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Keratoacanthoma: Facts and controversies
Clinics in Dermatology (2010) 28, 254–261
Keratoacanthoma: Facts and controversies Christine J. Ko, MD ⁎ Department of Dermatology, Yale University School of Medicine, 333 Cedar St, PO Box 208059, New Haven, CT 06520, USA
Abstract The keratoacanthoma and its variants are clinically and histologically heterogenous. Some consider the keratoacanthoma to be benign, whereas others classify it as a subtype of squamous cell carcinoma. The keratoacanthoma is generally treated rather than observed for spontaneous resolution. This hampers evaluation of the true natural history of lesions diagnosed as keratoacanthoma. In addition, studies have not found a reliable marker to differentiate keratoacanthoma from squamous cell carcinoma. It currently remains unclear how the keratoacanthoma relates to squamous cell carcinoma, and continued investigation is necessary. © 2010 Elsevier Inc. All rights reserved.
Introduction The keratoacanthoma (KA) is a fascinating tumor. The KA may present clinically as a solitary lesion or multiple lesions, in a sporadic fashion or in an inherited syndrome, or in association with inflammatory diseases. Histologically, the KA can have slightly different features depending on the clinical presentation. Some KAs may metastasize, and there is debate over the relationship to squamous cell carcinoma (SCC) and classification of KA as benign or malignant.
Clinical
although a broad range of ages has been reported.1 There is a male predominance.2 The clinical lesion, once well-developed, is a 1- to 2-cm firm, pink nodule with a stretched, shiny epidermis with a central crust/horn.1 The background normal skin may lack actinic keratoses.1,2 After several months, or sometimes longer, the lesion will regress spontaneously; however, local destruction and unacceptable scarring are possible. 2,4 Recurrence of 3% to 5% of KAs is also documented.2 There does not appear to be an increased incidence in internal malignancy in patients with solitary KAs.2 KAs have also been associated with other lesions like nevus sebaceus and inflammatory disorders.5
Solitary/sporadic
Variants
The KA is most often a solitary lesion with a clinical history of rapid growth over 4 to 5 weeks, with resolution after 6 months.1 KAs are generally located on sun-exposed skin of the face and arms1,2 in patients in their 40s to 60s,3
The giant KA is considered to be a lesion greater than 2 to 3 cm.6 KA centrifugum marginatum shows persistent peripheral growth with central scarring and may become very extensive.7,8 Subungual KAs may cause pain and local destruction; they are most often found on the thumb, index, and middle fingers.9 Mucosal KAs have been described.10 Subungual and mucosal KAs do not tend to regress.11
⁎ Tel.: +1 203 785 4094; fax: +1 203 785 6869. E-mail address: [email protected]. 0738-081X/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2009.06.010
Keratoacanthoma: Facts and controversies
255
Multiple/syndromic There are several disorders with multiple KAs (Table 1). Ferguson-Smith syndrome is seen predominantly in Scottish kindreds, although non-Scottish families with multiple selfhealing squamous epitheliomas have been described.12 Although a founder mutation that occurred before 1790 was suggested,13 this is unsupported by haplotype analysis in non-Scottish and Scottish families with an identical clinical phenotype.14 This syndrome has been mapped to a region on chromosome 9q22-q31,15,16 and the gene is thought to function as a tumor suppressor.17 Inheritance is autosomal dominant. These patients generally present through adolescence onward with lesions that tend to heal, sometimes with disfiguring scars; a patient may have only a few or up to a 100 lesions during his or her lifetime.18 Men and women are affected equally.13 Lesions tend to present on the head, neck, and extremities.13 Metastasis has not been reported.13,19 Multiple KAs of Grzybowski syndrome are diagnosed in patients with hundreds to thousands of eruptive 1- to 5-mm KAs presenting in the fifth to seventh decade, with a negative family history of such lesions.20 Progression of disease is associated with ectropion and a mask-like facies.21,22 Within this background of smaller lesions, larger nodular lesions like those of Ferguson-Smith may develop and show spontaneous regression with scar formation.23 Mucosal involvement and pruritus are common.23 In the Witten-Zak syndrome of multiple KAs, there are larger cherry-sized nodular, intermediate pea-sized, and smaller miliary lesions; a mask-like facies has not been described.24 Patients may present in childhood, and the syndrome may be inherited in an autosomal dominant fashion.25 Aside from Ferguson-Smith, Grzybowski, and WittenZak, multiple KAs are seen in other situations. They may be part of the Muir-Torre syndrome.26 Other authors have described multiple, noneruptive KAs, with a clinical course
Table 1
more similar to the Ferguson-Smith type, in patients with no family history.27,28 Multiple persistent KAs that do not involute have also been described,29 and they are perhaps better classified as SCCs.30 Multiple KAs were documented in a patient with deficient cell-mediated immunity.31 Finally, the subungual tumors that may develop in patients with incontinentia pigmenti have histologic features of KA.9 These tumors are a late feature of incontinentia pigmenti, and rapid growth is associated with secondary destruction of the underlying bone.32
Histology Histopathologic criteria have been suggested for the diagnosis of KA. Features of a typical KA include an exophytic-endophytic architecture with a central keratotic horn, overhanging epithelial lips, glassy keratinocytes, a surrounding polymorphonuclear infiltrate, intracytoplasmic glycogen, and intraepithelial elastic fibers.33-35 Eosinophilic or neutrophilic epithelial microabscesses, or both, may be present.4 Mitoses and atypical keratinocytes are generally not prominent.4 The tumor, in almost all cases, does not extend into the dermis to a depth below the eccrine glands.4 Perineural or vascular invasion, or both, may be seen,36,37 but these lesions retain a good prognosis.38 The regressing KA shows a more flattened base of the tumor epithelium with surrounding fibrosis.39 Histologic differences between the typical solitary KA and KAs in other settings have been documented (Table 2): • The large nodular tumors of Ferguson-Smith and WittenZak may extend down to the fat with a surrounding lymphocytic infiltrate, invade lymphatics, have a less well-developed central keratotic crater, and display smaller keratinocytes without a glassy appearance.19,24
Disorders with multiple keratoacanthomas
Disorder
Inheritance Genetic findings
FergusonSmith Grzybowski
AD
Witten-Zak Muir-Torre Incontinentia pigmenti
Sporadic
AD AD XLD
Xeroderma AR pigmentosum
Clinical characteristics
Mapped to 9q22-q31
1 to several nodules in succession; up to 100s in a lifetime; begin in adolescence None 1- to 5-mm follicular papules (100s to 1000s), eruptive and progressive, in adulthood; also larger nodules as in Ferguson-Smith that heal with scarring; ectropion, mask-like facies Unknown 1-5 mm follicular papules and larger nodules; begin in childhood Defect in mismatch repair genes Association of ≥1 sebaceous neoplasms or ≥1 KAs with internal malignancy Defect in NEMO gene Subungual tumors
Defect in nuclear excision repair genes
Initial Blaschkoid blisters to verrucous lesions to hyperpigmentation to eventual hypopigmentation Ocular, skeletal, central nervous system, hair/teeth findings Photodamage with early development of cutaneous cancers
AD, autosomal dominant; AR, autosomal recessive; KA, keratoacanthoma; NEMO, NF-κB essential modulator; XLD, X-linked dominant.
