Cancer of the Kidney - Clinical Tree

Summary of Key Points

Renal cell carcinoma (RCC) accounts for 4% to 5% of malignancies in adults.
Cigarette smoking (in more than 20% of cases) and obesity (in more than 30%) are established causal factors for RCC.
Four percent of cases of RCC arise from hereditary syndromes.
Different subtypes of RCC are characterized by distinct clinical behavior, genetic abnormalities, and molecular signatures.
Clear cell RCC is the most common histologic subtype, representing approximately 70% of all sporadic RCCs.
The von Hippel-Lindau tumor suppressor gene is genetically and epigenetically altered in more than 75% of sporadic cases of clear cell RCC.
Prognosis for RCC is dependent on tumor histologic type, grade, and stage.
Nephron-sparing surgery has become the gold standard, when feasible.
Follow-up guidelines for resected RCC include history, physical examination, periodic metabolic panels, and abdominal and chest computed tomography (CT) studies 4 to 6 months after surgery.
Anti–vascular endothelial growth factor (anti-VEGF) targeted drugs are the current standard of care in the first-line setting for metastatic clear cell RCC.
Anti-PD-1 therapy (nivolumab) has proven benefit in patients previously treated with anti-VEGF therapy. Additional immunotherapeutic approaches (with or without anti-VEGF targeted therapy) are under development in first-line metastatic patients.
Clinical benefit has also been shown with VEGF and mammalian target of rapamycin (mTOR) inhibitors in subsequent lines of therapies either alone or in combination (i.e., lenvatinib and everolimus). Novel targets for therapeutic interventions have been identified and are under clinical development.
Optimal treatment for non–clear cell RCC remains a challenge because of the genetic differences and little knowledge of the dysregulated molecular biology driving these cancers.

Renal cell carcinoma (RCC) accounts for approximately 4% of adult malignancies, including approximately 90% of primary renal tumors. RCC arises from the renal cortex and consists of several distinct subtypes of adenocarcinoma, with the most common being clear cell carcinoma and papillary carcinoma. In addition to RCC, other benign and malignant tumors occur in the kidney. For example, urothelial (transitional) cell carcinoma of the renal pelvis is a disease that is clinically, pathologically, and biologically distinct from RCC and is much less common, representing only 8% of kidney tumors. Other kidney tumors of benign histologic type include oncocytomas, angiomyolipomas (AMLs), fibromas, lipomas, lymphangiomas, and hemangiomas.

RCC exists in sporadic and hereditary forms. The sporadic form of the disease is usually first seen in the fifth decade of life or later. The clinical presentation of RCC has been described with the classic triad of symptoms of hematuria, flank pain, and fever. With the increased general use of imaging techniques, however, the vast majority of kidney tumors are now being detected incidentally. Improved surgical techniques for treatment of localized disease and novel systemic therapies for metastatic renal cell carcinoma (mRCC) have changed the management of this condition.

Epidemiology

The incidence of kidney cancer varies substantially worldwide, with the highest rates observed in Europe, North America, and Australia and the lowest rates in Asia. This suggests that genetic variation and lifestyle factors play a role in the development of RCC. Globally, kidney cancer incidence rates increased from the 1970s to the mid-1990s, then plateaued or decreased. However, in the United States, annual incidence rates of RCC have continued to rise, and the estimated number of new cases of kidney and renal pelvis tumors for 2018 is 65,340. The continued upward trend is largely driven by increasing rates of localized disease, whereas rates of regional or metastatic disease have remained relatively stable. The increasing incidence of RCC has been attributed to increased detection as a result of the widespread use of imaging modalities such as computed tomography (CT), ultrasonography, and magnetic resonance imaging (MRI). RCC is more common in men, with an approximately 2 : 1 male-to-female predominance. In the United States, incidence is lowest among Asian/Pacific Islanders and roughly equivalent among white, black, American Indian/Alaska Natives, and Hispanics.

