Pathology of Clear Cell Renal Cell Carcinoma

Clear cell renal cell carcinoma (CCRCC) is a renal cortical tumor typically characterized by malignant epithelial cells with clear cytoplasm and a compact-alveolar (nested) or acinar growth pattern interspersed with intricate, arborizing vasculature. A variable proportion of cells with granular eosinophilic cytoplasm may be present. See the image below.

See Renal Cell Carcinoma: Recognition and Follow-up, a Critical Images slideshow, to help evaluate renal masses and determine when and what type of follow-up is necessary.

Tumors in which eosinophilic cells predominate were previously classified as "granular cell" carcinoma but are currently included among CCRCCs in the 2004 World Health Organization classification of renal tumors based on the presence of vasculature and genetic alterations typical of CCRCC.

The inclusion of tumors with granular cells prompted some classifications to adopt the terminology "conventional" rather than "clear cell" renal cell carcinoma (RCC); however, current classifications have reverted to CCRCC. ^[1] CCRCC is characterized genetically by alterations to chromosome 3p.

Go to Renal Cell Carcinoma and Sarcomatoid and Rhabdoid Renal Cell Carcinoma for more complete information on these topics.

The incidence of renal cell carcinoma (RCC) has been rising steadily in Europe and the United States for the past 3 decades, with a particular rise in the proportion of small, asymptomatic tumors detected incidentally via abdominal imaging.

Evidence of geographic variation exists, with the highest incidences occurring in northern Europe and North America and the lowest occurring in Asia and Africa. Higher rates are reported for men than women (the male-to-female ratios range between 1.5:1 and 2:1), for black versus white Americans, and for urban compared with rural populations. ^{[2, 3, 4]} These trends mainly reflect the incidence of clear cell renal cell carcinoma (CCRCC), which is the most common histologic variant, accounting for 75-88% of RCCs in contemporary surgical series. ^{[5, 6]}

The average age at diagnosis of CCRCC is 60-64 years. ^{[5, 7, 8]} However, 7% of sporadic CCRCC is diagnosed in patients younger than 40 years, ^[9] and rare cases have been reported in patients aged 14-18 years without evidence of familial disorders. ^[10] Some tumors previously diagnosed as CCRCC in younger patients may in fact represent the Xp11 translocation tumor type, which has recently been analyzed. ^[11]

Smoking, obesity, and hypertension are the 3 most well-established risk factors associated with development of sporadic renal cell carcinoma (RCC). Smoking is calculated to play a role in the development of RCC in 10-20% of cases among women and 20-30% of cases among men. Obesity is calculated to contribute to the development of 30% of cases in Europe and up to 40% in the United States and Canada. Relative risks for RCC reported for hypertension range from 1.3-2.0. ^{[2, 3, 4]} By contrast, only 1-5% of RCC in contemporary surgical series are associated with recognized hereditary genetic disorders. ^{[7, 12]}

The main inherited disorder predisposing to development CCRCC is von Hippel-Lindau (VHL) disease, which involves a germline mutation of the VHL gene at chromosome 3p25. Affected individuals are susceptible to tumors of multiple organ systems, including cysts and tumors of the kidney, which occur in 25-45% of cases with a mean age at onset of 40 years. The renal tumors are frequently multifocal and/or bilateral and are always of the clear cell renal cell carcinoma (CCRCC) histologic type. ^[13]

Other familial disorders that carry an increased risk for the development of CCRCC include constitutional chromosome 3 translocations, which have been described in 8 families to date. They involve germline translocations between chromosome 3 and chromosomes 1, 2, 4, 6, or 8, which result in loss of genetic material from chromosome 3. ^[14]

Finally, familial nonsyndromic CCRCC involves families in which multiple relatives develop CCRCCs that often have the hallmarks of hereditary tumors (multifocality, bilaterality, and early age of onset) but for which no genetic cause has yet been discovered. ^[15] CCRCC may also arise in patients with tuberous sclerosis complex or Birt-Hogg-Dubé syndrome, although these syndromes mainly predispose to renal angiomyolipomas and chromophobe or oncocytic hybrid tumors, respectively. ^{[16, 17]}

