Keratoacanthoma: hyperplasia, benign neoplasm, or a type of squamous cell carcinoma?

Seminars in Diagnostic Pathology (2009) 26, 150-163

Keratoacanthoma: hyperplasia, benign neoplasm, or a type of squamous cell carcinoma? Joshua C. Mandrell, MD,a Daniel J. Santa Cruz, MD, FASDb From the aSt. Johns Mercy Medical Center, and b WCP Laboratories, St. Louis, Missouri. KEYWORDS Keratoacanthoma; Squamous cell carcinoma; Pseudomalignancy; Sweat duct hyperplasia; Biological markers; Metastasis

Keratoacanthomas are common self limited squamous proliferations. They have been considered a benign neoplasm with involution and complete resolution within few months. Although considered the prototypical example of cutaneous pseudomalignancy, some believe that these tumors are squamous cell carcinomas and through the years there have been sporadic reports of “metastasizing keratoacanthomas.” The question has been raised as to whether keratoacanthoma is an unreliable histological diagnosis or these tumors have a latent, albeit rare, malignant potential. To date, just a handful of “metastasizing keratoacanthomas” have been reported. Since a benign lesion is incapable of metastasis, some other explanation must be considered; the most likely one being a misdiagnosis. While it is clear that in some cases, the histological and cytological features of squamous cell carcinoma and keratoacanthoma are difficult to distinguish by current techniques, these occasional limitations in diagnosis do not make keratoacanthomas a carcinoma. We believe the evidence supports that keratoacanthomas are benign squamous proliferations. The diagnosis can be made with confidence in appropriate biopsies and using well established clinicopathological criteria. © 2009 Published by Elsevier Inc.

Keratoacanthomas are crater shaped squamous proliferations characterized by rapid growth and spontaneous involution. The understanding of the nature of keratoacanthoma has been controversial since its original description. Between 1950 and 1980, the consensus of the dermatology and dermatopathology community has been to classify these lesions as benign conditions.1 Although perceived by some as a benign neoplasm, papers describing aggressive behavior in keratoacanthomas have been published periodically.2-7 In 1993, Hodak, Jones, and Ackerman wrote that “keratoacanthoma is, in actuality, an expression of squamous-cell carcinoma” based on three cases they presented

Address reprint requests and correspondence: Daniel J. Santa Cruz, MD, FASD, 2326 Millpark Drive, St. Louis, MO 63043. E-mail address: [email protected].

0740-2570/$ -see front matter © 2009 Published by Elsevier Inc. doi:10.1053/j.semdp.2009.09.003

and one found in the literature, after these “keratoacanthomas” were viewed to have metastasized.3 Although it is clear that, in some cases, the histologic and cytologic features of squamous cell carcinoma and keratoacanthoma are difficult to distinguish by current techniques, these occasional limitations in diagnosis do not make keratoacanthomas a carcinoma. We believe the evidence supports that keratoacanthomas are benign squamous proliferations. We do not believe that a handful of cases with difficult-todistinguish lesions that were diagnosed as keratoacanthomas and later metastasized warrant changing the way these lesions are conceptualized. By doing so, we may stifle further research in the area to find other ways to distinguish these histologically similar, but biologically different, lesions. This review focuses mainly on the actinic keratoacanthoma.

Mandrell and Santa Cruz Table 1

Keratoacanthoma: Hyperplasia, Neoplasm, Carcinoma?

Historical terms

Crateriform ulcer of the face (Hutchinson 1889)9 Verrucome (Gougerot 1929)10 Kyste sébacé atypique (Dupont 1930)11 Multiple, primary squamous cell carcinomas of the skin with spontaneous healing (Ferguson Smith 1934)12,13 Molluscum sebaceum (MacCormack and Scarff 1936)14 Keratoacathoma (Freudenthal)8 Tumorlike keratoses (Poth 1939)15 Diverticule epidermique á paroi végétante (Dupont 1952)16 Molluscum pseudocarcinomatosum (Halnan 1953)17,18 Benign keratoacanthoma (Winer 1955)19 Idiopathic cutaneous pseudoepitheliomatous hyperplasia (Grinspan and Abulafia (1955)20) Squamous cell pseudoepithelioma (Duany 1958)21 Inverted wart (Brothers, et al. 1960)22 Pseudocarcinoma (Peterkin 1962)23 Cutaneous sebaceous neoplasm (Rulon and Helwig 1974)24 Keratocarcinoma (Kwitten 1975)25 Button epithelioma (Rook and Whimster 1979)2

History Hutchinson is credited with the first description of this lesion in 1889, and Freudenthal is attributed with coining the term “keratoacanthoma” in 1936.8 The current concept of keratoacanthoma as a benign lesion was proposed by Rook and Whimster in 1950.1 The names ascribed throughout the last 100 years to what is now known as “keratoacanthoma” show the controversy existing as to whether this is a benign or malignant lesion (Table 1). Historically, Hutchison described the crateriform lesion in 1889 as a squamous cell carcinoma.9 The multiple lesions seen and described by Ferguson Smith in 1934 were also termed “multiple, primary squamous cell carcinomas of the skin, with spontaneous healing.”12 Rook and Whimster in 1950 first distinguished benign keratoacanthoma and squamous cell carcinoma as separate entities, which has been the predominant concept in subsequent years.1,2,26,27 They emphasized four points of histologic difference between the two: (1) keratoacanthomas arise in normal skin with no signs of precancerous change; (2) epithelial hyperplasia principally affects the appendages with little hyperplasia of the surface epidermis and no signs of spontaneous ulceration in keratoacanthoma; (3) there is minimal pleomorphism of keratoacanthoma cells; and (4) there is no truly invasive growth in keratoacanthoma.2 Since then, most have seen keratoacanthoma as a pseudomalignancy distinct from squamous cell carcinoma.28 However, the four features mentioned by Rook and Whimster do not seem to be as straightforward as once suspected, and deeper dermal invasion has been seen in lesions previously classified as keratoacanthomas.29 In addition, some keratoacanthomas may display substantial cellular pleomorphism. Kwittken, in 1979, reclassified keratoacanthomas as squamous cell carcinomas.25 The controversy ensues and evolves in the literature and among individual authors.

