Influence of Histology on Management of Advanced Renal Cell Carcinoma

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Introduction

The American Cancer Society estimates that in 2007, 51,190 new cases of kidney cancer will be diagnosed in the United States, and 12,890 individuals will die of the disease. ¹ The incidence of this tumor has steadily increased from 2% to 4% annually for unknown reasons. Patients with this neoplasm are generally curable when the disease is localized and in early stages. In this setting, partial or radical nephrectomy results in a high recurrence-free survival rate.^2,3 In contrast, advanced and metastatic renal cell cancer (RCC) has been resistant to most systemic therapies. However, recent reports utilizing vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) inhibitors have noted significant improvements in response rates, progression-free survival, and in some instances overall survival.^4-7  

Heterogeneous Histology

RCC represents a group of diverse histologic subtypes with unique morphologic and genetic characteristics. The delineation of these subtypes and their molecular biology has led to an understanding of the pathogenesis of renal cell tumors. The Heidelberg classification subdivides renal cell tumors into benign and malignant varieties with associated genetic alterations.⁸ Figure 1 illustrates the various histologic subtypes, including the associated genetic abnormalities.

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Clear cell renal carcinoma is the most common renal tumor, accounting for more than 70% of renal epithelial malignancies. It arises from the proximal convoluted tubule and is characterized by clear cytoplasm with occasional eosinophilic areas.⁹ More than 60% of sporadic clear cell tumors are associated with defects in the von Hippel-Lindau (VHL) gene.^8,10 Papillary renal cancer is the second most common variety overall, comprising 10%-15% of renal tumors.

Chromophobe carcinoma represents the second most common non-clear cell subtype, with an overall incidence of 6%-11%.¹¹ Recognition of the association between histologic subtypes and gene alterations now provides the opportunity to develop specific therapeutic agents for the various types of RCC and has played a major role in changing the treatment paradigm for clear cell carcinoma.

RCC tumorigenesis is complex and involves overexpression of various growth factors and defects in selected signaling pathways. VEGF and hypoxia inducible factor (HIF) have been identified as therapeutic targets, because they are overexpressed in hereditary and sporadic clear cell carcinomas as a result of mutations and/or inactivation of the VHL gene and subsequently the increased expression of the nuclear transcription factor HIF.^8,10 A variety of novel agents that target these pathways, as well other growth factors such as platelet-derived growth factor (PDGF) and their receptor tyrosine kinases, have been developed and now provide a series of new treatment options for patients with advanced clear cell carcinoma.

The genetic abnormalities in papillary and chromophobe tumors¹² are therefore of interest. For example, in hereditary papillary carcinoma (type 1), activating mutations of c-Met have been described.¹² However, in sporadic papillary tumors, the frequency of this abnormality is low. Clinical investigation of c-Met inhibitors such as ARQ-197¹³ and XL-990¹⁴ is now in progress. In patients with the hereditary leiomyomatosis and renal cancer syndrome, papillary carcinoma (type 2) contains mutations of the Krebs cycle enzyme fumarate hydratase.¹² In chromophobe carcinoma, a variety of molecular abnormalities have been reported, including mutations of the folliculin gene (17p11.2) in patients with the Birt-Hogg-Dubé syndrome and chromophobe tumors¹⁵ and c-Kit overexpression without activating mutations in more than 80% of sporadic tumors.¹⁶

Histology and Outcome

The importance of RCC histology and its impact on treatment outcome and prognosis has been demonstrated by examining overall survival and progression-free survival (PFS).  Three reports^17-19 have noted that individuals with clear cell carcinoma have a worse prognosis than those with either papillary or chromophobe subtypes. The report by Beck and colleagues,¹⁸ which investigated 1,057 patients, noted clear cell carcinoma was associated with a less favorable 5-year disease-free survival than papillary and chromophobe carcinomas. When tumor size and stage were controlled, only the chromophobe type influenced outcome.

Sarcomatoid differentiation in renal tumors is associated with aggressive clinical behavior and is reported in from 5%−13% of renal tumors.²⁰ Pathologically, this represents a spindle cell phenotype and can occur in any histologic RCC subtype. Most of these patients present with advanced disease and develop metastases.   

Rare non-clear cell subtypes include collecting duct, medullary, and unclassified carcinomas. As a group, these tumors are characterized by a poor prognosis.²¹ The unclassified group is a heterogeneous collection of RCC tumors that cannot be classified pathologically.²²