256 Table 2
C.J. Ko The solitary keratoacanthoma and comparison with accepted variants of keratoacanthoma
KA variant
Clinical
Histologic
Similarities to the solitary KA
Differences from the solitary KA
Solitary
Rapid growth to 1-2 cm Crateriform Sun-exposed skin Age: generally 40s to 60s Male N Female
Crateriform Glassy keratinocytes Epithelial lip Neutrophilic abscesses Infiltrate of neutrophils/ eosinophils Intraepithelial elastic fibers Generally does not extend below the eccrine glands Fibrosis Same as solitary
N/A
N/A
Spontaneous involution
Giant
N2-3 cm
Clinical and histologic Size similarity to solitary KA KA centrifugum Persistent peripheral growth with Advancing edge shows similar Clinical central involution Clinical morphology marginatum central involution or scarring features to the solitary KA and size Tends to be on the lower Histologic similarity of the extremities advancing edge to the solitary KA Subungual Tends to affect the thumb, Usually lacks a crateriform Histologic similarity of the glassy Does not involute index, and middle fingers shape keratinocytes that lack cytologic atypia to the solitary KA Not crateriform Slow growth with associated Few mitoses and atypical pain and bony destruction keratinocytes When multiple may be Glassy keratinocytes Prominent associated with disorders dyskeratotic cells with multiple KAs Many dyskeratotic cells Lacks fibrosis Mucosal When multiple may be Usually lacks a crateriform Histologic similarity of the glassy Does not involute associated with disorders shape keratinocytes that lack cytologic with multiple KAs atypia to the solitary KA Few mitoses and atypical Usually not keratinocytes crateriform Glassy keratinocytes Lymphoplasmacytic infiltrate Lymphoplasmacytic infiltrate Lacks fibrosis Ferguson-Smith See Table 1 Endophytic tumor of slightly Spontaneous involution Not crateriform basaloid keratinocytes Deep extension Keratinocytes not glassy Lymphocytic infiltrate Deep extension Lymphatic invasion Lymphocytic infiltrate Lymphatic invasion Grzybowski See Table 1 Nodules: similar to solitary KA Spontaneous involution of nodules Miliary lesions: follicular epidermal hyperplasia Witten-Zak See Table 1 Nodular lesions: like Ferguson- Spontaneous involution of Nodular lesions are Smith lesions of nodular lesions not crateriform and lack glassy keratinocytes Intermediate pea-sized lesions: epithelial hyperplasia with acantholysis Miliary lesions: follicular plugging and irregular follicular epithelial hyperplasia KA, keratoacanthoma; N/A, not applicable.
Keratoacanthoma: Facts and controversies • A well-developed nodule in Grzybowski syndrome will have typical features of a KA; however, the smaller miliary lesions may show only follicular epidermal hyperplasia.23 • The smaller miliary lesions of Witten-Zak showed irregular off-shoots of epithelium from follicles with follicular plugging. The intermediate-sized lesion of Witten-Zak displayed a down-growth of epithelium with apparent acantholysis of cells.24 • KAs associated with Muir-Torre syndrome sometimes have associated sebocytes.5 • Subungual KAs are not crateriform and have more dyskeratotic cells.9 Lack of staining with p53 and low expression of Ki67 are suggestive of subungual KA rather than subungual SCC.32 • Mucosal KAs may lack a crateriform architecture and tend to have a lymphoplasmacytic infiltrate.11
KA vs SCC In practice, there are tumors that are difficult to classify as either KA or SCC. Two examiners who studied 296 cases independently arrived at a consensual diagnosis of KA or SCC in 262. These 262 were then examined for different criteria, and no single criterion was found useful to clearly favor KA vs SCC, or vice versa. Helpful criteria for the diagnosis of a KA included epithelial lip, sharp outline between tumor and stroma, and ulceration. Criteria more commonly seen in SCCs included numerous mitoses and marked cellular pleomorphism.40 In a study of 100 KAs and 100 SCCs, 81% of KAs and 86% of SCCs could be diagnosed using common criteria. The remainder showed conflicting features, such as a generally crateriform architecture with prominent nuclear atypia at the borders of the tumor.41 Because differentiating some cases of KA from welldifferentiated SCC can be quite challenging on routine histologic sections, numerous studies have attempted to resolve this quandary. Many authors have looked at markers of epidermal differentiation and of intercellular adhesion. Filaggrin staining is much more likely to be present in KAs than SCCs,42 although another study did not confirm this.43 Fully developed KAs express vascular cell adhesion molecule and intercellular adhesion molecule, whereas SCCs seem to only focally express these markers. 44 Syndecan-1, a mediator of intercellular and cell to matrix adhesion,45 and E-cadherin 46,47 are more highly expressed in KAs than invasive SCCs. The desmoglein staining pattern of KAs is similar to healthy epidermis.48,49 KAs express involucrin and keratins 5 and 14 in a similar pattern to the outer root sheath below the follicular infundibulum.50 βCatenin is expressed more strongly in SCCs.47,51 The presence of H blood group antigens favors KA over SCC.52 KAs express transforming growth factor-α diffusely.53 Overall, these studies suggest that KA has a pattern of differentiation that is different from SCC.
