Keratoacanthoma 

Updated: Jul 25, 2018
Author: Tsu-Yi Chuang, MD, MPH, FAAD; Chief Editor: William D James, MD 

Overview

Background

Keratoacanthoma (KA) is a relatively common low-grade tumor that originates in the pilosebaceous glands and closely resembles squamous cell carcinoma (SCC). In fact, strong arguments support classifying keratoacanthoma as a variant of invasive SCC.[1, 2] In most pathology/biopsy reports, dermatopathologists refer to the lesion as "squamous cell carcinoma, keratoacanthoma-type." Recently, however, some have argued for a distinction between keratoacanthoma and SCC based on gene expression[3] or cutaneous marker.[4]

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 these cases were SCC or keratoacanthoma, the reports highlight the difficulty of distinctly classifying individual cases.[5, 6, 7, 8]

The image below depicts keratoacanthoma of the left forehead.

Keratoacanthoma of the left forehead. Keratoacanthoma of the left forehead.

See Nonmelanoma Skin Cancers You Need to Know, a Critical Images slideshow, to help correctly identify these lesions.

Pathophysiology

Trauma, ultraviolet light, chemical carcinogens, human papillomavirus, genetic factors, and immunocompromised status have been implicated as etiologic or triggering factors. The introduction of BRAF inhibitor therapy for melanoma and hedgehog pathway inhibitor therapy for advanced basal cell carcinoma have elicited a surge in keratoacanthoma (KA) incidence.[9]

Keratoacanthoma and conventional SCC share very similar epidemiological features, which suggests a possible common pathogenesis, such as actinic damage.[10] Interestingly, in Palm Springs, California, this author has seen more patients with SCC/keratoacanthoma than straightforward SCC. In population-based studies in Kauai, Hawaii, keratoacanthoma and SCC had a comparable incidence (106 cases per 100,000 population for keratoacanthoma and 118.2 cases per 100,000 population for SCC).[10, 11] Most keratoacanthomas and SCCs developed on head/neck and limbs (keratoacanthoma, 78%; SCC, 85%). 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. Male-to-female ratios for both conditions were similar, at 2:1.[10]

Etiology

The definitive cause of keratoacanthoma (KA) remains unclear; however, several potentiating factors should be considered. Epidemiologic data of keratoacanthoma is 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.[12] Additionally, a 2006 study suggested a strong association between cigarette smoking and the development of keratoacanthoma.[13]  

Trauma (iatrogenic or noniatrogenic), human papillomavirus (specifically types 9, 11, 13, 16, 18, 24, 25, 33, 37, and 57),[14, 15] genetic factors, and immunocompromised status also have been implicated as etiologic factors.

Merkel cell polyomavirus does not play a pathogenic role in keratoacanthoma.[16]

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.[17]

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.[18, 19, 20, 21]

Epidemiology

Frequency

United States

The sole published study on keratoacanthoma (KA) 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. Peak incidence occurs in the seventh decade or beyond. Keratoacanthoma is uncommon in darker-skinned patients.[10, 22, 23, 24]

International

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 American whites. In other studies, the ratio of keratoacanthoma to SCC has ranged from 1:0.6 to 1:5 in different geographic locations.[10, 22, 23, 24]

Race

Keratoacanthoma is less common in darker-skinned individuals.

Sex

The male-to-female ratio for keratoacanthoma is 2:1.

Age

Keratoacanthoma has been reported in all age groups, but incidence increases with age. Keratoacanthoma is rare in persons younger than 20 years.

Prognosis

The prognosis for keratoacanthoma is excellent following excisional surgery. Recurrent tumors may require more aggressive therapy. Follow patients with a history of keratoacanthoma for development of new primary skin cancers (SCC in particular). It has been reclassified as SCC-KA type to reflect 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.[25, 26]

Patient Education

Educate patients about prevention (including sunscreen), sun-protection techniques, and skin self-examination.

 

Presentation

History

Keratoacanthoma (KA) typically grows 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.

Physical Examination

Pertinent physical findings in keratoacanthoma (KA) are limited to the skin. Lesions typically are solitary and begin as firm, roundish, skin-colored or reddish 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 on sun-exposed areas. The face, neck, and dorsum of the upper extremities are common sites. Truncal lesions are rare. Lesions usually are skin-colored to pinkish-red. Unaffected skin retains its normal appearance. Note the images below.

Keratoacanthoma (squamous cell carcinoma-keratoaca Keratoacanthoma (squamous cell carcinoma-keratoacanthoma or SCC-KA type) on inner canthus.
Keratoacanthoma of the left forehead. Keratoacanthoma of the left forehead.
Close-up view of the keratoacanthoma. Close-up view of the keratoacanthoma.
Keratoacanthoma lesion (squamous cell carcinoma-ke Keratoacanthoma lesion (squamous cell carcinoma-keratoacanthoma or SCC-KA type).
 

DDx

Diagnostic Considerations

See the list below:

  • Eruptive keratoacanthoma (KA) of Grzybowski: This is characterized by a generalized eruption of numerous dome-shaped, skin-colored papules from 2-7 mm in diameter. Multiple larger typical keratoacanthomas may also appear. The eruption is usually generalized, but spares the palms and soles. Severe pruritus may be a feature. The papular lesions typically do not involute.