Risk Factors for Sporadic Renal Cell Adenocarcinoma

The best established risk factors for RCC are cigarette smoking and obesity. A meta-analysis of 24 RCC studies, including 17,245 patients with RCC and 12,501 control subjects, demonstrated increased rates of RCC and worse disease-specific mortality in smokers compared with nonsmokers. In this meta-analysis, the pooled relative risk (RR) rates of RCC incidence were 1.31 (95% confidence interval [CI], 1.22–1.40) for all smokers, 1.36 (95% CI, 1.19–1.56) for current smokers, and 1.16 (95% CI, 1.08–1.25) for former smokers. The related RCC disease-specific mortality risks were, respectively, 1.23 (95% CI, 1.08–1.40), 1.37 (95% CI, 1.19–1.59), and 1.02 (95% CI, 0.90–1.15). In addition, smoking has been associated with more advanced RCC stage at presentation. Based on these data, smoking significantly increases the risk of developing and dying from RCC, and smoking cessation reduces the risk back close to baseline.

In addition to smoking, obesity is also an established independent risk factor for RCC. This has been demonstrated in several prospective cohort studies, including the National Institutes of Health (NIH) and AARP Diet and Health Study, which followed 528,772 participants from 1995 to 2003 and identified an association between the incidence of RCC and elevated body mass index (BMI). In this study, the RR of RCC increased consistently from lower baseline BMI to higher baseline BMI, and this association persisted after adjustment for hypertension and other variables ( P -trend < .0005). The multivariate RR of RCC at a BMI of 25 to less than 27.5 kg/m ² was 1.43 (95% CI, 1.07–1.92) for men and 1.57 (95% CI, 1.07–2.29) for women, compared with the 18.5 to less than 22.5 kg/m ² control group. The RR of RCC for participants with BMI ≥35 kg/m ² was 2.47 (95% CI, 1.72–3.53) for men and 2.59 (95% CI, 1.70–3.96) for women. The mechanisms underlying the association between obesity and cancer are not fully understood but may relate to dysregulation of three hormonal systems: insulin and insulin-like growth factor, androgens, and adipokines. Other possible causes include chronic tissue hypoxia, obesity-induced inflammatory response, and lipid peroxidation and oxidative stress.

With regard to other RCC risk factors, there is evidence that hypertension is associated with an increased risk of kidney cancer, independent of smoking, obesity, or use of antihypertensives. Patients with end-stage renal disease also have an increased incidence of RCC when compared with the general population. Patients undergoing prolonged dialysis tend to develop acquired renal cystic disease, possibly as a result of disordered proliferation within the native kidney. In these patients, the tumors often are bilateral and multifocal, with a papillary histologic type. Accordingly, these patients should be monitored regularly with renal ultrasonography, CT, or MRI. If the patient is on dialysis, then nephrectomy is typically preferred, even when the tumor is smaller than 4 cm, providing the risk of surgery is reasonable. Additional evidence suggests a potential role in RCC for alcohol consumption, occupational exposure to trichloroethylene, and high parity among women. However, further research is needed into the potential causal effects of genetic factors and their interaction with environmental exposures. Large studies employing genome-wide scanning technology are in progress to provide novel discoveries in renal carcinogenesis.

Pathology

Kidney tumors usually are unilateral but are bilateral in 2% to 4% of cases. Vascular involvement is present in 4% to 10% of patients at the time of presentation. From a pathologic and surgical prospective, it is important to distinguish a tumor thrombus from a positive margin at the vascular surface, because a true positive margin (with actual invasion into the wall of the vessel) portends a poor prognosis.