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Etiology and clinical course The etiology of keratoacanthomas has also been discussed thoroughly. Rook and Whimster proposed trauma, light, exogenous carcinogens, impaired cell-mediated immunity, and immunosuppressive drugs as possible etiologies.2 An “unknown factor,” a viral infection, occupational heat, aging, and contact with oils have also been suggested as contributing factors by others.26,30,31 Although the etiology is likely multifactorial, an infectious component was further suggested by the findings of juxtaposed lesions on lips, onset at sites of herpes simplex, location at sites of trauma, occurrence in a small pox vaccination site, and by appearance in transplant graft sites.26,30,32-38 Some have tried human papillomavirus (HPV) virus detection to distinguish between keratoacanthoma and squamous cell carcinoma, but results are inconclusive in light of viruses being found in both.39-53 Although a viral etiology can be an argument for a benign phenomenon, it is known that viruses can be carcinogenic as is HPV in cervical carcinoma. Thus, the presence of HPV does not have meaning in the argument for or against keratoacanthomas as squamous cell carcinomas, because HPV can exist as an inducer of carcinoma as seen in HPV 16 and HPV 18, can exist as a cause of keratoacanthoma in the argument of “keratoacanthoma as hyperplasia,” or can have an unrelated presence in these lesion.53 Many feel there is a role of cell-mediated immunity as Langerhans’ cells are increased in inflamed keratoacanthoma but not in squamous cell carcinoma, which may be evidence of the Langerhans’ cell’s role in the regression of keratoacanthoma.54,55 Other factors, in addition to those already discussed, stimulating the production of keratoacanthomas have been suggested, including the hereditary factor, coal tar and oil products, thermal burns or exposure, podophyllin, smoking and air pollution, and other carcinogens.32 Elucidating an etiology can be important in prevention and treatment measures. The cell or structure of origin has also been discussed in the literature. The earliest thoughts were that keratoacanthoma originates from hair follicles and its course is related to the cycle of the hair follicle.56-60 This would not explain those keratoacanthomas arising on mucosal sites. The keratoacanthoma is typically seen on sun-exposed, hair-bearing skin, especially that of the face, hands, wrists, forearms, neck, ears, trunk, and scalp, in light-skinned individuals.32,61 Patients affected are most commonly in the fifth, sixth, and seventh decades of life.32,59 The true incidence is unknown but has been reported to be as high as 150 per 100,000 adults with a higher incidence in warmer regions.62 A keratoacanthoma starts as a small, red macule, which becomes a firm papule with scale.32 The papule rapidly enlarges for 2-8 weeks, becoming a round, firm, elevated, hemispheric, skin-colored to pink nodule with a central plug of keratin at its peak.25,32 It can be asymptomatic, slightly tender, or pruritic.32 The lesion may appear as a giant molluscum contagiosum or appear “volcano-like”

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Figure 3 Keratoacanthoma. Fully developed phase. Early formation of the central keratin plug. Figure 1

Clinical appearance of an actinic keratoacanthoma.

with a central crater.32 This molluscum-like appearance led to the names of “molluscum sebaceum” given by MacCormack and Scarff in 193614 and “molluscum pseudocarcinomatosum” given in a 1953 Lancet editorial by Halnan.17,18 A keratinous plug is firmly embedded into this volcano-like crater.32 The mature, fully developed keratoacanthoma is typically 5-25 mm in diameter with smooth borders that merge with the surrounding skin25,32,63 (Figure 1). Some keratoacanthomas present with erythema surrounding the base of the lesion and with fine telangiectases running over the surface of the tumor.32 Most keratoacanthomas remain freely movable over the underlying structures.32 After the 2to 3-month period of growth and development stages, spontaneous involution usually occurs over an additional 2-8 weeks by expulsion of the keratinous plug and resorption of the tumoral mass.32,64,65 The complete appearance and dis-

appearance of the lesion lasts from 2 to 9 months.32,61 Most of the time, an atrophic, depressed, hypopigmented, and alopecic scar with slightly overhanging borders is left behind.32 Bleeding is rare.32 However, there are exceptions to the clinical rules, and keratoacanthomas that ulcerate and that take longer to involute have been described.32,61,66 Historically, when certain of the histologic diagnosis of keratoacanthoma, the practice has been to treat keratoacanthomas with excision, injection of cytostatic agents, or close clinical follow-up. Many clinicians prefer to eradicate the lesion due to the perceived difficulty in distinguishing the benign keratoacanthoma and the malignant squamous cell carcinoma. The concept of keratoacanthomas being squamous cell carcinomas has made this practice more common.

Histology The typical solitary keratoacanthoma has different histologic features depending on the evolutionary stage of the lesion when biopsied. Like many tumors, including mycosis fungoides and Kaposi’s sarcoma, there are three recogniz-

Figure 2

Early phase. Note the solid appearance.

Figure 4

Typical profile of a mature keratoacanthoma.

Mandrell and Santa Cruz

Figure 5

Keratoacanthoma: Hyperplasia, Neoplasm, Carcinoma?

Tumor cells with “glassy” cytoplasm.

able stages both clinically and histologically: (1) earlygrowing phase; (2) fully developed phase or stationary phase; and (3) senescent phase. Unlike the other neoplasms, the third phase of keratoacanthomas is regression or spontaneous involution and not progression to nodular stages.

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Figure 7 Lichenoid inflammatory response to a keratoacanthoma. Note the similarity to lichen planus.

Most keratoacanthomas are biopsied in the developed phase (Figures 3 and 4). At this stage, they are symmetric,

crateriform, exophytic lesions containing a central keratin plug and deep bulbous lobules of squamous cells with abundant eosinophilic, pale cytoplasm that is typically termed “glassy” (Figure 5). There is a “lip” of normal epidermis at the periphery that extends partially over the central keratinous crater. Cytologically, the keratinocytes vary from monomorphous and uniform to pleomorphic with numerous mitotic figures. There is a gradient of cellular pleomorphism with most of the pleomorphic keratinocytes at the periphery of the deep lobules. This contrasts with squamous cell carcinomas in which the pleomorphism is usually random. Yet, architectural features are more helpful than cytologic features in establishing the diagnosis.67 Apoptotic keratinocytes are usually present in the lobules. Fully keratinized cells are seen in microcavities. When these occur, they are usually parakeratotic and are often associated

Figure 6 Neutrophilic abscesses in the deep lobules of a keratoacanthoma.

Figure 8 Fibrosis and inflammation at the base of a keratoacanthoma. Note the presence of eosinophils.

Early-growing phase The early keratoacanthoma is a small, mostly solid tumor with scant keratinization and inflammation (Figure 2). There is variable cellular pleomorphism with an inflammatory infiltrate that undergoes a progression from lymphocytes and histiocytes to a mixture of eosinophils, neutrophils, plasma cells, and histiocytic giant cells.57

Fully developed or stationary phase

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Figure 9 Elastic fibers and elastotic material incorporated in the growing edge of a keratoacanthoma.

Figure 11 a poroma.

with neutrophilic microabscesses as well as elastic and collagen fibers68 (Figure 6). The inflammatory infiltrate around the periphery of the lesion is lichenoid in nature with lymphocytes and eosinophils (Figure 7), and plasma cells are found only rarely. In fact, the presence of abundant plasma cells is usually indicative of a squamous cell carcinoma (Figure 8). A band of fibrosis beneath the lesion can be seen at this stage. This represents an early sign of regression and is a useful diagnostic finding. The penetration and presence of intraepithelial elastic fibers, elastotic material, and collagen is highly characteristic of keratoacanthomas (Figure 9). This finding can also be seen in squamous cell carcinomas but usually in lesser degree. The trapping of elastic tissue is seen in all of the growth phases of keratoacanthoma. This phenomenon is more evident at the peripheral areas of the tumor lobules.

