Keratoacanthoma

Mod Pathol. 2006 Sep;19(9):1203-12. Abstract quote

Keratoacanthomas are rapidly growing hyperproliferative skin tumors that may clinically or histologically be difficult to distinguish from well-differentiated squamous cell cancers (SCCs). UV light, trauma, and immune suppression represent their etiological factors. As matrix metalloproteinases (MMPs) are implicated at all stages of tumorigenesis, we investigated the expression profile of several cancer-related MMPs to find markers that would differentiate keratoacanthomas from SCCs and shed light to the pathobiology of keratoacanthoma. Samples from 31 keratoacanthomas and 15 grade I SCCs were studied using immunohistochemistry for MMP-2, -7, -8, -9, -10, -13, and -19 and p16 and laminin-5gamma2 chain. In situ hybridization for MMP-7, -10, and -13 was performed in a subset of tumors. Keratinocytes with atypia, presence of neovascularization, and composition of the inflammatory infiltrate were graded from hematoxylin-eosin stainings. MMP-7 was present in the epithelium of 4/31 keratoacanthomas and 9/15 SCCs, MMP-8 in 3/30 keratoacanthomas and 0/15 SCCs, but MMP-13 in 16/31 keratoacanthomas and 10/15 SCCs, and MMP-10 in 28/31 keratoacanthomas and all cancers. MMP-9 was detected in the epithelium in 5/31 keratoacanthomas and 8/15 SCCs, whereas MMP-2 was only present in fibroblasts in both tumors. MMP-19 was upregulated in proliferating epithelium of keratoacanthomas as was p16. Cytoplasmic laminin-5gamma2 was particularly abundant in keratinocytes at the pushing border of MMP-13-positive keratoacanthomas.

We conclude that although some MMPs (MMP-10 and -13) are abundantly expressed in keratoacanthomas, the presence of MMP-7 and -9 in their epithelial pushing border is rare and should raise suspicion of SCC. Further, the loss of MMP-19 and p16 could aid in making the differential diagnosis between well-differentiated SCC and keratoacanthoma. Frequent expression of the transformation-specific MMP-13 in keratoacanthomas suggests that they are not benign tumors but incomplete SCCs.

Disease Associations
Pathogenesis
Laboratory/Radiologic/ Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