RCC is a clinically and pathologically heterogeneous disease. The 2004 World Health Organization (WHO) classification for renal neoplasms recognized several distinct histologic subtypes of RCC ( Table 79.1 ). These subtypes include clear cell RCC, papillary RCC, chromophobe RCC, hereditary cancer syndromes, multilocular cystic RCC, collecting duct carcinoma, medullary carcinoma, mucinous tubular and spindle cell carcinoma, neuroblastoma-associated RCC, Xp11.2 translocation– TFE3 carcinoma, and unclassified lesions. The 2016 WHO update to the RCC classification added several other subtypes: hereditary leiomyomatosis and RCC syndrome–associated RCC, succinate dehydrogenase–deficient RCC, tubulocystic RCC, acquired cystic disease–associated RCC, and clear cell papillary RCC (previously called renal angioadenomatous tumors). Clear cell RCC is the most common adult RCC, representing 70% of all RCCs. Less common subtypes include papillary RCC types I and type II (10% to 15%), chromophobe RCC (4% to 6%), collecting duct carcinoma (less than 1%), and unclassified RCC (4% to 5%). Tumors may be composed of mixed histologic subtypes, and each subtype may feature high-grade sarcomatoid characteristics. The conventional histologic pattern is the most common, characterized by large clear cells with abundant cytoplasm. The chromophobe pattern is granular with abundant mitochondria. The papillary or tubulopapillary variant may represent a different type of tumor, because they tend to be smaller with fewer anaplastic features. The most widely used grading system for RCC is the nuclear grading system developed by Fuhrman and colleagues. This system assigns a grade from I to IV, based on nuclear size, roundness, and other morphologic features, such as the prominence of nucleoli and the presence or absence of clumped chromatin. Patients with tumors of high Fuhrman grade tend to have poorer clinical outcomes. However, many pathologists omit Fuhrman grade when the apparent aggressiveness of the histologic type is not related to prognosis (e.g., chromophobe carcinoma, which tends to have a favorable prognosis even when the cellular characteristics appear aggressive).

Table 79.1

Histologic Classification of Renal Cell Carcinoma

Modified from Prasad SR, Humphrey PA, Catena JR, et al. Common and uncommon histologic subtypes of renal cell carcinoma: imaging spectrum with pathologic correlation. Radiographics. 2006;26:1795–1806.

SPORADIC RENAL CELL CARCINOMA (RCC) 2004 WORLD HEALTH ORGANIZATION (WHO) CLASSIFICATION
Histologic Tumor Type	Prevalence (%)	Cytogenetic Findings
Clear cell RCC	70	3p25-26 (VHL)
Papillary RCC	10–15	Trisomy of chromosomes 7 and 17, loss of Y chromosome, 7q34 (c-MET)
Chromophobe RCC	4–6	Loss of multiple chromosomes: 1, 2, 6, 10, 13, 17, 21
Multilocular cystic RCC	<1	Extracellular matrix gene
Collecting duct carcinoma	<1	Loss of multiple chromosomes: 1, 6, 8, 13, 14
Medullary carcinoma	<1	Sickle cell trait
Mucinous tubular and spindle cell carcinoma	<1
Neuroblastoma-associated RCC	<1
Xp11.2 translocation– TFE3 carcinoma	1–2	Translocations involving Xp11.2 ( TFE3 )
Unclassified lesions	4–5
HEREDITARY RCC: SYNDROMES AND HISTOLOGIC TUMOR TYPES

Hereditary Syndrome	Chromosome (Gene) Abnormality	Histologic Type of Renal Tumor	Systemic Manifestations
von Hippel-Lindau	3p26 (VHL)	Clear cell RCC	Retinal angiomas, central nervous system hemangioblastomas, pheochromocytoma
Hereditary papillary RCC	7q34 (MET)	Type 1 papillary RCC	None
Hereditary leiomyoma RCC	1q42–43 (FH)	Type 2 papillary RCC	Cutaneous and uterine leiomyomas
Birt-Hogg-Dube syndrome	17p11.2 (BHD)	Chromophobe RCC, oncocytoma, hybrid tumors	Skin lesions, lung cysts

Genetics and Biologic Characteristics of Renal Cell Carcinoma

Until recently, RCC was thought to represent a monomorphic disease arising from a probable common precursor cell but with different histologic and clinical manifestations. Genetic characterization based on cytogenetics and molecular biology has established that different subtypes of RCCs are characterized by distinct genetic abnormalities and molecular signatures reflecting the differences in the cell type, biology, and underlying molecular mechanisms ( Fig. 79.1 ). Additional alterations in metabolic pathways in addition to epigenetic changes may explain the biologic diversity of RCC.

