Keratoacanthoma

BASICS

DESCRIPTION

Rapidly proliferating, solitary, dome-shaped, erythematous or flesh-colored papule or nodule with a central keratinous plug, typically reaching 1 to 2 cm in diameter
Highly debated as to whether keratoacanthoma (KA) is a benign or malignant variant of squamous cell carcinoma (SCC). Majority are benign and resolve spontaneously, but lesions do have the potential for invasion and metastasis; therefore require treatment.
Three clinical stages of KAs (1):
- Proliferative: rapid growth of the lesion over weeks to several months
- Maturation/stabilization: Lesion stabilizes and growth subsides.
- Involution: spontaneous resolution of the lesion, leaving a hypopigmented, depressed scar; most but not all lesions will enter this stage.
System(s) affected: integumentary

EPIDEMIOLOGY

Greatest incidence over the age of 50 years but may occur at any age
Presentation increased during summer and early fall seasons
Most frequently on sun-exposed, hair-bearing skin but may occur anywhere
Predominant sex: male > female (2:1)
Most commonly in fair-skinned individuals; highest rates in Fitzpatrick I " III
104 cases per 100,000 individuals

ETIOLOGY AND PATHOPHYSIOLOGY

Derived from an abnormality causing hyperkeratosis within the follicular infundibulum
Squamous epithelial cells proliferate to extend upward around the keratin plug and proceed downward into the dermis; followed by invasion of elastic and collagen fibers
Cellular mechanism responsible for the hyperkeratosis is currently unknown; role of human papillomavirus has been discussed but has no established causality (2).
Regression may be due to immune cytotoxicity or terminal differentiation of keratinocytes.
Multiple etiologies have been suggested:
- UV radiation
- May be provoked by surgery, cryotherapy, chemical peels or laser therapy
- Viral infections: human papillomavirus (HPV) or Merkel cell polyomavirus
- Genetic predisposition: Muir-Torre syndrome, xeroderma pigmentosum, Ferguson-Smith syndrome
- Immunosuppression
- Chemical carcinogen exposure

Genetics

Mutation of p53 or H-ras
Ferguson-Smith (AD)
Witten-Zak (AD)
Muir-Torre (AD)
Xeroderma pigmentosum (AR)
Gzybowski (sporadic)
Incontinentia pigmenti (XLD)

RISK FACTORS

UV exposure/damage: outdoor and/or indoor tanning
Fitzpatrick skin type I " III
Trauma (typically appears within 1 month of injury): laser resurfacing, surgery, cryotherapy, tattoos
Chemical carcinogens: tar, pitch, and smoking
Immunocompromised state
Discoid lupus erythematosus

GENERAL PREVENTION

Sun protection

COMMONLY ASSOCIATED CONDITIONS

Frequently, the patient has concurrent sun-damaged skin: solar elastosis, solar lentigines, actinic keratosis, nonmelanoma skin cancers (basal cell carcinoma, SCC)
In Muir-Torre syndrome, KAs are found with coexisting sebaceous neoplasms and malignancy of the GI and GU tracts.

DIAGNOSIS

HISTORY

Lesion begins as a small, solitary, pink macule that undergoes a rapid growth phase; classically reaching a diameter of 1 to 2 cm; size may vary.
Once the proliferative stage has subsided, lesion size remains stable.
May decrease in size, indicating regression
Asymptomatic, occasionally tender
If multiple lesions present, important to elicit a family history and recent therapies or treatments.
If sebaceous neoplasms present, must review history for signs/symptoms of GI or GU malignancies

PHYSICAL EXAM

Firm, solitary, erythematous or flesh-colored, dome-shaped papule or nodule with a central keratin plug, giving a crateriform appearance
Surrounding skin and borders of lesion may show telangiectasia, atrophy, or dyspigmentation.
Solitary; although multiple lesions can occur.
Most commonly seen on sun-exposed areas: face, neck, scalp, dorsum of upper extremities, and posterior legs
May also be seen on areas without sun exposure: buttocks, anus, subungual, mucosal surfaces
Subungual KAs are very painful and seen on the first 3 digits of the hands.
Examine for regional lymphadenopathy due to chance of lesion invasion and metastasis.
Dermoscopy (3)[B]
- Central keratin
- White circles, blood spots
- Cannot reliably distinguish between AK and SCC

