A rare case of multiple keratoacanthomas treated with oral acitretin and intralesional methotrexate.

Sir,

Keratoacanthoma (KA) is a rapidly growing cutaneous neoplasm derived from the hair follicle. KA usually occurs on sun-exposed sites in elderly people and is rare in young adults. We report a young patient with multiple keratoacanthomas that responded to intralesional methotrexate (MTX) and oral acitretin.

A 25-year-old male patient presented with multiple asymptomatic raised lesions on the leg, elbow, and buttocks since one year. There was no history of trauma or similar complaints in his family. On examination, multiple erythematous dome-shaped papules and nodules measuring 3–6 cm were seen on the legs, buttocks, elbow, and hand. Surrounding skin on the leg showed atrophic scars. [Figures 1 and 2] There were no oral lesions or lesions on his finger nails or toe nails, and his teeth and hair were normal.

Figure 1

Multiple dome-shaped papulonodules present over legs

Figure 2

Dome-shaped papules and nodules present over buttock

A biopsy was obtained from an early lesion on the right elbow. Histology revealed an exo–endophytic growth with a central crater containing keratinous material. The crater was surrounded by markedly hyperplastic squamous epithelium with large squamous epithelial cells having abundant glassy cytoplasm. Some cells were dyskeratotic. Within the dermis was a dense, chiefly mononuclear inflammatory infiltrate. A buttress of epidermis surrounded the crater [Figure 3a and b]. The clinical and pathologic data were consistent with keratoacanthomas. His complete blood count (CBC), serum creatinine, serum cholesterol, serum triglycerides, and serum glutamic pyruvic transaminase (SGPT) were within normal limits. ELISA for HIV was nonreactive.

Figure 3

(a) Exo–endophytic growth showing a central crater containing keratinous material. (H and E, 10X). (b) Exo–endophytic growth with a central crater containing keratinous material, surrounded by markedly hyperplastic squamous epithelium with large squamous epithelial cells having abundant glassy cytoplasm. Dyskeratotic cells seen. Dermis shows a dense, chiefly mononuclear inflammatory infiltrate. A buttress of epidermis surrounded the crater. (H and E, 40X)

He was initially put on oral isotretinoin 40 mg per day for six months, but was still developing new lesions. He was then put on oral acitretin 25 mg and given intralesional MTX 12.5 mg/mL on the first visit along with tazarotene and 5-flourouracil for topical application. Oral folic acid was given on day following the injection. CBC, SGPT, and serum creatinine were repeated after every injection, which were normal. After two injections of methotrexate 12.5 mg/mL given 4 weeks apart, the lesions regressed in size [Figures 4 and 5]. Currently, the patient is on alternate day acitretin along with topical tazorotene and topical 5-fluorouracil.

Figure 4

Posttreatment regression of lesions over legs showing few scars and postinflammatory hyperpigmentation

Figure 5

Presence of scars and postinflammatory hyperpigmentation after regression of lesion on buttock

The most commonly described multiple keratoacanthomas are of Ferguson–Smith type. The patients usually develop medium- to large-sized lesions that typically number from tens to hundreds.[1] Patients tend to present at an earlier age, have lesions that can regress to form deep scars, and may or may not show a familial pattern of inheritance. Because keratoacanthoma often regresses spontaneously, some authorities claim that it does not require treatment. However keratoacanthoma may take a long time to involute spontaneously[2] and may continue to enlarge during that time, resulting in impingement of important structures. Thus, early treatment can hasten cure, prevent functional loss, and improve overall cosmesis. Many treatment options are available for keratoacanthoma. Excisional surgery is recommended for the majority of keratoacanthoma cases. However, an excision can cause significant cosmetic or functional problems, because of the surgical defects resulting from the size or location of the tumor. Our patient had multiple lesions, hence surgical therapy was not preferred. Intralesional MTX, as an example of a nonsurgical treatment modality, offers an efficacious, less invasive treatment option with acceptable cosmetic results.

MTX is appropriate for rapidly growing tumors since it inhibits DNA synthesis in actively dividing cells.[3] MTX is a folic acid analog that binds to dihydrofolate reductase, blocking the formation of tetrahydrofolate and preventing synthesis of the purine nucleotide thymidine.[4] Intralesional injections enable the local delivery of potent chemotherapeutic agents such as methotrexate and can help avoid a systemic toxicity.[5]

Contraindications for intralesional methotrexate include renal insufficiency, hepatic insufficiency, or immunosuppression. Two cases of pancytopenia have been reported in patients with renal insufficiency treated with intralesional MTX.[6] Thus, obtaining a baseline and 1 week postinjection CBC for all patients is reasonable.

DESCRIPTION OF TECHNIQUE

Our standard practice for injection is as follows: Using a 27-gauge needle, 0.3–2.0 cc of methotrexate in a concentration of either 12.5 or 25 mg/mL is injected at each treatment session. Shortly after the MTX injection, a uniform tumor blanching was achieved. We adjusted the injection site, the interval between injections, and the concentration and amount of MTX depending on the clinical response. We repeated the injections with an interval that ranged from 4 to 30 days. When total tumor necrosis is achieved, the treatment can be discontinued. We tend to favor lower concentration for smaller tumors. Small keratoacanthomas less than 1 cm, are typically injected in a single central point at the base of the lesion whereas larger KAs are injected in four quadrants as well as at the central lesion base.[7]

Leakage of methotrexate through the central crust or prior biopsy incisions is expected and should not reduce clinical efficacy. Methotrexate is injected until an endpoint of uniform tumor blanching is achieved.

Local side effects of intralesional MTX are pain at the site of injection and prior injection of local anesthetic may decrease the pain.

MTX causes tumor necrosis. Keratoacanthomas typically become more friable, and eventually ulcerate before resolution.

Oral retinoids including isotretinoin, etretinate and acitretin are the most commonly used approach that has been associated with the best therapeutic efficacy. Unfortunately, the efficacy was not standard in all patients where the response was mild or absent in some patients and the resolution was temporary. It has also been observed that oral retinoids were more successful in clearing the typical large keratoacanthoma lesions than the numerous small follicular papules. The dose of oral retinoids ranged from 0.5 to 2 mg/kg/day, and a lower dose maintenance therapy has been suggested by some authors to decrease or prevent recurrence commonly reported after stoppage of treatment.[8] The mode of action of oral retinoids in keratoacanthoma is not completely understood; however, they seem to inhibit keratinization, modulate terminal differentiation of epidermal cells, and increase both IL-2 production and mitogen-induced lymphocyte proliferation.

While working up the case, we faced the limitation of access to genetic analysis in a resource-poor setup. Since our patient was not responding to oral retinoids alone intralesional injections of methotrexate were given.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.