An interesting phenomenon, not exclusive but frequent, in keratoacanthomas is the presence of reactive proliferation of ducts from the eccrine glands present beneath the tumor lobules. The ducts lose their two-layer cellular configuration to acquire an adenomatoid appearance. Sometimes, the ductal cells have a disorganized appearance and nuclear pleomorphism. Sometimes the glandular hyperplasia is so prominent as to resemble an adenomatoid or glandular component. These proliferations are varied and may resemble adnexal tumors, such as syringoma (Figure 10), eccrine poroma (Figure 11), and papillary eccrine adenoma (Figure 12). Perineural involvement may be observed, sometimes extensively, along the deep portion of the tumor (Figure 13). Its presence is not particularly helpful in differentiating keratoacanthoma from squamous cell carcinoma.69,70

Figure 10 Sweat duct hyperplasia beneath a keratoacanthoma. This proliferation resembles a syringoma.

Figure 12 Florid adenomatoid sweat gland hyperplasia with close resemblance to a papillary eccrine adenoma.

Solid sweat duct hyperplasia. These lobules resemble

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Figure 13

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Mature keratoacanthoma. There is extensive perineural spread at the base of the tumor.

Vascular invasion may occur rarely but is not necessarily associated with an adverse outcome,71 although it is certainly a worrisome feature.

Senescent phase

Figure 14 Regressing keratoacanthoma. The tumor resembles a cyst or comedone.

Figure 15 Regressed keratoacanthoma. Note the resemblance to a seborrheic keratosis.

In the regressive or senescent phase, keratoacanthomas hollow out, and the crater is filled with keratin. The solid lobules of keratinocytes largely disappear and are replaced by a mature keratinous cyst-like epithelium. The lesion

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Figure 16 Regressed keratoacanthoma. The tumor lost most of the keratin of the crater but still possesses the overhanging lips of keratoacanthoma.

becomes shallow and loses the crater-like qualities (Figure 14). At this time, the lesion closely resembles an inflamed seborrheic keratosis (Figures 15 and 16). Dense, confluent fibrosis is present, and it replaces the reticular dermis. If keratoacanthoma is benign and squamous cell carcinoma is malignant and these are separate entities, one may ask if they can be differentiated. Differentiation of keratoacanthoma and squamous cell carcinoma is made clinically and histologically based on cytologic features and growth patterns, as summarized in Table 2 (Figure 17).

Types of keratoacanthomas When authors refer to keratoacanthoma, they usually refer to the “actinic” keratoacanthomas. These are lesions that

Table 2

Figure 17 Multiple keratoacanthomas in a chronic renal insufficiency patient.

usually develop on the sun-exposed skin of the elderly.72 This tumor is very common, and it is the one that generates more commonly the diagnostic difficulties with well-differentiated squamous cell carcinoma (Table 3). If keratoacanthoma is recognized as a condition different from squamous cell carcinoma, there is a spectrum of similar lesions with shared clinical and histologic features that may also belong in this group. They range from multiple

Differential diagnosis between keratoacanthoma and squamous cell carcinoma

Criterion

Keratoacanthoma

Squamous carcinoma

Growth rate Resolution Symmetry

Rapid growth (weeks to months) Spontaneous Symmetric dome with overhanging “lips” vertical “gradient”

Keratin plug Growth pattern

Central, common Exophytic and endophytic with central horn-filled crater Abrupt transition between tumor and epidermis

Slow growth (months to years) None, without therapeutic intervention Asymmetric and slightly raised or ulcerated Rare Endophytic with no crater

Transition zone Actinic keratosis Subcutaneous involvement Fibrosis Cytologic pleomorphism Cytoplasm Acantholysis Intraepithelial neutrophilic abscesses Keratinization patterns Intraepithelial elastic tissue Elastophagocytosis Inflammatory infiltrate Eosinophils Plasma cells Langerhans’ cells54,55 Melanocytes Lymph node involvement Perineural invasion Adenomatoid sweat duct hyperplasia

May be present but not contiguous Not common, but may be present in large tumors Dense, band-like, located deep to the lesion Variable, some are very pleomorphic Abundant, often “glassy” or eosinophilic Not seen Common

Gradual transition of normal epidermis epidermal pleomorphism to tumor Present contiguous Not uncommon in large tumors When present, surrounds tumor nests More common. diffuse Irregular, abundant or scant Frequent Rare

Orthokeratotic with frequent granular layer Common in peripheral tumor nests Common Common, dense and lichenoid Common and abundant Rare Increased (especially in inflamed variety) Absent Absent Rare, but present in deeper tumors Common

Usually parakeratotic, acantholysis Uncommon Rare Variable Rare Common and abundant No increased amount Present Present Rare Rare

Mandrell and Santa Cruz Table 3

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Types and categories of keratoacanthomas

Actinic Non-actinic Follicular Giant or confluent Multinodular Verrucous Keratoacanthoma centrifugum marginatum (KCM) (Miedzinski and Kozakiewicz80) Subungual74-76 Keratoacanthomas arising on mucous membranes77-79 Multiple and syndromic forms ● Eruptive (Grzybowski) ● Ferguson-Smith ● Muir-Torre ● Witten-Zak Keratoacanthomas superimposed on dermatoses

Figure 19 Multinodular giant keratoacanthoma. The lesion responded to 5-fluorouracil and regressed completely leaving a shallow scar.

lesions, eruptive forms, to lesions of considerable size (Figures 18 and 19). Less common variants include those that occur on sun-protected skin and those in immunosuppressed individuals.73 There are many classification schemes and types of keratoacanthomas described throughout the literature.

overhanging lips of epithelium, a sharp outline between the tumor nests and stroma, lack of cellular pleomorphism, and the presence of stromal desmoplasia in the central parts of the tumor.

Keratoacanthoma centrifugum marginatum

Ferguson-Smith syndrome

Keratoacanthoma centrifugum marginatum (KCM) is an extremely rare variant of keratoacanthoma, with about 30 cases reported since it was first described in 1962.80 It is clinically characterized by a larger diameter with continuous centrifugal spread, concurrent central atrophy, and lack of spontaneous remission. Histologically, KCM is similar to KA, with a wide central keratin-filled crater,

Multiple self-healing squamous epithelioma of Ferguson-Smith (MSSE) is a rare autosomal dominantly inherited disease, almost exclusively reported in patients of Scottish origin, with recurrent squamous tumors that undergo spontaneous regression.

Multiple and syndromic forms

Muir-Torre syndrome The Muir-Torre syndrome (MTS) is an autosomal-dominant genodermatosis characterized by the presence of sebaceous gland tumors, with or without keratoacanthomas, associated with visceral malignancies.

Witten-Zak This syndrome represents a combination of FergusonSmith and Grzybowski syndromes.12,59,81,82

Generalized eruptive keratoacanthoma

Figure 18

Giant keratoacanthoma.