DIFFERENTIAL DIAGNOSIS

SCC
Nodular or ulcerative basal cell carcinoma
Cutaneous horn
Hypertrophic actinic keratosis
Amelanotic melanoma
Merkel cell carcinoma
Metastasis to the skin
Molluscum contagiosum
Prurigo nodularis
Verruca vulgaris
Verrucous carcinoma
Sebaceous adenoma
Hypertrophic lichen planus
Hypertrophic lupus erythematosus
Deep fungal infection
Atypical mycobacterial infection
Nodular Kaposi sarcoma

DIAGNOSTIC TESTS & INTERPRETATION

Excisional biopsy including the center of the lesion as well as the margin is the best diagnostic test (2)[C].
A shave biopsy may be insufficiently deep to distinguish KA from an SCC.
If unable to perform an excisional biopsy, a deep shave (saucerization) of the entire lesion, extending into the subcutaneous fat, can be done.
Punch biopsies should be avoided because they give an insufficient amount of tissue to represent the entire lesion.

Initial Tests (lab, imaging)

Subungual KA: radiograph of the digit to monitor for osteolysis (cup-shaped radiolucent defect)
Aggressive tumors may need CT with contrast for evaluation of lymph nodes and MRI if there is concern of perineural invasion.
Most lesions do not need any form of imaging.

Test Interpretation

Pathology of biopsy: a well-demarcated central core of keratin surrounded by well-differentiated, mildly pleomorphic, atypical squamous epithelial cells with a characteristic glassy eosinophilic cytoplasm
May see elastic and collagen fibers invading into the squamous epithelium
Histologic differentiation of a KA from an SCC may be difficult and unreliable, although immunochemical staining for cellular protein Ki-67 may help do this (4).
KAs have a greater tendency than SCC to display fibrosis and intraepidermal abscesses of neutrophils and eosinophils.
Regressing KA shows flattening and fibrosis at base of lesion.

TREATMENT

Treatment of choice is an excisional procedure plus electrodessication and curettage; however, there are many treatment options available (2)[C].
Aggressive tumors (>2 cm) or lesions in cosmetically sensitive areas (face, digits, genitalia) that require tissue sparing, consider Mohs micrographic surgery
- Mohs is the treatment of choice in cases with perineural or perivascular invasion.
Small lesions (<2 cm) of the extremities may undergo electrodessication and curettage.
Immunocompromised patients should receive immediate surgical treatment.

MEDICATION

Nonsurgical management is a viable and relatively cost-effective option in these select cases not amenable to surgery due to lesion number, size, or location; also for patients with multiple comorbidities who are unwilling or unable to withstand surgery
Evidence for the following treatments based on case reports and retrospective reviews:
- Intralesional methotrexate 12.5 to 25 mg in 0.5 mL normal saline every 2 to 3 weeks for one to four treatment sessions (5)[B]
  - Monitor for pancytopenia with complete blood count (5)[C].
- 5% Imiquimod cream 3 times per week for 11 to 13 weeks (5)[B]
- Topical 5% 5-fluorouracil cream daily, 61 " 92% cure rate (5)[B]
- Intralesional 5-fluorouracil of 50 mg/mL on a weekly basis for three to eight treatment sessions " 98% cure rate (5)[B]
- Intralesional IFN a-2a or a-2b (83%, 100% cure rate, respectively) (5)[B]
- Intralesional bleomycin " 100% cure rate (5)[B]
- Isotretinoin oral 0.5 to 1 mg/kg/day

ISSUES FOR REFERRAL

Dermatology referral if lesions are >2 cm, numerous, mucosal, or subungual

ADDITIONAL THERAPIES

Photodynamic therapy with methyl aminolevulinic acid and red light, successful case reports (6)[B] but also reported aggravation following treatment
Cryotherapy
Argon or YAG lasers
Radiotherapy, primary or adjuvant: KAs may regress with low doses of radiation but may require doses up to 25 to 50 Gy in low-dose (5 to 10 Gy) fractions for possible SCC (7)[B].
Erlotinib (EGFR inhibitor) 150 mg daily for 21 days, single case report (8)[B]

SURGERY/OTHER PROCEDURES

Excisional and office-based procedures as discussed above.

