Molecular and Clinical Prognostic Factors in Renal Cell Carcinoma
Brian Shuch
David S. Finley
Frederic Pouliot
Arie S. Belldegrun
INTRODUCTION
Renal cell carcinoma is a diverse disease in its presentation and clinical behavior. While many patients present with small, indolent tumors, others present with bulky, aggressive disease. Even among those with metastatic disease, a broad clinical spectrum exists. A wide variety of anatomic, histologic, and clinical factors have long been recognized to be prognostic markers of tumor progression and influence survival in RCC. Advancements in molecular biology and genetics have not only provided insight into the molecular pathways involved in kidney cancer but may also influence prognosis.
In this chapter, prognostic factors important to localized and metastatic RCC are summarized, and attention is given to new molecular markers that may be important in future prognostic models. Useful integrated staging systems and nomograms are summarized as they can be applied to individual patients in clinical practice.
ANATOMIC FACTORS
T Classification
The American Joint Committee on Cancer (AJCC) determines staging in renal cell carcinoma by a TNM classification system. The combination of TMN variables is utilized to separate patients into four tumor stages (I-IV) (Table 40.1). The T classification allows stratification according to the size of the primary tumor and the degree of local extension.
Size
Even with complete resection of an organ-confined renal tumor, patients may experience disease recurrence. Tumor size is an important prognostic factor and is the sole determinant of staging for organ-confined tumors. The T1 criteria previously had been reserved for tumors 2.5 cm or less in the 1987 AJCC TMN classification; however, this cutoff changed to 7.0 cm or less in the 1997 version. Later studies demonstrated that tumors larger than 4 cm had worse outcome than smaller tumors (1,2). Thus, the 2002 AJCC TMN system divided T1 into two subdivisions, T1a (≤4 cm) and T1b (>4 cm). The 5-year cancer-specific survival rates after surgery is excellent with T1a and T1b tumors demonstrating a 97% and 87% survival, respectively (3).
The current TNM staging system considers a T2 tumor to be an organ-confined tumor >7.0 cm. T2 tumors demonstrate a 5-year cancer-specific survival of 71% (4). Several groups have reported improved stratification between T1 and T2 tumors with values anywhere from 4.5 to 5.5 cm (1,2,3,5,6,7). The optimal size cutoff for T1 and T2 tumors is still debated. Additionally, it has been suggested that T2 tumors be subdivided into a T2a and T2b category, but this subdivision has been debated in the literature, with studies supporting a 10 cm and a 13 cm cut-point (8,9).
Tumor Extent
T3 and T4 tumors represent locally advanced tumors with regional extension into the perinephric fat, adrenal gland, the renal vein and vena cava, or beyond Gerota’s fascia and into adjacent organs. The classification of T3 and T4 disease has greatly changed between the sixth and seventh editions of the TNM system.
The 5-year cancer-specific survival for T3a tumors in the 2002 edition is 56% to 64% (3,10). T3a tumors with perirenal fat invasion do significantly worse than those with T2 disease and have almost double the risk of death from RCC (11). Recent data question the inclusion of adrenal involvement as a criterion for T3a tumors, as these patients appear to have similar outcome to patients with T4 disease (10,12). Therefore, the new seventh edition of the AJCC TNM system now stages tumors with adrenal invasion as T4 disease.
Renal tumors commonly invade into the vascular space and can lead to a tumor thrombus in up to 10% of patients (13,14). The 2002 TMN system distinguishes T3b (renal vein involvement and inferior vena cava involvement below diaphragm) from T3c (IVC involvement above diaphragm). The 5-year disease-specific survival in the 2002 system for N0M0, T3b or T3c disease is approximately 60% (15). High-level tumor thrombus cases are much more technically challenging and therefore the perioperative mortality is greater. Different series demonstrate conflicting data on whether higher extent changes long-term outcome (13,14,16). Recent series demonstrate that biologic factors rather than tumor extent have a greater influence on prognosis (11,15,17). However, the seventh edition of the TNM system stages tumors with renal vein tumor thrombus as T3a, while those in the vena cava below the diaphragm are T3b.
Nodal Involvement
Prior to 2002, the AJCC TNM system distinguished pathologic nodal involvement based on the number of involved lymph nodes as pN0 = 0, pN1 = 1, pN2 = 2, or more. However, the seventh edition of the AJCC TNM system eliminated N2 and incorporates only N0 and N1 based on the absence or presence of nodes. Performing a regional lymphadenectomy can accurately stage localized disease but may increase survival or disease control (18). For small, localized tumors, the risk of lymph node metastasis is <10% (19). In the setting of metastatic disease, lymph node metastases are found in approximately 50% of patients (20).
The presence of lymph node metastases in the absence of other metastases has a significant impact on overall outcome, with 5-year disease-specific survival of 11% to 35% (21,22,23). Lymph node density may also be important in prognosis; those with >60% density have double the risk of death (24). Patients
with limited nodal involvement may be rendered disease-free with 30% of N1,2M0 patients demonstrating 10-year cancerspecific survival.
with limited nodal involvement may be rendered disease-free with 30% of N1,2M0 patients demonstrating 10-year cancerspecific survival.