Grzybowski syndrome, or generalized eruptive keratoacanthoma, refers to a very rare disease in which hundreds of keratoacanthoma-like papules appear.83 The cause is unknown. It should be distinguished from an inherited disorder, Fergusson Smith familial keratoacanthomas, in which multiple keratoacanthomas appear in children and young adults.

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Seminars in Diagnostic Pathology, Vol 26, No 3, August 2009 Despite those shared features, they seem to be unrelated to one another. Not only does one type begin from follicles and the other does not, but they behave differently.”8

Discussion

Figure 20 Follicular keratoacanthoma. Instead of a single crater-like structure, there are multiple vertical mature squamous proliferations.

Clinical features of Grzybowski syndrome Only about 30 cases of Grzybowski’s syndrome have been described worldwide. The syndrome affects middleaged adult males and females equally. It starts abruptly and extends over some months. Untreated, it is reported to persist indefinitely. The main features are: ● severe itch; ● numerous firm nodules on the affected areas (face, scalp, trunk, and limbs); ● white nodules in the mouth (lips, tongue, inside the cheeks); ● larger hyperkeratotic nodules that persist for a few weeks, then disappear by themselves; ● Koebnerization—the nodules may appear at sites of skin injury; ● mask-like facial appearance, due to thickened face skin; ● ectropion and retraction of eyelid skin; and ● hoarseness due to nodules on the larynx.

Keratoacanthomas superimposed on dermatoses Keratoacanthomas have been reported in association with lichen planus and discoid lupus erythematosus. An alternative view is that, although the verrucous lesions have similar architecture of small keratoacanthomas, they are actually part of the spectrum of those dermatoses, and a more appropriate name is verrucous lupus erythematosus. These lesions are usually small and multiple without a tendency to regress and are located within the patches of the dermatoses. Keratoacanthomas have histologic and behavior variation. Some authors use the term follicular keratoacanthoma for squamous lesions that are generally devoid of a single crateriform structure, and instead develop multiple, more or less individual, parallel, downwards growths (Figure 20). Choonhakarn and Ackerman have concluded that “keratoacanthomas are not a single neoplasm, but represent at least two different types of squamous-cell carcinoma that have clinical and histopathologic features in common.

The concept of keratoacanthoma has evolved through the years, perceived traditionally as a benign regressing neoplasm or “pseudoepitheliomatous” tumor that does not metastasize or directly cause death.32 The sporadic report of “metastasizing keratoacanthomas” rang as an alarm, but most reports included a single case. In fact, up until 1994, only four cases were acceptable and properly recorded.3 Kopf writes, “If malignant transformation of keratoacanthoma to squamous cell carcinoma does occur, it must be exceedingly uncommon, since there now have been thousands of keratoacanthomas reported and only a few, usually poorly documented cases of malignant transformation resulting in metastases or death.”32 Many now believe these two entities represent a biological spectrum with many lesions with features intermediate between the two.84 Some view keratoacanthomas as a histologic subgroup of squamous cell carcinoma, in which the tumor may progress from noninvasive to invasive depending on its environment and local factors,2,85-88 which may include impaired cellular immunity.3,89 Dermatologists and dermatopathologists continue to be divided as to whether keratoacanthoma is a benign, selflimited neoplasm different from squamous cell carcinoma or if keratoacanthoma is a variant of squamous cell carcinoma and, in itself, malignant. Some authors reject the diagnosis altogether,3,25 whereas others embrace the diagnosis as one that can be made but must be used with caution.1,32,67,90-92 The term keratoacanthoma denotes a spectrum of benign, cup-shaped proliferation of keratinocytes that develop rapidly and undergo spontaneous regression. It is morphologically similar to well-differentiated squamous carcinoma and, in fact, some authors believe it is an abortive carcinoma.85 Dunn and Smith’s description of this lesion as a “self-healing primary squamous cell carcinoma of the skin” echoes this thought.32 Some may propose that the keratoacanthoma is initially a benign and selflimited entity that, in some cases, gets “transformed” and becomes progressive and oncogenic somewhere in its clinical course due to an unknown factor or “hit.”2,93 The concept of keratoacanthoma has evolved not only in the general literature but also among individual authors, as some have changed their opinion more drastically than others. Rook and Whimster originally stated in 1950 that they felt keratoacanthoma was “wholly benign, reactive and nonneoplastic” and that it was likely “simple epithelial hyperplasia” and “evidently not cancerous or precancerous.”1,2 Thirty years later, Rook and Whimster concluded, “In short it is now believed from histological evidence that keratoacanthoma is itself a reactive hyperplasia capable of spontaneous involution. But that it is also capable of summating as

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a co-carcinogen with solar damage to produce a rapidly growing squamous carcinoma. How often this would happen if all keratoacanthomas were left untreated can obviously not be assessed.”2 The opinions of other authorities have had more drastic changes upon further review:

sessed by silhouette and those that pertain to cytopathologic findings, but because of biologic behavior, in particular, capability for metastasis and for destruction of important structures locally.

If a proper biopsy is submitted, an accurate differentiation of keratoacanthoma from squamous cell carcinoma can be made in the overwhelming majority of cases.

The publication by Hodak, Jones, and Ackerman in 1993 has been extremely influential and a turning point from changing the perception of keratoacanthoma from a selflimited, benign neoplasm to considering it a potentially aggressive tumor, namely squamous cell carcinoma. The authors describe three cases of clinical solitary keratoacanthoma with histologic features fitting the criteria for diagnosis of keratoacanthoma, which subsequently metastasized resulting in death of one of the three patients, although it appears that an autopsy was not performed in this patient looking for other primary lesions.3 In their literature review searching for similar cases, nine cases of “metastasizing keratoacanthomas” were whittled down to one, after the cases were not verified histopathologically and the cases in which the original diagnosis was changed to squamous cell carcinoma after further review were eliminated.3 The only other well-documented case of suspected metastasizing keratoacanthoma was described by Piscioli and coworkers in 1984.89 However, the Piscioli case is one of a suspected “gigantic metastasizing keratoacanthoma,” which is different from the typical solitary keratoacathomas described in the original three cases of Hodak, Jones, and Ackerman. Regardless, in these four cases, biopsy of the metastatic lesion showed histology also compatible with that seen in the original keratoacanthoma biopsy.3,89 By definition, they conclude, if these lesions cannot be distinguished from squamous cell carcinoma by cytology and if they eventually metastasize, these lesions must be squamous cell carcinomas at the onset.3 In unusual cases, lesions in the histologic spectrum typical of keratoacanthoma will pursue an aggressive clinical course. We agree that this suggests one of four possibilities:

