Keratoacanthoma (KA) is a relatively common low-grade tumor that originates in the pilosebaceous glands. KA is a subtype of squamous cell carcinoma (SCC) with a tendency toward spontaneous regression.[1, 2, 3] Dermatopathologists refer to the lesion as squamous cell carcinoma, keratoacanthoma type (SCC–KA type). However, some have argued for a distinction between keratoacanthoma and SCC based on gene expression[4] or a cutaneous marker.[5]
Keratoacanthoma is characterized by rapid growth over a few weeks to months, followed by spontaneous resolution over 4-6 months in most cases. Keratoacanthoma may progress rarely to invasive or metastatic carcinoma. Whether such cases were initially SCC or keratoacanthoma, the reports highlight the difficulty of distinctly classifying individual cases.[6, 7, 8, 9]
The image below depicts keratoacanthoma of the left forehead.
Trauma/local injury, ultraviolet light, chemical carcinogens, human papillomavirus, genetic factors (mutations in p53 or H-Ras), and immunocompromised status have been implicated as etiologic or triggering factors. Cancer immunotherapies, such as immune checkpoint inhibitors, can have cutaneous adverse effects, and the flourishing of these targeted therapies has led to a marked increase in keratoacanthoma incidence.[10, 11]
Keratoacanthoma is associated with syndromes such as Muir-Torre syndrome, Ferguson-Smith syndrome, xeroderma pigmentosum, and incontinentia pigmenti. A rare disorder, generalized eruptive keratoacanthoma of Grzybowski, is discussed in further detail in DDx.
Keratoacanthoma and conventional SCC share similar epidemiologic features, which suggests a possible common pathogenesis such as actinic damage.[12] In population-based studies in Kauai, Hawaii, similarities between keratoacanthoma and SCC included the following:
Incidence – 106 cases per 100,000 population for keratoacanthoma and 118.2 cases per 100,000 population for SCC[12, 13]
Anatomic site – Most keratoacanthomas and SCCs developed on head/neck and limbs (keratoacanthoma, 78%; SCC, 85%)
Patient age – The incidence of keratoacanthoma and SCC increased significantly after age 64 years; the average age of patients was 67 years in keratoacanthoma and 66 years in SCC[12]
Male predominance – Male-to-female ratios for both conditions were 2:1[12]
The definitive cause of keratoacanthoma remains unclear; however, several potentiating factors should be considered. Epidemiologic data on keratoacanthoma are notably similar to SCC and Bowen disease (SCC in situ) concerning age, sex, and the anatomic site of lesions. These data strongly support a common etiology among keratoacanthoma, SCC, and Bowen disease. Epidemiologic data support ultraviolet light as an important etiologic factor.
Industrial workers exposed to pitch and tar have been well established as having a higher incidence of keratoacanthoma, as well as SCC.[14] Additionally, a 2006 study suggested a strong association between cigarette smoking and the development of keratoacanthoma.[15]
Trauma (iatrogenic or non-iatrogenic), human papillomavirus infection (specifically with types 9, 11, 13, 16, 18, 24, 25, 33, 37, and 57),[16, 17] genetic factors, and immunocompromise also have been implicated as etiologic factors.
Merkel cell polyomavirus does not play a pathogenic role in keratoacanthoma. [18]
Twenty percent of patients who had metastatic melanoma and were treated with vemurafenib, a novel BRAF V600E inhibitor, may develop eruptive keratoacanthoma or squamous cell carcinoma. [19]
Finally, research has identified that up to one third of keratoacanthomas harbor chromosomal aberrations. Recurrent aberrations include gains on 8q, 1p, and 9q with deletions on 3p, 9p, 19p, and 19q. One other report identified a 46,XY,t(2;8)(p13;p23) chromosomal aberration.[20, 21, 22, 23]
The sole published study on keratoacanthoma in a White US population took place in Hawaii and estimated the incidence at 106 cases per 100,000. This study reported keratoacanthoma incidence equal to SCC and challenged the commonly reported incidence ratio of keratoacanthoma to SCC of 1:3.[12, 13]
Race-, sex-, and age-based demographics
Based on the Hawaiian data, the incidence of keratoacanthoma in ethnic Japanese, Filipino, and Hawaiian populations has been estimated to be 22, 7, and 6 cases per 100,000 population, respectively—approximately one fifth to one sixteenth of the incidence rate found in US Whites. In other studies, the ratio of keratoacanthoma to SCC has ranged from 1:0.6 to 1:5 in different geographic locations.[12, 24, 25, 26]
Keratoacanthoma is less common in darker-skinned individuals. [12, 24, 25, 26]
The male-to-female ratio for keratoacanthoma is 2:1.
