Molecular subtyping of metastatic renal cell carcinoma: implications for targeted therapy

2014-02-26 16:48:01

Molecular Cancer; 2014 February 26; DOI:10.1186/1476-4598-13-39

Lisha Wang, Sean R Williamson, Mingsheng Wang, Darrell D Davidson, Shaobo Zhang, Lee Ann Baldridge, Xiang Du, Liang Cheng


Renal cell carcinoma (RCC) is known for its ability to metastasize synchronously or metachronously to various anatomic sites. Distinguishing histologic subtypes of metastatic RCC has become increasingly important, as prognosis and therapy can differ dramatically between subtypes. We propose a combination of immunohistochemistry (IHC) and molecular cytogenetics for subtyping metastatic RCC in light of these potential therapeutic implications.


Renal cell carcinoma (RCC) comprises a heterogeneous group of epithelial neoplasms with diverse biologic behaviors and variable clinical outcomes. RCC is the most lethal of the urologic malignancies. Between 20% and 30% of patients with RCC have metastatic disease at the time of diagnosis, and another 30% subsequently develop metastasis after resection. The majority of tumors are of the clear cell (CCRCC) subtype (70%-75%), characteristically harboring abnormalities of the von Hippel-Lindau (VHL) gene, located at chromosome 3p25. Defects in VHL expression result in constitutive activation of the hypoxia-inducible factor (HIF) pathway and overexpression of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and other products. Inactivation of the
VHL gene also enhances tumor cell growth though the mammalian target of rapamycin (mTOR) pathway. In contrast, papillary renal cell carcinoma (PRCC) is the most
common non-clear cell subtype of RCC, accounting for 10%-15% of tumors. PRCC is associated with activation of the MET pathway in a subset of tumors, resulting in a cascade of intracellular signaling leading to tumor cell growth, angiogenesis, migration and invasion.

Knowledge of these gene pathways has enabled novel approaches to the management of metastatic RCC. Currently, clinical trials with targeted therapeutic strategies for both metastatic CCRCC and PRCC have been intensively planned and carried out.

Although recent advances have gradually improved patient outcomes, these targeted agents are not without toxic effects. Optimizing the clinical outcome and knowing when to persist with these therapies highlight the need for accurate RCC subtyping.

Histopathologic examination of a completely resected primary tumor is often sufficient for tumor subtyping, as a component with prototypical morphologic features can usually be readily appreciated. However, in the metastatic setting, it is often challenging to discriminate between subtypes of RCC based on morphology alone, particularly since metastatic foci are often sampled only by core needle biopsy and can be preferentially composed of high-grade
tumor. Immunohistochemical analysis is valuable to identify the histogenetic origin of metastatic malignancy. Nevertheless, its use for discriminating different histologic subtypes is limited and rarely applied in prospective treatment outcome studies. A cytogenetic hallmark of CCRCC is loss of chromosome 3p, which distinguishes it from other RCC subtypes. PRCC frequently exhibits chromosomal polysomies, of which trisomy of chromosomes 7 and/or 17 are the most consistent and characteristic. Because CCRCC and PRCC show different immunophenotypes and different characteristic cytogenetic abnormalities, we sought to combine these two ancillary tests in an effort to reduce ambiguity in subtyping of metastatic RCC. Immunophenotypes of 103 cases of metastatic RCC were analyzed in conjunction with cytogenetic characteristics as determined by fluorescence in situ hybridization (FISH), in order to improve classification of these neoplasms.

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