–Chalet, Connors, and Ackerman (1975)94 Keratoacanthoma is a singular neoplasm. No other cutaneous new growth evolves so rapidly and yet resolves so predictably and completely . . . Squamous carcinoma that develops on sun-damaged skin metastasizes with exceeding rarity, but keratoacanthoma, by definition, never metastasizes. –Ackerman (1976)95 The prototype of a cutaneous pseudomalignant neoplasm is a keratoacanthoma. Ordinarily, this essentially benign neoplasm springs from the epithelium of the hair follicles, often displays considerable cytological atypia in its development, and extends deep into the dermis or into the subcutaneous fat before eventually resolving spontaneously. –Ackerman (1976)28 Keratoacanthoma may be differentiated from squamous-cell carcinoma with near certainty by architectural pattern if an adequate biopsy specimen has been submitted to the pathologist. –Ackerman (1982)96 Because of this capability for metastasis, albeit infrequent, keratoacanthoma must be considered a type of squamous-cell carcinoma. –Ackerman, Jacobson, and Vitale (1991)97 We now add three more examples of what seem to us to be metastasizing keratoacanthomas. Observations of these neoplasms has led us to conclude that keratoacanthoma is, in actuality, an expression of squamouscell carcinoma . . . keratoacanthoma is neither a benign nor pseudomalignant neoplasm, and it is not a precursor of squamous cell carcinoma . . . It is a squamouscell carcinoma from the onset . . . We now regard solitary keratoacanthoma as a squamous-cell carcinoma, a type that has a distinctive appearance and in the vast majority of instances undergoes resolution without therapy. –Hodak, Jones, and Ackerman (1993)3 All keratoacanthomas, irrespective of site of origin, qualify as being squamous-cell carcinomas, not only for reasons that relate to architectural features as as-

–Choonhakarn and Ackerman (2001)8

1. the initial lesion was diagnosed incorrectly as keratoacanthoma and the differentiation from some squamous carcinomas is not always possible by conventional microscopy and clinicopathologic correlation currently3 2. two tumors are located in the same location3,32 3. malignant transformation took place, although exceedingly rare2,3,32 4. the lesion was a squamous cell carcinoma and is following a normal biological course3,7,8,25,89,98 Hodak, Jones, and Ackerman would argue that the three cases they present in their article and one additional case in the literature of Piscioli and coworkers89 do not fulfill criteria 1-3, and therefore, 4 must be true—that these keratoacanthomas must be squamous cell carcinomas.3 They then conclude that, if these keratoacanthomas are really squamous cell carcinomas, all keratoacanthomas are really squamous cell carcinomas.3

160 We believe that keratoacanthoma and squamous cell carcinoma can be very similar, but yet distinct entities that are difficult to distinguish in some cases. Evidence exists showing that the incorrect diagnosis of keratoacanthoma in actual squamous cell carcinoma is possible in some cases, and some papers have reported a near 20% error in classification of keratoacanthoma from squamous cell carcinoma.85 We do not dispute that the three cases presented by Hodak, Jones, and Ackerman show lesions that appear to be keratoacanthomas. However, it appears that these lesions biologically behaved as squamous cell carcinomas and, although indistinguishable by biopsy, these lesions (both the original biopsy and biopsy of the metastatic lesion) are squamous cell carcinomas. We do not believe that this means other lesions, which appear to be keratoacanthomas and behave in a benign fashion, are not keratoacanthomas. Despite the argument proposed by others, these three cases of squamous cell carcinoma with close histologic similarity to keratoacanthoma, but yet malignant behavior do not make all keratocanthomas a type of squamous cell carcinoma. Distinction has been difficult even from the first description of keratoacanthoma and continues to plague pathologists today. In 1955, Ereaux wrote: In accord with Marshall and Findlay we find it difficult to distinguish between these two conditions. In our reported case there are early lesions, which clinically and histologically fit perfectly with the description of keratoacanthoma even to the point of displaying the molluscum-like architecture that was described in the original paper by MacCormac and Scarff. However, we also find older lesions, which are clinically and histologically similar to the Ferguson Smith-type epitheliomas showing well-differentiated hyperplasia, some atypical cells, and a tendency towards invasiveness. These findings may easily be considered as those of squamous cell carcinoma, Grade 1, and in our case were so diagnosed by others.30 There have been attempts to find a way to differentiate keratoacanthoma from squamous cell carcinoma using modern techniques. These endeavors have not been met with great success.87 For instance, there have been efforts to show that the expression of p53 might differentiate the two conditions.85,99,100 However, even controls, such as pseudocarcinomatous hyperplasia, express p53, and it appears that the expression of p53 protein, mutant or wild-type, is an indicator of immaturity and the proliferative capacity of the cell, rather than one type of neoplasia or malignancy.100 Some studies have shown that overproduction of p53 is found in both keratoacanthomas and squamous cell carcinomas.87,99 Telomerase and cyclooxygenase-2 (COX-2) activities have also been shown to be increased in squamous cell carcinoma compared with keratoacanthoma, but the significance or reproducibility of this has yet to be determined.101 The expression of bcl-2, a proto-oncogene recog-

Seminars in Diagnostic Pathology, Vol 26, No 3, August 2009 nized to be involved in protecting cells from undergoing apoptosis, is diminished in keratoacanthomas when contrasted with squamous carcinomas, suggesting that keratoacanthoma, for unknown reasons, is programmed to involute,102 but one would hardly base a diagnosis on this parameter alone. The proliferation antigen, Ki-67, is likewise expressed in both types of lesions and will not serve to differentiate them.3,87,99 Other methods, such as immunohistochemical demonstration of desmosomal glycoproteins,103 VCAM and ICAM adhesion molecules,104 and syndecan-1 adhesion proteoglycan105 may be useful adjuncts, but are not definitive. As mentioned previously, the distinction between keratoacanthoma and squamous cell carcinoma is not merely a theoretic exercise, as treatment options may be approached differently. It is understandable that this controversy makes it difficult for the clinician attempting to find the best treatment for keratoacanthoma. Levy and coworkers concluded, “It is, therefore, necessary to correlate the clinical with the histopathologic features [in these lesion].”106 This is true especially in the residuum of cases where the distinction is not conclusive and the distinguishing histopathologic characteristics are difficult to find. Although we continue to propose that squamous cell carcinoma and keratoacanthoma are most often distinguishable and have different biological potential even in these lesions and thus prognosis, one cannot argue with the clinician who opts to excise these lesions. Some propose treating all keratoacanthomas as squamous carcinomas regardless of whether they are.31 In Ereaux’s publication, Weidman states: In short, operation can be withheld in those cases which(1) the lesion is a typical keratoacanthoma with a crater that is disproportionately large for a cancer; (2) is of such short duration as to discredit cancer; (3) is not located on the lip; and, (4) the dermatologist is willing to run the risk of one of the very rare instances in which cancer is a masquerader.”30 Conservative approach to these “borderline” lesions that may be “masqueraders” is not an unfounded approach in the current environment.

