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-5c2 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-5c2 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 transformationspecific MMP-13 in keratoacanthomas suggests that they are not benign tumors but incomplete SCCs.

Differential expression of stromal MMP-1, MMP-9 and TIMP-1 in basal cell carcinomas of immunosuppressed patients and controls

“…The finding of MMP-7 expression associated with mitoses agrees with findings in cell culture [3]. Previous studies have shown the transformation specific nature of MMP-7 [23,30], but our current data do not support the idea that this MMP would be upregulated by immunosuppression. The other matrilysin now studied for the first time in a large set of BCCs, MMP-26, was only rarely seen in the BCC epithelium or stromal cells, suggesting that it is not essential for the growth or angiogenesis in BCCs.…”

“…Sections were pretreated with 10 mg/ml trypsin or incubation in citrate buffer in a +95°C water bath. We used mostly mouse monoclonal antibodies to study the localization of MMP-1 [24], TIMP-1 (1:100, IM63L, Calbiochem), and TIMP-3 (1:400, IM43L, Calbiochem) as previously described [23,30]. Diaminobenzidine (DAB) or aminoethylcarbazole (AEC) were used as chromogenic substrates and Mayer hematoxylin as counterstain.…”

The Role of p16, p21, p27, p53 and Ki-67 Expression in the Differential Diagnosis of Cutaneous Squamous Cell Carcinomas and Keratoacanthomas: An Immunohistochemical Study

“…Some KA cases that were initially diagnosed as benign progressed to be metastatic, exhibiting aggressive behavior (3)(4)(5). The immunohistochemical markers that have been used for years to distinguish between SCC and KA in studies are: p53, proliferating cell nuclear antigen , telomerase and COX-2 , transforming growth factor-α, angiotensin-type I receptor, vascular cell adhesion molecule, intercellular adhesion molecule, Ki-67, p16 tumor suppressor antigen, matrix metalloproteinases, syndecan-1 and Bcl-2 (6)(7)(8)(9)(10)(11)(12)(13)(14)(15). However, none of these studies have been able to provide reliable and specific criteria with which to distinguish between these two tumors.…”

The Bcl‐xL inhibitor of apoptosis is preferentially expressed in cutaneous squamous cell carcinoma compared with that in keratoacanthoma

“…Advantages in distinguishing the two diagnoses would bring about fewer unnecessary surgeries, lower burden on the healthcare system and most importantly less anxiety for the patients. Over the years, elaborate work of investigating possible biomarkers for the distinction of KA from SCC has been performed, including studies of p53,8 proliferating cell nuclear antigen,9 angiotensin type I receptor,10 vascular cell adhesion molecule, intracellular adhesion molecule,11 telomerase, cyclo‐oxygenase‐2,12 KI‐67,13 p16 tumour suppressor antigen,14 matrix metalloproteinases,15 syndecan‐116 and Bcl‐2 17. Still, none of these studies have provided specific or reliable distinguishing criteria.…”