Clear cell renal cell carcinoma (CCRCC) is proposed to arise from epithelial cells of the proximal convoluted tubules of the nephron, within the renal cortex. ^{[1, 18]} Extension into the renal sinus is the most common pathway of spread for most histologic types of RCC because no connective tissue separates the cortical columns of Bertin from the abundant lymphatics and vasculature within the sinus fat. ^[19]

CCRCCs have a higher propensity for vascular invasion than for lymphatic invasion, ^[20] with malignant cells found within small intrarenal veins even in 18-29% of organ-confined tumors. ^{[21, 22]} Thus, for CCRCC, invasion into the renal sinus usually involves extension within the renal vein, leading to a higher propensity for distant metastasis than for locoregional spread and involvement of the regional lymph nodes, which are more common pathways of spread in chromophobe and papillary RCC, respectively. ^{[21, 23, 24, 25]}

Detailed pathologic examination of 120 consecutive CCRCCs showed renal sinus invasion in 59 (49%) tumors, with 53 (44%) involving the renal vein and 6 (5%) invading renal sinus fat alone. By contrast, only 30 (25%) tumors invaded the renal capsule, and all of these also had renal sinus invasion. ^[26]

Other studies have found spread of CCRCC along the inferior vena cava and/or renal vein in 22-24% of cases. ^{[21, 24]} Analysis of metastatic CCRCC deposits has shown the most commonly involved sites to be as follows ^{[21, 25]} :

• Lung (33-72%)

• Intra-abdominal lymph nodes (3-35%)

• Bone (21-25%)

• Brain (7-13%)

• Liver (5-10%)

Clear cell renal cell carcinoma (CCRCC) is more likely to be symptomatic at presentation compared with other histologic variants of RCC (46% of CCRCC compared with 35% of papillary RCC and 42% of chromophobe RCC). ^[27]

The most common signs and symptoms reported for patients presenting clinically with RCC in modern surgical series include the following:

• Anemia (52% of cases)

• Hepatic dysfunction (32%)

• Gross hematuria (24%)

• Weight loss (23%)

• Hypoalbuminemia (20%)

• Flank pain (20%)

• Malaise (19%)

• Hypercalcemia (13%)

• Anorexia (11%)

Symptoms reported in less than 10% of patients include the following:

• Thrombocytosis

• Night sweats

• Fever

• A flank or abdominal mass

• Hypertension

• Erythrocytosis

• Chills

All of the above signs and symptoms can occur in patients with localized as well as metastatic disease. Many of them represent paraneoplastic syndromes. ^[28]

However, approximately 46% of patients with RCC in modern surgical series are asymptomatic, with the tumor diagnosed incidentally during abdominal radiologic imaging for unrelated symptoms. ^[28] This reflects the introduction of high-resolution ultrasonography and computed tomography (CT) in the 1980s, which has increased the detection rate for RCC, in particular the detection of tumors smaller than 3 cm in maximal diameter. ^[29]

The differential diagnosis of clear cell renal cell carcinoma (CCRCC) is as follows:

• Chromophobe RCC, eosinophilic variant

• Multilocular cystic RCC

• Papillary RCC with clear cell change

• Clear cell papillary RCC

• Translocation RCC

The use of preoperative diagnosis by percutaneous needle core biopsy has shown 78-98% accuracy for determining the histological subtype of renal tumors, even in masses smaller than 5 cm in maximal diameter. ^{[30, 31, 32]}

Although ultrasonography is commonly involved in the detection of renal cell carcinoma (RCC), CT or magnetic resonance imaging (MRI) is better suited for determining detailed staging information, and contrast-enhanced biphasic or triphasic helical CT also has some value in preoperative distinction between histologic subtypes of RCC. ^[33]

A mixed enhancement pattern of both high-attenuation hypervascular soft-tissue components and low-attenuation areas indicative of necrotic or cystic changes is highly predictive of clear cell renal cell carcinoma (CCRCC) (80-90% of cases), compared with other RCC subtypes. However, this pattern is also seen in a considerable proportion (40-60%) of benign oncocytomas. ^[34]

Imaging studies of CCRCC have shown that extensive cystic degeneration with associated necrosis occurs in less than 15% of cases, ^[35] whereas focal cystic necrosis is relatively common. Focal calcification can be seen in 11-26% of CCRCCs, ^{[34, 36, 37]} and ossification may also be present in rare cases. ^[38]

Go to Imaging of Renal Cell Carcinoma for more complete information on this topic.