Keratoacanthoma has been reported in all age groups, but incidence increases with age. Keratoacanthoma is rare in persons younger than 20 years. Peak incidence occurs in the seventh decade or beyond.
The prognosis for keratoacanthoma is excellent following excisional surgery. Recurrent tumors may require more aggressive therapy. It is important to follow patients with a history of keratoacanthoma for development of new primary skin cancers (SCC in particular). The reclassification of keratoacanthoma as SCC–KA type reflects the difficulty in histologic differentiation.
Uncommonly, keratoacanthomas may exhibit an aggressive growth pattern. Keratoacanthoma infrequently presents as multiple tumors and may enlarge (5-15 cm), become aggressive locally, or rarely, metastasize.[27, 28]
Keratoacanthomas typically are solitary lesions and begin as firm, roundish, skin-colored to pinkish-red papules that rapidly progress to dome-shaped nodules with a smooth shiny surface and a central crateriform ulceration or keratin plug that may project like a horn. Most keratoacanthomas occur in sun-exposed areas. The face, neck, and dorsum of the upper extremities are common sites. Truncal lesions are rare. Unaffected skin retains its normal appearance. Note the images below.
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Keratoacanthoma (squamous cell carcinoma-keratoacanthoma or SCC-KA type) on inner canthus.
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Keratoacanthoma of the left forehead.
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Close-up view of the keratoacanthoma.
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Keratoacanthoma lesion (squamous cell carcinoma-keratoacanthoma or SCC-KA type).
Keratoacanthomas typically grow rapidly, attaining 1-2 cm within weeks, followed by a slow involution period lasting up to 1 year and leaving a residual scar if not excised preemptively. Since expedient therapy almost always is instituted, the true natural course of the tumor cannot be confirmed with certainty.
One component of establishing the diagnosis of keratoacanthoma (KA) is tissue examination for histopathology. Shave biopsy results from a keratoacanthoma are indistinguishable from invasive squamous cell carcinoma (SCC); therefore, an excisional or deep incisional biopsy of the lesion is preferred.
Keratoacanthomas (KAs) are composed of singularly well-differentiated squamous epithelium that show only a mild degree of pleomorphism and likely form masses of keratin that constitute the central core of the lesion.
Pseudocarcinomatous infiltration in keratoacanthoma typically presents a smooth, regular, well-demarcated front that does not extend beyond the level of the sweat glands.
The term SCC–KA type has been introduced for otherwise classic keratoacanthomas that reveal a peripheral zone formed by squamous cells with atypical mitotic figures, hyperchromatic nuclei, and loss of polarity to some degree. These marginal cells also may penetrate surrounding tissue in a more aggressive pattern.
Treatment of keratoacanthoma (KA) is has to be invidualized. Although surgical excision is the primary therapy, medical treatment may be appropriate in patients with multiple lesions, in lesions not amenable to surgery because of size or location, and in patients with comorbidities that make them poor candidates for a surgical procedure. Note that much of the literature concerning medical intervention for keratoacanthoma is limited to case reports or case series.