Figure 79.1, Genetic signatures in renal cell carcinoma (RCC). Determining the genetic signature in renal tumors not only has advanced the tumor classification but also will contribute to the optimal selection of therapies. (A) Kinase expression in RCC. These data show the gene expression of approximately 80 kinases (of 518) that have differential expression across the subtypes, with red indicating strong expression. Recognition of c-MET and c-Kit expression allows clustering the samples in specific subtypes. These types of data will guide the selection of patients undergoing treatment with kinase inhibitors. Chromo, Chromophobe; Onco, oncocytoma; PapI, papillary type I; PapII, papillary type II. (B) Summary of the common 3p deletion/5q amplification signature that characterizes clear cell carcinoma. Interesting to note, the 3p region that harbors the VHL gene also contains histone-modifying genes that have been reported to be commonly mutated in this histotype.

Sporadic Renal Cell Carcinoma

Clear Cell Renal Cell Carcinoma

A common genetic feature signature of sporadic clear cell RCC is the loss of chromosome 3p, suggesting the presence of one or more RCC tumor suppressor genes at this site. The von Hippel-Lindau tumor suppressor gene (VHL), which resides on chromosome 3p25, is mutated or silenced in more than 50% of sporadic clear cell RCCs. Germline mutations in VHL give rise to von Hippel-Lindau syndrome, which is characterized by an increased risk of blood vessel tumors (hemangioblastomas), endocrine tumors, and RCC. The VHL gene product, pVHL, is the substrate recognition module of an E3 ubiquitin ligase that targets the hypoxia-inducible factor (HIF) α transcription factors (HIF-1α, HIF-2α, and HIF-3α) for destruction in the presence of oxygen. Hypoxic cells, or cells lacking pVHL (“pseudohypoxic”), accumulate high levels of HIF, which activates the transcription of a variety of genes, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF-3) B, and transforming growth factor alpha (TGF-α). Restoration of pVHL function in VHL− / − mutant renal carcinoma cells suppresses their ability to form tumors experimentally by reducing HIFα levels. Inhibition of HIFα is necessary and sufficient for tumor suppression by pVHL in RCC nude mouse xenograft assays. This provides a rationale for treating VHL− / − RCC with inhibitors of HIFα or its downstream targets. Although the HIF-1α isoform was initially believed to be more important, increasing literature supports HIF-2α as the more important HIFα member in mediating tumorigenesis. Although most investigation has focused on the role of HIFα isoforms, the pVHL protein also has several other targets in addition to HIFα, postulated by some to contribute to tumorigenesis. Elucidating these targets will lead to further knowledge of how pVHL suppresses tumor growth. Analysis of mutations in exon 3 of the VHL gene may be useful in refining the diagnostic criteria for conventional RCC versus chromophobe RCC with clear cell features.

Papillary Types I and II Renal Cell Carcinoma

Genetic studies in familial RCC have led to the identification of genes responsible for non–clear cell histiotypes as well. However, unlike clear cell RCC, gene mutations identified in hereditary non–clear cell RCC are absent in the vast majority of sporadic cases. Activating mutations in the MET oncogene responsible for hereditary papillary renal cell carcinoma (HPRCC) are found in only approximately 10% of sporadic papillary type I RCC cases. The MET tyrosine kinase receptor localizes to the cell membrane, where it binds its extracellular ligand, hepatocyte growth factor, triggering intracellular activation of the Akt, Ras, and MAP kinase signaling pathways, promoting cell proliferation and migration. Hyperactivation of MET signaling is believed to promote tumorigenesis by upregulation of these downstream pathways. Both MET and hepatocyte growth factor (HGF) localize to chromosome 7, which is commonly amplified in sporadic papillary type I RCC.

