Kidney Transplant Modifies the Architecture and Microenvironment of Basal Cell Carcinomas

Abstract

Background/Aims: Basal cell carcinoma (BCC) is a frequent type of nonmelanoma skin cancer, which shows a greater prevalence in kidney-transplanted (KT) patients than in the general population. The study of this tumor in KT patients may allow us to understand the influence of the tumor inflammatory microenvironment on cancer behavior, and to design new image analysis methods to determine prognosis and apply personalized medicine. The major hypothesis of the present work is that antirejection drugs, by modifying the B-cell/T-cell balance, induce measurable differences in tumoral cell microarchitecture and in the inflammatory microenvironment in KT patients compared to nontransplanted controls. Methods: In this retrospective study in an Italian cohort including 15 KT patients and 15 control subjects from the general population who developed BCC, we analyzed tissue microarchitecture and inflammatory infiltrates of BCC using state-of-the-art nonlinear image analysis techniques such as fractal dimension and sample entropy of internuclear distances. Results: KT patients showed a nonsignificant trend to a greater number of nuclei in the basal cell layer compared to non-KT controls and subtle changes in the intact skin compared to controls. Similarly, the number of mitoses per unit length was almost doubled in the patients with KT compared to controls. However, when the number of mitotic cells was normalized by the total number of cells in the basal layer (mitotic index), these differences were not significant, although a clear trend was still present. Finally, KT patients showed a nonsignificant trend to an increased density of inflammatory cells close to the tumoral cell layer. When considering the intact skin, this difference was significant, with a 70% increase in the density of inflammatory cells. Conclusion: Data comparing the microarchitecture of BCC in normal subjects and KT patients are scanty, and the present study is the first to use nonlinear image analysis techniques to this aim. The observed differences underscore the relevance of T-cell suppression in cancer behavior. These data suggest that BCC develops in treated patients with specific biological characteristics which should be further analyzed in terms of therapeutic response.pipeline image analysis strategy to evaluate and assess the histology of basal cell layers in KT patients with BCC. Previous observations showed that BCC was clinically similar in the KT and the general population [12]: BCC occurrence was increased at the level of the head and neck region at an advanced age and the level of the trunk at a younger age. Furthermore, the literature on gender prevalence is somewhat inconsistent regarding BCC in KT, but in the general population males are more often affected than females (as in our sample). Finally, BCC is reported to have poor or scanty inflammatory response in the general popu-

Skin Architecture, Kidney Transplantation, and Their Relationship to Basal and Squamous Cell Carcinomas

“…The main result of the present study is that KT patients who developed BCC or SCC showed an increased number of inflammatory cells in the intact skin, compared to non-KT patients. In a previous study focusing on BCC, we noticed a greater inflammatory infiltrate in KT patients (12). The present work confirms this observation and extends it to KT patients with SCC.…”

“…Subsequently the entire skin (whole slide images, WSI) was reconstructed using the Image Composite Editor 2.0.3.0 64bit by Microsoft. The reconstructed wide fields were then quantitatively analyzed using the ImageJ image analysis software using a validated algorithm described elsewhere (12).…”

A new hypothesis to explain skin cancer risk in kidney allograft recipients

“…35 However, when examining the intact skin close to the BCC or SCC site, a more intense inflammatory reaction can be observed. 36,37 Conversely, the peritumoral inflammatory infiltrate was increased in BCC and decreased in SCC in KT patients compared to their non-transplanted controls. 36…”

Review of the Tumor Microenvironment in Basal and Squamous Cell Carcinoma

“…Using state-of-the-art nonlinear image analysis techniques such as fractal dimension and sample entropy of internuclear distances and comparing tissue microarchitecture and inflammatory infiltrates of BCC in kidney transplant patients to healthy controls, Capasso et al found that there is a 70% increase in the density of inflammatory cells in the kidney transplant patients' samples. Since tumors still develop in this setting, this does not speak to the activity of these inflammatory cells [6].…”

“…In addition to tumor cells themselves, the TME includes nerve cells, epithelial cells, fibroblasts, plasmacytoid cells, dendritic cells, Langerhans cells, macrophages, and lymphocytes (Figure 1). This composition varies based on the type of cancer and a patient's immune status [6]. Each of these cell types may act in either an anti-or pro-oncogenic manner, depending on their interactions with other components of the TME [7].…”