Dermatology

Keratoacanthoma (Squamous cell carcinoma of the keratoacanthoma type, molluscum sebaceum)

Are You Confident of the Diagnosis?

Keratoacanthomas closely resemble squamous cell carcinomas. Many observers consider them to be low-grade squamous cell carcinomas. There is much debate in the literature about the relationship of these two entities. They are clinically distinguished by the initial rapid growth of a keratoacanthoma, stabilization, and frequent spontaneous regression, as contrasted with squamous cell carcinomas.

  • Characteristic findings on physical examination

Findings include a firm dome-shaped nodule with a central keratin filled crater (Figure 1,Figure 2,Figure 3).

Figure 1.

Classic keratoacanthoma. (Courtesy of Marlene Willen, MD)

Figure 2.

Giant keratoacanthoma. (Courtesy of Marlene Willen, MD)

Figure 3.

Giant Keratoacanthoma. (Courtesy of Marlene Willen, MD)

Figure 4.

Low magnification of a keratoacanthoma showing an endophytic crateriform neoplasm.

Figure 5.

A different example, showing an endophytic cup-shaped tumor.

  • Expected results of diagnostic studies

Histopathology shows a central keratin-filled crater with a lip of epithelium extending over the edges of the lesion. There is usually a sharp demarcation between tumor nests and stroma. Proliferating keratinocytes often display glassy eosinophilic cytoplasm with mild cytologic atypia and mitoses. A perivascular or lichenoid infiltrate with lymphocytes, occasional eosinophils, and plasma cells may be seen (Figure 6,Figure 7,Figure 8,Figure 9,).

Figure 6.

Intradermal islands of pleomorphic keratinocytes at the base of the tumor.

Figure 7.

Intradermal tumor islands extend to the level of eccrine glands and may incorporate neutrophils.

Figure 8.

Giant keratoacanthoma, post-treatment with intralesional interferon. (Courtesy of Marlene Willen, MD)

Figure 9.

Giant keratoacanthoma, post-treatment with intralesional interferon. (Courtesy of Marlene Willen, MD)

Punch biopsy shows the depth of the lesion but not the overall architecture of the tumor, while shave biopsy shows the architecture but not the pattern of growth at the base of the neoplasm.

Some observers have classified keratoacanthomas as squamous cell carcinomas of the keratoacanthoma type. Others disagree with this classification and regard keratoacanthomas as tumors that involute because of lichenoid inflammation. Histologic features that favor an invasive squamous cell carcinoma include greater pleomorphism of proliferating tumor cells, abnormal mitoses, ulceration, and stromal desmoplasia. At a molecular level, squamous cell carcinomas have a higher degree of chromosomal instability.

  • Diagnosis confirmation

The differential diagnosis includes squamous cell carcinoma, basal cell carcinoma, prurigo nodule, deep fungal or mycobacterial infection, molluscum contagiosum.

Solitary Keratoacanthoma

  • Rapidly proliferating nodule usually on sun-exposed skin (Figure 1,Figure 2,Figure 3)

  • Grows rapidly in the first few weeks, stabilizes, and often spontaneously regresses within 4-8 months

  • Healed keratoacanthomas can leave an atrophic scar

  • Subungual keratoacanthomas can cause significant nail dystrophy and do not usually regress

  • Giant keratoacnathomas can be locally destructive and invasive (Figure 2,Figure 3)

Keratoacanthoma centrifugum marginatum

  • Solitary nodule or multiple annular plaques that demonstrate peripheral expansion with central regression

  • Range in size from 5-30cm

  • Spontaneous involution does not occur

Multiple Keratoacanthomas of the Ferguson Smith type

  • Autosomal dominant disorder

  • Hundreds of keratoacanthomas appearing early in adolescence

  • Often spontaneously resolve within a few years

  • Increased incidence in people of Scottish ancestry

Generalized eruptive keratoacanthomas of the Gryzbowski variant

  • Generalized eruption of keratoacanthomas

  • Onset in the fifth to seventh decade of life

  • Facial involvement may cause ectropion and a masked facies

Multiple keratoacanthomas of Witten and Zak

  • Autosomal dominant

  • Onset in early childhood

  • Large and small miliary lesions

Summary of Multiple Keratoacanthoma Variants

The multiple keratoacanthoma variants are summarized in Table I.

Table I.