Clear cell renal cell carcinoma (CCRCC) is typically a solitary tumor, with multifocality and bilaterality only occurring in 2-7% and 1-2% of sporadic cases, respectively. ^{[8, 39, 40]} Tumor sizes in contemporary series range from 0.3-30 cm in maximal diameter, with a mean of 6-7 cm, ^{[5, 8]} although current trends are toward smaller tumors.

The tumor commonly presents as a bosselated, well-circumscribed mass with a capsule or pseudocapsule and a pushing margin. Occasionally, an infiltrative margin is seen. On cut section, CCRCC is typically a golden color because of the accumulation of lipid in the malignant cells, while areas of hemorrhage (brown), fibrosis (gray), necrosis, and cystic degeneration often give a variegated appearance. ^[41] See the images below.

Cytomorphology

Typically, clear cell renal cell carcinoma (CCRCC) is characterized by epithelial cells with clear cytoplasm and a well-defined cell membrane, interspersed within a highly vascularized stroma. The transparency of the cytoplasm results from accumulated droplets of glycogen, phospholipids, and neutral lipids-in particular, cholesterol ester. ^{[42, 43]} Glycogen can be demonstrated by periodic-acid Schiff (PAS) stain, whereas neutral lipids can be identified using the Oil red O stain on unfixed tissue but are dissolved by histological processing.

CCRCC may also contain a variable proportion of cells with granular eosinophilic cytoplasm. Rarely, these granular cells are the predominant or even the only cell type. ^[41] See the images below.

Nuclear characteristics form the basis of the Fuhrman nuclear grading system and are currently used for grading CCRCC, as follows ^[44] :

• Grade 1: Nuclei are small (< 10µm) and round, with dense chromatin and inconspicuous nucleoli

• Grade 2: Nuclei are slightly larger (15 µm), with finely granular chromatin and small nucleoli

• Grade 3: The nuclei are 20 µm in size and may be oval in shape, with coarsely granular chromatin and prominent nucleoli

• Grade 4: The nuclei are pleomorphic, with open chromatin and single or multiple macronucleoli

Increasing nuclear grade is associated with several histologic tumor characteristics, including an increasing proportion of eosinophilic cells ^{[43, 44]} and hyaline globules, which are often associated with granular cytoplasm. These can be identified either intracellularly or extracellularly in 17% of CCRCCs as bright eosinophilic globules that stain positively with PAS stain or red with the Masson trichrome stain. ^{[43, 45]}

Histologic coagulative necrosis occurs in 28-37% of CCRCCs, most commonly in those with high nuclear grade. ^{[39, 46, 47]} Other variations associated with a high grade include cells with sarcomatoid or rhabdoid differentiation. Sarcomatoid differentiation is seen in 5-25% of CCRCCs and is identified as focal to extensive regions of malignant spindled cells growing as whorled or intersecting fascicles, or in a storiform pattern.

Association with histologic necrosis is particularly common. Tumors are usually classified as Fuhrman grade 4 based on the presence of these sarcomatoid elements. ^{[48, 49, 50]}

Rhabdoid differentiation occurs in 3-5% of RCCs, most commonly in CCRCC, and is identified as focal to extensive regions of large, high-grade malignant cells with abundant eosinophilic cytoplasm, irregular eccentric nuclei, and large globular eosinophilic intracytoplasmic inclusions that stain strongly for vimentin. ^{[51, 52, 53, 54]} Occasionally, both forms of differentiation may coexist within a tumor.