257 Cell cycle markers, growth factors, and apoptosis regulatory proteins have been studied in KAs and SCCs. Silver-stained organizer regions, when seen in tissue sections, are suggestive of cell proliferation, and SCCs have an increased number of these regions compared with KAs.54 This is in agreement with studies showing obvious Ki67 expression in SCCs.55,56 KAs have lower bcl-2 expression57,58 and p53 expression compared with SCCs. Taken as a whole, SCCs are more proliferative, with increased expression of antiapoptotic markers compared with well-developed KAs. Studies that have not shown differences between KAs and SCCs abound. Flow cytometry of the DNA index and the proliferative index showed no statistical differences between KAs and SCCs.59 DNA image cytometry also does not differentiate them.60 Expression of β-2-microglobulin61 and p1662 are similar in both tumors. Stromelysin-3 tends to stain the stroma around SCCs only slightly more than KAs.63 Staining of expression of cyclins, cyclin-dependent kinases,64 and oncostatin M65 are similar in SCCs and KAs. No marker has yet been found that will differentiate KAs and SCCs with high sensitivity and specificity. Nonetheless, because many of these studies compared a small number of KAs and SCCs, it is possible that they lacked sufficient power to detect a true difference. With a smaller number of tumors, misclassification of one or more tumors as a KA or as a SCC could also have had a marked effect on the results. Confounding these issues are reports of tumors with classic histologic features of a KA and a clinical history of rapid growth that have metastasized.66,67 Some authors believe the KA is a subtype of SCC,11 whereas others suggest the KA is a precursor lesion to SCC.4 In practice, the recommendation is that KAs be treated rather than observed in order to prevent potential aggressive behavior68-70 and significant scarring.6 From a practical point of view, therefore, the distinction between a KA and SCC does not necessarily have a profound effect on management. Regression has been suggested as the gold standard for the diagnosis of a KA.71 Both KAs and SCCs may grow rapidly and have a crateriform architecture. There may be more similarities than differences histologically, particularly when comparing the growth phase of KAs and SCCs.71 Because clinical and histologic features may be misleading, a tumor with a suspected diagnosis of KA, clinically or histologically, or both, could be monitored for 1 month. If the tumor shows signs of regression, it may be more definitively classified as a KA.71 Alternatively, if the lesion has grown larger or is unchanged, the tumor is more likely a SCC, and treatment may be initiated.71
Pathogenesis What are the mechanisms that induce KAs? Different theories have been proposed. Some authors have found human papilloma virus infection in KAs,72-74 but others have
258 not.75 Most KAs are found on sun-exposed skin, and there likely is some relationship to exposure to ultraviolet radiation.2,76 Carcinogens like tar have been implicated,77 and trauma may also be an inciting factor.1,78 There are several reports of KAs arising in a background of a tattoo.79-81 It is unclear whether the trauma from the tattoo or possibly the tattoo dye is related to tumor formation. KAs also may arise in other tumors or inflammatory dermatoses.5 Comparative genomic hybridization suggests that different genetic mechanisms underlie KAs and SCCs. KAs more frequently show loss from 9p,82 whereas gains from 1p, 14q, 16q, and 20q and loss from 4p are more common in SCCs.83 Trisomy 7 has been identified in KAs.84 On the molecular level in a mouse model of carcinogenesis, increased p53 expression in the basal layer of the skin released inhibition of p21waf, leading to increased keratinocyte differentiation and the formation of highly differentiated KAs.85
Mechanisms of regression The controversy about classification of the KA sometimes overshadows the documented potential of the KA to regress. A dense infiltrate of CD8-positive T cells has been documented at the base of KAs,86,87 which means cytotoxic T cells may have an effect in the regression of KAs. The cytotoxic T cells may mediate regression through release of granzyme B.87 KAs also have a greater number of intratumoral CD3-positive and interleukin-2 receptor-expressing CD4-positive lymphocytes than SCCs.87,88 Langerhans cells and CD30-positive cells are increased in inflamed KAs.89,90 Although there is some evidence for an immunologic basis to regression in KAs, regression may be nonimmunologic.91 A rabbit model of KAs suggested against immunologic regression. 92 In KAs, the keratinocytes express markers of initiation of apoptosis as well as end-stage markers of apoptosis in the same cells that are proliferating.46 Regressing KAs express p27, an inhibitor of a variety of cyclin-dependent kinases, 93 and Le(Y), an antigen related to apoptosis.94 Thus, triggering of keratinocyte apoptosis may have an effect in regression.7 A follicular origin of the KA has been proposed.24,95 The KA may be derived from the outer root sheath below the infundibulum, a portion of the follicle that undergoes regression and regrowth as part of the normal hair cycle.50 The ability of the KA to regress could be related to the mechanisms that underlie normal hair cycling.
Classification: Benign or malignant? Considered by some to be benign,4 others believe that the KA is unequivocally a subtype of SCC.11 This debate is difficult to resolve because the separation of benign and malignant is not always clear. Criteria that are often advanced
C.J. Ko to support a malignant lesion are (1) metastasis; (2) aggressive clinical behavior apart from metastasis, that is, local recurrence/destruction on the clinical side; (3) abnormal cytology of cells; (4) vascular or perineural invasion, or both; (5) highly infiltrative growth pattern; and (6) high proliferative index with or without necrosis on histopathologic evaluation. Lesions that are benign generally lack all or most of these criteria. The KA does occasionally metastasize.66 Solitary KAs may grow quite rapidly and lead to local pain and destruction. Giant KAs or KA centrifugum marginatum, or both, often grow very extensively and may not regress.6-8 Vascular and perineural invasion may be seen, and when extensive, would certainly qualify as an infiltrative growth pattern. Logically, KAs in their growth phase are mitotically active. There are numerous reasons to classify the KA as a malignant tumor or a subtype of SCC. Why, then, do some argue vehemently against this? In the strictest definition, the KA does not display prominent mitoses or cytologic atypia. Most KAs do not metastasize and even may regress spontaneously. Spontaneous regression would seem to be a polar opposite to aggressive clinical behavior, and KAs that display prominent vascular/perineural invasion may also regress. Although the ability for lymphomatoid papulosis to resolve spontaneously caused it to be classified as a benign process for many years, it is now considered a lymphoma in the 2005 World Health Organization European Organization for Research and Treatment of Cancer Classification of cutaneous lymphomas.96 Thus, even spontaneous resolution in itself is not universally considered a sign of benignancy. It is standard practice to treat KAs rather than monitor them for spontaneous resolution.70 Many dermatopathologists give a diagnosis of SCC, KA type (or some such variation). A diagnosis of “squamous cell carcinoma” undoubtedly is more tangible to most patients compared with an explanation of the relevant characteristics of KA. In sum, classification may be more of an academic question without clinical relevance at this time.
Conclusions There is no simple answer on how to pigeon hole the KA, the variants of which are heterogeneous clinically and histologically (Table 2). Expert opinions are divided, with some classifying the KA as a subtype of SCC66 and others considering it a separate entity that may progress to SCC.4 Because most KAs do have a good prognosis with conservative treatment and the diagnosis of multiple KAs has relevance for genetic syndromes like Muir-Torre, it is useful to continue to use and include the term “keratoacanthoma” for lesions with a compatible clinical history and histopathology. Until a reliable method for distinguishing the KA from SCC is established, however, patients are likely best served by regarding KA as a subtype of SCC in terms of
Keratoacanthoma: Facts and controversies treatment and management.97 Despite this, I emphasize that this classification is specifically for optimal patient care and should not prevent further investigation into the nature of KA. Continued study of this fascinating tumor may lead to more satisfactory answers.