PATHOGENESIS	CHARACTERIZATION
HUMAN PAPILLOMAVIRUS
Identification of human papillomavirus in keratoacanthomas. Forslund O, DeAngelis PM, Beigi M, Schjolberg AR, Clausen OP. Department of Medical Microbiology, Malmo University Hospital, Lund University, Sweden, and Institute and Department of Pathology, University of Oslo, Rikshospitalet, Oslo, Norway.	J Cutan Pathol. 2003 Aug;30(7):423-9 Abstract quote BACKGROUND: Keratoacanthomas are benign, clinically distinct skin tumors that may infiltrate and show cellular atypia. A viral etiology has been suggested, and the aim was to search for human papillomavirus (HPV) in keratoacanthomas. METHODS: From 21 immunosuppressed organ transplant recipients and 11 non-immunosuppressed patients, 72 fresh biopsies with diagnosis of keratoacanthomas were analyzed. For detection of cutaneous and genital HPV DNA, single-tube nested 'hanging droplet' polymerase chain reaction (PCR) and another PCR (GP5+ and 6+) were used, respectively. RESULTS: Among 21 immunosuppressed patients, 71% (15/21) harbored HPV DNA at least in one sample. Of the keratoacanthoma lesions, 55% (33/60) were HPV DNA positive. Fourteen samples from eight immunosuppressed patients contained HPV types 5, 9, 10, 14, 19, 20, 21, 38, 49, 80, putative HPV types as HPVvs20-4, HPVvs75, and HPVvs92 and FA16.1, FA23.2, FA37, FA75, and FA81. Among 11 non-immunosuppressed patients, 36% (4/11) harbored HPV DNA at least in one sample, and 33% (4/12) of their keratoacanthomas were HPV DNA positive. In total, HPV DNA was detected in 51% (37/72) of the keratoacanthomas. CONCLUSIONS: By the use of PCR, cutaneous HPV DNA was detected in 51% (37/72) of the keratoacanthomas. No predominating HPV type or genital HPV type was identified. The role of HPV in keratoacanthomas remains thus elusive.
METALLOPROTEINASES
Transformation-specific matrix metalloproteinases, MMP-7 and MMP-13, are present in epithelial cells of keratoacanthomas. Kuivanen TT, Jeskanen L, Kyllonen L, Impola U, Saarialho-Kere UK. 1Department of Dermatology, Helsinki University Central Hospital and Biomedicum Helsinki, Helsinki, Finland.	Mod Pathol. 2006 Sep;19(9):1203-12. Abstract quote Keratoacanthomas are rapidly growing hyperproliferative skin tumors that may clinically or histologically be difficult to distinguish from well-differentiated squamous cell cancers (SCCs). UV light, trauma, and immune suppression represent their etiological factors. As matrix metalloproteinases (MMPs) are implicated at all stages of tumorigenesis, we investigated the expression profile of several cancer-related MMPs to find markers that would differentiate keratoacanthomas from SCCs and shed light to the pathobiology of keratoacanthoma. Samples from 31 keratoacanthomas and 15 grade I SCCs were studied using immunohistochemistry for MMP-2, -7, -8, -9, -10, -13, and -19 and p16 and laminin-5gamma2 chain. In situ hybridization for MMP-7, -10, and -13 was performed in a subset of tumors. Keratinocytes with atypia, presence of neovascularization, and composition of the inflammatory infiltrate were graded from hematoxylin-eosin stainings. MMP-7 was present in the epithelium of 4/31 keratoacanthomas and 9/15 SCCs, MMP-8 in 3/30 keratoacanthomas and 0/15 SCCs, but MMP-13 in 16/31 keratoacanthomas and 10/15 SCCs, and MMP-10 in 28/31 keratoacanthomas and all cancers. MMP-9 was detected in the epithelium in 5/31 keratoacanthomas and 8/15 SCCs, whereas MMP-2 was only present in fibroblasts in both tumors. MMP-19 was upregulated in proliferating epithelium of keratoacanthomas as was p16. Cytoplasmic laminin-5gamma2 was particularly abundant in keratinocytes at the pushing border of MMP-13-positive keratoacanthomas. We conclude that although some MMPs (MMP-10 and -13) are abundantly expressed in keratoacanthomas, the presence of MMP-7 and -9 in their epithelial pushing border is rare and should raise suspicion of SCC. Further, the loss of MMP-19 and p16 could aid in making the differential diagnosis between well-differentiated SCC and keratoacanthoma. Frequent expression of the transformation-specific MMP-13 in keratoacanthomas suggests that they are not benign tumors but incomplete SCCs.
MICROSATELLITE INSTABILITY
Assessment of microsatellite instability and loss of heterozygosity in sporadic keratoacanthomas. Langenbach N, Kroiss MM, Ruschoff J, Schlegel J, Landthaler M, Stolz W. Department of Dermatology, University of Regensburg, Germany.	Arch Dermatol Res 1999 Jan;291(1):1-5 Abstract quote Variations in the length of simple repetitive tandem repeats (microsatellite instability, MIN) between constitutive and tumour DNA, which is characteristic of tumours in patients affected with hereditary nonpolyposis colon cancer (HNPCC), have been found to be very important in the carcinogenesis of a variety of human neoplasms. Recently, MIN has been found in sebaceous and colorectal tumours as well as in keratoacanthomas of Muir-Torre syndrome. In order to elucidate the significance of both MIN and loss of heterozygosity (LOH) in the pathogenesis of sporadic keratoacanthomas, the presence of MIN and LOH at five loci [chromosome 5q21 (D5S346, APC), 9p21 (D9S171, p16), 10pter (D10S89, Mfd28), 11p (D11S904) and 17p12 (D17S520, p53)] was evaluated. MIN was found at only one locus (p53) in 1 of 12 keratoacanthomas and no evidence for the presence of LOH could be detected. Our results suggest that, in contrast to keratoacanthomas associated with Muir-Torre syndrome, neither MIN nor LOH appear to be significant in the induction of sporadic keratoacanthomas.