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

After the surgical site has healed or lesion has resolved, patient should be seen every 6 months due to increased risk of developing new lesions or skin cancers, annually at minimum (3)[C].
Patient Monitoring

Skin self-exams should be routinely performed with detailed instructions (see "Additional Reading " ).
If multiple KAs are present in patient or family members, evaluate for Muir-Torre syndrome and obtain a colonoscopy beginning at age 25 years, as well as testing for genitourinary cancer (3)[C].

PATIENT EDUCATION

Sun protection measures: sun block with SPF >30, wide-brimmed hats, long sleeves, dark clothing, avoiding indoor tanning
Arc welding may produce harmful UV radiation and skin should not be exposed.
Tar, pitch, and smoking should be avoided.

PROGNOSIS

Atrophic scarring and hypopigmentation can occur with self-resolution but may be significantly reduced by intervention.
52 of 445 cases (12%) spontaneously regressed without treatment and none of these recurred (2).
393 (88%) regressed following medical or excisional treatment (2).
445 cases reported with no metastases or deaths attributable to the KA (2).
4 " 8% recurrence
Mucosal and subungual lesions do not regress, must undergo treatment

REFERENCES

11 Zalaudek I, Bonifazi E, Ferrara G, et al. Keratoacanthomas and spitz tumors: are they both "self-limiting " variants of malignant cutaneous neoplasms? Dermatology. 2009;219(1):3 " 6.22 Savage JA, Maize JCSr. Keratoacanthoma clinical behavior: a systematic review. Am J Dermatopathol. 2014;36(5):422 " 429.33 Rosendahl C, Cameron A, Argenziano G, et al. Dermoscopy of squamous cell carcinoma and keratoacanthoma. Arch Dermatol. 2012;148(12):1386 " 1392.44 Scola N, Segert HM, St Όcker M, et al. Ki-67 may be useful in differentiating between keratoacanthoma and cutaneous squamous cell carcinoma. Clin Exp Dermatol. 2014;39(2):216 " 238.55 Chitwood KL, Etzkorn J, Cohen G. Topical and intralesional treatment of nonmelanoma skin cancer: efficacy and cost comparisons. Dermatol Surg. 2013;39(9):1306 " 1316.66 Jeon HC, Choi M, Paik SH, et al. Treatment of keratoacanthoma with 5% imiquimod cream and review of the previous report. Ann Dermatol. 2011;23(3):357 " 361.77 Bruscino N, Corradini D, Campolmi P, et al. Superficial radiotherapy for multiple keratoacanthomas. Dermatol Ther. 2014;27(3):163 " 167.88 Reid DC, Guitart J, Agulnik M, et al. Treatment of multiple keratoacanthomas with erlotinib. Int J Clin Oncol. 2010;15(4):413 " 415.

ADDITIONAL READING

The American Academy of Dermatology: https://www.aad.org/spot-skin-cancer/learn-about-skincancer/types-of-skin-cancer
The Skin Cancer Foundation: http://www.skincancer.org/

CODES

ICD10

D23.9 Other benign neoplasm of skin, unspecified
D48.5 Neoplasm of uncertain behavior of skin
L85.8 Other specified epidermal thickening

ICD9

216.9 Benign neoplasm of skin, site unspecified
238.2 Neoplasm of uncertain behavior of skin
701.1 Keratoderma, acquired

SNOMED

254662007 keratoacanthoma (disorder)
417264005 keratoacanthoma of skin (disorder)
254663002 Solitary keratoacanthoma (disorder)
254664008 Eruptive keratoacanthoma (disorder)
403908007 Subungual keratoacanthoma (disorder)

CLINICAL PEARLS

Suspect KA with a solitary, dome-shaped, erythematous or flesh-colored papule or nodule with a central keratinous plug.
If KA is in the differential diagnosis, elicit time frame of onset during patient encounter; rapid onset supports diagnosis.
Due to the broad differential diagnosis of a suspected KA and unreliable clinical differentiation between these, strongly consider surgical excision as first-line diagnostic test and therapy.
Medical and radiation therapies are reasonable and effective options available for patients who are not surgical candidates or for lesions that are not amenable for surgery.

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