References 1. Rook A, Whimster I. Keratoacanthoma—a thirty year retrospect. Br J Dermatol 1979;100:41-7. 2. Kingman J, Callen JP. Keratoacanthoma. A clinical study. Arch Dermatol 1984;120:736-40. 3. Sarabi K, Selim A, Khachemoune A. Sporadic and syndromic keratoacanthomas: diagnosis and management. Dermatol Nurs 2007; 19:166-70. 4. Weedon D. Skin pathology. 2nd ed. London: Churchill Livingstone; 2002. 5. Schwartz RA. Keratoacanthoma. J Am Acad Dermatol 1994;30:1-19 [quiz 20-2]. 6. Rapaport J. Giant keratoacanthoma of the nose. Arch Dermatol 1975; 111:73-5. 7. Weedon D, Barnett L. Keratoacanthoma centrifugum marginatum. Arch Dermatol 1975;111:1024-6. 8. Eliezri YD, Libow L. Multinodular keratoacanthoma. J Am Acad Dermatol 1988;19:826-30. 9. Baran R, Goettmann S. Distal digital keratoacanthoma: a report of 12 cases and a review of the literature. Br J Dermatol 1998;139:512-5. 10. Habel G, O'Regan B, Eissing A, et al. Intra-oral keratoacanthoma: an eruptive variant and review of the literature. Br Dent J 1991;170:336-9. 11. Choonhakarn C, Ackerman AB. Keratoacanthomas: a new classification based on morphologic findings and on anatomic site. Dermatopathol Pract Concept 2001;7:7-16. 12. Broesby-Olsen S, Bygum A, Gerdes AM, et al. Multiple self-healing squamous epithelioma of Ferguson-Smith: observations in a Danish family covering four generations. Acta Derm Venereol 2008;88:52-6. 13. Ferguson-Smith MA, Wallace DC, James ZH, et al. Multiple selfhealing squamous epithelioma. Birth Defects Orig Artic Ser 1971;7: 157-63. 14. D'Alessandro M, Coats SE, Morley SM, et al. Multiple self-healing squamous epithelioma in different ethnic groups: more than a founder mutation disorder? J Invest Dermatol 2007;127:2336-44. 15. Goudie DR, Yuille MA, Leversha MA, et al. Multiple self-healing squamous epitheliomata (ESS1) mapped to chromosome 9q22-q31 in families with common ancestry. Nat Genet 1993;3:165-9. 16. Richards FM, Goudie DR, Cooper WN, et al. Mapping the multiple self-healing squamous epithelioma (MSSE) gene and investigation of xeroderma pigmentosum group A (XPA) and PATCHED (PTCH) as candidate genes. Hum Genet 1997;101:317-22. 17. Bose S, Morgan LJ, Booth DR, et al. The elusive multiple self-healing squamous epithelioma (MSSE) gene: further mapping, analysis of candidates, and loss of heterozygosity. Oncogene 2006;25:806-12. 18. Alexander JO, Lyell A. Multiple keratoacanthomas. J Am Acad Dermatol 1985;12:376-7. 19. Jackson IT, Alexander JO, Verheyden CN. Self-healing squamous epithelioma: a family affair. Br J Plast Surg 1983;36:22-8. 20. Grzybowski M. A case of peculiar generalized epithelial tumours of the skin. Br J Dermatol Syphilol 1950;62:310-3. 21. Consigli JE, Gonzalez ME, Morsino R, et al. Generalized eruptive keratoacanthoma (Grzybowski variant). Br J Dermatol 2000;142:800-3. 22. Haas N, Schadendorf D, Henz BM, et al. Nine-year follow-up of a case of Grzybowski type multiple keratoacanthomas and failure to demonstrate human papillomavirus. Br J Dermatol 2002;147:793-6. 23. Winkelmann RK, Brown J. Generalized eruptive keratoacanthoma. Report of cases. Arch Dermatol 1968;97:615-23.
259 24. Witten VH, Zak FG. Multiple, primary, self-healing prickle-cell epithelioma of the skin. Cancer 1952;5:539-50. 25. Agarwal M, Chander R, Karmakar S, et al. Multiple familial keratoacanthoma of Witten and Zak—a report of three siblings. Dermatology 1999;198:396-9. 26. Muir EG, Bell AJ, Barlow KA. Multiple primary carcinomata of the colon, duodenum, and larynx associated with kerato-acanthomata of the face. Br J Surg 1967;54:191-5. 27. Feldman RJ, Maize JC. Multiple keratoacanthomas in a young woman: report of a case emphasizing medical management and a review of the spectrum of multiple keratoacanthomas. Int J Dermatol 2007;46:77-9. 28. Benoldi D, Alinovi A. Multiple persistent keratoacanthomas: treatment with oral etretinate. J Am Acad Dermatol 1984;10:1035-8. 29. Schwartz RA. Multiple persistent keratoacanthomas. Oncology 1979; 36:281-5. 30. Affleck AG. Multiple persistent keratoacanthomas. Int J Dermatol 2007;46:1105. 31. Claudy A, Thivolet J. Multiple keratoacanthomas: association with deficient cell mediated immunity. Br J Dermatol 1975;93:593-5. 32. Connolly M, Narayan S, Oxley J, de Berker DA. Immunohistochemical staining for the differentiation of subungual keratoacanthoma from subungual squamous cell carcinoma. Clin Exp Dermatol 2008;33:625-8. 33. Chalet MD, Connors RC, Ackerman AB. Squamous cell carcinoma vs. keratoacanthoma: criteria for histologic differentiation. J Dermatol Surg 1975;1:16-7. 34. King DF, Barr RJ. Intraepithelial elastic fibers and intracytoplasmic glycogen: diagnostic aids in differentiating keratoacanthoma from squamous cell carcinoma. J Cutan Pathol 1980;7:140-8. 35. Skirpan P, Haserick JR. Keratoacanthoma; histopathologic criteria for diagnosis. Cleve Clin Q 1954;21:153-7. 36. Lapins NA, Helwig EB. Perineural invasion by keratoacanthoma. Arch Dermatol 1980;116:791-3. 37. Calonje E, Jones EW. Intravascular spread of keratoacanthoma. An alarming but benign phenomenon. Am J Dermatopathol 1992;14:414-7. 38. Godbolt AM, Sullivan JJ, Weedon D. Keratoacanthoma with perineural invasion: a report of 40 cases. Australas J Dermatol 2001;42:168-71. 39. Blessing K, al Nafussi A, Gordon PM. The regressing keratoacanthoma. Histopathology 1994;24:381-4. 40. Cribier B, Asch P, Grosshans E. Differentiating squamous cell carcinoma from keratoacanthoma using histopathological criteria. Is it possible? A study of 296 cases. Dermatology 1999;199:208-12. 41. Kern WH, McCray MK. The histopathologic differentiation of keratoacanthoma and squamous cell carcinoma of the skin. J Cutan Pathol 1980;7:318-25. 42. Klein-Szanto AJ, Barr RJ, Reiners Jr JJ, et al. Filaggrin distribution in keratoacanthomas and squamous cell carcinoma. Arch Pathol Lab Med 1984;108:888-90. 43. Ito Y, Kurokawa I, Nishimura K, et al. Keratin and filaggrin expression in keratoacanthoma. J Eur Acad Dermatol Venereol 2008;22:353-5. 44. Melendez ND, Smoller BR, Morgan M. VCAM (CD-106) and ICAM (CD-54) adhesion molecules distinguish keratoacanthomas from cutaneous squamous cell carcinomas. Mod Pathol 2003;16:8-13. 45. 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 2002;15:45-9. 46. Slater M, Barden JA. Differentiating keratoacanthoma from squamous cell carcinoma by the use of apoptotic and cell adhesion markers. Histopathology 2005;47:170-8. 47. Papadavid E, Pignatelli M, Zakynthinos S, et al. The potential role of abnormal E-cadherin and alpha-, beta- and gamma-catenin immunoreactivity in the determination of the biological behaviour of keratoacanthoma. Br J Dermatol 2001;145:582-9. 48. Krunic AL, Garrod DR, Madani S, et al. Immunohistochemical staining for desmogleins 1 and 2 in keratinocytic neoplasms with squamous phenotype: actinic keratosis, keratoacanthoma and squamous cell carcinoma of the skin. Br J Cancer 1998;77:1275-9.