Conclusion We believe that keratoacanthoma is a useful diagnosis and, if made in a proper clinical context, is a service to the patient and to the clinician treating the patient. As Brown and Fryer objected to the term “self-healing epidermoid carcinoma” in 1955, we also believe that, if lesions that appear to be carcinomas histologically heal themselves, they probably are not carcinomas and the microscopic findings are not absolutely dependable.26,107,108 The distinction between keratoacanthoma and squamous cell carcinoma can be made with confidence most of the time, particularly if the dermatopathologist or pathologist is provided with an ade-

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quate clinical history and biopsy. The keratoacanthoma, which has been detailed and described since the late 1800s, behaves in a benign, self-involuting fashion. The evidence in the literature, which suggests differently, is not at this point substantial enough to change this historical perspective. The controversy continues as many consider whether keratoacanthoma is a sui generis self-limited, regressing epithelial neoplasm or a variant of squamous cell carcinoma. If this lesion represents a squamous cell carcinoma, one should wonder if it has the same biological potential, since most cutaneous squamous cell carcinomas follow a usual, nonmetastasizing clinical course. Also to be asked: Is the diagnosis of “squamous cell carcinoma, keratoacanthoma type” a bona fide diagnosis, or just a euphemism to avoid making a committed diagnosis of a benign neoplasm? We believe that lesions that end up metastasizing, although virtually indistinguishable by current methods of diagnosis, including light microscopy, were incorrectly diagnosed as keratoacanthoma, while they were, in fact, squamous cell carcinoma. Keratoacanthoma should continue to be classified as benign as the historical evidence and biological behavior of the entity still overwhelm the evidence to the contrary. We do not argue with conservative treatment and excision, especially in the context of difficult-todistinguish lesions. This is especially true until other advanced methods, including histochemical techniques, prove to make the distinction easier or until the keratoacanthoma as a squamous cell carcinoma opinion can further be elucidated. In the current legal climate, it is understandable why one might want to abandon the concept of keratoacanthoma, but we do not believe that this serves our patients well. In the vast majority of lesions, benign keratoacanthoma is a legitimate diagnosis, and one does not have to fear missing a malignant growth.

References 1. Rook A, Whimster IW: Le keratoacanthome. Arch Belg Dermatol Syphilol 6:137-146, 1950 2. Rook A, Whimster I: Keratoacanthoma—A thirty year retrospect. Br J Dermatol 100:41-47, 1979 3. Hodak E, Jones RE, Ackerman AB: Solitary keratoacanthoma is a squamous-cell carcinoma: Three examples with metastases. Am J Dermatopathol 15:332-342, discussion; 343-352, 1993 4. Alyahya GA, Heegaard S, Prause JU: Malignant changes in a giant orbital keratoacanthoma developing over 25 years. Acta Ophthalmol Scand 78:223-225, 2000 5. Gross DA: Metastasizing keratoacanthoma? Plast Reconstr Surg 63: 258-259, 1979 6. Grossniklaus HE, Wojno TH, Yanoff M, et al: Invasive keratoacanthoma of the eyelid and ocular adnexa. Ophthalmology 103:937-941, 1996 7. Goldenhersh MA, Olsen TG: Invasive squamous cell carcinoma initially diagnosed as a giant keratoacanthoma. J Am Acad Dermatol 10:372-378, 1984

161

8. Choonhakarn C, Ackerman AB: Keratoacanthomas: A new classification based on morphological findings. Dermatopathol Pract Conceptual 7, 2001 9. Hutchinson J: The crateriform ulcer of the face: A form of acute epithelial cancer. Trans Pathol Soc London 40:275-281, 1889 10. Gougerot H: Verrucome avec adenite, a structure epitheliomatiforme, curable par le 914. Arch Dermatol Syphiligr 1:374-385, 1929 11. Dupont A: Kyste sébaceé atypique. Bull Soc Belg Dermatol Syphiligr 177-179, 1930 12. Smith JF: A case of multiple primary squamous-celled carcinomata of the skin in a young man, with spontaneous healing. Br J Dermatol 46:267-272, 1934 13. Dunn JS, Ferguson-Smith J: Self-healing primary squamous carcinoma of the skin. Br J Dermat Syph 46:519-523, 1934 14. MacCormac H, Scarff RW: Molluscum sebaceum. Br J Dermatol 48:624-627, 1936 15. Poth DO: Tumor-like keratoses: Report of a case. Arch Dermatol Syphilol 39:228-238, 1939 16. Dupont A: Kystes sébacés végétans, kératoacanthomes, verrucomes. Bull Soc Fr Dermatolol Syphiligr 59:340, 1952 17. Halnan KE: Molluscum pseudocarcinomatosum. Lancet 265:1358, 1953 18. Marshall J, Pepler WJ: Mollusca pseudocarcinomatosa: Discussion of a case of the Ferguson-Smith type, of unilateral distribution. Br J Cancer 8:251-254, 1954 19. Winer LH: In discussion of papers of Binkely GW, Johnson HH, and Ereaux, et al. Arch Dermatol Forsch 71:66, 1955 20. Grinspan D, Abulafia J: Idiopathic cutaneous pseduoepitheliomatous hyperplasia. Cancer 8:1047-1056, 1955 21. Duany NP: Squamous cell pseudoepithelioma (keratoacanthoma): A new clinical variety, gigantic, multiple, and localized. AMA Arch Derm 78:703-709, 1958 22. Brothers WS, New WN, Nickel WR: Keratoacanthoma. A review of histopathological specimens previously diagnosed as keratoacanthoma or as squamous cell carcinoma of the skin. Arch Dermatol 81:369-372, 1960 23. Peterkin GA, Macmillan JB, Maclean S: Pseudocarcinoma of the skin. A follow-up of cases of keratoacanthoma seen in the 10 years 1951-60. Scott Med J 7:27-35, 1962 24. Rulon DB, Helwig EB: Cutaneous sebaceous neoplasm. Cancer 265: 82-102, 1974 25. Kwittken J: A histologic chronology of the clinical course of the keratocarcinoma (so-called keratoacanthoma). Mt Sinai J Med 42: 127-135, 1975 26. Pillsbury DM, Beerman H: Multiple keratoacanthoma. Am J Med Sci 236:614-624, 1958 27. Epstein NN, Biskind GR, Pollack RS: Multiple primary self-healing squamous-cell ‘epitheliomas’ of the skin. AMA Arch Derm 75:210223, 1957 28. Connors RC, Ackerman AB: Histologic pseudomalignancies of the skin. Arch Dermatol 112:1767-1780, 1976 29. Lloyd KM, Hall JH: Ferguson Smith’s syndrome of multiple keratoacanthoma. Cutis 5:1093-1097, 1969 30. Ereaux LP, Schopflocher P, Fournier CJ: Keratoacanthoma. AMA Arch Derm 71:73-83, 1955 31. Tobias N: Keratoacanthoma; differential diagnosis from squamouscell carcinoma of the skin. Mo Med 55:979-980, 1958 32. Kopf AW: Keratoacanthoma, in Andrade G, Popkin, Rees (eds): Cancer of the Skin: Biology, Diagnosis, Management. Philadelphia, PA, WB Saunders, 1976, pp 755-781 33. Whittle CH, Davis RA: Keratoacanthoma of lower-lip red margin. Lancet 272:1019-1020, 1957 34. Clendenning WE, Auerbach R: Keratoacanthomata in generalized pustular psoriasis. Acta Derm Venereol 43:68-75, 1963 35. Elschner H: [Molluscum pseudocarcinomatosum (keratoacanthoma) after trauma.] Hautarzt 7:368-369, 1956

