AUTHOR INFORMATION

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Authored by Tsu-Yi Chuang, MD, MPH, Medical Director of Melanoma Profram, Arthur L Norins Professor, Department of Dermatology, Indiana University Medical Center

Coauthored by Ryan Brashear, MD, Staff Physician, Department of Dermatology, Indiana University School of Medicine

Tsu-Yi Chuang, MD, MPH, is a member of the following medical societies: American Academy of Dermatology, American Society for Dermatologic Surgery, International Society for Dermatologic Surgery, and Society for Investigative Dermatology

Edited by Susan M Swetter, MD, Director of Pigmented Lesion and Cutaneous Melanoma Clinic, Assistant Professor, Department of Dermatology, Stanford University Medical Center/VA Palo Alto Health Care System; Michael J Wells, MD, Staff Physician, Department of Dermatology, Texas Tech University Health Sciences Center; John G Albertini, MD, Clinical Assistant Professor, Department of Dermatology, University of Texas Health Science Center at San Antonio; Chief, Mohs Micrographic Surgery, Department of Dermatology, San Antonio Uniformed Services Health Education Consortium; Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University; and William D James, MD, Program Director, Vice-Chair, Albert M Kligman Professor, Department of Dermatology, University of Pennsylvania School of Medicine

November 7 2001

INTRODUCTION

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Background: Keratoacanthoma (KA) is a relatively common low-grade malignancy that originates in the pilosebaceous glands and closely and pathologically resembles squamous cell carcinoma (SCC). In fact, strong arguments support classifying KA as a variant of invasive SCC. KA is characterized by rapid growth over a few weeks to months, followed by spontaneous resolution over 4-6 months in most cases. KA reportedly progresses, although rarely, to invasive or metastatic carcinoma; therefore, aggressive surgical treatment often is advocated. Whether these cases were SCC or KA, the reports highlight the difficulty of distinctly classifying individual cases.

Pathophysiology: Both sunlight and chemical carcinogens have been implicated as pathologic factors in growth of the tumor. Trauma, human papilloma virus, genetic factors, and immunocompromised status also have been implicated as etiologic factors.

Frequency:

• In the US: The sole published study in a white US population took place in Hawaii and estimated the incidence at 104 cases per 100,000. This study reported KA incidence equal to SCC and challenged the commonly reported incidence ratio of KA to SCC of 1:3. Peak incidence occurs in the seventh decade or beyond. KA is uncommon in darker-skinned patients.

• Internationally: Based on the Hawaiian data, the incidence of KA in ethnic Japanese, Filipino, and Hawaiian populations has been estimated to be 22, 7, and 6 per 100,000, respectively, approximately one fifth to one sixteenth of the incidence rate found in American whites. In other studies, the ratio of KA to SCC has ranged from 1:0.6 to 1:5 in different geographic locations.

Mortality/Morbidity: KA is believed to have a good prognosis; however, it recently was reclassified as SCC-KA type to reflect the difficulty in histologic differentiation, as well as the uncommon but potentially aggressive nature of KA. KA infrequently presents as multiple tumors and may enlarge (5-15 cm), become aggressive locally, or rarely, metastasize.

Race: KA is less common in darker-skinned individuals.

Sex: Male-to-female ratio is 2:1.

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

CLINICAL

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History: 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:

• Pertinent physical findings 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 (Picture 1, Picture 2, Picture 3, Picture 4).

• Most KAs 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.

Causes:

• The definitive cause of KA remains unclear; however, several potentiating factors should be considered.

• Epidemiologic data of KA is notably similar to SCC and Bowen disease (BD; SCC in situ) concerning age, sex, and the anatomic site of lesions. This data strongly supports a common etiology among KA, SCC, and BD. Epidemiologic data support sunlight as an important etiologic factor.

• Industrial workers exposed to pitch and tar have been well established as having a higher incidence of KA, as well as SCC.

• Trauma, human papilloma virus (specifically types 9, 11, 13, 16, 18, 24, 25, 33, 37, and 57), genetic factors, and immunocompromised status also have been implicated as etiologic factors. See Human Papillomavirus.

DIFFERENTIALS

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Actinic Keratosis
Cutaneous Horn
Merkel Cell Carcinoma
Metastatic Carcinoma of the Skin
Molluscum Contagiosum
Muir-Torre Syndrome
Prurigo Nodularis
Sporotrichosis
Squamous Cell Carcinoma
Verrucous Carcinoma

Other Problems to be Considered:

Eruptive keratoacanthoma of Grzybowski: Generalized distribution of multiple KAs that typically do not involute.

Multiple Ferguson-Smith keratoacanthoma: Rare autosomal dominant self-healing type of KA, with lesions arising in early adulthood.

Internal malignancy

Muir-Torre syndrome: KA 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.

WORKUP

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Procedures:

• One component of establishing the diagnosis is tissue examination for histopathology. Shave biopsy of KA is indistinguishable from invasive SCC; therefore, excisional or deep incisional biopsy of the lesion is preferred.

Pseudocarcinomatous infiltration in KA 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 KAs 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

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Medical Care: Treatment of 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, 5-fluorouracil, bleomycin, and topical 5-fluorouracil 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.