Multiple keratoacanthoma variants.
Multiple eruptive keratoacanthomas of Gryzbowski Multiple keratoacanthomas of Witten and Zak Ferguson Smith type
Hereditary None Autosomal dominant Autosomal dominant 9q22-q31Two large Scottish kindreds
Age of onset Fifth to seventh decade Early childhood Childhood to adolescence
Lesions Hundreds to thousands Larger and smaller lesions Crops of keratoacanthomas, few to hundreds
Course Possible ectropion and masked facies Mixed eruptive and self healing Appear suddenly, involute, and then reappear.

Sorafenib-induced keratoacanthomas

Keratoacanthomas have been reported in association with sorafenib, a multikinase inhibitor approved for the treatment of metastatic renal cell carcinoma and hepatocellular carcinoma. Sorafenib inhibits multiple tyrosine and serine/threonine kinases (vascular endothelial growth factor receptor 2 and 3, platelet derived growth factor receptor beta, B-RAF, Raf-1, Flt3, c-kit, and RET).

Keratoacanthomas have occurred 2-14 months after initiation of sorafenib. In one case, the size of the lesions correlated with the dose of sorafenib. Withdrawal of sorafenib has been reported to decrease the size and the number of lesions.

Who is at Risk for Developing this Disease?

Peak incidence occurs at 50-69 years of age, with few reports occurring in patients younger than 20. In a Japanese-Hawaiian population, the incidence of keratoacanthomas was reported at 22.1 per 100,000.

Ultraviolet light exposure is a major risk factor for the development of keratoacanthomas.

Other associations include immunosuppression and chemical carcinogens.

Trauma, including excision, radiation, cryosurgery, and carbon dioxide laser resurfacing have also been implicated as a cause of keratoacanthomas.

What is the Cause of the Disease?

  • Etiology

The exact etiology is unknown.

Ultraviolet light exposure is likely the main cause for the formation of keratoacanthomas.

There is a genetic predisposition.

There is a possible association with the human papillomavirus (HPV). Human papillomavirus has been detected in solitary keratoacanthomas and immunocompromised patients with keratoacanthomas. There are conflicting reports of the role of HPV in multiple keratoacanthomas.

  • Pathophysiology

The apoptosis regulatory protein bcl-2/Bak and the p53 are implicated in the pathogenesis.

Systemic Implications and Complications

Keratoacanthomas can occur in Muir-Torre syndrome, an autosomal dominant hereditary nonpolyposis colorectal cancer syndrome with numerous sebaceous neoplasms and associated visceral malignancies, including colorectal, endometrial, urologic, and upper gastrointestinal cancer.The disease is caused by a mismatch repair gene alteration (MSH2 on chromosome 2 and MLH1 on chromosome 3). Appropriate diagnostic work-up for patients with possible Muir-Torre syndrome includes colonoscopy and genetic testing.

Treatment Options

SURGICAL

Primary excision with 3-5mm margins or Mohs micrographic surgery

PHYSICAL MODALITIES

Electrodessication and curettage, cryotherapy, radiation, YAG, CO2 laser therapy, photodynamic therapy with topical 5-aminolaevulinic acid

MEDICAL

Topical

Imiquimod 5% cream (every other day for 4-12 weeks), 5-fluorouracil 5% cream (once daily for 4-8 weeks).

Systemic

- Isotretinoin (0.5-1mg/kg/day), acitretin (0.7mg/kg/day for 5 months, complete clearance in one patient with Ferguson-Smith multiple keratoacanthomas and keratoacanthoma centrifugum marginatum), cyclophosphamide 100mg/day (remission after 8 months in a patient with generalized eruptive keratoacanthomas of Grzybowski)

- Erlotinib, epidermal growth factor receptor inhibitor, tyrosine kinase inhibitor (150mg daily)

- Cytoxan 1gm/month x 6 months caused resolution in 2 patients who failed acitretin and methotrexate

- Intralesional options include:

  • Intralesional methotrexate (12.5 or 25mg/ml, average dose per treatment 12mg, average number of treatments 2.2, average total dose 33.8mg, weekly or every 2 weeks, response 91.7% of thirty-six tumors)

  • Intralesional 5-fluorouracil (50mg/ml, 120mg/treatment, average 8 treatments weekly, total average dose 341mg, 98.5% response rate of seventy-three tumors)

  • Intralesional bleomycin (0.5mg/ml, 0.1mg-0.4mg single injection or weekly for 1-2 weeks, total dose 0.1 to 0.4mg, 100% response rate of six tumors)

  • Intralesional interferon alpha-2a, interferon alpha-2b 3mU/ml, 4 to 9 weekly treatments, total average dose of 37.3mU, 100% response rate of eleven tumors).Clinical example of a giant keratoacanthoma treated with intralesional interferon alpha-2a with resolution photos (Figure 4,Figure 5).