162 36. Pattee SF, Silvis NG: Keratoacanthoma developing in sites of previous trauma: a report of two cases and review of the literature. J Am Acad Dermatol 48:S35-S38, 2003 (suppl) 37. Bruner JM: Keratoacanthoma. Plast Reconstr Surg 31:281-288, 1963 38. Haider S: Keratoacanthoma in a smallpox vaccination site. Br J Dermatol 90:689-690, 1974 39. Norgauer J, Rohwedder A, Schaller J: Human papillomavirus and Grzybowski’s generalized eruptive keratoacanthoma. J Am Acad Dermatol 49:771-772, 2003 40. Shamanin V, zur Hausen H, Lavergne D, et al: Human papillomavirus infections in nonmelanoma skin cancers from renal transplant recipients and nonimmunosuppressed patients. J Natl Cancer Inst 88:802-811, 1996 41. Saftic M, Batinac T, Zamolo G, et al: HPV 6-positive giant keratoacanthoma in an immunocompetent patient. Tumori 92:79-82, 2006 42. Forslund O, DeAngelis PM, Beigi M, et al: Identification of human papillomavirus in keratoacanthomas. J Cutan Pathol 30:423-429, 2003 43. Payne D, Newman C, Tyring S: Human papillomavirus DNA in nonanogenital keratoacanthoma and squamous cell carcinoma of patients with HIV infection. J Am Acad Dermatol 33:1047-1049, 1995 44. Stockfleth E, Meinke B, Arndt R, et al: Identification of DNA sequences of both genital and cutaneous HPV types in a small number of keratoacanthomas of nonimmunosuppressed patients. Dermatology 198:122-125, 1999 45. Hsi ED, Svoboda-Newman SM, Stern RA, et al: Detection of human papillomavirus DNA in keratoacanthomas by polymerase chain reaction. Am J Dermatopathol 19:10-15, 1997 46. Euvrard S, Chardonnet Y, Pouteil-Noble C, et al: Association of skin malignancies with various and multiple carcinogenic and noncarcinogenic human papillomaviruses in renal transplant recipients. Cancer 72:2198-2206, 1993 47. Moy RL, Quan MB: The presence of human papillomavirus type 16 in squamous cell carcinoma of the proximal finger and reconstruction with a bilobed transposition flap. J Dermatol Surg Oncol 17:171-175, 1991 48. Kawashima M, Favre M, Obalek S, et al: Premalignant lesions and cancers of the skin in the general population: Evaluation of the role of human papillomaviruses. J Invest Dermatol 95:537-542, 1990 49. Magee KL, Rapini RP, Duvic M, et al: Human papillomavirus associated with keratoacanthoma. Arch Dermatol 125:1587-1589, 1989 50. Trowell HE, Dyall-Smith ML, Dyall-Smith DJ: Human papillomavirus associated with keratoacanthomas in Australian patients. Arch Dermatol 126:1654, 1990 51. Scheurlen W, Gissmann L, Ikenberg H, et al: Molecular cloning of two new HPV types (HPV 37 and HPV 38) from a keratoacanthoma and a malignant melanoma. Int J Cancer 37:505-510, 1986 52. Gassenmaier A, Pfister H, Hornstein OP: Human papillomavirus 25-related DNA in solitary keratoacanthoma. Arch Dermatol Res 279:73-76, 1986 53. Hurt MA: Keratoacanthoma vs. squamous cell carcinoma in contrast with keratoacanthoma is squamous cell carcinoma. J Cutan Pathol 31:291-292, author reply 292-293, 2004 54. Korenberg R, Penneys NS, Kowalczyk A, et al: Quantitation of S100 protein-positive cells in inflamed and non-inflamed keratoacanthoma and squamous cell carcinoma. J Cutan Pathol 15:104-108, 1988 55. Stephenson TJ, Nichols CE, Cotton DWK: Keratoacanthomas contain a higher density of Langerhans’ cells than well differentiated squamous cell carcinomas. J Pathol 152:238A, 1987 56. Ghadially FN: The role of the hair follicle in origin and evolution of some cutaneous neoplasm in experimental animals. Cancer 14:801816, 1961 57. Wade TR, Ackerman AB: The many faces of keratoacanthomas. J Dermatol Surg Oncol 4:498-501, 1978 58. Dupont A: Kerato-acanthoma, cyst sebaceous vegetans; molluscum sebaceum. Ann Dermatol Syphiligr (Paris) 81:621-633, 1954