Note much of the literature concerning medical intervention for KA is limited to case reports and of unproved efficacy. 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 KA 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 KA and invasive SCC.
• In some patients, smaller lesions may be treated with deep excisional shave and curettage or other destructive techniques.
• Since the biological behavior of an individual KA cannot be predicted, many consider surgical treatment of KA to be equivalent to treatment for SCC.
• Mohs micrographic surgery may be indicated for large or recurrent KAs or KAs located in anatomic areas with cosmetic or functional considerations.

• KAs 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 KAs, in KAs found in difficult to treat locations, and as an adjunct to surgical removal.

Consultations: Dermatologist: Consult to exclude invasive SCC.

MEDICATION

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Although primary consideration of treatment is surgical, in patients with clear-cut and multiple KAs, a number of medical alternatives have been used with success.

Drug Category: Antineoplastic agents -- Useful in patients with large or multiple tumors or tumors that are inoperable because of anatomic location or the patient's poor medical status. Agents (eg, topical 5-fluorouracil, intralesional methotrexate, interferon alfa-2a, and bleomycin) also have been used with some success in treating KAs. 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 wk the lesion has not responded fully to medical therapy, surgical removal is indicated.

Drug Name	Methotrexate (Folex, Rheumatrex) -- Antimetabolite that inhibits DNA synthesis and cell reproduction in malignant cells. May suppress immune system. Satisfactory response seen within 3-6 wk following administration. Marked response noticed after 2 injections (1 study).
Adult Dose	0.4-1.5 mL of 12.5 mg/mL injected intralesionally q2wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; alcoholism; hepatic insufficiency; immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia); renal insufficiency; pregnancy or breastfeeding
Interactions	Oral aminoglycosides may decrease absorption and blood levels of concurrent oral methotrexate (MTX); charcoal lowers MTX levels; coadministration with etretinate may increase hepatotoxicity of MTX; folic acid or its derivatives contained in some vitamins may decrease response to MTX; coadministration with NSAIDs may be fatal; indomethacin and phenylbutazone can increase MTX plasma levels; may decrease phenytoin serum levels; probenecid, salicylates, procarbazine, and sulfonamides, including TMP-SMZ, may increase effects and toxicity of MTX; may increase plasma levels of thiopurines
Pregnancy	D - Unsafe in pregnancy
Precautions	Excreted mainly via kidney; monitor CBCs monthly, and liver and renal function q1-3mo during therapy (monitor more frequently during initial dosing, dose adjustments, or when risk of elevated MTX levels, eg, dehydration); MTX has toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems; discontinue if significant drop in blood counts; aspirin, NSAIDs, or low dose steroids may be administered concomitantly with MTX (possibility of increased toxicity with NSAIDs including salicylates has not been tested)

FOLLOW-UP

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Further Outpatient Care:

• Patients who develop nonmelanoma skin cancer, such as KA, SCC, BD, 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.

Prognosis:

• Prognosis is excellent following excisional surgery.

• Recurrent tumors may require more aggressive therapy.

• Follow patients with a history of KA for development of new primary skin cancers (SCC in particular).

Patient Education:

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

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Failure to diagnose KA can result in substantial morbidity and, occasionally, mortality. Since both metastatic disease and local destruction have been reported with KA, accurate diagnosis is critical. Physicians diagnosing and/or treating KA are held legally responsible for actions (or actions not taken) that fall outside of the standard of care.

• Failure to treat KA appropriately may result in unacceptably high levels of recurrence and metastasis, or in other cases, may result in an unfavorable risk-to-benefit ratio. Since over or under treating KA can have untoward effects, physicians treating KA bear the liability for selecting and performing the appropriate level of treatment.

• Failure to educate patients about prevention, self-examination, and the nature of the tumor may result ultimately in an unacceptable level of morbidity and mortality. Since KA is a strong risk factor for future occurrences of nonmelanoma skin cancer and may be a marker for internal malignancy in the context of some syndromes, appropriate education and follow-up must be performed.

Special Concerns:

• Be sure to rule out SCC.

TEST QUESTIONS

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CME Question 1: Which of the following patients is at greatest risk for keratoacanthoma?

A: A 20-year-old African woman
B: A 65-year-old white man
C: A 65-year-old white woman
D: A 45-year-old Hispanic man
E: A 45-year-old Japanese woman

The correct answer is B: Incidence rises dramatically in the sixth and seventh decades and is higher in men and in individuals with fair skin.

CME Question 2: Which of the following modalities is the treatment of choice for most solitary keratoacanthomas?

A: Surgical excision
B: Cryotherapy
C: Intralesional methotrexate
D: Radiation
E: Isotretinoin

The correct answer is A: Surgical excision is the best choice since histopathologic examination of the tumor excludes invasive squamous cell carcinoma and typically provides a good cosmetic outcome.

Pearl Question 1 (T/F): Sunlight and heavy oils (eg, pitch, tar) are the 2 most clearly identified exposure risk factors for keratoacanthoma.

The correct answer is True: Epidemiologic data support sunlight as an important etiologic factor, and industrial workers exposed to pitch and tar have been well established as having a higher incidence of keratoacanthoma.