260 49. 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 1996;76:394-8. 50. Ichikawa E, Ohnishi T, Watanabe S. Expression of keratin and involucrin in keratoacanthoma: an immunohistochemical aid to diagnosis. J Dermatol Sci 2004;34:115-7. 51. Tataroglu C, Karabacak T, Apa DD. Beta-catenin and CD44 expression in keratoacanthoma and squamous cell carcinoma of the skin. Tumori 2007;93:284-9. 52. Schaumburg-Lever G, Gavris V, Lever WF, et al. Cell-surface carbohydrates in proliferative epidermal lesions. Distribution of A, B, and H blood group antigens in benign and malignant lesions. Am J Dermatopathol 1984;6:583-9. 53. Ho T, Horn T, Finzi E. Transforming growth factor alpha expression helps to distinguish keratoacanthomas from squamous cell carcinomas. Arch Dermatol 1991;127:1167-71. 54. Aroni K, Mastoraki A, Kyriazi E, et al. Silver-stained organizer regions and immunoglobulins in cutaneous keratoacanthomas and squamous cell carcinomas. Pathol Res Pract 2007;203:659-65. 55. Basta-Juzbasic A, Klenkar S, Jakic-Razumovic J, et al. Cytokeratin 10 and Ki-67 nuclear marker expression in keratoacanthoma and squamous cell carcinoma. Acta Dermatovenerol Croat 2004;12:251-6. 56. Biesterfeld S, Josef J. Differential diagnosis of keratoacanthoma and squamous cell carcinoma of the epidermis by MIB-1 immunohistometry. Anticancer Res 2002;22:3019-23. 57. Batinac T, Zamolo G, Coklo M, et al. Expression of cell cycle and apoptosis regulatory proteins in keratoacanthoma and squamous cell carcinoma. Pathol Res Pract 2006;202:599-607. 58. Sleater JP, Beers BB, Stephens CA, et al. Keratoacanthoma: a deficient squamous cell carcinoma? Study of bcl-2 expression. J Cutan Pathol 1994;21:514-9. 59. Randall MB, Geisinger KR, Kute TE, et al. DNA content and proliferative index in cutaneous squamous cell carcinoma and keratoacanthoma. Am J Clin Pathol 1990;93:259-62. 60. Herzberg AJ, Kerns BJ, Pollack SV, et al. DNA image cytometry of keratoacanthoma and squamous cell carcinoma. J Invest Dermatol 1991;97:495-500. 61. Graham RM, MacFarlane AW, Curley RK, et al. Beta 2 microglobulin expression in keratoacanthomas and squamous cell carcinoma. Br J Dermatol 1987;117:441-9. 62. Kaabipour E, Haupt HM. Stern JB, et al. p16 expression in keratoacanthomas and squamous cell carcinomas of the skin: an immunohistochemical study. Arch Pathol Lab Med 2006;130:69-73. 63. Asch PH, Basset P, Roos M, et al. Expression of stromelysin 3 in keratoarcanthoma and squamous cell carcinoma. Am J Dermatopathol 1999;21:146-50. 64. Tran TA, Ross JS, Boehm JR, et al. Comparison of mitotic cyclins and cyclin-dependent kinase expression in keratoacanthoma and squamous cell carcinoma. J Cutan Pathol 1999;26:391-7. 65. Tran TA, Ross JS, Sheehan CE, et al. Comparison of oncostatin M expression in keratoacanthoma and squamous cell carcinoma. Mod Pathol 2000;13:427-32. 66. Hodak E, Jones RE, Ackerman AB. Solitary keratoacanthoma is a squamous-cell carcinoma: three examples with metastases. Am J Dermatopathol 1993;15:332-42 [discussion 43-52]. 67. Jackson IT. Diagnostic problem of keratoacanthoma. Lancet 1969;1: 490-2. 68. Fisher ER, McCoy 2nd MM, Wechsler HL. Analysis of histopathologic and electron microscopic determinants of keratoacanthoma and squamous cell carcinoma. Cancer 1972;29:1387-97. 69. 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 1960;81: 369-72. 70. Cohen N, Plaschkes Y, Pevzner S, et al. Review of 57 cases of keratoacanthoma. Plast Reconstr Surg 1972;49:138-42.
C.J. Ko 71. Magalhaes RF, Cruvinel GT, Cintra GF, et al. Diagnosis and follow-up of keratoacanthoma-like lesions: clinical-histologic study of 43 cases. J Cutan Med Surg 2008;12:163-73. 72. Forslund O, DeAngelis PM, Beigi M, et al. Identification of human papillomavirus in keratoacanthomas. J Cutan Pathol 2003; 30:423-9. 73. Trowell HE, Dyall-Smith ML, Dyall-Smith DJ. Human papillomavirus associated with keratoacanthomas in Australian patients. Arch Dermatol 1990;126:1654. 74. Magee KL, Rapini RP, Duvic M, et al. Human papillomavirus associated with keratoacanthoma. Arch Dermatol 1989;125:1587-9. 75. Viviano E, Sorce M, Mantegna M. Solitary keratoacanthomas in immunocompetent patients: no detection of papillomavirus DNA by polymerase chain reaction. New Microbiol 2001;24:295-7. 76. Dufresne RG, Marrero GM, Robinson-Bostom L. Seasonal presentation of keratoacanthomas in Rhode Island. Br J Dermatol 1997;136: 227-9. 77. Letzel S, Drexler H. Occupationally related tumors in tar refinery workers. J Am Acad Dermatol 1998;39:712-20. 78. Sullivan JJ, Donoghue MF, Kynaston B, et al. Multiple keratoacanthomas: report of four cases. Australas J Dermatol 1980;21:16-24. 79. Goldenberg G, Patel S, Patel MJ, et al. Eruptive squamous cell carcinomas, keratoacanthoma type, arising in a multicolor tattoo. J Cutan Pathol 2008;35:62-4. 80. Kluger N, Minier-Thoumin C, Plantier F. Keratoacanthoma occurring within the red dye of a tattoo. J Cutan Pathol 2008;35:504-7. 81. Chorny JA, Stephens FV, Cohen JL. Eruptive keratoacanthomas in a new tattoo. Arch Dermatol 2007;143:1457-8. 82. Clausen OP, Beigi M, Bolund L, et al. Keratoacanthomas frequently show chromosomal aberrations as assessed by comparative genomic hybridization. J Invest Dermatol 2002;119:1367-72. 83. Clausen OP, Aass HC, Beigi M, et al. Are keratoacanthomas variants of squamous cell carcinomas? A comparison of chromosomal aberrations by comparative genomic hybridization. J Invest Dermatol 2006;126: 2308-15. 84. Cheville JC, Bromley C, Argenyi ZB. Trisomy 7 in keratoacanthoma and squamous cell carcinoma detected by fluorescence in-situ hybridization. J Cutan Pathol 1995;22:546-50. 85. Yao D, Alexander CL, Quinn JA, et al. Fos cooperation with PTEN loss elicits keratoacanthoma not carcinoma, owing to p53/p21 WAF-induced differentiation triggered by GSK3beta inactivation and reduced AKT activity. J Cell Sci 2008;121:1758-69. 86. Bayer-Garner IB, Ivan D, Schwartz MR, et al. The immunopathology of regression in benign lichenoid keratosis, keratoacanthoma and halo nevus. Clin Med Res 2004;2:89-97. 87. Batinac T, Zamolo G, Hadzisejdic I, et al. A comparative study of granzyme B expression in keratoacanthoma and squamous cell carcinoma. J Dermatol Sci 2006;44:109-12. 88. Patel A, Halliday GM, Cooke BE, et al. Evidence that regression in keratoacanthoma is immunologically mediated: a comparison with squamous cell carcinoma. Br J Dermatol 1994;131:789-98. 89. 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 1988;15: 104-8. 90. Fernandez-Flores A. CD30+ cell population in common keratoacanthomas: a study of 21 cases. Rom J Morphol Embryol 2008;49: 159-62. 91. Stone OJ. Non-immunologic enhancement and regression of selfhealing squamous cell carcinoma (keratoacanthoma)—ground substance and inflammation. Med Hypotheses 1988;26:113-7. 92. Ramselaar CG, van der Meer JB. Non-immunological regression of dimethylbenz(A) anthracene-induced experimental keratoacanthomas in the rabbit. Dermatologica 1979;158:142-51. 93. Hu W, Cook T, Oh CW, et al. Expression of the cyclin-dependent kinase inhibitor p27 in keratoacanthoma. J Am Acad Dermatol 2000; 42:473-5.