Seminars in Diagnostic Pathology, Vol 26, No 3, August 2009 59. Schwartz RA: Keratoacanthoma: a clinico-pathologic enigma. Dermatol Surg 30:326-333, 2004 60. Schwartz RA: Keratoacanthoma. J Am Acad Dermatol 30:1-19, quiz 20-22, 1994 61. Karaa A, Khachemoune A: Keratoacanthoma: A tumor in search of a classification. Int J Dermatol 46:671-678, 2007 62. Sullivan JJ: Keratoacanthoma: The Australian experience. Australas J Dermatol 38:S36-S39, 1997 (suppl 1) 63. Beham A, Regauer S, Soyer HP, et al: Keratoacanthoma: A clinically distinct variant of well differentiated squamous cell carcinoma. Adv Anat Pathol 5:269-280, 1998 64. Griffiths RW: Keratoacanthoma observed. Br J Plast Surg 57:485501, 2004 65. Seifert A, Nasemann T: [Keratoacanthoma and its clinical variants. Review of the literature and histopathologic analysis of 90 cases.] Hautarzt 40:189-202, 1989 66. Venkei T, Sugar J: [Keratoacanthoma of precarcinomatous character keratoacanthoma A and B.] Dermatol Wochenschr 138:957-965, 1958 67. Kern WH, McCray MK: The histopathologic differentiation of keratoacanthoma and squamous cell carcinoma of the skin. J Cutan Pathol 7:318-325, 1980 68. King DF, Barr RJ: Intraepithelial elastic fibers and intracytoplasmic glycogen: Diagnostic aids in differentiating keratoacanthoma from squamous cell carcinoma. J Cutan Pathol 7:140-148, 1980 69. Cooper PH, Wolfe JT III: Perioral keratoacanthomas with extensive perineural invasion and intravenous growth. Arch Dermatol 124: 1397-1401, 1988 70. Lapins NA, Helwig EB: Perineural invasion by keratoacanthoma. Arch Dermatol 116:791-793, 1980 71. Calonje E, Jones EW: Intravascular spread of keratoacanthoma. An alarming but benign phenomenon. Am J Dermatopathol 14:414-417, 1992 72. Dufresne RG, Marrero GM, Robinson-Bostom L: Seasonal presentation of keratoacanthomas in Rhode Island. Br J Dermatol 136:227229, 1997 73. Reed RJ: Actinic keratoacanthoma. Arch Dermatol 106:858-864, 1972 74. Allen CA, Stephens M, Steel WM: Subungual keratoacanthoma. Histopathology 25:181-183, 1994 75. Oliwiecki S, Peachey RD, Bradfield JW, et al: Subungual keratoacanthoma—A report of four cases and review of the literature. Clin Exp Dermatol 19:230-235, 1994 76. Stoll DM, Ackerman AB: Subungual keratoacanthoma. Am J Dermatopathol 2:265-271, 1980 77. Maruani A, Michenet P, Lagasse JP, et al: [Keratoacanthoma of the anal margin.] Gastroenterol Clin Biol 28:906-908, 2004 78. Freedman PD, Kerpel SM, Begel H, et al: Solitary intraoral keratoacanthoma. Report of a case. Oral Surg Oral Med Oral Pathol 47:74-76, 1979 79. Janette A, Pecaro B, Lonergan M, et al: Solitary intraoral keratoacanthoma: Report of a case. J Oral Maxillofac Surg 54:1026-1030, 1996 80. Miedzinski F, Kozakiewicz J: [Keratoacanthoma centrifugum—a special variety of keratoacanthoma.] Hautarzt 13:348-352, 1962 81. Schnitzler L, Schubert SB, Verret JL, et al: Épithéliomatose familiale de Ferguson-Smith. Ann Dermatol Venereol 104:206-216, 1977 82. Agarwal M, Chander R, Karmakar S, et al: Multiple familial keratoacanthoma of Witten and Zak—A report of three siblings. Dermatology 198:396-399, 1999 83. Grzbowski M: A case of peculiar generalized epithelial tumors of the skin. Br J Dermatol 62:310-313, 1950 84. Manstein CH, Frauenhoffer CJ, Besden JE: Keratoacanthoma: Is it a real entity? Ann Plast Surg 40:469-472, 1998 85. Cain CT, Niemann TH, Argenyi ZB: Keratoacanthoma versus squamous cell carcinoma. An immunohistochemical reappraisal of p53 protein and proliferating cell nuclear antigen expression in keratoacanthoma-like tumors. Am J Dermatopathol 17:324-331, 1995

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Keratoacanthoma: Hyperplasia, Neoplasm, Carcinoma?

86. Ledo E: Wart, keratoacanthoma, and squamous cell carcinoma: a spectrum of the same neoplastic process? Int J Dermatol 31:777-778, 1992 87. LeBoit PE: Is keratoacanthoma a variant of squamous cell carcinoma. New insights into an old controversy . . . soon? Am J Dermatopathol 17:319-320, 1995 88. Sullivan JJ, Colditz GA: Keratoacanthoma in a sub-tropical climate. Australas J Dermatol 20:34-40, 1979 89. Piscioli F, Boi S, Zumiani G, et al: A gigantic, metastasizing keratoacanthoma. Report of a case and discussion on classification. Am J Dermatopathol 6:123-129, 1984 90. Schnur PL, Bozzo P: Metastasizing keratoacanthomas? The difficulties in differentiating keratoacanthomas from squamous cell carcinomas. Plast Reconstr Surg 62:258-262, 1978 91. Caro WA, Pronstein BR: Tumors of the skin, in Moschella SL, Hurley HJ (eds): Dermatology. Philadelphia, PA, WB Saunders, 1985, p 1546 92. Mackie RM: Epidermal skin tumors, in Champion RH, Burton JL, Ebling EJG (eds): Rook/Wilkinson/Ebling Textbook of Dermatology. Oxford, Blackwell Scientific, 1992, pp 1465-1470 93. Poleksic S, Yeung KY: Rapid development of keratoacanthoma and accelerated transformation into squamous cell carcinoma of the skin: A mutagenic effect of polychemotherapy in a patient with Hodgkin’s disease? Cancer 41:12-16, 1978 94. Chalet MD, Connors RC, Ackerman AB: Squamous cell carcinoma vs. keratoacanthoma: Criteria for histologic differentiation. J Dermatol Surg 1:16-17, 1975 95. Ackerman AB: Histopathology of keratoacanthoma, in Andrade G, Popkin, Rees (eds): Cancer of the Skin: Biology, Diagnosis, Managment. Philadelphia, PA, WB Saunders, 1976, pp 781-796 96. Ackerman AB: Squamous-cell carcinoma vs. keratoacanthoma. J Dermatol Surg Oncol 8:418, 1982 97. Ackerman AB, Jacobson M, Vitale P: Clues to Diagnosis in Dermatology, vol 59. Chicago, ASCP Publishing, 1991

163

98. Schwartz RA: The keratoacanthoma: A review. J Surg Oncol 12:305317, 1979 99. Kerschmann RL, McCalmont TH, LeBoit PE: p53 oncoprotein expression and proliferation index in keratoacanthoma and squamous cell carcinoma. Arch Dermatol 130:181-186, 1994 100. Lee YS, Teh M: p53 expression in pseudoepitheliomatous hyperplasia, keratoacanthoma, and squamous cell carcinoma of skin. Cancer 73:2317-2323, 1994 101. Putti TC, Teh M, Lee YS: Biological behavior of keratoacanthoma and squamous cell carcinoma: Telomerase activity and COX-2 as potential markers. Mod Pathol 17:468-475, 2004 102. Sleater JP, Beers BB, Stephens CA, et al: Keratoacanthoma: A deficient squamous cell carcinoma? Study of Bcl-2 expression. J Cutan Pathol 21:514-519, 1994 103. Krunic AL, Garrod DR, Smith NP, et al: Differential expression of desmosomal glycoproteins in keratoacanthoma and squamous cell carcinoma of the skin: an immunohistochemical aid to diagnosis. Acta Derm Venereol 76:394-398, 1996 104. Melendez ND, Smoller BR, Morgan M: VCAM (CD-106) and ICAM (CD-54) adhesion molecules distinguish keratoacanthomas from cutaneous squamous cell carcinomas. Mod Pathol 16:8-13, 2003 105. Mukunyadzi P, Sanderson RD, Fan CY, et al: The level of syndecan-1 expression is a distinguishing feature in behavior between keratoacanthoma and invasive cutaneous squamous cell carcinoma. Mod Pathol 15:45-49, 2002 106. Levy EJ, Cahn MM, Shaffer B, et al: Keratoacanthoma. J Am Med Assoc 155:562-564, 1954 107. Brown JB, Fryer MP: Fallacy of term self-healing epidermoid carcinoma and limitations of microscopic interpretations. Surg Gynecol Obstet 100:179-183, 1955 108. Brown J, Fryer M: The limits and inadequacies of microscopic interpretation of tumors. Plast Reconstr Surg 16:23-30, 1955