Architectural growth patterns

CCRCC may grow in various architectural patterns, with the most common types being compact-alveolar (nested), tubular (acinar), and microcystic. In the compact-alveolar or nested pattern, solid rounded nests of epithelial cells are separated by a delicate branching network of connective tissue that is highly vascularized with thin walled blood vessels, resulting in a sinusoidal appearance. See the images below.

In the tubular or acinar pattern, epithelial cells line the septa of vascularized connective tissue and form central lumens. In regions of cystic degeneration, these structures dilate to form a microcystic and/or macrocystic pattern with luminal spaces containing necrotic material, pale eosinophilic fluid, and red blood cells. ^{[41, 55]} CCRCCs often contain more than one architectural pattern, and focal regions of papillary or pseudopapillary architecture may also occur. See the images below.

When mixed patterns are seen, the possibility of an Xp11 translocation RCC must be considered. These tumors commonly show both papillary architecture and a nested pattern with vascular stroma similar to compact-alveolar (nested) CCRCC. ^[11]

In addition, rare tumors are described in which the malignant clear cell epithelial component is embedded within prolific metaplastic spindle cell stroma (see the image below). ^{[56, 57]}

The spindle cells show evidence of smooth muscle differentiation and, in some cases, merge with the walls of blood vessels, suggestive of vascular proliferation in response to angiogenic factors produced by the tumor. ^[56] Genetic analysis has demonstrated loss of chromosome 3 or 3p in all 3 cases analyzed, ^[57] supporting the authors' proposed classification as a variant of CCRCC.

When papillary areas are noted, care must be taken to exclude the more recently described entity of clear cell papillary renal carcinoma. These tumors are characterized by low-grade nuclear features, usually Fuhrman grade 1 or occasionally grade 2. The tubulopapillary areas are lined by cells with nuclei orientated away from the basement membrane. More classical clear-cell–like areas are often seen. Immunostains for CK7 and CA9 are characteristically positive, while stains for CD10 and AMACAR are negative. Cytogenetic analysis shows no 3p deletions or trisomy 7/17. ^[58]

Ultrastructural studies

Ultrastructurally, CCRCC shows tubular differentiation, with tumor cells clustered around microlumens and separated from the stroma by a well-defined basal lamina. Distinctive features include long microvilli typical of the brush border seen in renal proximal tubules and abundant lipid vacuoles and glycogen deposits.

Other organelles such as Golgi bodies and rough endoplasmic reticulum tend to be absent or sparse and may be pushed to the cell periphery by accumulations of lipid and glycogen. ^[43] Cells with eosinophilic granular cytoplasm still display high levels of lipid and glycogen but also contain increased numbers of mitochondria, which tend to be large, pleomorphic, and haphazardly distributed through the cytoplasm. ^[59]

Immunohistochemistry in typical CCRCC

CCRCC tends to express the low molecular weight cytokeratins (CK) characteristic of simple epithelia (CK7, 8, 18, and 19), in particular, the CK expressed most strongly by epithelial cells of the proximal convoluted tubules (CK8 and 18). Between 94-100% of CCRCCs stain positively with antibodies against CK18, while 14-40% are positive for CK8.

Immunoreactivity for CK7 (14-20%) and CK19 (13-20%) is less common. ^{[60, 61]} Coexpression of these CK has been associated with genomic stability, low grade, and favorable prognosis in CCRCC. ^[62]

Expression of CK7 was observed in all of the recently reported CCRCC variants with smooth muscle stroma, consistent with their low nuclear grades; however, CK19 expression was not determined. ^{[56, 57]} Most (87-100%) CCRCCs strongly express the intermediate filament vimentin, ^{[61, 63]} whereas positive immunostaining for high-molecular-weight cytokeratins (CKs 1-6 and 9-16) is extremely rare. ^{[60, 61]}

Overexpression of the epithelial marker EMA/MUC1 (determined as cytoplasmic and/or total cell membrane staining) is seen in 77-100% of CCRCCs. The proportion of positive cells increases with tumor grade. ^{[64, 65, 66, 67]}