Keratoacanthoma: Facts and controversies 94. Tsuji T. Keratoacanthoma and squamous cell carcinoma: study of PCNA and Le(Y) expression. J Cutan Pathol 1997;24:409-15. 95. Kossard S, Tan KB, Choy C. Keratoacanthoma and infundibulocystic squamous cell carcinoma. Am J Dermatopathol 2008;30:127-34.
261 96. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005;105:3768-85. 97. Canas GC, Robson KJ, Arpey CJ. Persistent keratoacanthoma: challenges in management. Dermatol Surg 1998;24:1364-9.
Keratoacanthoma: Facts and controversies Christine J. Ko, MD ⁎ Department of Dermatology, Yale University School of Medicine, 333 Cedar St, PO Box 208059, New Haven, CT 06520, USA
Abstract The keratoacanthoma and its variants are clinically and histologically heterogenous. Some consider the keratoacanthoma to be benign, whereas others classify it as a subtype of squamous cell carcinoma. The keratoacanthoma is generally treated rather than observed for spontaneous resolution. This hampers evaluation of the true natural history of lesions diagnosed as keratoacanthoma. In addition, studies have not found a reliable marker to differentiate keratoacanthoma from squamous cell carcinoma. It currently remains unclear how the keratoacanthoma relates to squamous cell carcinoma, and continued investigation is necessary. © 2010 Elsevier Inc. All rights reserved.
Introduction The keratoacanthoma (KA) is a fascinating tumor. The KA may present clinically as a solitary lesion or multiple lesions, in a sporadic fashion or in an inherited syndrome, or in association with inflammatory diseases. Histologically, the KA can have slightly different features depending on the clinical presentation. Some KAs may metastasize, and there is debate over the relationship to squamous cell carcinoma (SCC) and classification of KA as benign or malignant.
Clinical
although a broad range of ages has been reported.1 There is a male predominance.2 The clinical lesion, once well-developed, is a 1- to 2-cm firm, pink nodule with a stretched, shiny epidermis with a central crust/horn.1 The background normal skin may lack actinic keratoses.1,2 After several months, or sometimes longer, the lesion will regress spontaneously; however, local destruction and unacceptable scarring are possible. 2,4 Recurrence of 3% to 5% of KAs is also documented.2 There does not appear to be an increased incidence in internal malignancy in patients with solitary KAs.2 KAs have also been associated with other lesions like nevus sebaceus and inflammatory disorders.5
Solitary/sporadic
Variants
The KA is most often a solitary lesion with a clinical history of rapid growth over 4 to 5 weeks, with resolution after 6 months.1 KAs are generally located on sun-exposed skin of the face and arms1,2 in patients in their 40s to 60s,3
The giant KA is considered to be a lesion greater than 2 to 3 cm.6 KA centrifugum marginatum shows persistent peripheral growth with central scarring and may become very extensive.7,8 Subungual KAs may cause pain and local destruction; they are most often found on the thumb, index, and middle fingers.9 Mucosal KAs have been described.10 Subungual and mucosal KAs do not tend to regress.11
⁎ Tel.: +1 203 785 4094; fax: +1 203 785 6869. E-mail address: [email protected]. 0738-081X/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2009.06.010
Keratoacanthoma: Facts and controversies
255
Multiple/syndromic There are several disorders with multiple KAs (Table 1). Ferguson-Smith syndrome is seen predominantly in Scottish kindreds, although non-Scottish families with multiple selfhealing squamous epitheliomas have been described.12 Although a founder mutation that occurred before 1790 was suggested,13 this is unsupported by haplotype analysis in non-Scottish and Scottish families with an identical clinical phenotype.14 This syndrome has been mapped to a region on chromosome 9q22-q31,15,16 and the gene is thought to function as a tumor suppressor.17 Inheritance is autosomal dominant. These patients generally present through adolescence onward with lesions that tend to heal, sometimes with disfiguring scars; a patient may have only a few or up to a 100 lesions during his or her lifetime.18 Men and women are affected equally.13 Lesions tend to present on the head, neck, and extremities.13 Metastasis has not been reported.13,19 Multiple KAs of Grzybowski syndrome are diagnosed in patients with hundreds to thousands of eruptive 1- to 5-mm KAs presenting in the fifth to seventh decade, with a negative family history of such lesions.20 Progression of disease is associated with ectropion and a mask-like facies.21,22 Within this background of smaller lesions, larger nodular lesions like those of Ferguson-Smith may develop and show spontaneous regression with scar formation.23 Mucosal involvement and pruritus are common.23 In the Witten-Zak syndrome of multiple KAs, there are larger cherry-sized nodular, intermediate pea-sized, and smaller miliary lesions; a mask-like facies has not been described.24 Patients may present in childhood, and the syndrome may be inherited in an autosomal dominant fashion.25 Aside from Ferguson-Smith, Grzybowski, and WittenZak, multiple KAs are seen in other situations. They may be part of the Muir-Torre syndrome.26 Other authors have described multiple, noneruptive KAs, with a clinical course
Table 1
more similar to the Ferguson-Smith type, in patients with no family history.27,28 Multiple persistent KAs that do not involute have also been described,29 and they are perhaps better classified as SCCs.30 Multiple KAs were documented in a patient with deficient cell-mediated immunity.31 Finally, the subungual tumors that may develop in patients with incontinentia pigmenti have histologic features of KA.9 These tumors are a late feature of incontinentia pigmenti, and rapid growth is associated with secondary destruction of the underlying bone.32
Histology Histopathologic criteria have been suggested for the diagnosis of KA. Features of a typical KA include an exophytic-endophytic architecture with a central keratotic horn, overhanging epithelial lips, glassy keratinocytes, a surrounding polymorphonuclear infiltrate, intracytoplasmic glycogen, and intraepithelial elastic fibers.33-35 Eosinophilic or neutrophilic epithelial microabscesses, or both, may be present.4 Mitoses and atypical keratinocytes are generally not prominent.4 The tumor, in almost all cases, does not extend into the dermis to a depth below the eccrine glands.4 Perineural or vascular invasion, or both, may be seen,36,37 but these lesions retain a good prognosis.38 The regressing KA shows a more flattened base of the tumor epithelium with surrounding fibrosis.39 Histologic differences between the typical solitary KA and KAs in other settings have been documented (Table 2): • The large nodular tumors of Ferguson-Smith and WittenZak may extend down to the fat with a surrounding lymphocytic infiltrate, invade lymphatics, have a less well-developed central keratotic crater, and display smaller keratinocytes without a glassy appearance.19,24
Disorders with multiple keratoacanthomas
Disorder
Inheritance Genetic findings
FergusonSmith Grzybowski
AD
Witten-Zak Muir-Torre Incontinentia pigmenti
Sporadic
AD AD XLD
Xeroderma AR pigmentosum
Clinical characteristics
Mapped to 9q22-q31
1 to several nodules in succession; up to 100s in a lifetime; begin in adolescence None 1- to 5-mm follicular papules (100s to 1000s), eruptive and progressive, in adulthood; also larger nodules as in Ferguson-Smith that heal with scarring; ectropion, mask-like facies Unknown 1-5 mm follicular papules and larger nodules; begin in childhood Defect in mismatch repair genes Association of ≥1 sebaceous neoplasms or ≥1 KAs with internal malignancy Defect in NEMO gene Subungual tumors
Defect in nuclear excision repair genes
Initial Blaschkoid blisters to verrucous lesions to hyperpigmentation to eventual hypopigmentation Ocular, skeletal, central nervous system, hair/teeth findings Photodamage with early development of cutaneous cancers
AD, autosomal dominant; AR, autosomal recessive; KA, keratoacanthoma; NEMO, NF-κB essential modulator; XLD, X-linked dominant.