  • All these agents require baseline and weekly complete blood counts with differential (cytopenias with methotrexate, 5-fluorouracil and the interferons). Intralesional therapy is associated with local pain, ulceration and necrosis.

Optimal Therapeutic Approach for this Disease

Management depends on the type of keratoacanthoma, the location, and the number of lesions.

Solitary keratoacanthomas: primary excision, Mohs micrographic surgery.

  • If anatomically sensitive area (e.g. lip, nose, etc), Mohs surgery.

  • Alternate treatment options for solitary keratoacanthomas: electrodessication and curretage

Large tumors in sensitive location not amenable to surgery or keratoacanthoma marginatum:

  • Intralesional methotrexate (12.5 or 25mg/ml, average dose per treatment 12mg, average number of treatments 2.2, average total dose 33.8mg, weekly or every 2 weeks, response 91.7%)

  • Intralesional 5-fluorouracil: (50mg/ml, 40-120mg/treatment, average 8 treatments, weekly, total average dose 341mg, 98.5% response rate)

For large tumors where excision may result in a cosmetic deformity or in patients who are not surgical candidates, consider radiation therapy.

Multiple keratoacanthomas have responded in one patient to intralesional 5-fluorouracil, 10-20mg per treatment for 7 weeks yielded 100% response in one patient with fourteen tumors.

Generalized eruptive keratoacanthomas or multiple keratoacanthomas: options include systemic administration of retinoids, isotretinoin, (0.5-1mg/kg/day, resolution in nine of twelve patients), acitretin, (0.7mg/kg/day for 5 months, complete clearance in one patient with Ferguson-Smith multiple keratoacanthomas and keratoacanthoma centrifugum marginatum). Cyclophoshpamide has also been used (100mg/day, remission after 8 months in a patient with generalized eruptive keratoacanthomas of Grzybowski).

Patient Management

Patients should be counseled on sun avoidance and sun protection, and have close follow-up to monitor for any signs of recurrence. Lymph node exams should be performed to monitor for possible metastasis (rare). Education, early detection, and treatment of actinic keratoses and skin cancers are important.

Unusual Clinical Scenarios to Consider in Patient Management

Multiple keratoacanthomas may be associated with visceral malignancy, as seen in Muir-Torre syndrome.

Subungual tumors may require high-resolution ultrasound with Doppler studies to assess the tumor size and extent prior to therapeutic intervention.

Close monitoring and follow-up is important to ensure complete regression as 5% of lesions may recur and there are rare reports of solitary keratoacanthomas that have metastasized.

What is the Evidence?

Nofal, A, Assaf, M, Ghonemy, S, Nofal, E, Yosef, A. "Generalized eruptive keratoacanthoma: a diagnostic and therapeutic challenge". Int J Dermatol. vol. 29. 2014 Jul.

(Decribes the use of pulse cytoxan in 3 patients who did not respond to acitretin 1mg/kg per day and methothrexate 15mg/week for 3 months. Cytoxan pulse therapy with 1 gm/month for 6 months cleared 2 of 3 patients; the third was lost to follow up.)

Aydin, F, Senturik, E, Sabanciler, E. "A case of Ferguson-Smith type multiple keratoacanthomas associated with keratoacanthoma centrifugum marginatum: response to oral acitretin". Clin and Exp Dermatol. vol. 32. 2007. pp. 683-686.

(Describes the use of acitretin for keratoacanthomas)

Batinac, T, Zamolo, G, Coklo, M. "Expression of cell-cycle and apoptosis regulatory proteins in keratoacanthoma and squamous cell carcinoma". Pathol Res Pract. vol. 202. 2006. pp. 599-607.

(A review of the possible etiology of keratoacanthomas and the role of apoptosis in the involution of keratoacanthomas)

Clausen, OP, D.Aass, HC, Beigi, M, Purdie, KJ, Proby, CM, Brown, VL. "Are keratoacanthomas variants of squamous cell carcinomas? A comparison of chromosomal aberrations by comparative genomic hybridization". J Invest Dermatol. vol. 16. 2006. pp. 2308-2315.

(Reviews the different histopathologic characteristics and chromosomal aberrations of keratoacanthomas and squamous cell carcinomas)

Dendorfer, M, Oppel, T, Wollenberg, A. "Topical treatment with imiquimod may induce regression of facial keratoacanthoma". Eur J Dermatol. vol. 13. 2003. pp. 80-82.

(Describes the use of topical imiquimod for the treatment of keratoacanthomas)

Goldberg, LH, Rosen, T, Becker, J. "Treatment of solitary keratoacanthomas with oral isotretinoin". J Am Acad Dermatol. vol. 23. 1990. pp. 934-936.

