Sporadic and Syndromic Keratoacanthomas: Diagnosis and Management

By Sarabi, Khashayar; Selim, Abdulhafez; Khachemoune, Amor

Keratoacanthomas are neoplasms of the skin and mucous membranes. Their nature continues to fuel controversies about the benign versus malignant nature of these tumors. The characteristics of keratoacanthomas (both the sporadic and syndromic types), the controversies about the benign versus malignant nature of keratoacanthomas, and current treatment options for keratoacanthomas are discussed.

Keratoacanthomas (KAs) are interesting neoplasms of the skin and mucous membranes. Their nature continues to fuel controversies about the benign versus malignant nature of these tumors. Even though the histopathology may resemble squamous cell carcinoma (SCC), their rapid growth from weeks to months followed by a swift and spontaneous resolution usually sets these two entities apart. Unlike SCC, these low-grade malignancies rarely become invasive or metastasize. Several pathological and chemical factors such as solar radiation, trauma, genetic factors, and even viral etiologies have been implicated as causative agents of these neoplasms. Finally, KAs can be isolated or appear in the context of syndromes. In this article, we will briefly present a patient with an isolated KA and review the pathology, clinical forms, and management of these entities.

Case Report

A 56-year-old Caucasian woman presented with a history of a rapidly growing lesion on the left thigh. Initially the lesion began as a round solid reddish papule, which grew to 1 cm within the first month. The patient reported that in the 2 months prior to her presentation to the clinic, the rate of growth had slowed and the lesion had become dome-like with a grayish-black plug in the center. Upon further investigation, the patient admits to having excessive exposure to sunlight for many years without the use of sunscreen. Her personal and family histories were negative for SCC or other skin cancers. Her skin examination showed a 2 x 2 cm erythematous hyperkeratotic nodule with irregular borders and an obvious central plug of keratin located on the left superior thigh (see Figures 1- 2). There were no associated constitutional symptoms; her physical examination and review of systems were unremarkable. Given the clinical picture, an excision of the lesion with a 4 mm margin was performed. The histopathology report was consistent with a clinical diagnosis of KA. Upon her return for a followup 4 months later, the surgical site had healed completely with a linear scar. No recurrence was noted; the clinical outcome was excellent. No other lesions suspicious for malignancy were identified upon a complete skin examination.

Introduction

Keratoacanthomas are tumors arising from follicles and pilosebaceous units. They are rapidly growing hyperkeratotic papules or nodules measuring up to a few centimeters and forming dome- shaped, colorful horns or flat dried-out ulcers with elevated borders. The shape resembles SCC, but the rapid progression and frequent swift resolution of KA differentiate it from SCC (Schwartz, 1994). Tumor markers and enzymes such as p53 or telomerase have been used to find molecular differences for help identifying these similar-appearing entities (Putti, The, & Lee, 2004). However, some researchers believe the progression of KA into a variant of SCC is possible. The process is not well understood, but studies have shown that the expression of a specific adhesion molecule is responsible for this transformation (Melendez, Smoller, & Morgan, 2003). Keratoacanthomas often affect older patients, typically above 50 years of age, and favors men over women in a 2:1 ratio. Etiologic factors of KA include sunlight (mostly in fair-skinned individuals), carcinogens (tar), teratogens (causing mutation in p53 or ras oncogenes), trauma, genetic aberrations of either deletions or gains on chromosomes, and immunodeficiency (Kim, Kim, Kim, Han, & Shon, 2003; Leon, Kamino, Steinberg, & Pellicer, 1998; Mantegna & Iuculano, 1995; Perez et al., 1997). There has also been debate regarding the presence of human papilloma virus (HPV) in KA. Two recent studies have taken different views in this matter and the debate regarding the absolute role of HPV in pathogenesis of KA is still unclear (Forslund, DeAngelis, Beigi, Schjolberg, & Clausen, 2003; Viviano, Sorce, & Mantegna, 2001).

Clinical Presentation

Keratoacanthomas typically present as reddish brown, dome-shaped papules or nodules with a central, keratin-filled plug and range from a few millimeters to several centimeters in size. They tend to occur most commonly on areas most prone to sunlight exposure, such as the nose, ears, dorsal surface of hands, and the cheeks (Wolff, Johnson, & Suurmond, 2005). Although most cases of KA occur as isolated solitary, giant, or subungual tumors, a small percentage are associated with varieties or syndromes that are listed in Table 1 (Ponti & Leon, 2005; Schwartz, 2004; Wee, 2004).