Positive staining for the proximal tubular brush border antigens CD10 and RCC marker is reported for 82-94% and 47-85% of CCRCCs, respectively. ^{[67, 68, 69]} Relatively few CCRCCs are positive for expression of E-cadherin (5-14%), CD117/KIT (0-15%), parvalbumin (8-22%), or AMACR (4-25%). ^{[63, 66, 70, 71, 72, 73, 74, 75]} Thus, a standard immunoprofile expected for CCRCC is vimentin+ /EMA+ /CD10+ /RCC marker+ /AMACR- /CK7- /CK19- /CD117- /E-cadherin- /parvalbumin-. ^[76]

In a 2012 study, epithelial adhesion molecule (EPCAM) was shown to impart independent prognostic value, particularly in low grade CCRCC. ^[77]

Immunostains for AMACR and CK7 are considered most useful for distinguishing CCRCC from papillary RCC, whereas vimentin, CK7, CD117, E-cadherin, and parvalbumin are considered most useful for distinguishing CCRCC from chromophobe RCC and oncocytoma. ^{[75, 76]} Recent evidence suggests that immunostaining for the calcium-binding protein secretagogin may also prove useful for distinguishing CCRCC from other RCC subtypes, with positive staining observed in 35/94 (37%) of CCRCCs but in none of 37 papillary RCC, 24 chromophobe RCC, or 30 oncocytomas. ^[78] This preliminary evidence also suggested an association between strong expression of secretagogin and a higher metastasis rate in CRCC; however, the numbers analyzed were small, and confirmation in a larger study is required.

Immunohistochemistry in atypical CCRCC variants

Distinguishing between unusual variants of the common RCC histologic types and other types of tumors can be difficult. For example, CCRCCs composed predominantly of granular eosinophilic cells may show a morphological resemblance to the eosinophilic variant of chromophobe RCC (chRCC) or to oncocytoma. Immunohistochemical markers suggested for this distinction include E-cadherin, CD117/KIT, or parvalbumin, which are rarely expressed in CCRCC.

By contrast, E-cadherin is positive in 95-100% of chRCC and 47% of oncocytomas, ^{[66, 75]} CD117/KIT is positive in 55-88% of chRCCs and 59-100% of oncocytomas, ^{[71, 72, 75]} and parvalbumin expression is positive in 80-100% of both chRCCs and oncocytomas. ^{[70, 74]}

Other markers that may prove useful include the RCC marker and vimentin. These are commonly expressed in CCRCC, including the granular eosinophilic variant. ^{[68, 69]} By contrast, the RCC marker is expressed in only 0-4% of chRCC and 0-14% of oncocytomas, ^{[67, 68, 75, 79]} while immunostaining for vimentin is positive in only 1-25% of oncocytomas and is negative in chRCC. ^{[63, 70, 75, 80]}

Rare tumors composed mainly of clear cells but with a predominant papillary architecture tend to be classified as papillary RCC with extensive clear cell change. However, genetic analysis has, in some cases, found specific translocations characteristic of Xp11 translocation RCC, a tumor with clear and/or eosinophilic cells that can show both papillary architecture and a nested pattern with vascular stroma similar to compact-alveolar (nested) CCRCC.

Xp11 translocation RCCs usually occur in children but can occasionally arise in adults. They can be identified by nuclear immunostaining for the TFE3 protein. ^[11] In other such cases, genetic analysis has revealed alterations typical of CCRCC (loss of chromosomes 3p, 7, and 17) ^[81] or a combination of the alterations seen in CCRCC (loss of 3p and 14, gain of 5q) and papillary RCC (gain of chromosomes 7 and 12). ^[82]

Histologic typing of such tumors remains controversial because the immunostaining profiles for CCRCC and papillary RCC can be similar regarding vimentin, CD10, RCC marker, and EMA/MUC1. ^{[75, 76]} Because few CCRCCs express AMACR or CK7, these immunohistochemical markers may prove useful for distinguishing CCRCC from papillary RCC with extensive clear cell change and/or predominantly nonpapillary (solid) architecture. AMACR is expressed in 87-100% of papillary RCCs of both type I and type 2, ^{[73, 75]} while CK7 expression is present in 80-87% of papillary RCCs. ^{[60, 61]}

RCC with predominantly papillary architecture but extensive clear cell cytology can be characterized using both genetic analysis (chromosomes 3p, 7, 17, and Y) and immunostaining (AMACR, CK7, TFE3). In a study of 14 such cases, ^[83] the immunostaining and genetic profiles correlated well, and this approach allowed classification of 9 tumors as papillary RCC and 3 as CCRCCs, leaving only 2 cases as unclassified RCC.

