to tolerate systemic MTX due to the adverse effects while, in others, the KAs do not respond to systemic MTX (11).
The purpose of the present study was to retrospectively review the patients at the Summa Health System, Crystal Clinic Orthopaedic Center, USA, from 1985 to 2009, in whom intralesional MTX was used as KA treatment.
After approval from the institutional review board of the Summa Health System, Northeastern Ohio Universities College of Medicine (USA), patient data from 1985 to 2009 were retrospectively reviewed. Charts of patients with KAs, who were treated by the senior author (ALC) using MTX, were identified. The following data were collected and recorded: age, sex, location of KAs, size, previous treatments, number of MTX injections, type of response to MTX and need for additional procedures.
Each patient had biopsy-proven KA. During the first office visit, the lesion was shaved with a No. 10 blade scalpel to debulk the KA. The central keratinous plug was removed. This was performed using a local anesthetic. A solution of 0.5 mL MTX (12.5 mg) and 0.5 mL sterile saline was injected at the base of the lesion using a 25-gauge needle.
The patient was seen weekly in the office. At each weekly office visit, a solution of MTX (12.5 mg to 25 mg, depending on initial response) mixed with 0.5 mL sterile saline was injected into the base of the KA. Weekly injections were continued as long as the KA responded. If there was no response after an injection, the patient underwent surgical excision of the KA. This was considered to be treatment failure.
Ten patients were included in the study; one patient was excluded because she was treated with oral MTX. The patient demographics and clinical characteristics of the KA in the remaining nine patients are outlined in Table 1. All patients had biopsy-proven KA. Patients ranged from 38 to 92 years of age. Six of nine (66.7%) patients in the study were younger than 70 years of age. Three of nine (33.3%) patients were between 81 and 92 years of age. Three patients were on anticoagulation medications. Five patients had KAs on the face, and four patients had KAs on the extremities. The size of the KAs ranged from 1.4 cm to 3 cm. The follow-up period ranged from six months to six years, with an average of 2.8 years.
Table 2 lists the number of injections performed and the response to methotrexate. Patients required one to four injections (12.5 mg to 25 mg per injection) before KA resolution. Eight of nine (88.9%) patients had complete resolution of the tumour (Figures 1 to to3).3). During an average follow-up of 2.8 years, there were no KA recurrences at the same site of treatment.
One patient initially responded to two injections of MTX. However, after the third injection, the KA showed no improvement. This was considered to be treatment failure with intralesional MTX. The patient underwent surgical excision of the KA. The pathology showed residual, moderately differentiating keratinizing squamous cell carcinoma (Figure 4). Another patient had complete resolution of the tumour proven by biopsy. However, this patient required kenalog injections for a hypertrophic scar.
KAs are well-differentiated, squamous cell carcinomas with potential for metastasis (7). Therefore, it is important to treat these tumours. There have been many treatment options for KAs including surgical excision, radiation and MTX.
A study (12) performed in Caucasians in the United States estimated the incidence of KAs at 104 cases/100,000 individuals. Peak incidence occurs in individuals 70 years of age or older. KAs are uncommon in dark-skinned individuals. In our practice, there seems to be an increasing number of patients between 30 and 69 years of age presenting with KAs. One factor for this increase within the younger age groups may be due to a potential relationship of KAs with the human papilloma virus (HPV). One study (13) tested for HPV DNA in patients with KA biopsies using polymerase chain reaction. It was found that 37 of 72 (51%) patients with KAs were HPV DNA positive (13).
The present retrospective study showed that using intralesional MTX after debulking the KA had an 88.9% resolution rate. Eight of nine patients had complete resolution after one to four injections. Each injection ranged from 12.5 mg to 25 mg of MTX. One patient initially responded after two injections. However, after the third MTX injection, there was no improvement in the lesion. At this time, a biopsy confirmed KA, and surgical excision was performed without delay.
Although it has been reported in the literature (7) that pancytopenia related to MTX can occur, none of the patients in the present study experienced adverse effects from the treatment. One patient complained of pain at the site after the MTX injection; the pain lasted for approximately one week. The average follow-up period of the present study was 2.8 years.
The results of the study were consistent with previous studies using intralesional MTX for the treatment of KA. Intralesional MTX for the treatment of KA was first described in 1991 (10). Nine patients with solitary KA, whose lesions resolved completely after one to two injections with a total dose ranging from 5 mg to 50 mg within two to four weeks, were reported. Subsequently, multiple case reports (6,10,14–16) have confirmed successful resolution of KAs following intralesional injection of MTX.
In 2007, Annest et al (7) published a series of KA cases treated with intralesional MTX using cases from their institution and those in the literature. MTX achieved resolution in 92% of cases, with an average of 2.1 injections for an average of 18 days. Limitations of the study included a short follow-up period, with an average of only 1.8 years. Furthermore, the initial diagnosis of KA in some of the patients in that study was not confirmed by histological studies. Third, the 92% resolution rate included the data from their institution and single case reports that were cited in the literature, thus including a favourable reporting bias (7).
Our study was unique in that all the patients underwent a histological biopsy, which confirmed the diagnosis. Also, the treatment protocol used by our institution varied from previous studies in that all of the tumours were debulked during the first office visit with a shave, using a No. 10 blade scalpel. Once the tumour was debulked, at the same setting, MTX was injected at the base. This was performed with the hypothesis that by debulking the tumour, the MTX would be more effective. The procedures were all performed in the office. The initial shave required a local anesthetic. All subsequent injections were performed without the use of local anesthesia.
There are many advantages of using intralesional MTX for the treatment of KAs after a shave debulking. Intralesional MTX is inexpensive and noninvasive, and cosmetic outcomes are very satisfactory compared with surgical excision. Additionally, no hospitalization or general anesthesia is required. The cost of a 2 mL vial (25 mg/mL) of MTX when purchased in bulk is US$10. Each vial can be used multiple times.
We propose that intralesional MTX injection with initial debulking of the KA should be used as a first line of treatment when KAs are present on the extremities, on cosmetically sensitive areas and in elderly patients with multiple comorbities. These patients should first undergo a biopsy to confirm that the lesion is a KA. We recommend an initial injection of 0.5 mL of methotrexate (25 mg/mL) with 0.5 mL of sterile saline. Subsequent weekly injections can range from 0.5 mL to 1 mL of MTX (25 mg/mL) plus 0.5 mL of sterile saline, depending on the response. Patients should also be followed very closely with weekly visits. If there is any indication that the lesion is not responding to the MTX or there is residual tumour, patients should undergo surgical excision without any delay. Contraindications for intralesional MTX include pregnancy or breastfeeding, and individuals with active infection, blood dyscrasias, drug interactions, hepatic disease or renal disease (14).