Version November 2024
INTRODUCTION — Keratoacanthoma (KA) is a cutaneous tumor that most commonly presents as a dome-shaped nodule with a central keratin-filled crater (picture 1A-E) [1,2]. KA most frequently develops on hair-bearing, sun-exposed skin. Middle-aged and older adults with lightly pigmented skin are most frequently affected [3].
A distinguishing feature of KA is a clinical course characterized by rapid initial growth followed by a variable period of lesion stability and subsequent spontaneous resolution [3]. The recognition of this unique characteristic in a tumor with clinical and histopathologic features that closely resemble cutaneous squamous cell carcinoma has led to significant debate over the classification of this lesion.
The epidemiology, risk factors, and diagnosis of KA will be discussed here. The management and prognosis of KA is reviewed separately. (See "Keratoacanthoma: Management and prognosis".)
EPIDEMIOLOGY — Although KA is a common tumor, the potential for spontaneous resolution, the variability in documentation of lesions as KA or squamous cell carcinoma, and the relative paucity of epidemiologic studies performed on this disease hinder definitive conclusions on tumor incidence. The vast majority of reported cases of KA have occurred in individuals with lightly pigmented skin [4]. (See 'Risk factors' below.)
KA can occur at any age, and may present as a solitary lesion (the most common presentation) or infrequently in the context of specific disorders associated with multiple KAs [5-8] (see 'Multiple keratoacanthomas' below). Solitary KA has a peak incidence between the ages of 50 and 69 [3]; rarely, lesions develop in individuals under the age of 20 [5]. Data on the distribution of KA among the sexes vary. Estimates of the sex ratio range from a similar incidence in males and females to a three times greater risk for KA among males [4,9,10].
PATHOGENESIS — The pathogenesis of KA is poorly understood. It is generally accepted that KA is most likely derived from the follicular infundibulum [11]. However, the mechanisms behind the characteristic phenomenon of rapid lesion growth followed by spontaneous resolution are not well defined. Based upon the available data, changes in the expression of genes and proteins involved in epidermal cell proliferation, cell adhesion, and cell survival may play significant roles in lesion development. Proposed contributors to lesion regression include the upregulation of factors that promote apoptosis, events related to normal cycling of the hair follicle, and activation of an immunologic response against the tumor [12].
Examples of specific factors identified as potentially relevant in the life cycle of KA include the homeodomain interacting protein kinase 2 (HIPK2) gene (a regulator of cell cycling and apoptosis) [13], the p53 tumor suppressor protein [14], the H-ras proto-oncogene [15,16], the adhesion molecules beta-catenin and CD44 [17], and levels of the bcl-2 apoptosis regulatory protein and Bak proapoptotic protein [14,18-20]. Additional potential contributors include granzyme B, a serine protease expressed by cytotoxic T cells and natural killer cells that promotes apoptosis [21], and p27 (kip), an inhibitor of cyclin dependent kinases that may promote lesion regression [22].
RELATIONSHIP WITH SQUAMOUS CELL CARCINOMA — The relationship between KA and squamous cell carcinoma is controversial [3,23]. While some authors perceive KA as a distinct follicular-based squamous proliferation that usually follows a benign clinical course [24-28], others counter that KA is actually a clinical variant of cutaneous squamous cell carcinoma prone to spontaneous regression and occasional aggressive behavior and metastasis [6,29-31]. Dissolution of this controversy is hampered by the lack of histopathologic criteria that definitively differentiate KA and squamous cell carcinoma [32]. Reports documenting transformation of KA to squamous cell carcinoma also raise questions about whether these lesions represent a continuum of a single disease rather than distinct entities [27,33,34]. (See 'Differentiation from squamous cell carcinoma' below.)