(A good case series of twelve keratoacanthomas treated with oral isotretinoin with no recurrence after 12 months)

Grey, RJ, Meland, NB. "Topical 5-fluorouracil as primary therapy for keratoacanthoma". Ann Plast Surg. vol. 44. 2000. pp. 82-85.

(Describes the use of topical 5-fluorouracil as a treatment for keratoacanthomas)

Grine, RC, Hendrix, JD, Greer, KE. "Generalized eruptive keratoacanthoma of Gryzbowski: response to cyclophosphamide". J Am Acad Dermatol. vol. 36. 1997. pp. 786-787.

(Case report describing the use of cyclophosphamide for the treatment of generalized keratoacanthomas)

Feldman, RJ, Maize, JC. "Multiple keratoacanthomas in a young woman: report of a case emphasizing medical management and a review of the spectrum of multiple keratoacanthomas". Int J Dermatol. vol. 46. 2007. pp. 77-79.

(A good review of the variants of keratoacanthomas)

Haas, N, Schadendorf, D, Henz, BM, Fuchs, PG. "Nine-year follow up of a case of Gryzbowski type multiple keratoacanthomas and failure to demonstrate human papillomavirus". Br J Dermatol. vol. 147. 2002. pp. 793-796.

(Reviews literature regarding the occurrence of HPV in keratoacanthomas and describes a case report of the Gryzbowski variant of keratoacanthomas that did not show the presence of HPV)

Hodak, E, Jones, RE, Ackerman, AB. "Solitary keratoacanthoma is a squamous-cell carcinoma: three examples with metastases". Am J Dermatopathol. vol. 15. 1993. pp. 332-342.

(Describes three cases of keratoacanthomas that have metastasized. Underscored the need for examination of lymph nodes in follow-up examinations)

Karaa, A, Khachemoune, A. "Keratoacanthoma: a tumor in search of a classification". Int Dermatol. vol. 46. 2007. pp. 671-678.

(Reviews keratoacanthomas, including their relationship to squamous cell carcinoma and their classification)

Kirby, JS, Miller, CJ. "Intralesional chemotherapy for non-melanoma skin cancer: A practical review". J Am Acad Dermatol. vol. 63. 2010. pp. 689-702.

(Excellent summary of data to date for nonsurgical options for keratoacanthomas)

Kwon, EJ, Kish, S, Jaworsky, C. "The histologic spectrum of epithelial neoplasms induced by sorafenib". J Am Acad Dermatol. vol. 61. 2009. pp. 522-7.

(Describes various hyperplastic epithelial neoplasms that evolved in a dose-related fashion with sorafenib treatment)

Reid, DC, Guitart, J, Agulnik, M. "Treatment of multiple keratoacanthomas with erlotinib". Int J Clin Oncol. vol. 15. 2010. pp. 413-415.

(Novel approach to treating keratoacanthomas with anti-epidermal growth factor receptor agent. This may be the category of agents best suited to treat multiple keratoacanthomas in the near future.)

Reizner, GT, Chuang, TY, Elpern, DJ. "Basal cell carcinoma and keratoacanthoma in Hawaiians: an incidence report". J Am Acad Dermatol Nov. vol. 29. 1993. pp. 780-2.

(Reports the incidence of keratoacanthomas in Hawaiians)

Sanchez, YE, Simon, P, Requena, L. "Solitary keratoacanthoma: a self healing proliferation that frequently becomes malignant". Am J Dermatopathol. vol. 22. 2000. pp. 305-310.

(Reviews the relationship between solitary keratoacanthomas and crateriform squamous cell carcinomas in a study of 220 cases. Describes the malignant transformation that occurs in keratoacanthomas.)

Schwartz, RA. "Keratoacanthoma: a clinico-pathologic enigma". Dermatol Surg. vol. 30. 2004. pp. 326-333.

(Discusses the malignant potential of keratoacanthomas and occurrence in Muir-Torre syndrome)

Schwartz, RA. "Keratoacanthoma". J Am Acad Dermatol. vol. 30. 1994. pp. 1-19.

(Describes different types of keratoacanthomas and their clinical behavior)

Yuge, S, Godoy, DAS, Coelho de Melo, MC, Sousa, DS, Soares, CT. "Keratoacanthoma centrifigum marginatum: response to topical 5-fluorouracil". J Am Acad Dermatol. vol. 54. 2006. pp. S218-9.

(Reviews keratoacanthoma centrifigum marginatum and describes the use of topical 5-fluorouracil in the treatment of keratoacanthomas.)
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