The fumarate hydratase (FH) gene encoding a Krebs cycle enzyme and mutated in hereditary papillary type II RCC (as part of hereditary leiomyomatosis and RCC syndrome) has not been identified in sporadic papillary type II. However, increased activity of the NRF2 transcription factor resulting from FH loss in hereditary papillary type II has also been demonstrated in sporadic papillary type II renal cancers.

The largest molecular analysis of papillary RCC to date included 161 tumors (75 type I, 60 type II, and 26 unclassifiable). This analysis underscored the tumor heterogeneity of papillary RCCs, as whole-exome sequencing identified 10,380 somatic mutations. The most common mutations (representing 24% of tumors) were found in a set of five genes ( MET, SETD2, NF2, KDM6A, and SMARCB1 ). Some of the mutations were associated with cancer-associated pathways, including the Hippo signaling pathway, the SWI/SNF complex, and several chromatin remodeling pathways. Papillary RCC was also clustered by mRNA expression panels into four subtypes associated with progressively worse prognosis (cluster C1 associated with type I papillary RCC, mutations in MET, and earlier stage; cluster C2a with type II papillary RCC and early stage; cluster C2b with exclusive type II papillary RCC and unclassified RCC, and later stage at diagnosis; and cluster C3c with a CpG island methylator phenotype in type II papillary RCC). Thus with the molecular heterogeneity within each subtype of papillary RCC, this analysis showed the distinct differences between type I and type II papillary RCC.

Chromophobe Renal Cell Carcinoma

As with papillary types of RCC, the genetic mutations underlying sporadic chromophobe RCC tumorigenesis remain to be elucidated, and appear to have little mutational overlap with hereditary chromophobe RCC. The folliculin gene mutated in the most common type of hereditary chromophobe RCC (Birt-Hogg-Dube syndrome [BHD]) is rarely mutated (0%–10%) in sporadic chromophobe RCC tumors. Whereas PTEN has been implicated in a rarer type of hereditary chromophobe RCC, its mutation is yet to be identified in the sporadic disease.

TFE3-Fusion Renal Cell Carcinoma

Also known as Xp11 translocation kidney cancer, TFE3-fusion RCC represents less than 1% of all sporadic renal cell cancers. It is the most recently designated histologic subtype of RCC by the WHO. TFE3-fusion RCC occurs in younger patients and is the most common mutation in pediatric RCC tumors. These tumors are clinically aggressive and commonly present with metastasis, particularly to regional lymph nodes. These tumors harbor a pathognomonic fusion between the TFE3 gene of chromosome Xp11.2 and one of a number of possible fusion partners on various chromosomes, most commonly PRCC, ASPRC1, and SFPQ. The TFE3 gene encodes a transcription factor involved in the regulation of many proteins implicated in carcinogenesis, including TGF, MET, Rb, folliculin, Ets, and E-cadherin. It is believed that the fusion promotes tumorigenesis by causing dysregulated transcriptional TFE3 activity. TFE3 and TFEB gene fusions were identified in 10.6% of 161 papillary RCC tumors. Immunohistochemical detection of nuclear TFE3 expression is suggestive of the underlying fusion mutation ; however, definitive diagnosis requires genetic confirmation by karyotype, fluorescence in situ hybridization, or polymerase chain reaction (PCR).

Rarely, fusions between the related transcription factor gene, TFEB, and the MALAT1/Alpha gene also are found in renal cancers. The histology of these tumors appears to be distinct from that of TFE3 -fusion tumors. TFEB -fusion cancers similarly occur in younger patients but, in contrast to TFE3 -fusion cancers, appear to confer an excellent prognosis. The function of the TFEB transcription factor is unknown, but a central role in lysosome biogenesis and autophagy regulation has been suggested.