DISEASE ASSOCIATIONS	CHARACTERIZATION
Muir-Torre syndrome	Association with internal malignancies and multiple sebaceous tumors

CLINICAL VARIANTS	CHARACTERIZATION
Giant	Tumors usually greater than 2-3 cm
Keratoacanthoma centrifugum marginatum (multinodular keratoacanthoma)	Progressive peripheral growth with central healing. Often 20 cm or more. May have a plaque-like variant called keratoacanthoma dyskeratoticum et segregans
Multiple-Ferguson Smith Type	Development of successive lesions on all parts of the body over many years. Heal with atrophic scars
Multiple-Grzybowski (Eruptive) Type	Multiple papules and nodules (usually over a hundred) developing within 5-6th decades. Develop on all sites including palms, soles, and mucous membranes.
Grzybowski's generalized eruptive keratocanthomas: a case report. Gjersvik P, Egass E, Clausen OP. Department of Dermatology, Rikshospitalet, University of Oslo, N-0027 Oslo, Norway.	Eur J Dermatol 2000 Mar;10(2):135-8 Abstract quote A 47-year old woman with Grzybowski's generalised eruptive keratoacanthomas is described. There was no history of skin disease in her family, except for an uncle's basal cell carcinoma. From 1995 she developed multiple lesions of various size, ranging from hundreds of small follicular lesions to large typical keratoacanthomas up to 5 cm in diameter, scleroderma-like facial skin and marked ectropion. Histological examination of small and large skin lesions was typical of keratoacanthoma, and no human papillomavirus was detected by polymerase chain reaction. Oral treatment with acitretin had no effect. Both cyclophosphamide and methotrexate therapy were refused by the patient despite the progressive course of the disease. Blepharoplastic surgery had some effect on eye symptoms. The etiology of this rare disease is unknown, but is probably related to some genetic defect.
SUBUNGUAL	Rapid growth and often fail to regress. May cause pressure erosion of the underlying distal phalanx.
Subungual keratoacanthoma. Stoll DM, Ackerman AB.	Am J Dermatopathol 1980 Fall;2(3):265-71 Abstract quote Only 12 cases of lesions reputed to be subungual keratoacanthomas have been reported to our knowledge, and those have not been unequivocal by histologic and biologic criteria. Those 12 lesions have been tabulated by us and reviewed critically. In addition, we now provide two cases of keratoacanthomas in the subungual region that are histologically typical of keratoacanthomas found on hair-bearing skin. It appears to us that subungual keratoacanthoma is a specific type of keratoacanthoma that differs from the common solitary keratoacanthoma on hair bearing skin by 1) its similarity to verruca vulgaris clinically; 2) having more dyskeratotic cells and fewer neutrophils and eosinophils histologically; 3) being more vertical in orientation (longer than it is broad); 4) its failure to regress spontaneously; 5) its longer course; and 6) its tendency to destroy bone. Paradoxically, keratoacanthoma situated in the subungual region is a more destructive neoplasm than a squamous cell carcinoma there.
Subungual keratoacanthoma. Report of a case and review of the literature. Keeney GL, Banks PM, Linscheid RL.	Arch Dermatol 1988 Jul;124(7):1074-6 Abstract quote Subungual keratoacanthoma (SUKA) is an uncommon and clinically distinctive tumor of the nail bed. It can easily be confused with well-differentiated subungual squamous cell carcinoma. Distinguishing features of SUKA include pain, rapid growth, and early underlying bony destruction. Unlike keratoacanthomas arising from sun-exposed skin, SUKAs seldom resolve spontaneously and are more locally destructive. Of 18 cases reported in the literature, five patients have developed recurrent disease, all within five months of the initial surgery. We describe a patient with SUKA initially treated by curettage followed two days later by a conservative amputation that revealed conspicuous residual keratoacanthoma. The deep, burrowing tendency of SUKA and the intimate association with underlying bone may explain the reported tendency for recurrence after curettage.