  • Multiple Ferguson-Smith keratoacanthoma: This is a rare autosomal dominant self-healing type of keratoacanthoma, with lesions arising in early adulthood.

  • Keratoacanthoma centrifugum margination: This variant is characterized by progressive peripheral growth and eventual size often 5-30 cm.

  • Muir-Torre syndrome: Keratoacanthoma may be a component of Muir-Torre syndrome, which is a cancer-associated genodermatosis with multiple sebaceous neoplasms (adenomas, epitheliomas, carcinomas), keratoacanthomas, and gastrointestinal malignancies (most commonly colon), although other carcinomas have been reported (genitourinary, pulmonary, endometrial). When Muir-Torre syndrome is diagnosed, an age-appropriate cancer screening workup is indicated. An approximately equal number of internal malignancies are diagnosed before and after the cutaneous neoplasm. These internal malignancies tend to be low grade, but early diagnosis is important. Colonoscopy, rather than flexible sigmoidoscopy, is recommended, since the colon cancer frequently is found in the right ascending colon, proximal to the hepatic flexure.

  • Sporotrichosis[27]

Differential Diagnoses

 

Workup

Procedures

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, excisional or deep incisional biopsy of the lesion is preferred.

Histologic Findings

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 keratoacanthoma.

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 into surrounding tissue in a more aggressive pattern.

 

Treatment

Medical Care

Treatment of keratoacanthoma (KA) is primarily surgical. Reserve medical treatment for exceptional cases where surgical intervention is either not feasible or desirable. For example, medical intervention 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 dissuade surgical procedure.

Systemic retinoids, such as isotretinoin, are a consideration for patients with lesions too numerous for surgical intervention.

Intralesional methotrexate (MTX),[28] 5-fluorouracil, bleomycin, and steroids have been used with success in patients who are either poor surgical candidates or have lesions not amenable to surgery because of size or location.[25, 29] A 2007 review of the use of intralesional injection of MTX on 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. Only 13% (5 patients) obtained histological confirmation.[30] Forty lesions in 30 patients were cleared with intralesional 5-fluorouracil with an average of three injections.[31] Topical 20% fluorouracil was also effective in 14 patients, but two developed allergic contact dermatitis.[32] Topical imiquimod has been used with anecdotal success.[33]

Note much of the literature concerning medical intervention for keratoacanthoma is limited to case reports or case series. Be cautious when making the decision to pursue medical in lieu of surgical intervention and perform appropriate follow-up.

Surgical Care

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 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 consider surgical treatment of keratoacanthoma to be equivalent to treatment for SCC.

Mohs micrographic surgery may be indicated for large or recurrent keratoacanthomas or keratoacanthomas located in anatomic areas with cosmetic or functional considerations.

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 will result in cosmetic deformity or for tumors that have recurred following attempted 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.

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.

Consultations

Consult a dermatologist to exclude invasive squamous cell carcinoma (SCC).

Long-Term Monitoring

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, periodic follow-up examinations, and early detection and treatment of actinic keratosis and skin cancer are important in these patients.

 

Medication

Medication Summary

Although surgical treatment is the modality for keratoacanthoma, in patients with clear-cut and multiple keratoacanthomas, a number of medical alternatives have been used with success.

Antineoplastic agents (eg, topical and intralesional 5-fluorouracil,[31, 32] intralesional methotrexate, interferon alfa-2a,[34] and bleomycin) have been used with some success in treating keratoacanthomas.

Retinoidlike agents are efficacious in the treatment of keratoacanthomas with good cosmetic outcome.[35]

Antineoplastics

Class Summary

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. Agents (eg, topical and intralesional 5-fluorouracil, intralesional MTX, interferon alfa-2a, and bleomycin) also have been used with some success in treating keratoacanthomas. When small amounts of medication are administered, the interactions and precautions listed below are less restrictive than when systemic doses are administered. As a rule, if after 4 weeks the lesion has not responded fully to medical therapy, surgical removal is indicated.

Methotrexate (Trexall, Rheumatrex)

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).

Fluorouracil (Adrucil)

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.

Bleomycin

Bleomycin is a glycopeptide antibiotic that inhibits DNA synthesis. The concentration usually is 1 mg/mL and diluted further with local anesthetic.

Retinoid-like Agents

Class Summary

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.

Isotretinoin (Amnesteem, Claravis, Sotret)

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.

Topical Skin Products

Class Summary

The agent imiquimod has been reported to show some efficacy. However, the mechanism of action of imiquimod cream in treating keratosis is unknown.

Imiquimod (Aldara, Zyclara)

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.

 

Questions & Answers

Overview

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?

Presentation

What is the clinical progression of keratoacanthoma?

Which physical findings are characteristic of keratoacanthoma?

DDX

Which conditions should be included in the differential diagnoses of keratoacanthoma?

What are the differential diagnoses for Keratoacanthoma?

Workup

What is the role of biopsy in the diagnosis of keratoacanthoma?

Which histologic findings are characteristic of keratoacanthoma?

Treatment

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?

Medications

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?