title: Transformation-specific matrix metalloproteinases, MMP-7 and MMP-13, are present in epithelial cells of keratoacanthomas.
abstract: 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.
authors.affiliation: Department of Dermatology, Helsinki University Central Hospital and Biomedicum Helsinki, Helsinki, Finland.
authors.forename: Tiina T
authors.initials: TT
authors.lastname: Kuivanen
authors.forename: Leila
authors.initials: L
authors.lastname: Jeskanen
authors.forename: Lauri
authors.initials: L
authors.lastname: Kyllönen
authors.forename: Ulla
authors.initials: U
authors.lastname: Impola
authors.forename: Ulpu K
authors.initials: UK
authors.lastname: Saarialho-Kere
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics; D017364:Collagenases / Q000235:genetics / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D003937:Diagnosis, Differential; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D006801:Humans; D017403:In Situ Hybridization; D015603:Keratinocytes / Q000201:enzymology* / Q000473:pathology; D007636:Keratoacanthoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D053509:Matrix Metalloproteinase 13; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012878:Skin Neoplasms / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7