TABLE 40.1 AJCC STAGING CHANGES FROM FIFTH TO SEVENTH EDITIONS | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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HISTOLOGIC
Subtype
RCC is the general term to designate any malignant epithelial tumor arising from kidney parenchyma. The current classification system was established to divide the subtypes by histologic appearance and cellular origin (25). The 5-year cancer-specific survival for clear cell RCC (ccRCC) is approximately 70%, while for papillary and chromophobe RCC, it is approximately 85% to 90% RCC (26,27,28). The histological subtypes appear to be associated with different clinical behavior as clear cell tumors present with a more advanced stage and grade, and more frequently demonstrate metastases (27,28). When controlling for the differences in advanced stage and grade, subtype may not be an independent predictor of prognosis (28,29).
Recent changes in subtypes include the subdivision in papillary RCC into two types (I and II). Type II also presents at advanced stage and grade and may be associated with worse prognosis (30,31). Two additional subtypes, renal medullary carcinoma and collecting duct carcinoma, arise from the collecting ducts and have very poor outcomes (32). Unclassified RCC are tumors that do not fit into a specific subtype and act extremely aggressively with over 50% of patients having metastatic disease at presentation (33).
Tumor Grade
Several grading systems in RCC have been developed over the past few decades for purposes of prognostication. The Fuhrman grading system is the most common, distinguishing tumors based on nuclear morphology (34). The Fuhrman nuclear grade correlates with tumor size, metastases, lymph node involvement, and the presence of invasive characteristics such as tumor thrombi or perirenal fat involvement (35). The role of Fuhrman grade in prognosis has been extensively studied with several series demonstrating that with increasing grade, there is an increased risk of cancer-specific mortality (4,36). The 5-year cancer-specific survival rates for grades 1, 2, and grade 3 or 4 are 89%, 65%, and 46.1%, respectively (4).
Controversies exist in the optimal grading system for RCC. Questions regarding intraobserver variability or the utility of Fuhrman grading to nonclear cell subtypes remain unanswered (37,38). Additionally, others have expressed concern over a fourtiered grading system due to intraobserver variability (39).
Tumor Necrosis
Tumor necrosis is a histologic feature associated with tumor aggressiveness. Rapid tumor growth with an inability of blood supply to match metabolic requirements is believed to be responsible for this feature. The presence of tumor necrosis is associated with increased stage, tumor size, and nuclear grade (40,41). The presence of necrosis has been associated with worse survival for localized tumors (40,41,42). The prognostic accuracy of tumor necrosis appears to be improved with a quantitative assessment of necrosis rather than simply designating its presence or absence (43).
Microvascular Invasion
Microvascular invasion is defined as the presence of cancer cells in microvessels and influences prognosis in many types of malignancies. The incidence of microvascular invasion in RCC has been estimated to be 25% to 30% (44,45,46). This feature is an independent predictor of both recurrence and cancer-specific survival and is associated with poor prognostic features such as tumor size, perirenal fat invasion, Fuhrman grade, lymph node involvement, and sarcomatoid features (44,45).
Presence of Sarcomatoid Features
Sarcomatoid features are now considered a high-grade form of RCC that may be present with all histological subtypes (38).
Histologically, the cellular architecture resembles a sarcoma with spindle-shaped cells, cellular atypia, and increased cellularity. While sarcomatoid features are found in <5% of renal tumors, when present, the tumor is usually locally advanced and/or metastastic at diagnosis (47). The 1- and 2-year overall survival rates are 48% and 34%, respectively (47). The percentage of tumor with sarcomatoid features may influence prognosis but several studies have failed to demonstrate a benefit (47,48). Greater percentage of sarcomatoid features leads to worse outcome, but a distinct cut-point has not been found (49).
Histologically, the cellular architecture resembles a sarcoma with spindle-shaped cells, cellular atypia, and increased cellularity. While sarcomatoid features are found in <5% of renal tumors, when present, the tumor is usually locally advanced and/or metastastic at diagnosis (47). The 1- and 2-year overall survival rates are 48% and 34%, respectively (47). The percentage of tumor with sarcomatoid features may influence prognosis but several studies have failed to demonstrate a benefit (47,48). Greater percentage of sarcomatoid features leads to worse outcome, but a distinct cut-point has not been found (49).
Other Features: Capsular Invasion and Collecting System
Other features that may have a role in prognosis are the presence of collecting system invasion and capsular invasion. Collecting system invasion for localized T1 and T2 tumors is rare (50,51). If present, however, these tumors may have a worse prognosis (50,52).
CLINICAL FACTORS
Presentation
The wide spread use of abdominal imaging has altered the presentation of RCC with 40% to 60% of renal tumors now being discovered incidentally (55,56,57). Incidental detection has led to stage migration for RCC (58,59,60,61,62,63,64,65,66,67,68,69). Almost 90% of incidentally discovered tumors are clinical stage I (57). Several studies demonstrate that incidental detection is a strong, independent predictor of survival (55,56); however, other series do not show this effect when controlling for the other variables (60).
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