RISK FACTORS — A variety of factors may influence the likelihood that an individual will develop KA [1]. Examples include skin pigmentation; exposure to ultraviolet radiation trauma, chemical carcinogens, or certain medications; and genetic abnormalities. These factors are discussed in greater detail below:
●Skin color – The risk for KA decreases with increasing skin pigmentation [3,10,35]. Among 22,000 patients seen at a specialized surgical skin cancer practice in Houston, Texas between 1998 and 2006, all 234 patients with KA were White with Fitzpatrick skin phototypes I, II, or III (table 1) [4]. In an Australian prospective cohort of over 40,000 participants, 80 percent of the 584 patients who developed a KA had lightly pigmented skin [36]. In addition, the differences in disease incidence reported in the late 20th century in the predominantly fair-skinned population of Australia (150 per 100,000 individuals), Japanese-Hawaiians (22 per 100,000 individuals), and Filipinos in Hawaii (7 per 100,000 individuals) also lend support to an important role for skin type [37-39].
●Ultraviolet radiation – Although human studies that definitively link exposure to ultraviolet radiation to the development of KA are lacking, the observation that KA most frequently occurs on sun-exposed skin and in individuals with lightly pigmented skin supports a role for ultraviolet radiation as a contributing factor [36]. Moreover, high numbers of treatments with psoralen plus ultraviolet A (PUVA) phototherapy have been linked to an increased risk for KA. In a retrospective study of approximately 500 patients with psoriasis who were treated with PUVA, patients who received high cumulative doses of PUVA were significantly more likely to develop KA than those who received lesser amounts of PUVA therapy [40].
●Trauma – Infrequently, KA develops in sites of iatrogenic (eg, surgery, laser therapy, cryotherapy) or accidental trauma [41-49]. Although most reported cases of trauma-induced KA have occurred in adults, this phenomenon has also been documented in an adolescent [42]. Postsurgical KA usually appears one to three months after surgery [43-45]. Treatment with ionizing radiation has also been linked with the development of multiple KAs in a patient with multiple self-healing squamous epithelioma (MSSE; also known as Ferguson-Smith disease) [50]. (See 'Multiple keratoacanthomas' below.)
The explanation for the development of KA at sites of trauma is unknown. Some authors have speculated that in skin previously exposed to carcinogens such as ultraviolet radiation, factors associated with the wound-healing response may promote the development of these tumors [23].
●Genetics – Several genetic syndromes are associated with KA, including the variant of Lynch syndrome known as Muir-Torre syndrome, xeroderma pigmentosum, and MSSE (Ferguson-Smith disease). (See "Muir-Torre syndrome" and "Xeroderma pigmentosum".)
Muir-Torre syndrome may present with KA, sebaceous tumors, and visceral malignancy. In this syndrome, tumor formation occurs as a result of germline mutations in deoxyribonucleic acid (DNA) mismatch repair genes. KAs may develop early in life in both xeroderma pigmentosum and MSSE. Xeroderma pigmentosum is an autosomal recessive syndrome associated with defects in DNA repair [51-53]. In contrast, MSSE is an autosomal dominant disorder associated with loss-of-function mutations in the transforming growth factor beta receptor 1 gene (TGFBR1 or ALK5) [54].
●Drug exposure – BRAF inhibitors and immune checkpoint inhibitors are molecularly targeted agents used in the treatment of multiple malignancies. The development of KA or cutaneous squamous cell carcinoma is a potential adverse effect of these therapies [55-60]. (See "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy", section on 'Squamoproliferative lesions' and "Cutaneous immune-related adverse events associated with immune checkpoint inhibitors", section on 'Rare cutaneous adverse events'.)
A paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway resulting in the proliferation and survival of abnormal cells may contribute to the occurrence of these lesions in patients treated with BRAF inhibitors [61].
Additional agents that have been associated with the development of KA include sorafenib, a tyrosine kinase inhibitor used in the treatment of cancer [62,63], and immunosuppressive therapy [64-69].
●Chemical carcinogens – Exposure to chemical carcinogens, such as tar, pitch, polyaromatic hydrocarbons in mineral oils, and cigarette smoking may increase risk for KA [9,23,70]. Smoking was associated with increased risk for solitary KA in a case-control study of 78 patients with KA and 199 controls; 69 versus 22 percent of subjects were smokers [9]. A contributory effect of acid refined mineral oils is supported by a Swedish study that found higher than expected rates of KA on the hands or forearms of workers exposed to these substances [70]. Concordant with an inciting effect of these particular oils, KAs were no longer detected after a switch to solvent-refined mineral oils, which contain much lower concentrations of polyaromatic hydrocarbons.