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
INFUNDIBULOCYSTIC SQUAMOUS CELL CARCINOMA
Keratoacanthoma and infundibulocystic squamous cell carcinoma. Kossard S, Tan KB, Choy C. Skin and Cancer Foundation Australia, Sydney, Australia.	Am J Dermatopathol. 2008 Apr;30(2):127-34. Abstract quote One of the major controversies in dermatopathology is the relationship of keratoacanthoma to squamous cell carcinoma. Leaders in the field remain polarized in their views. Carcinomas with distinct follicular pattern of differentiation have been described in reference to the isthmus as trichilemmal carcinomas, to the follicular bulb as pilomatricomal carcinomas, and to the stem cell or rapidly amplifying cell compartment as basal cell carcinomas (trichoblastic carcinomas). We have employed the term infundibulocystic or infundibular squamous cell carcinoma to identify a subset of squamous cell carcinomas that demonstrate this pattern of differentiation. The recognition of infundibular squamous cell carcinoma is important in that well-differentiated examples are likely to have been diagnosed as keratoacanthoma, whereas moderately or poorly differentiated tumors would be more often reported as squamous cell carcinomas, leading to underrecognition of these infundibular variants of squamous cell carcinoma. The descriptive term infundibulocystic or infundibular squamous cell carcinoma may help to better define an alternative follicular-based pathway to squamous cell carcinoma distinct from the more common evolution from solar keratoses and also refine the classification of keratoacanthoma.
SQUAMOUS CELL CARCINOMA
VCAM (CD-106) and ICAM (CD-54) Adhesion Molecules Distinguish Keratoacanthomas from Cutaneous Squamous Cell Carcinomas. Melendez ND, Smoller BR, Morgan M. Department of Pathology (N.D.M.M.M.), University of South Florida, Tampa, Florida, and James A. Haley Veterans Administration Hospital.	Mod Pathol 2003 Jan;16(1):8-13 Abstract quote Keratoacanthomas are rapidly growing benign epithelial derived neoplasms that may evolve into squamous cell carcinomas, or represent a variant of squamous cell carcinoma. ICAM (CD-54) is a ligand for the cell adhesion receptor LFA-1, shown to be important in immune stimulation that is upgraded in inflammatory cutaneous disorders. VCAM (CD-106) is an adhesion molecule normally found in stimulated endothelium, that plays a critical role in the migration of leukocytes. We examined the immunohistochemical expression of ICAM (CD-54) and VCAM (CD-106) in a series of 50 evolving, fully developed, resolving keratoacanthoma and well-differentiated and poorly differentiated squamous cell carcinoma to evaluate the possible temporal and pathogenic relation of these immune recognition markers and epithelial derived tumors. ICAM (CD-54) showed an increase in expression in the fully developed keratoacanthoma and was absent in the evolving and resolved keratoacanthoma. In the squamous cell carcinomas, expression was focally observed in the well-differentiated squamous cell carcinomas with a dramatic increase seen in the poorly differentiated squamous cell carcinomas. Similarly, VCAM (CD-106) was expressed in the fully developed keratoacanthoma and was absent in the evolving and resolved keratoacanthoma. Moderate expression for VCAM (CD-106) was seen in the well-differentiated squamous cell carcinoma, and intense expression was seen in the fully developed keratoacanthoma and poorly differentiated squamous cell carcinoma. As a group, keratoacanthoma and squamous cell carcinoma are immunophenotypically distinct. There is a temporal related increase in expression of VCAM (CD-106) in conjunction with the evolution of keratoacanthoma. Increased expression of both markers is seen with squamous cell carcinoma dedifferentiation. Application of these markers might be an important adjunct in predicting the biologic behavior and pathogenesis of these lesions.

PROGNOSIS AND TREATMENT
PROGNOSIS
SYNDECAN-1
Level of Syndecan-1 Expression is a Distinguishing Feature in Behavior between Keratoacanthoma and Invasive Cutaneous Squamous Cell Carcinoma Perkins Mukunyadzi, M.D., Ralph D. Sanderson, Ph.D., Chun-Yang Fan, M.D., Ph.D. and Bruce R. Smoller, M.D. Departments of Pathology (PM, RDS, CYF, BS) and Dermatology (BRS), University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, Arkansas	Mod Pathol 2002;15:45-49 Abstract quote Keratoacanthoma (KA) resolves spontaneously but is regarded by some as a variant of squamous cell carcinoma (SCC). However, others consider KA a totally benign entity. Syndecan-1 is one of the heparan sulfate proteoglycans that mediates intercellular and cell to matrix adhesion. Its expression appears to be inversely correlated with tumor aggressiveness and invasiveness. Previous studies have shown decreased levels of syndecan-1 expression in invasive cutaneous SCC, correlating with tumor de-differentiation. However, a similar study has never been done on KA. To investigate syndecan-1 expression in classic KA and compare the results with those of classic invasive SCC, 24 KAs were immunostained for syndecan-1 (CD 138) using the monoclonal antibody B-B4 on formalin-fixed paraffin-embedded tissue. Results were semi-quantitatively scored as either negative or positive (mild, moderate, or strong) and compared with those previously obtained on 23 invasive SCC and in situ lesions. All 24 KAs were positive for syndecan-1 expression. Staining intensity of 18 cases was comparable with that of SCC in situ or adjacent normal epidermis. By comparison, invasive SCC showed significantly diminished staining. Reduced staining in focal areas of cytologic atypia at the base was present in three KAs. Syndecan-1 expression in KA mirrors that of SCC in situ and normal epidermis, providing a molecular basis that biologically KA may be closely related to SCC in situ but distinctively different from invasive SCC.
TREATMENT	Simple excision