Towards Personalized Sampling in Clear Cell Renal Cell Carcinomas

Abstract

Intratumor heterogeneity (ITH) is a constant evolutionary event in all malignant tumors, and clear cell renal cell carcinoma (CCRCC) is a paradigmatic example. ITH is responsible for most therapeutic failures in the era of precision oncology, so its precise detection remains a must in modern medicine. Unfortunately, classic sampling protocols do not resolve the problem as expected and several strategies have been being implemented in recent years to improve such detection. Basically, multisite tumor sampling (MSTS) and the homogenization of the residual tumor tissue are on display. A next step of the MSTS strategy considering the recently discovered patterns of ITH regionalization is presented here, the so-called personalized MSTS (pMSTS). This modification consists of paying more attention to sample the tumor periphery since it is this area with maximum levels of ITH.

Keywords: clear cell renal cell carcinoma; intratumor heterogeneity; multisite tumor sampling.

Figure 1

Schematic of tumor sampling evolution in clear cell renal cell carcinoma. The classical sampling protocol (A) calls for one block per centimeter of tumor diameter. Multisite tumor sampling (B) randomly selects a large number of small tumor samples across the tumor using the same number of blocks as the classic protocol. Advanced multisite tumor sampling (C) takes a few samples at the tumor center, where intratumor heterogeneity is low but metastatic genotypes and necrosis (pink areas) are common, and many small samples at the periphery, where intratumor heterogeneity and local invasiveness are high. Here, the small fragments selected are grouped in blocks by sectors, thus enabling the precise location of any key change in any sample to be monitored. Note that tumor/non-tumor, tumor/renal sinus, and tumor/perinephric fat interfaces are similar in the three methods (block shown in red).

Figure 2

Multisite tumor sampling (pink blocks) consists on including six to eight small tumor tissue fragments in each paraffin block instead of one large tumor fragment proposed by the classic protocol (green blocks). This way, the same number of paraffin blocks sample many more tumor regions.