●Human papillomavirus infection – Similar to cutaneous squamous cell carcinoma, the role of human papilloma virus (HPV) in KA is uncertain. Although multiple serotypes of HPV have been detected in lesions from immunocompetent and immunocompromised patients with KA, data are insufficient to confirm a causative association between KA and this ubiquitous virus [23,71-73]. (See "Cutaneous squamous cell carcinoma: Epidemiology and risk factors", section on 'Human papillomavirus infection'.)
CLINICAL FEATURES — Multiple clinical presentations of KA are described in the literature including solitary KA (the most common manifestation) and several less common variants characterized by isolated or multiple lesions (table 2).
Solitary keratoacanthoma — Solitary KA usually, but not always, develops on sun-exposed areas of the skin [34]. The face (especially the eyelids, nose, cheek, and lower lip), neck, hands, and arms are common sites for involvement [12]. Findings of consistent sun damage (eg, dyspigmentation, telangiectasias, and atrophy) are often present in the surrounding skin.
Although solitary KA is classically described as a dome-shaped, bud-shaped, or berry-shaped 1 to 2 cm papule with a central keratinous plug, the appearance of lesions varies with the stage of lesion development (picture 1A-E) [10]. Three phases characterize the evolution of KA: proliferation, maturation, and involution.
●Proliferation – Proliferation, the first stage of KA development, is defined by rapid growth that may persist for up to six to eight weeks. The initial lesion is usually a small pink macule that subsequently takes on a papular quality and eventually forms a circumscribed nodule. The periphery of the nodule tends to be skin-colored or mildly erythematous and may have accompanying telangiectasias [10]. The center of the nodule typically demonstrates a prominent keratinous core. Removal of this core results in a crateriform appearance.
Solitary KA typically grows to a diameter of 1 to 2 cm [29,74]. Lesions that exceed 2 cm in size are classified as giant KAs (picture 2) [12]. (See 'Clinical variants' below.)
●Maturation – In the maturation phase, growth ceases. The KA maintains the nodular or crateriform appearance but may begin to demonstrate signs of fragmentation [10,34,75]. This phase often lasts for several weeks to several months.
●Involution – The involution stage is characterized by spontaneous lesion regression. This process often takes four to six weeks but may take longer. During involution, the remaining central keratin plug is expelled. The tumor eventually completely resolves leaving an atrophic, often hypopigmented scar [76,77].
The time course for lesions to proceed through the three phases is usually around four to nine months [3,10,78]. However, some KAs persist for greater than one year, complicating the clinical distinction of these lesions from cutaneous squamous cell carcinoma. (See "Keratoacanthoma: Management and prognosis", section on 'Deferring therapy'.)
Clinical variants — The major clinical variants of solitary KA include giant KA, subungual KA, mucosal KA, and keratoacanthoma centrifugum marginatum (KCM).
●Giant KA – KAs can develop into large lesions, with diameters ranging from greater than 2 cm to up to 15 cm (picture 2) [79-84]. Such lesions are referred to as giant KAs. Giant KA has a predilection for the nose and eyelids [83]. Although spontaneous resolution usually eventually occurs, these lesions can cause considerable cosmetic disfigurement via the destruction of underlying structures [81,85].
●Subungual KA – Subungual KA develops on the nail beds and may present with pain, swelling, and inflammation [86,87]. As with classic KA, lesions develop quickly. The thumbs, index fingers, and middle fingers are the most frequently affected digits [12]. In addition, erosion of underlying bone is frequently evident on radiologic examination. Compared with classic KAs, spontaneous resolution is less likely to occur in this variant [87].
●Mucosal KA – Rarely, KAs develop on mucosal surfaces. The oral mucosa, conjunctiva, genitalia, or nasal mucosa may be affected [8,10,88,89]. Mucosal lesions may also be seen in patients with generalized eruptive KAs of Grzybowski (see 'Multiple keratoacanthomas' below). Spontaneous resolution of mucosal lesions usually does not occur.
●KCM – KCM is distinguished from giant KA by its prominent horizontal growth pattern. The lesion exhibits progressive peripheral growth accompanied by central involution. Lesions of KCM may reach diameters of 20 or more centimeters and may occur on the face, trunk, or extremities (picture 3) [10]. Spontaneous resolution is unlikely [90].