256 Table 2
C.J. Ko The solitary keratoacanthoma and comparison with accepted variants of keratoacanthoma
KA variant
Clinical
Histologic
Similarities to the solitary KA
Differences from the solitary KA
Solitary
Rapid growth to 1-2 cm Crateriform Sun-exposed skin Age: generally 40s to 60s Male N Female
Crateriform Glassy keratinocytes Epithelial lip Neutrophilic abscesses Infiltrate of neutrophils/ eosinophils Intraepithelial elastic fibers Generally does not extend below the eccrine glands Fibrosis Same as solitary
N/A
N/A
Spontaneous involution
Giant
N2-3 cm
Clinical and histologic Size similarity to solitary KA KA centrifugum Persistent peripheral growth with Advancing edge shows similar Clinical central involution Clinical morphology marginatum central involution or scarring features to the solitary KA and size Tends to be on the lower Histologic similarity of the extremities advancing edge to the solitary KA Subungual Tends to affect the thumb, Usually lacks a crateriform Histologic similarity of the glassy Does not involute index, and middle fingers shape keratinocytes that lack cytologic atypia to the solitary KA Not crateriform Slow growth with associated Few mitoses and atypical pain and bony destruction keratinocytes When multiple may be Glassy keratinocytes Prominent associated with disorders dyskeratotic cells with multiple KAs Many dyskeratotic cells Lacks fibrosis Mucosal When multiple may be Usually lacks a crateriform Histologic similarity of the glassy Does not involute associated with disorders shape keratinocytes that lack cytologic with multiple KAs atypia to the solitary KA Few mitoses and atypical Usually not keratinocytes crateriform Glassy keratinocytes Lymphoplasmacytic infiltrate Lymphoplasmacytic infiltrate Lacks fibrosis Ferguson-Smith See Table 1 Endophytic tumor of slightly Spontaneous involution Not crateriform basaloid keratinocytes Deep extension Keratinocytes not glassy Lymphocytic infiltrate Deep extension Lymphatic invasion Lymphocytic infiltrate Lymphatic invasion Grzybowski See Table 1 Nodules: similar to solitary KA Spontaneous involution of nodules Miliary lesions: follicular epidermal hyperplasia Witten-Zak See Table 1 Nodular lesions: like Ferguson- Spontaneous involution of Nodular lesions are Smith lesions of nodular lesions not crateriform and lack glassy keratinocytes Intermediate pea-sized lesions: epithelial hyperplasia with acantholysis Miliary lesions: follicular plugging and irregular follicular epithelial hyperplasia KA, keratoacanthoma; N/A, not applicable.
Keratoacanthoma: Facts and controversies • A well-developed nodule in Grzybowski syndrome will have typical features of a KA; however, the smaller miliary lesions may show only follicular epidermal hyperplasia.23 • The smaller miliary lesions of Witten-Zak showed irregular off-shoots of epithelium from follicles with follicular plugging. The intermediate-sized lesion of Witten-Zak displayed a down-growth of epithelium with apparent acantholysis of cells.24 • KAs associated with Muir-Torre syndrome sometimes have associated sebocytes.5 • Subungual KAs are not crateriform and have more dyskeratotic cells.9 Lack of staining with p53 and low expression of Ki67 are suggestive of subungual KA rather than subungual SCC.32 • Mucosal KAs may lack a crateriform architecture and tend to have a lymphoplasmacytic infiltrate.11
KA vs SCC In practice, there are tumors that are difficult to classify as either KA or SCC. Two examiners who studied 296 cases independently arrived at a consensual diagnosis of KA or SCC in 262. These 262 were then examined for different criteria, and no single criterion was found useful to clearly favor KA vs SCC, or vice versa. Helpful criteria for the diagnosis of a KA included epithelial lip, sharp outline between tumor and stroma, and ulceration. Criteria more commonly seen in SCCs included numerous mitoses and marked cellular pleomorphism.40 In a study of 100 KAs and 100 SCCs, 81% of KAs and 86% of SCCs could be diagnosed using common criteria. The remainder showed conflicting features, such as a generally crateriform architecture with prominent nuclear atypia at the borders of the tumor.41 Because differentiating some cases of KA from welldifferentiated SCC can be quite challenging on routine histologic sections, numerous studies have attempted to resolve this quandary. Many authors have looked at markers of epidermal differentiation and of intercellular adhesion. Filaggrin staining is much more likely to be present in KAs than SCCs,42 although another study did not confirm this.43 Fully developed KAs express vascular cell adhesion molecule and intercellular adhesion molecule, whereas SCCs seem to only focally express these markers. 44 Syndecan-1, a mediator of intercellular and cell to matrix adhesion,45 and E-cadherin 46,47 are more highly expressed in KAs than invasive SCCs. The desmoglein staining pattern of KAs is similar to healthy epidermis.48,49 KAs express involucrin and keratins 5 and 14 in a similar pattern to the outer root sheath below the follicular infundibulum.50 βCatenin is expressed more strongly in SCCs.47,51 The presence of H blood group antigens favors KA over SCC.52 KAs express transforming growth factor-α diffusely.53 Overall, these studies suggest that KA has a pattern of differentiation that is different from SCC.