Pearl Question 2 (T/F): Excision of a solitary keratoacanthoma with 4-mm margins should be followed by radiation therapy.

The correct answer is False: Excision of keratoacanthoma with 3- to 5-mm margins usually is accepted as adequate treatment. Chemotherapeutic regimens typically are not indicated in the treatment of keratoacanthoma.

Pearl Question 3 (T/F): Sun-exposed areas of the body are most likely to present with keratoacanthoma.

The correct answer is True: Sun-exposed areas, especially the face, neck, and extensor upper extremities are most likely to develop keratoacanthomas.

Pearl Question 4 (T/F): Ferguson-Smith syndrome should be included in the differential in a patient who presents with multiple keratoacanthomas.

The correct answer is True: Ferguson-Smith (autosomal dominant), eruptive keratoacanthomas of Gryzbowski, and Muir-Torre syndrome should be considered. Multiple keratoacanthomas also have been seen in immunosuppressed transplant patients.

PICTURES

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Caption: Picture 1. Keratoacanthoma (squamous cell carcinoma-keratoacanthoma or SCC-KA type) on inner canthus
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Caption: Picture 2. Keratoacanthoma of the left forehead
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Caption: Picture 3. Close-up view of the keratoacanthoma lesion seen in Picture 2
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Caption: Picture 4. Keratoacanthoma lesion (squamous cell carcinoma-keratoacanthoma or SCC-KA type)
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BIBLIOGRAPHY

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• Canas GC, Robson KJ, Arpey CJ: Persistent keratoacanthoma: challenges in management. Dermatol Surg 1998 Dec; 24(12): 1364-9[Medline].
• Chuang TY, Reizner GT, Elpern DJ, et al: Keratoacanthoma in Kauai, Hawaii. The first documented incidence in a defined population. Arch Dermatol 1993 Mar; 129(3): 317-9[Medline].
• Chuang TY, Reizner GT, Elpern DJ, et al: Non-melanoma skin cancer and keratoacanthoma in Filipinos: an incidence report from Kauai, Hawaii. Int J Dermatol 1993 Oct; 32(10): 717-8[Medline].
• Fitzpatrick T, Eisen A, Wolff K, et al, eds: Keratoacanthoma. In: Dermatology in General Medicine. 4th ed. New York, NY: McGraw-Hill; 1993: 848-855.
• Frank TL, Maguire HC Jr, Greenbaum SS: Multiple painful keratoacanthomas. Int J Dermatol 1996 Sep; 35(9): 648-50[Medline].
• Grob JJ, Suzini F, Richard MA: Large keratoacanthomas treated with intralesional interferon alfa-2a. J Am Acad Dermatol 1993 Aug; 29(2 Pt 1): 237-41[Medline].
• Hsi ED, Svoboda-Newman SM, Stern RA, et al: Detection of human papillomavirus DNA in keratoacanthomas by polymerase chain reaction. Am J Dermatopathol 1997 Feb; 19(1): 10-5[Medline].
• Letzel S, Drexler H: Occupationally related tumors in tar refinery workers. J Am Acad Dermatol 1998 Nov; 39(5 Pt 1): 712-20[Medline].
• Lu S, Syrjanen SL, Havu VK, Syrjanen S: Known HPV types have no association with keratoacanthomas. Arch Dermatol Res 1996 Mar; 288(3): 129-32[Medline].
• Manstein CH, Frauenhoffer CJ, Besden JE: Keratoacanthoma: is it a real entity? Ann Plast Surg 1998 May; 40(5): 469-72[Medline].
• Meffert JJ: Cutaneous sporotrichosis presenting as a keratoacanthoma. Cutis 1998 Jul; 62(1): 37-9[Medline].
• Reizner GT, Chuang TY, Elpern DJ, et al: Keratoacanthoma in Japanese Hawaiians in Kauai, Hawaii. Int J Dermatol 1995 Dec; 34(12): 851-3[Medline].
• Reizner GT, Chuang TY, Elpern DJ, et al: Basal cell carcinoma and keratoacanthoma in Hawaiians: an incidence report. J Am Acad Dermatol 1993 Nov; 29(5 Pt 1): 780-2[Medline].
• Sayama S, Tagami H: Treatment of keratoacanthoma with intralesional bleomycin. Br J Dermatol 1983 Oct; 109(4): 449-52[Medline].
• Schwartz RA: Keratoacanthoma. J Am Acad Dermatol 1994 Jan; 30(1): 1-19; quiz 20-2[Medline].

NOTE:

Medicine is a constantly changing science and not all therapies are clearly established. New  research changes drug and treatment therapies daily. The authors, editors, and publisher of this journal have used their best efforts to provide information that is up-to-date and accurate and is generally accepted within medical standards at the time of publication. However, as medical science is constantly changing and human error is always possible, the authors, editors, and publisher or any other party involved with the publication of this article do not warrant the information in this article is accurate or complete, nor are they responsible for omissions or errors in the article or for the results of using this information. The reader should confirm the information in this article from other sources prior to use. In particular, all drug doses, indications, and contraindications should be confirmed in the package insert.

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