Keratoacanthoma
Key Points
Keratoacanthoma is a common tumor
It is seen most frequently in fair-skinned individuals with a predilection for sun-damaged skin
Keratoacanthoma can be solitary or multiple
Solitary KA presents as a rapidly growing nodule with a central keratotic crater
After a stable phase lasting several months, they often undergo spontaneous regression
Multiple KAs are rare and can be sporadic or familial
The pathophysiology of KA and its relation to squamous cell carcinoma is unknown, but they have been thought either to be separate entities, or related, lying on two ends of the same disease spectrum
Surgical excision with histologic control of margins is considered the gold standard for the management of KA
Keratoacanthoma (KA) is a common tumor, originally described by Hutchinson in 1889.1 It is seen most frequently in fair-skinned individuals and has a predilection for sun-damaged skin.2 KA has been reported to show a seasonal presentation with a peak incidence noted in the summer and early autumn months.3 The annual incidence of cutaneous KA varies depending on the geographic location. In Hawaii, the annual incidence was estimated to be 104 cases per 100,000 population,4 and in northern Australia, the incidence was 150 cases per 100,000 population.5
KA is seen most frequently in middle-aged individuals.6 The peak age at presentation is between 45 and 69 years old.7 In a series of 108 patients with KA, lesions were seen in patients from teens to old age, with 80% older than 40 years and a mean age of 56 years. Males are affected more commonly than females, in a ratio of 2:1.8 These tumors can occur on any part of the body but show a predilection for the face.9 Periocular involvement is uncommon, and in one review of 592 cases of KA, more than 70% were located on the face, and 5.6% involved periorbital skin.10
The two major types of KA are solitary and multiple KA. Solitary KA is the most common type, and this group is further subdivided into several subtypes.11 Typical solitary KAs present as a rapidly growing nodule with a shiny epidermis and a central keratotic crater. They generally are small, ranging in size from a few mm to 2 cm, with a multilocular keratin-filled central crater where dermal papillae undergo necrosis.12 After a stable phase lasting several months, these lesions generally undergo complete regression. Giant KA rapidly grows to sizes larger than 3 cm. They are seen mostly in males (74%), with a predilection for the head, predominantly on the eyelids and nose. They show a downward vertical growth pattern, invading the dermis with the destruction of underlying tissue, and persist for long periods before undergoing variable degrees of regression.13,14 Subungual KA is a rare solitary variant appearing under nails. It usually occurs in Caucasian men with a predilection for the first three fingers of the hand.15 It grows rapidly over several weeks and shows an aggressive behavior with destruction of the underlying bone of the terminal phalanx and rarely undergoes spontaneous regression. Mucosal KA is another rare variant seen mostly in the oral cavity and occasionally on the conjunctiva or vulva. Lesions grow rapidly over 2 to 8 weeks, and like some other variants, they show little tendency to regress. KA centrifugum marginatum is another variant reported to occur after trauma and is characterized by progressive peripheral extension with raised rolled-out margins showing multiple comedonal orifices. They are seen more frequently on the dorsum of hands and legs, can attain a size of up to 20 cm, and do not show a tendency for spontaneous regression.16,17
Multiple KAs are rare and can be sporadic or familial.2 They have been described in the literature as several types. Multiple familial KAs of Ferguson-Smith type, also known as multiple self-healing squamous epithelioma, are a rare autosomal dominant genodermatosis characterized by the development of recurrent KAs and well-differentiated squamous cell carcinomas (SCCs).18 Slow-growing lesions appear in continuous waves on the face and limbs at any age from childhood to old age. Like common KAs, they do tend to undergo spontaneous regression over several months. Generalized eruptive KA of Grzybowski is an extremely rare variant of KA affecting the skin and mucous membranes on both sun-exposed and sun-protected sites. It occurs in older individuals in the fifth to seventh decades of life. Hundreds to thousands of tiny 1 to 2 mm dome-shaped KA lesions without a central crater appear with an eruptive onset.2,19 Multiple KAs of Witten and Zak type are assumed to have a familial predisposition. Lesions have a predilection for sun-exposed areas and arise as 1 to 30 papules that can remain small or increase to a very large size. These lesions undergo regression over several months.20
Three clinical stages are recognized in the natural history of solitary KA.21 An initial proliferative stage is characterized
by rapid growth over 1 to 2 months. This is followed by a mature stage appearing as a nodule, often with a central keratotic crater. After several months to years depending on the size, a spontaneous involutional phase is seen resulting in a hypopigmented scar.2,22 The spontaneous regression can be partial or complete.
by rapid growth over 1 to 2 months. This is followed by a mature stage appearing as a nodule, often with a central keratotic crater. After several months to years depending on the size, a spontaneous involutional phase is seen resulting in a hypopigmented scar.2,22 The spontaneous regression can be partial or complete.
In a retrospective histopathologic study of 50 patients with KA, Lawrence and Reed21 found carcinoma-like foci (invasive cords of atypical epithelium) in the majority of specimens, most of which occurred in stable-stage lesions. They speculated that stage I lesions break into the reticular dermis and incite an immune response. Typical, possibly neoplastic clones of keratinocytes are held in check by the body’s immune response in stage II. Stage III lesions are equivalent to a senescent phase of a cell-mediated immune response with an associated desmoplastic reaction.21 In some instances, alteration in the immune response may allow the emergence of neoplastic clones with the possible development of SCC.