In addition to these four major subtypes of solitary KA, other uncommon presentations have been described, including vulvar KA in women [91-95] and KA within nevus sebaceous, a presentation primarily reported in children and young adults [96,97].
Multiple keratoacanthomas — Several named disorders may present with multiple KAs (picture 4 and table 2). The major disorders characterized by this presentation are multiple self-healing squamous epithelioma (MSSE), generalized eruptive KAs of Grzybowski, and eruptive squamous atypia (eruptive KA).
●MSSE – MSSE (Ferguson-Smith disease, OMIM #132800) is an autosomal dominant disorder attributed to loss-of-function mutations in the transforming growth factor beta receptor 1 (TGFBR1 or ALK5) gene [54]. TGFBR1 mutations may lead to defects in TGF-beta function that result in the deregulation of cell proliferation and migration. Most affected families are of Scottish origin. (See 'Risk factors' above.)
Features of MSSE most frequently appear during adolescence or early adulthood, but may also first occur earlier or later in life [10,98]. Affected patients develop several to hundreds of KAs that spontaneously resolve, often leaving deep, destructive scars [23]. Sun-exposed areas are most frequently affected but may not be the only sites of involvement. Exacerbation of this disorder has been reported following radiation therapy [50,99].
●Generalized eruptive KAs of Grzybowski – Generalized eruptive KAs of Grzybowski is a rare, sporadic disorder characterized by the abrupt appearance of numerous KAs [10,100,101]. The disorder usually occurs between the fifth and seventh decades of life [102].
Patients with generalized eruptive KAs of Grzybowski abruptly develop hundreds to thousands of follicular-based 1 to 5 mm papules with central keratotic cores on the trunk and extremities [12]. Palm, sole, genital, and mucosal involvement may also be present [10]. Affected individuals may experience pruritus, ectropion due to eyelid involvement, and sclerodermoid changes of the face due to extensive involvement in this area [3,10,23,103].
●Eruptive squamous atypia (eruptive KA) – Eruptive squamous atypia (eruptive KA) is an idiopathic proliferation of well-differentiated squamous cell carcinoma with atypia. This process is sometimes prone to koebnerization, and thus, surgical excision may result in further development of eruptive squamous atypia at the sites of surgery [104]. Some of these lesions may not meet the histologic criteria for KAs and may represent other entities, such as pseudoepitheliomatous hyperplasia or infundibulocystic hyperplasia. The use of intralesional fluorouracil has been described as a successful treatment for eruptive squamous atypia [104]. (See "Keratoacanthoma: Management and prognosis", section on 'Intralesional therapy'.)
●Multiple familial KA of Witten and Zak – A rare presentation of multiple KAs characterized by features of both MSSE and generalized eruptive KAs of Grzybowski has been reported and is referred to as multiple familial KA of Witten and Zak [100,105].
●KA associated with Muir-Torre syndrome – Patients with the variant of Lynch syndrome known as Muir-Torre syndrome, a genetic autosomal dominant condition characterized by cutaneous sebaceous tumors and visceral malignancies, may also present with several KAs [103,106-111]. (See "Muir-Torre syndrome".)
In addition, a clinical presentation characterized by the coexistence of prurigo nodules and multiple KAs on pruritic, actinically damaged skin has been described in several patients [112].
DIAGNOSIS — Due to the difficulty in clinically distinguishing KA from cutaneous squamous cell carcinoma, we biopsy all lesions suspicious for KA. The recognition of both clinical and histopathologic features consistent with KA is used to make the diagnosis.
Observation of lesions with clinical features consistent with KA from the proliferative phase through spontaneous resolution has been used by some clinicians to diagnose and manage KA [77]. However, this process typically takes at least several months, and the diagnosis remains in question until lesion regression. A major concern related to this approach is the misdiagnosis of cutaneous squamous cell carcinoma, a lesion with a relatively greater risk for metastasis and death.
Clinical assessment
●History – The clinical assessment of patients with lesions suspicious for KA should always involve obtaining a clear account of the lesion time course since a history of rapid growth within weeks favors this diagnosis. Patients should also be questioned regarding a history of prior similar lesions, sebaceous tumors, and visceral malignancies. These questions may help to identify the presence of a syndromic disorder. (See 'Multiple keratoacanthomas' above.)