257 Cell cycle markers, growth factors, and apoptosis regulatory proteins have been studied in KAs and SCCs. Silver-stained organizer regions, when seen in tissue sections, are suggestive of cell proliferation, and SCCs have an increased number of these regions compared with KAs.54 This is in agreement with studies showing obvious Ki67 expression in SCCs.55,56 KAs have lower bcl-2 expression57,58 and p53 expression compared with SCCs. Taken as a whole, SCCs are more proliferative, with increased expression of antiapoptotic markers compared with well-developed KAs. Studies that have not shown differences between KAs and SCCs abound. Flow cytometry of the DNA index and the proliferative index showed no statistical differences between KAs and SCCs.59 DNA image cytometry also does not differentiate them.60 Expression of β-2-microglobulin61 and p1662 are similar in both tumors. Stromelysin-3 tends to stain the stroma around SCCs only slightly more than KAs.63 Staining of expression of cyclins, cyclin-dependent kinases,64 and oncostatin M65 are similar in SCCs and KAs. No marker has yet been found that will differentiate KAs and SCCs with high sensitivity and specificity. Nonetheless, because many of these studies compared a small number of KAs and SCCs, it is possible that they lacked sufficient power to detect a true difference. With a smaller number of tumors, misclassification of one or more tumors as a KA or as a SCC could also have had a marked effect on the results. Confounding these issues are reports of tumors with classic histologic features of a KA and a clinical history of rapid growth that have metastasized.66,67 Some authors believe the KA is a subtype of SCC,11 whereas others suggest the KA is a precursor lesion to SCC.4 In practice, the recommendation is that KAs be treated rather than observed in order to prevent potential aggressive behavior68-70 and significant scarring.6 From a practical point of view, therefore, the distinction between a KA and SCC does not necessarily have a profound effect on management. Regression has been suggested as the gold standard for the diagnosis of a KA.71 Both KAs and SCCs may grow rapidly and have a crateriform architecture. There may be more similarities than differences histologically, particularly when comparing the growth phase of KAs and SCCs.71 Because clinical and histologic features may be misleading, a tumor with a suspected diagnosis of KA, clinically or histologically, or both, could be monitored for 1 month. If the tumor shows signs of regression, it may be more definitively classified as a KA.71 Alternatively, if the lesion has grown larger or is unchanged, the tumor is more likely a SCC, and treatment may be initiated.71
Pathogenesis What are the mechanisms that induce KAs? Different theories have been proposed. Some authors have found human papilloma virus infection in KAs,72-74 but others have
258 not.75 Most KAs are found on sun-exposed skin, and there likely is some relationship to exposure to ultraviolet radiation.2,76 Carcinogens like tar have been implicated,77 and trauma may also be an inciting factor.1,78 There are several reports of KAs arising in a background of a tattoo.79-81 It is unclear whether the trauma from the tattoo or possibly the tattoo dye is related to tumor formation. KAs also may arise in other tumors or inflammatory dermatoses.5 Comparative genomic hybridization suggests that different genetic mechanisms underlie KAs and SCCs. KAs more frequently show loss from 9p,82 whereas gains from 1p, 14q, 16q, and 20q and loss from 4p are more common in SCCs.83 Trisomy 7 has been identified in KAs.84 On the molecular level in a mouse model of carcinogenesis, increased p53 expression in the basal layer of the skin released inhibition of p21waf, leading to increased keratinocyte differentiation and the formation of highly differentiated KAs.85
Mechanisms of regression The controversy about classification of the KA sometimes overshadows the documented potential of the KA to regress. A dense infiltrate of CD8-positive T cells has been documented at the base of KAs,86,87 which means cytotoxic T cells may have an effect in the regression of KAs. The cytotoxic T cells may mediate regression through release of granzyme B.87 KAs also have a greater number of intratumoral CD3-positive and interleukin-2 receptor-expressing CD4-positive lymphocytes than SCCs.87,88 Langerhans cells and CD30-positive cells are increased in inflamed KAs.89,90 Although there is some evidence for an immunologic basis to regression in KAs, regression may be nonimmunologic.91 A rabbit model of KAs suggested against immunologic regression. 92 In KAs, the keratinocytes express markers of initiation of apoptosis as well as end-stage markers of apoptosis in the same cells that are proliferating.46 Regressing KAs express p27, an inhibitor of a variety of cyclin-dependent kinases, 93 and Le(Y), an antigen related to apoptosis.94 Thus, triggering of keratinocyte apoptosis may have an effect in regression.7 A follicular origin of the KA has been proposed.24,95 The KA may be derived from the outer root sheath below the infundibulum, a portion of the follicle that undergoes regression and regrowth as part of the normal hair cycle.50 The ability of the KA to regress could be related to the mechanisms that underlie normal hair cycling.
Classification: Benign or malignant? Considered by some to be benign,4 others believe that the KA is unequivocally a subtype of SCC.11 This debate is difficult to resolve because the separation of benign and malignant is not always clear. Criteria that are often advanced
C.J. Ko to support a malignant lesion are (1) metastasis; (2) aggressive clinical behavior apart from metastasis, that is, local recurrence/destruction on the clinical side; (3) abnormal cytology of cells; (4) vascular or perineural invasion, or both; (5) highly infiltrative growth pattern; and (6) high proliferative index with or without necrosis on histopathologic evaluation. Lesions that are benign generally lack all or most of these criteria. The KA does occasionally metastasize.66 Solitary KAs may grow quite rapidly and lead to local pain and destruction. Giant KAs or KA centrifugum marginatum, or both, often grow very extensively and may not regress.6-8 Vascular and perineural invasion may be seen, and when extensive, would certainly qualify as an infiltrative growth pattern. Logically, KAs in their growth phase are mitotically active. There are numerous reasons to classify the KA as a malignant tumor or a subtype of SCC. Why, then, do some argue vehemently against this? In the strictest definition, the KA does not display prominent mitoses or cytologic atypia. Most KAs do not metastasize and even may regress spontaneously. Spontaneous regression would seem to be a polar opposite to aggressive clinical behavior, and KAs that display prominent vascular/perineural invasion may also regress. Although the ability for lymphomatoid papulosis to resolve spontaneously caused it to be classified as a benign process for many years, it is now considered a lymphoma in the 2005 World Health Organization European Organization for Research and Treatment of Cancer Classification of cutaneous lymphomas.96 Thus, even spontaneous resolution in itself is not universally considered a sign of benignancy. It is standard practice to treat KAs rather than monitor them for spontaneous resolution.70 Many dermatopathologists give a diagnosis of SCC, KA type (or some such variation). A diagnosis of “squamous cell carcinoma” undoubtedly is more tangible to most patients compared with an explanation of the relevant characteristics of KA. In sum, classification may be more of an academic question without clinical relevance at this time.
Conclusions There is no simple answer on how to pigeon hole the KA, the variants of which are heterogeneous clinically and histologically (Table 2). Expert opinions are divided, with some classifying the KA as a subtype of SCC66 and others considering it a separate entity that may progress to SCC.4 Because most KAs do have a good prognosis with conservative treatment and the diagnosis of multiple KAs has relevance for genetic syndromes like Muir-Torre, it is useful to continue to use and include the term “keratoacanthoma” for lesions with a compatible clinical history and histopathology. Until a reliable method for distinguishing the KA from SCC is established, however, patients are likely best served by regarding KA as a subtype of SCC in terms of
Keratoacanthoma: Facts and controversies treatment and management.97 Despite this, I emphasize that this classification is specifically for optimal patient care and should not prevent further investigation into the nature of KA. Continued study of this fascinating tumor may lead to more satisfactory answers.
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