CCRCC with extensive cystic degeneration must be distinguished from multilocular cystic renal cell carcinoma (MCRCC), which is recognized in the 2004 WHO classification as a separate type of low-grade tumor with a very good prognosis. ^[84] MCRCC may have clear cells lining the cysts and small nests of clear cells within the fibrous septa; however, this tumor can be distinguished from CCRCC with cystic change, or from CCRCC arising within the wall of a pre-existing cyst, by the absence of expansile solid nodules. ^[85]

Low-grade CCRCC with a predominant component of metaplastic smooth muscle stroma must be distinguished from mixed epithelial and stromal tumor of the kidney (MESTK), a benign tumor in which the epithelial components are predominantly cystic, clear cells are rare, the epithelial cells do not express S100 protein, and the spindled cells are immunopositive for ER in 64% and PR in 32% of cases. ^{[86, 87]}

By contrast, in all CCRCCs with smooth muscle stroma tested to date, cystic components were rare, the epithelial components were positive for S100, and the spindled cells were negative for ER and PR. ^{[56, 57]} The smooth muscle component of this CCRCC variant has a morphological resemblance to muscle-predominant renal angiomyolipoma or to leiomyoma but can be distinguished by immunostaining for HMB45, which is positive in the latter 2 tumor types. ^[88]

Molecular and genetic aspects of CCRCC

Studies in patients with VHL disease established the importance of genetic alterations involving chromosome 3p in the development of CCRCC, while subsequent research has shown that chromosome 3 or 3p is lost in 80-98% of sporadic CCRCCs. ^{[89, 90, 91]}

Inactivation or loss of the VHL gene results in the absence of a functional VHL protein, which under normoxic conditions usually targets the alpha subunit of the transcription factor hypoxia-inducible factor (HIF) for degradation. Loss of functional VHL protein therefore leads to accumulation of HIF and activation of its hypoxia-inducible target genes under normoxic rather than hypoxic conditions. HIF target genes include the vascular endothelial growth factor gene VEGF, which may explain the prolific angiogenesis associated with CCRCC. ^[13]

Although alterations at 3p are believed to be the initiating genetic event, recent work suggests that CCRCC can subsequently progress along at least 2 distinct genetic pathways. ^[91] The most common pathway (80% of CCRCC) mainly involves losses of entire chromosomes and partial losses through unbalanced translocations, resulting in a hypodiploid karyotype. In this pathway, loss of 3p often occurs together with gain of 5q via a translocation between chromosomes 3 and 5. Gain of 5q is seen in 40-70% of cases, and this tends to be followed by losses of chromosomes 14 or 14q (40-60%), 8 or 8p (20-30%), 9 or 9p (15-25%), and 6 or 6p (15-25%). Furthermore, as a result of the HIF1A gene residing on chromosome 14, loss of 14q has been associated with differential expression of HIF1α and subsequent prognostic phenotypes. ^{[92, 93]}

A less common pathway followed in 18% of CCRCCs mainly involves gains of entire chromosomes resulting in a hyperdiploid karyotype. Common gains involve chromosomes 7 (18-30%), 16 (11%), 20 (10%), 12 (10-15%), and 2 (9-14%). This second pathway is similar to the genetic events seen in papillary RCC, except that most (67%) papillary RCCs also show gain of chromosome 17.