Antineoplastic agents (eg, topical and intralesional 5-fluorouracil,[33] intralesional methotrexate (MTX),[34] interferon alfa-2a,[35] and bleomycin) have been used with some success in treating keratoacanthomas.[36, 27, 37]
A 2007 review of the use of intralesional MTX in 38 patients, including 18 of the researchers' patients, showed a 92% clinical resolution rate; however, patients needed an average of 2.1 injections to achieve it, and histologic confirmation was obtained in only 13% (5 patients).[38] A study of weekly intralesional 5-fluorouracil injections reported that 40 lesions in 30 patients cleared after an average of three injections.[39]
A study comparing intralesional injections of MTX versus 5-fluorouracil found no statistically significant difference in efficacy. However, complete response was achieved with a lower median number of injections with 5-fluorouracil than with MTX (2 vs 3, respectively).[40]
Topical 20% fluorouracil was also effective in 14 patients, but two developed allergic contact dermatitis.[33] Severe inflammatory reactions resulting in reactive KAs have been reported following use of topical fluorouracil.[41]
Topical imiquimod has been used with anecdotal success.[42]
Retinoid-like agents are efficacious in the treatment of keratoacanthomas, with good cosmetic outcome.[43] Systemic retinoids, such as isotretinoin, are a consideration for patients with lesions too numerous for surgical intervention.
The primary therapy for keratoacanthoma is surgical excision of the tumor. Excise tumors with adequate margins (3-5 mm) and histopathologic evaluation to exclude invasive squamous cell carcinoma (SCC). Partial shave biopsy usually inadequately distinguishes between keratoacanthoma and invasive SCC. In some patients, smaller lesions may be treated with deep excisional shave and curettage or other destructive techniques. Because the biological behavior of an individual keratoacanthoma cannot be predicted, many experts consider surgical treatment of keratoacanthoma to be equivalent to treatment for SCC.
Mohs surgery or other excision with en face processing and margin control may be indicated for large or recurrent keratoacanthomas or keratoacanthomas located in anatomic areas with cosmetic or functional considerations. Use of intralesional 5-fluorouracil or methotrexate are good alternatives in selected patients.[36]
Both laser therapy and cryotherapy have been used successfully in small keratoacanthomas, in keratoacanthomas found in difficult-to-treat locations, and as an adjunct to surgical removal.
Keratoacanthomas are radiosensitive and respond well to low doses of radiation (< 10 Gy). Radiation therapy may be useful in selected patients with large tumors in whom resection would result in cosmetic deformity or for tumors that have recurred following excisional surgery. Radiation therapy is less appealing in younger patients, in whom radiation damage worsens with time. Radiation therapy is an important alternative treatment for selected patients who understand the risks and benefits, who are not good surgical candidates, or who lack access to Mohs surgery.
Patients who develop nonmelanoma skin cancer, such as keratoacanthoma, squamous cell carcinoma (SCC), Bowen disease, or basal cell carcinoma, are at high risk for developing subsequent nonmelanoma skin cancer. Education about prevention (ie, sunscreen use and other sun-protection techniques, skin self-examination), periodic follow-up examinations, and early detection and treatment of actinic keratosis and skin cancer are important in these patients.
Although surgical treatment is the preferred modality for keratoacanthoma, in non-surgical candidates or patients with clear-cut and multiple keratoacanthomas, a number of medical alternatives have been used with success. Administration is usually topical or intralesional, although systemic retinoids, such as isotretinoin, are a consideration for patients with lesions too numerous for surgical intervention.
Clinical Context:
Methotrexate is an antimetabolite that inhibits DNA synthesis and cell reproduction in malignant cells. It may suppress the immune system. Satisfactory response may be seen within 3-6 weeks following administration. A marked response may be noticed after 2 injections (1 study).
Clinical Context:
Fluorouracil is a fluorinated pyrimidine antimetabolite that inhibits thymidylate synthase (TS) and interferes with RNA synthesis and function. It has some effect on DNA. It is useful in symptom palliation for patients with progressive disease.
Clinical Context:
Bleomycin is a glycopeptide antibiotic that inhibits DNA synthesis. The concentration usually is 1 mg/mL and diluted further with local anesthetic.
These agents are useful in patients with large or multiple tumors or tumors that are inoperable because of anatomic location or the patient's poor medical status. They also are useful for eruptive keratoacanthomas of the lower legs. As a rule, if after 4 weeks the lesion has not responded fully to medical therapy, surgical removal is indicated.
Clinical Context:
Isotretinoin is an oral agent that treats serious dermatologic conditions. It is a synthetic 13-cis isomer of naturally occurring tretinoin (trans-retinoic acid). Both agents are structurally related to vitamin A. Acitretin is another retinoid. However, oral retinoids are more often used in patients with multiple keratoacanthomas.