Pathology

Keratoacanthomas stem from the proliferation of squamous epithelial cells that extend upward and around the keratin-filled crater, and downward into the dermis. The large atypical epithelial cells have a characteristic “glassy” eosinophilic cytoplasm, which produce keratin. These cells are well-differentiated, showing only a mild degree of pleomorphism. This type of keratinization is followed by an invasion of elastic and collagen fibers. KA demonstrates elastic tissue trapping, and the presence of microabscesses, and eosinophilic infiltration within the dermis of the skin. Pseudocarcinomatous infiltration in KA typically presents a smooth, regular, well-demarcated front that does not extend beyond the level of the sweat glands (Kumar, Fausto, & Abbas, 2005; Schwartz, 2004).

Differential Diagnosis

The most important differential diagnosis of KA is SCC. The involution of large portions of the KA tumor and rapid growth following a biopsy favor the diagnosis of KA; the formation of ulcers and atypical cells favor the diagnosis of SCC. Other important differential diagnoses to consider are actinic keratoses and verrucous carcinomas. Actinic keratoses develop as a gradually progressing single, small papule or plaque on sun-exposed areas, commonly the face, of patients older than 30 with fair-skin and significant sun exposure. Actinic keratoses have much slower growth. Histologically, the epidermal changes are characterized by acanthosis, parakeratosis, and dyskeratosis. Cellular atypia is present, and the keratinocytes vary in size and shape. Mitotic figures are common. Verrucous carcinomas are also slow-growing tumors that may penetrate skin and may go as deep as the bone. They present as a verrucous, exophytic, or endophytic masses that typically develop at sites of chronic irritation and inflammation. Verrucous carcinomas have intracytoplasmic glycogen stores that help differentiate them from KAs (Kumar et al., 2005).

Controversies on the Benign vs. Malignant Nature of KA

The controversies regarding the true origins of KA are ongoing. It is thought that KA is either of a hyperplastic origin or a true neoplasm. There have been experiments with results that favor both. The rapid growth (within weeks) and the rapid regression of the tumor both favor the benign theory. The malignant origin is supported by cytological atypia, infiltrating margins (which are morphologically similar to SCC), expression of mutated tumor suppressor genes, and aneuploidy (Seidman, Berman, Yetter, & Moore, 1992). A more detailed study recently examined whether KA is more similar to SCC in situ or to invasive SCC. Syndecan-1, an adhesion molecule of which expression has been correlated to decreased tumor invasiveness, was shown to stain intensely in KA lesions. The study also showed that invasive SCC does not contain much of this adhesion molecule, hence providing more fuel for the theory that KA is more similar to SCC in situ (Mukunyadzi, Sanderson, Fan, & Smoller, 2002).

Treatment Options

Small KA lesions on the extremities are treated with cryosurgery or electrodessication and curettage. For more aggressive tumors with a rapid growth rate, Mohs micrographic surgery may be the treatment of choice. Some physicians choose an excisional surgery for single solitary lesions due to the added benefit of complete resection and a followup for histologic examination (Ratner, 2004). Oral medications and creams are prescribed for patients exhibiting multiple KA tumors to decrease tumor burden for individuals who are not able to afford surgery. Successful treatment options have been topical 5-fluorouracil (FU), imiquimod cream, and oral isotretinoin using different regimens (Gray & Meland, 2000; Ratner, 2004; Wong, Kolbusz, Goldberg, & Guana, 1994). Intralesional injection every 2 weeks of methotrexate 12.5 mg/ml, 5-FU 50 mg/ml, and interferon alpha-2a have been successful in clearing lesions in approximately 4 to 6 weeks. In Muir-Torre syndrome, isotretinoin and interferon Alpha-2a have both been successful in controlling and treating KAs in cases of recurrence (Ponti & Leon, 2005), and etretinate at 0.5 mg/kg to 1.0 mg/kg daily has been successful in treating keratoacanthoma centrifugum marginatum (Ogasawara et al., 2003). Radiation treatment has also been used in cases where recurrence of KA was noted, in addition to occurrences of KA in areas where surgical treatment would cause a deformity to a sensitive body part (Wong et al., 1994).

Outcomes

Patients with Mui\r-Torre syndrome, and in particular patients with KA or sebaceous neoplasms, need strict observation. It is recommended that following the initial presentation, the patient be seen yearly by a dermatologist (Ponti & Leon, 2005). Prognosis is usually excellent after therapy for single, isolated KAs. Education about prevention, such as the use of sunscreen and self-skin examination, is important in preventing recurrence of tumors. The patient should also be closely followed by the physician for development of nonmelanoma skin cancer such as SCC.