●Skin examination – Careful examination of the entire skin surface should also be performed. The incidental detection of multiple lesions suspicious for sebaceous tumors during the skin examination may suggest the possibility of the Muir-Torre variant of Lynch syndrome. (See "Muir-Torre syndrome".)
●Dermoscopy – Dermoscopy may aid in clinically distinguishing KA from other lesions but cannot reliably distinguish KA from squamous cell carcinoma [113]. Dermoscopic findings in KA include white circles; shiny, white blotches; and looped to twisted-looped (hairpin) vessels with a whitish halo at the periphery (picture 5). (See "Dermoscopic evaluation of skin lesions".)
Biopsy — The preferred method for obtaining a biopsy specimen is an excisional biopsy extending into the subcutaneous fat. At least a 4 mm margin is usually taken when feasible to concurrently suffice for treatment. (See "Keratoacanthoma: Management and prognosis", section on 'First-line therapy'.)
An alternative method for obtaining the tissue specimen is the performance of a deep shave biopsy (also known as a saucerization procedure) that removes the entire lesion and extends into the subcutaneous fat. Since improperly performed shave biopsies are often inadequate for diagnosis, shave biopsies of KA should only be performed by clinicians with extensive experience with the shave procedure [3]. Punch biopsies do not allow for the examination of the lesion architecture, and therefore, are not recommended. (See "Skin biopsy techniques", section on 'Shave biopsy'.)
Removal of the entire lesion for diagnosis may be impossible in patients with giant lesions or keratoacanthoma centrifugum marginatum (KCM). In such cases, a fusiform incisional biopsy through the center of the lesion that includes a cross-section of the lesion (periphery and center) and extends into the underlying fat can be performed [10,114]. This provides a specimen that represents the lesion architecture without total removal of the lesion.
Histopathology — Although no single histopathologic finding reliably confirms a diagnosis of KA, an overall picture of consistent histopathologic and clinical findings is used to support the diagnosis. The histopathologic features that typically characterize KA include [32,115]:
●Epidermal hyperplasia with large eosinophilic keratinocytes
●Central invagination with a keratotic core (this may be less evident in early-stage lesions)
●"Lipping" or "buttressing" of the epidermis over the peripheral rim of the central keratotic plug
●Sharp demarcation between the tumor and the surrounding stroma
●Mixed inflammatory infiltrate in the dermis
The majority of keratinocytes in KA do not exhibit signs of atypia, and mitoses are not a prominent feature, though they may be observed in the deepest components of some lesions [32]. Islands of tumor cells may be present underlying the main portion of the tumor. The tumor islands usually do not extend beyond the depth of the eccrine glands.
Aggressive features such as perineural invasion and intravascular involvement may be seen in a minority of specimens from lesions of KA, and have been used by some authors to support the classification of KA as a variant of cutaneous squamous cell carcinoma [29,116]. The significance of perineural invasion, a negative prognostic factor in cutaneous squamous cell carcinoma, is unclear in KA. (See "Keratoacanthoma: Management and prognosis", section on 'Metastasis'.)
Differentiation from squamous cell carcinoma — Differentiating KA from cutaneous squamous cell carcinoma based on histopathologic examination is challenging [30,32]. An analysis of approximately 300 KAs and squamous cell carcinomas found that no histopathologic criterion was sufficiently sensitive or specific to reliably distinguish between these lesions [32]. However, among the pathologic features typically ascribed to KA, the presence of an epithelial lip and a sharp outline between the tumor and stroma appeared to be the most useful factors for the diagnosis of KA. In contrast, the presence of ulceration, mitoses, and pleomorphism or anaplasia favored a diagnosis of squamous cell carcinoma.
Due to the lack of histopathologic features that definitively distinguish KA from squamous cell carcinoma, studies of specific biomarkers and genetic analyses have attempted to identify additional methods for differentiating these lesions [25,28,117-132]. Promising examples include recognition of the labelling pattern of the cytolytic calcium channel receptor p2X7, a marker of apoptosis [25], and the detection of specific chromosomal aberrations within these lesions [28].