Progression of CCRCC can eventually involve reduplication of the entire genome to give a polyploid karyotype, followed by further losses or gains of genetic material. ^{[89, 90, 91]} Complex polyploid karyotypes are particularly common in tumors with sarcomatoid differentiation. ^{[94, 95]}

Clear cell renal cell carcinoma (CCRCC) is currently staged according to the 2002 version of the American Joint Committee on Cancer's TNM (tumor-node-metastasis) staging system for renal tumors. ^[96] Most criteria of this revised system reflect the pattern of spread common in CCRCC.

Tumors restricted to the kidney are stratified as follows:

• T1a (4 cm or less in maximal diameter)

• T1b (greater than 4 cm but not greater than 7 cm)

• T2 (greater than 7 cm)

Tumors not restricted to the kidney are stratified as follows:

• T3a (invading adrenal gland or perinephric and/or renal sinus fat but not beyond Gerota's fascia)

• T3b (extending into the renal vein, or the inferior vena cava [IVC] but below the diaphragm)

• T3c (extending into the IVC above the diaphragm or invading into the wall of the IVC)

• T4 (extension beyond Gerota's fascia)

Tumors are stratified according to regional lymph node metastasis as follows:

• NX (nodes not assessed)

• N0 (no nodal involvement)

• N1 (involvement of a single node)

• N2 (involvement of more than one node)

Finally, tumors are stratified according to distant metastasis as follows:

• MX (distant metastasis not assessed)

• M0 (no distant metastasis)

• M1 (distant metastasis present)

Treatment for organ-confined CCRCC is primarily surgical, with partial nephrectomy usually considered for tumors smaller than 4 cm in diameter (stage pT1a) and radical nephrectomy for tumors larger than 4 cm. ^[97] Trials of cryoablation and radiofrequency ablation for small tumors have shown local recurrence rates of 5% and 12%, respectively, compared with 3% for partial nephrectomy. ^[98]

Approximately 20% of patients with metastatic clear cell renal cell carcinoma (CCRCC) respond to cytokine immunotherapy with interleukin-2, although the median survival is increased only from 10 months to 34 months. ^{[55, 99]} Clinical trials show slightly more promising results for treatment of metastatic CCRCC with antiangiogenic agents (sunitinib, sorafenib; see the image below) and mTOR kinase inhibitors (temsirolimus), which have been approved for treatment of RCC in the United States and Europe. ^[99]

Patients with clear cell renal cell carcinoma (CCRCC) tend to have a worse prognosis than patients with other histologic subtypes of RCC, with 5-year disease-specific survival rates of 50-69%, compared with 67-87% for papillary RCC and 78-87% for chRCC. ^{[7, 8, 46, 100]} However, analysis of 1000 patients showed very similar 5-year disease-specific survival rates for CCRCC (10.5%) and papillary RCC (10.3%) once metastatic disease was present. ^[5]

Multivariate analyses indicate that histologic RCC subtype has no significant independent value for predicting cancer-specific survival because prognosis is primarily dependent upon TNM stage and Fuhrman nuclear grade. ^{[5, 8, 40]} Multivariate analysis specifically of CCRCC cases shows that in addition to the 3 separate components of tumor staging (T, N and M stage), other significant independent predictors of poor prognosis are nuclear grade, tumor size, and the presence of histologic necrosis or sarcomatoid differentiation. ^{[39, 46, 47, 24]}

Rhabdoid differentiation is also observed in CCRCC and seems to impart a poor outcome similar to sarcomatoid change ^{[51, 53, 54]} ; however, this factor has not yet been tested in predictive models. Interestingly, histological necrosis is seen more commonly in papillary RCC (39-46%, compared with 28-37% for CCRCC) but is not a significant predictor of poor prognosis for papillary RCC, even in univariate analyses. ^{[7, 46, 47]}

Assessment of molecular pathways may further contribute to predicting ultimate prognosis. The association between loss of chromosome 14q and differential expression of HIFα1 on clinical outcome in patients with nonmetastatic CCRC may advocate these as molecular markers of poor prognosis. ^{[92, 93]} In addition, recent data related to mTor and hypoxia-induced pathways in CCRCC appear encouraging and may provide improved prognostication for the individual patient. ^[101]