Nursing Measures

Educating nursing staff about the different clinical forms and the syndromes associated with KA may lead to identification of minor forms of syndromes and internal malignancies. Emphasis should be put on the regular self-skin examination and the necessity of followup with a dermatologist at least once a year.

Patient Education Needed When Using 5-FU, Imiquimod, and Oral Retinoids

5-Fluorouracil. Topical 5-fluorouracil is usually applied twice daily for a period of at least 3 weeks. KA lesions may require longer treatment. Patients should be warned that during the treatment phase, the lesions become increasingly erythematous and the treatment itself can be temporarily disfiguring, with ulcerations and crust formation. The pain associated with the treatment can be severe at times, and patients should be informed about this possibility. Excessive sunlight exposure should be avoided during the treatment period. Topical 5-FU treatment can be repeated on several occasions.

Imiquimod. No established treatment regimen exists for KA with imiquimod, but it should be administered at least 2 times/week before going to bed for 16 weeks. Apply to dry skin and leave on for about 8 hours, then wash area with mild soap and water.

Avoid exposure to sunlight or artificial tanning; regular use of sunscreen is encouraged; avoid contact with lips, eyes, or nostrils. Common adverse effects include erythema, edema, vesicles, erosion or ulceration, weeping, exudate, scaling, dryness, and crusting.

Oral retinoids. Patients should be educated about the multiple potential adverse effects of retinoids including hyperlipidemia, hepatitis, pseudotumor cerebri, myalgias, adverse mucocutaneous and dermatologic changes, and hyperostosis. Pregnancy is permitted at least 1 month after the last dose. Patients should also be told that retinoids may decrease night vision; inflammatory bowel disease may occur. Retinoids use may be associated with development of hepatitis. Occasional exaggerated healing response of acne lesions (excessive granulation) may occur. Patients with diabetes may experience problems in controlling blood sugar. Avoid exposure to UV light or sunlight until tolerance is achieved. Patients should discontinue treatment if rectal bleeding, abdominal pain, or severe diarrhea occur. Mood swings or depression may occur and caution should be exercised if history of depression is present.

Conclusion

Keratoacanthomas (KA) are typically present as reddish brown, dome-shaped papules or nodules with a central, keratin-filled plug, ranging from a few millimeters to several centimeters in size, and arising from follicles and pilosebaceous units. KA stems from the proliferation of squamous epithelial cells that extend upward and around the keratin-filled crater and downward into the dermis. The most important differential diagnosis of KA is SCC. Involution of large portions of KA tumor, and the rapid growth following a biopsy favor the diagnosis of KA; the formation of ulcers and atypical cells favor the diagnosis of SCC. KAs are often treated with cryosurgery or electrodessication and curettage. For more aggressive tumors with a rapid growth rate, regular excision or Mohs micrographic surgery may be the treatment of choice. Prognosis is usually excellent after therapy for single isolated KAs. The patient should also be followed closely by the physician for development of non-melanoma skin cancer such as SCC. Current investigations are underway for treatments of various forms of KA, and will soon shed a brighter light into the current understanding of the disease.

References

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Additional Readings

Goldman, G. (2005). Squamous cell carcinoma. Retrieved on February 1, 2006, from http://emedicine.com

Habif, T. (2004). Clinical dermatology (4th ed.). Philadelphia: Mosby.

His, E.D., Svoboda-Newman, S.M., Stern, R.A., Nickoloff, B.J., & Frank, T.S. (1997). Detection of human papillomavirus DNA in keratoacanthomas by polymerase chain reaction. American Journal of Dermatopathology, 19(1), 10-15.

Sanchez, Y., Simon, L., & Ambrojo, E. (2000). Solitary keratoacanthoma: A self-healing proliferation that frequently becomes malignant. American Journal of Dermatopathology, 22(4), 305- 310.

Tsu-Yi, C. (2006). Keratoacanthoma. Retrieved on February 1, 2006, from http://www.emedicine.com

Khashayar Sarabi, BS, MS4, is a Medical Student, George Washington University Medical Center, Washington, DC.

Abdulhafez Selim, MD, PhD, is Research Fellow, Massachusetts General Hospital, Endocrine Unit, Harvard Medical School, Boston, MA.

Amor Khachemoune, MD, CWS, is Assistant Professor, Department of Dermatology, New York University School of Medicine, New York, NY.

Copyright Anthony J. Jannetti, Inc. Apr 2007

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