||Section 1 of 12 |
Tsu-Yi Chuang, MD,
MPH, Medical Director of Melanoma Profram, Arthur L Norins
Professor, Department of Dermatology, Indiana University Medical
Coauthored by Ryan Brashear, MD, Staff Physician, Department
of Dermatology, Indiana University School
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
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
November 7 2001
||Section 2 of 12 |
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.
- 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
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.
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.
- 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
- 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
||Section 4 of 12 |
Merkel Cell Carcinoma
Metastatic Carcinoma of the Skin
Squamous Cell Carcinoma
Other Problems to be Considered:
Eruptive keratoacanthoma of Grzybowski: Generalized distribution of multiple
KAs that typically do not involute.
keratoacanthoma: Rare autosomal dominant self-healing type of KA, with lesions
arising in early adulthood.
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.
Histologic Findings: 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 KA.
- 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
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.
||Section 6 of 12 |
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
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
- 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
- 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
- Mohs micrographic surgery may be indicated for large or recurrent KAs or KAs
located in anatomic areas with cosmetic or functional
- KAs are radiosensitive and respond well to low doses of radiation (<10
- 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
Consultations: Dermatologist: Consult to exclude invasive
||Section 7 of 12 |
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
||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
Marked response noticed after 2 injections (1
||0.4-1.5 mL of 12.5 mg/mL injected
||Documented hypersensitivity; alcoholism;
hepatic insufficiency; immunodeficiency syndromes; preexisting blood dyscrasias
(eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia);
renal insufficiency; pregnancy or breastfeeding
||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
||D - Unsafe in pregnancy
||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)
||Fluorouracil (Efudex, Adrucil, Fluoroplex) --
Fluorinated pyrimidine antimetabolite that inhibits thymidylate synthase (TS)
and also interferes with RNA synthesis and function. Has some effect on DNA.
Useful in symptom palliation for patients with progressive disease.
||0.1 mL of 5% sol injected intralesionally qd
into KA base and at 4 peripheral quadrants for 2 wk (1 study) or 0.1-0.3 mL (of
50 mg/mL sol) injected circumferentially and 0.1-0.2 mL (of 50 mg/mL sol)
injected sublesionally qwk for 3 wk (second study)
||Administer as in adults
||Documented hypersensitivity; bone marrow
suppression, pregnancy, severe renal function impairment, hepatic function
impairment, chicken pox or herpes zoster, potentially serious infections
||Increased risk of bleeding with anticoagulants,
NSAIDs, platelet inhibitors, thrombolytic agents; enhanced bone marrow toxicity
with other immunosuppressive agents
||D - Unsafe in pregnancy
||Monitor mouth for ulceration; monitor CBCs;
monitor for GI ulceration and bleeding; inflammatory reactions may occur with
occlusive dressings; porous gauze dressing may be applied for cosmetic reasons
without increase in reaction
||Bleomycin (Blenoxane) -- Glycopeptide
antibiotic that inhibits DNA synthesis.
Concentration usually is 1 mg/mL
and diluted further with local anesthetic.
||0.2-0.4 mg as single intralesional injection
(case reports) or 0.2 mg qwk for 4 wk (other reports)
||Documented hypersensitivity; significant renal
function impairment; compromised pulmonary function; pregnancy or breastfeeding
||May decrease plasma levels of digoxin and
phenytoin; cisplatin may increase toxicity of bleomycin
||D - Unsafe in pregnancy
||Caution in renal impairment; possibly secreted
in breast milk; may cause mutagenesis and pulmonary toxicity (10%);
idiosyncratic reactions similar to anaphylaxis (1%) may occur; monitor for
adverse effects during and after treatment; vaso-occlusive phenomenon with
distal necrosis of digit; permanent damage to nail matrix may occur; pain with
injection, local urticaria, tissue necrosis, and Raynaud phenomenon may
Drug Category: Retinoids
-- Efficacious in treatment of KAs with good cosmetic
Decrease sebaceous gland size and sebum production. May inhibit
sebaceous gland differentiation and abnormal keratinization.
||Isotretinoin (Accutane) -- Oral agent that
treats serious dermatologic conditions. Synthetic 13-cis isomer of naturally
occurring tretinoin (trans-retinoic acid). Both agents are structurally related
to vitamin A.
||20 mg PO qd; can increase to 80 mg PO qd if
tolerated and lab results allow
||Documented hypersensitivity; pregnancy;
significant liver disease
||Toxicity may occur with vitamin A
coadministration or excessive alcohol intake; pseudotumor cerebri or papilledema
may occur when coadministered with tetracyclines; may reduce plasma levels of
||X - Contraindicated in pregnancy
||Monitor CBCs, blood sugar in patients with
diabetes, triglycerides, hepatic function, and pregnancy in women of
childbearing age; adverse effects include teratogenicity, hepatotoxicity,
hypertriglyceridemia, hyperostosis, pseudotumor cerebri; may decrease night
vision; may be associated with development of hepatitis; occasional exaggerated
healing response of acne lesions (excessive granulation with crusting) may
occur; patients with diabetes may experience problems in controlling blood
sugar; avoid exposure to UV light or sunlight until tolerance
Drug Category: Immunomodulatory
agents -- Mechanism of antitumor activity is not clearly understood;
however, direct antiproliferative effects against malignant cells and modulation
of host immune response may be important factors.
||Interferon alfa-2a (Roferon-A) -- Protein
product manufactured by recombinant DNA technology.
Dosing is in 1 series
providing 3 intralesional injections/wk. Adult dosing schedule provided
clearance of KA in 6-year-old patient; however, patient developed neutropenia.
||3 million U initial; increase rapidly to 6
million U over a period of up to 7 wk; total dose may range from 24-117 million
||Documented hypersensitivity; anaphylactic
sensitivity to mouse immunoglobulin (IgG), egg protein or neomycin; autoimmune
||Theophylline may increase toxicity of
interferon alpha by reducing clearance; cimetidine may increase antitumor
effects of interferon alpha; zidovudine and vinblastine may increase toxicity of
||C - Safety for use during pregnancy has not
||Depression and suicidal ideation may be side
effects of treatment; infrequently, severe or fatal GI hemorrhage reported in
association with alpha interferon therapy; bone marrow suppression (prior to
initiation of therapy, perform tests to quantitate peripheral blood hemoglobin,
platelets, granulocytes, hairy cell, and bone marrow hairy cells); monitor
patient periodically (eg, monthly) during treatment to determine response to
treatment; if patient does not respond within 6 mo, discontinue treatment; if
response occurs, continue treatment until no further improvement observed (not
known whether continued treatment after that time is
||Section 8 of 12 |
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
- 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).
- Educate patients about prevention (including sunscreen), sun-protection
techniques, and skin self-examination.
||Section 9 of 12 |
- 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
||Section 10 of 12 |
Question 1: Which of the following patients is at greatest risk for
A: A 20-year-old African woman
65-year-old white man
C: A 65-year-old white woman
D: A 45-year-old Hispanic man
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
C: Intralesional methotrexate
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
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
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
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.
||Section 11 of 12 |
||Section 12 of 12 |
- 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;
- 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:
- 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):
- 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
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.