Transcriptomic studies have shown differential gene expression in KA and well-differentiated cutaneous squamous cell carcinoma [133,134].
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of KA is broad and includes other nodular tumors and growths of the skin. The combination of a history of rapid growth, central keratotic crater formation, and consistent histopathologic findings are often helpful for distinguishing KA from other disorders.
As noted above, squamous cell carcinoma is the most difficult disorder to distinguish from KA due to the multiple clinical and histopathologic similarities between these lesions. Examples of additional lesions to consider in the differential diagnosis of solitary KA include the following:
●Nodular basal cell carcinoma (picture 6) (see "Basal cell carcinoma: Epidemiology, pathogenesis, clinical features, and diagnosis", section on 'Nodular')
●Merkel cell carcinoma (picture 7) (see "Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma", section on 'Clinical features')
●Prurigo nodule (picture 8) (see "Prurigo nodularis", section on 'Clinical manifestations')
●Giant molluscum contagiosum (picture 9) (see "Molluscum contagiosum", section on 'Clinical features')
●Deep fungal infection (eg, sporotrichosis) (picture 10)
●Nodular Kaposi sarcoma (picture 11) (see "Classic Kaposi sarcoma: Clinical features, staging, diagnosis, and treatment", section on 'Clinical features')
●Cutaneous metastases [135,136]
The combination of clinical assessment and biopsies are also useful for narrowing the differential diagnosis for other presentations of KA. The possibility of paronychia, periungual squamous cell carcinoma, viral warts, and subungual tumors associated with incontinentia pigmenti should be considered in patients with lesions suspicious for subungual KA [137]. (See "Incontinentia pigmenti", section on 'Extracutaneous findings'.)
In addition, the clinical appearance of KCM may resemble giant porokeratosis of Mibelli or halogenoderma [138]. (See "Porokeratosis", section on 'Porokeratosis of Mibelli'.)
In patients with suspected multiple KA syndromes, the possibility of other disorders that may present with widespread nodular lesions, including prurigo nodularis and perforating disorders (eg, Kyrle disease), should be considered. (See "Perforating dermatoses".)
SUMMARY AND RECOMMENDATIONS
●Epidemiology and risk factors – Keratoacanthoma (KA) is a cutaneous tumor that most commonly occurs in middle-aged and older individuals with lightly pigmented skin. Controversy exists over whether KA represents a distinct disease entity or a variant of cutaneous squamous cell carcinoma. Risk factors associated with KA include lightly pigmented skin, exposure to ultraviolet radiation or chemical carcinogens, genetic abnormalities, and certain medications. The role of human papillomavirus in KA remains uncertain. (See 'Epidemiology' above and 'Risk factors' above.)
●Clinical presentation – Solitary KA is the most common manifestation of KA. Lesions are usually 1 to 2 cm in diameter and are most commonly found on sun-exposed skin (picture 1A-E). Solitary KAs undergo three phases of evolution: a proliferative period of several weeks, a maturation phase that may persist for several months, and eventual lesion regression. (See 'Solitary keratoacanthoma' above.)
●Clinical variants – A variety of additional variants of KA have been described, including giant KA (picture 2), subungual KA, mucosal KA, and keratoacanthoma centrifugum marginatum (KCM). KAs may also present as a feature of multiple KA syndromes, such as multiple self-healing squamous epithelioma (MSSE; Ferguson-Smith disease), generalized eruptive KAs of Grzybowski, and eruptive squamous atypia (eruptive KA). In addition, the Muir-Torre variant of Lynch syndrome may present with KA, sebaceous tumors, and visceral cancer. (See 'Clinical variants' above and 'Multiple keratoacanthomas' above.)
●Diagnosis – The diagnosis of KA is based upon the combination of clinical and histopathologic findings, as the differentiation of KA from cutaneous squamous cell carcinoma based upon histopathologic examination is challenging. Complete removal of the lesion via surgical excision extending into the subcutaneous fat is the preferred procedure for the diagnosis of lesions suspicious for KA. Alternatively, a deep shave biopsy (also known as a saucerization procedure) that removes the entire lesion and extends into the subcutaneous fat can be performed by clinicians experienced in this procedure. (See 'Biopsy' above and 'Histopathology' above.)
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