There is no consensus as to whether KA is a benign or malignant neoplasm.23 KA progressing to SCC with metastatic spread is rare,24,25,26,27 and KA-like SCCs have been described in numerous publications.6,12 Perineural invasion of facial KA is uncommon, seen in only 1% to 4% of excised specimens.28 This can lead to tumor extension into facial mimetic muscles, tumor recurrence, and metastasis to regional lymph nodes.29
Etiology and Pathogenesis
Debate concerning the pathogenesis of KA has persisted for more than 60 years, and it is not clear whether these tumors always regress or whether, under certain circumstances, they can progress to invasive SCC.30 One thought is that KA and SCC are separate entities, KA being a benign lesion undergoing rapid initial growth followed by spontaneous regression and SCC being a malignant invasive tumor with metastatic potential.31 Another thought is that KA and SCC are distinct but related entities on two ends of the same disease spectrum.32,33,34
While the pathogenesis of KA is unknown, several features of this tumor are suggestive of possible etiologies. These include its apparent derivation from hair follicles, its association with ultraviolet (UV) radiation exposure, the proposed linkage with occupational chemicals such as tars and mechanical oils, association with human papillomaviruses (HPVs), genetic abnormalities in the Ferguson-Smith type of multiple KA, the association of KA with syndromes such as the Muir-Torre syndrome and familial incontinentia pigmenti, and the expression of tumor suppressor genes, oncogene expressions, and mutations, and telomeric alterations in some KAs.30,35,36,37,38 The epithelium of the hair follicle has been proposed as the origin of some KAs,39 although this does not explain the occurrence of KA on mucosal surfaces. It has been proposed that KAs arising in mucous membranes represent a variant of pseudoepitheliomatous hyperplasia.21
Cabibi et al40 studied 43 lesions of KA and SCC and reported differences in GLUT1 antibody expression that distinguished typical KA from SCC and also highlighted an intermediate group of atypical KA, supporting the hypothesis of a progression along the spectrum from KA to SCC. The atypical KA showed focal areas with some features of KA that overlapped with those of SCC, consisting of a higher degree of cytologic atypia, a higher nuclear/cytoplasmic ratio, several mitoses, and focal aspects of irregular infiltration at the deep boundary.40 When these features were limited to less than 30% of the tumor, it was defined as an atypical KA. The authors suggested that KA may regress as the result of functioning immunity, but when local immunity was deficient, some KAs might develop into SCCs.
The predilection of KA for sun-exposed areas suggests UV radiation might be an important etiological factor, similar to SCC.3,4,5,6,41 This is supported by the association of KA with other UV-induced tumors such as xeroderma pigmentosum.6 Papillomavirus-related DNA has been found in some KAs,42 but the relationship is inconsistent, and no conclusive etiology has yet been established.43 Occupational exposure to pitch, tar, coal, or machine oil was reported to occur in 20.3% of 108 patients with KA compared with only 2.7% in 147 controls without KA, suggesting a possible chemical-induced KA etiology.8 KA has also been reported as a complication of damaged skin previously treated with CO2 laser, radiotherapy, and PUVA photochemotherapy.44,45,46
Some gene alterations have been found in KA.47,48 Expression of Bcl-2 protooncogene was found in some KA, but to a much less degree than in SCC. Sleater et al49 suggested that KA could be an SCC that is deficient in Bcl-2 expression. Transforming growth factor beta receptor 1 also has been described in KA lesions associated with multiple familial KAs of Ferguson-Smith type,50 and mismatch repair genes were found in KA seen with the Muir-Torre syndrome.51
KA is known to have a relationship with some systemic syndromes. Muir-Torre syndrome is an autosomal dominant genodermatosis combining malignancies, most notably colon cancer, with sebaceous neoplasms.52 The syndrome is caused by germline mutations of hMSH2 and hMLH1 genes, involved in the mismatch repair system, and KA are seen in Muir-Torre syndrome as solitary or multiple lesions. KA occurring with this syndrome is explained by the common pilosebaceous gland origin of sebaceous neoplasms and KA.6 KAs have also been observed in patients with xeroderma pigmentosum, a rare autosomal recessive genodermatosis that results from mutations in nucleotide excision repair. Patients demonstrate severe photosensitivity, skin pigmentary changes, malignant tumor development, and sometimes progressive neurologic degeneration,53,54 resulting in the development of cutaneous melanoma, basal cell carcinoma, SCC, and KA in early childhood. Other rare associations include florid cutaneous papillomatosis55 and nevus sebaceous of Jadassohn.56,57
Clinical Characteristics
KAs are frequently seen in older individuals with light skin and a history of chronic sun exposure.58 Common areas of involvement include the lips, cheeks, nose, eyelids, and the
back of the hands. Males are affected slightly more frequently than females.7,59 During the initial proliferative phase, the tumor grows rapidly as a firm papule. The border is skin colored or erythematous, occasionally with fine telangiectatic vessels (Figure 76.1).6 In the mature phase, it becomes dome shaped with a central keratinous crater (Figure 76.2). During the involutional phase, the lesion becomes flattened with less of a crater, more hyperkeratotic, with granulation tissue at the base (Figure 76.3), ultimately resulting in an atrophic scar.41,60
back of the hands. Males are affected slightly more frequently than females.7,59 During the initial proliferative phase, the tumor grows rapidly as a firm papule. The border is skin colored or erythematous, occasionally with fine telangiectatic vessels (Figure 76.1).6 In the mature phase, it becomes dome shaped with a central keratinous crater (Figure 76.2). During the involutional phase, the lesion becomes flattened with less of a crater, more hyperkeratotic, with granulation tissue at the base (Figure 76.3), ultimately resulting in an atrophic scar.41,60
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