An FDA–mandated registry now in place for all individuals prescribing, dispensing, or taking isotretinoin. For more information, see iPLEDGE. The registry aims to further decrease the risks of pregnancy and other unwanted and potentially dangerous adverse effects during a course of isotretinoin therapy.
These agents are efficacious in the treatment of keratoacanthomas with good cosmetic outcome. They decrease sebaceous gland size and sebum production and may inhibit sebaceous gland differentiation and abnormal keratinization.
Clinical Context:
Imiquimod is an immune response modifier currently approved for the treatment of genital and perianal warts. It is capable of inducing IFN-alpha, TNF-alpha, IL-1, IL-6, and IL-8. Studies using 5% cream in mice showed significant induction of IFN-alpha at the application site occurring as early as 2 hours after treatment. At 4 hours after application, increases in IFN-alpha mRNA levels were found, indicating an increase in transcription. It is not approved by the FDA for use in hypertrophic scars and keloids.
What is keratoacanthoma?What is the pathophysiology of keratoacanthoma?What causes keratoacanthoma?What is the prevalence of keratoacanthoma in the US?What is the global prevalence of keratoacanthoma?What is the racial predilection of keratoacanthoma?What is the sexual predilection of keratoacanthoma?Which age groups are at highest risk for keratoacanthoma?What is the prognosis of keratoacanthoma?What is included in patient education about keratoacanthoma?What is the clinical progression of keratoacanthoma?Which physical findings are characteristic of keratoacanthoma?Which conditions should be included in the differential diagnoses of keratoacanthoma?What are the differential diagnoses for Keratoacanthoma?What is the role of biopsy in the diagnosis of keratoacanthoma?Which histologic findings are characteristic of keratoacanthoma?How is keratoacanthoma treated?What is the role of surgery in the treatment of keratoacanthoma?Which specialist consultations are beneficial to patients with keratoacanthoma?What is included in the long-term monitoring of patients with keratoacanthoma?Which medications are used in the treatment of keratoacanthoma?Which medications in the drug class Topical Skin Products are used in the treatment of Keratoacanthoma?Which medications in the drug class Retinoid-like Agents are used in the treatment of Keratoacanthoma?Which medications in the drug class Antineoplastics are used in the treatment of Keratoacanthoma?
Lauren Abigail Hoffpauir, Doctor of Osteopathy Candidate, Texas College of Osteopathic Medicine
Disclosure: Nothing to disclose.
Coauthor(s)
Edward J Zabawski, Jr, DO, MBA, Adjunct Assistant Professor, Clinical Sciences
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Steven R Feldman, MD, PhD, Professor, Departments of Dermatology, Pathology and Public Health Sciences, and Molecular Medicine and Translational Science, Wake Forest Baptist Health; Director, Center for Dermatology Research, Director of Industry Relations, Department of Dermatology, Wake Forest University School of Medicine
Disclosure: Received honoraria from Amgen for consulting; Received honoraria from Abbvie for consulting; Received honoraria from Galderma for speaking and teaching; Received consulting fee from Lilly for consulting; Received ownership interest from www.DrScore.com for management position; Received ownership interest from Causa Reseasrch for management position; Received grant/research funds from Janssen for consulting; Received honoraria from Pfizer for speaking and teaching; Received consulting fee from No.
Chief Editor
William D James, MD, Emeritus Professor, Department of Dermatology, University of Pennsylvania School of Medicine
Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier<br/>Served as a speaker for various universities, dermatology societies, and dermatology departments.
Additional Contributors
Arash Taheri, MD, Research Fellow, Center for Dermatology Research, Department of Dermatology, Wake Forest University School of Medicine
Disclosure: Nothing to disclose.
Ryan Brashear, MD, Staff Physician, Department of Dermatology, Indiana University School of Medicine
Disclosure: Nothing to disclose.
Tsu-Yi Chuang, MD, MPH, FAAD, Clinical Professor, Department of Dermatology, Keck School of Medicine of the University of Southern California; Dermatologist, HealthCare Partners
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