Variations in the expression of TIMP1, TIMP2 and TIMP3 in cutaneous melanoma with regression and their possible function as prognostic predictors

Abstract

Regression in melanoma is a frequent biological event of uncertain prognostic value as the lesion exhibits heterogeneous phenotypical features, both at the morphological and immunohistochemical level. In the present study, we examined the expression of tissue inhibitors of metalloproteinases (TIMP1, TIMP2 and TIMP3) in melanoma with regression. We specifically examined the expression levels of these TIMPs in regressed components (RC) and non-regressed components (NRC) of the tumor and compared their expression levels with those in non-regressed melanomas. We found that TIMP1 was overexpressed in the NRC of melanomas with partial regression (PR) compared with the NRC in melanomas with segmental regression (SR) (P=0.011). TIMP2 was overexpressed in the NRC of melanomas with PR compared with the NRC in melanomas with SR (PR/SR, P=0.009); or compared with the NRC in melanomas with simultaneous SR-PR (P=0.002); or compared with melanomas without regression (absence of regression) (P=0.037). Moreover, TIMP3 was overexpressed in the NRC of all melanomas with SR as compared to the RC component (P=0.007). Our findings on the differential expression of TIMP1, TIMP2 and TIMP3 in melanomas with regression support the hypothesis that the morphological differences identified in the melanoma regression spectrum may have a correlation with prognosis. This may explain the controversial findings within the literature concerning the biological and prognostic role of regression in melanoma.

Keywords: melanoma with regression; prognosis; tissue inhibitors of metalloproteinases.

Figure 1.

Histopathological aspects of melanomas. (A) Distribution of superficial spreading melanomas according to the pT stage. (B) Distribution of nodular melanomas according to the pT stage. (C) Nests of epithelioid cells in non-regressed part of superficial spreading melanoma with regression. Hematoxylin and eosin (H&E) staining, ×200 magnification. (D) Nests and fascicles of spindle cells in nodular melanoma. H&E, ×200 magnification.

Figure 2.

Expression of tissue inhibitors of metalloproteinases (TIMPs) in regressed and non-regressed melanoma. (A) Intense diffuse expression of TIMP1 in areas of partial regression (x200 magnification); (B) Faint diffuse positivity of TIMP1 in areas of partial and segmental regression (x200 magnification). (C) Faint diffuse positivity for TIMP1 in melanomas without regression (x400 magnification). (D) Intense diffuse expression of TIMP2 in areas of partial regression (x400 magnification); (E) Faint diffuse positivity of TIMP2 in areas of partial and segmental regression (x200 magnification). (F) Faint diffuse positivity for TIMP2 in melanomas without regression (x400 magnification). (G-I) Similar expression of TIMP3 in (G) areas of partial regression, ×400 magnification, (H) non-regressed component of melanoma with regression, ×400 magnification, or (I) melanomas without regression, ×200 magnification.

Figure 3.

Expression of tissue inhibitors of metalloproteinases (TIMPs) in different types of regression. (A) TIMP1 expression in non-regressed component (NRC) and absence of regression (AR) according to the type of regression. (B) TIMP2 expression in NRC and AR according to the type of regression. (C) Differences in TIMP1 expression in NRC versus RC in melanoma. (D) Differences in TIMP2 expression in NRC versus RC in melanoma. (E) Differences in TIMP3 expression in NRC versus RC in melanoma. (F) Differences in TIMP3 expression in NRC versus RC based on type of regression.