Familial Renal Cell Carcinoma

In a small percentage (5%) of cases, RCC is a feature of one of several hereditary syndromes. Such syndromes are associated with distinct histologic subtypes of RCC, and in each case patients have increased risk of multifocal tumor development. Management is dependent on preservation of renal function. Close surveillance and minimization of surgical procedures constitute the mainstay of treatment.

von Hippel-Lindau syndrome is a disorder of autosomal dominant inheritance that occurs in 1 in 40,000 births. The mean age at onset is in the fourth decade of life. The syndrome is inherited as a result of a germline mutation in a single allele of the VHL gene tumor suppressor gene located on chromosomal band 3p25–26. Sporadic loss of the remaining wild-type VHL allele provides the “second hit” necessary for tumorigenesis, most commonly via chromosome 3p deletion. Multifocal tumorigenesis is observed in multiple organ systems, with each tumor harboring an independent second VHL mutation. Renal manifestations include cysts and clear cell RCC tumors. Both tend to be multifocal and bilateral and are found in the majority of patients with von Hippel-Lindau disease. Hundreds of independent clear cell cancers may be present in a single kidney, including dozens of macroscopic tumors. VHL syndrome patients are at high risk for chronic renal insufficiency because of the lifelong risk of multifocal RCC tumor development and need for repeat renal surgeries. As a result, VHL patients should undergo active surveillance until the largest tumor reaches 3 cm, at which time attempts may be made to resect all tumors in that kidney. Resection by enucleation without clamping of the main renal artery is recommended to maximize nephron sparing. Surgical candidates, particularly those with numerous tumors, are counseled as to the high possibility of local recurrence from de novo tumor formation and future ipsilateral surgery. The discovery of the VHL gene in hereditary clear cell RCC enabled the subsequent identification of a VHL mutation in sporadic clear cell RCC tumors (see earlier).

In addition to renal cysts and cancer, common manifestations of the VHL syndrome include benign vascular tumors of the spinal cord, cerebellum, and retina, manifesting with neurologic and visual symptoms. The endocrine system may also be affected by adrenal pheochromocytomas and pancreatic neuroendocrine tumors, in addition to pancreatic cysts. Benign papillary cystadenomas of the epididymis or broad ligament also develop in a minority of patients, which, when bilateral are pathognomonic for von Hippel-Lindau disease. The finding of firm epididymal nodules at physical examination should prompt scrotal ultrasonography and with a family history of VHL provides an easy method to confirm the diagnostic suspicion. Endolymphatic sac tumors of the inner ear also may be seen.

Birt-Hogg-Dube syndrome is a disorder of autosomal dominant inheritance. Signs and symptoms usually manifest in the fifth decade of life and include renal tumors and cysts, benign skin tumors (fibrofolliculomas) and pulmonary cysts, which can lead to spontaneous pneumothorax. The renal neoplasms may be multifocal and bilateral tumors and most often have pure chromophobe histologic features or a “hybrid” mixture of chromophobe and oncocytoma; infrequently, pure oncocytoma tumors may be present. Patients can have several different tumor types within the same kidney, and the presence of benign tumors (oncocytoma) and malignant tumors within the same kidney should immediately prompt the suspicion of BHD syndrome. The BHD gene mutated in this syndrome encodes the protein folliculin and is located on chromosome 17p11.2. The BHD gene appears to have the characteristics of a loss-of-function tumor suppressor gene. Folliculin has unknown function but is found in complexes with adenosine monophosphate–activated protein kinase, the major sensor of cell energy and a negative regulator of the mammalian target of rapamycin (mTOR) pathway. Multiple studies have implicated folliculin in adherens junction formation and signaling.

Tuberous sclerosis is a syndrome of autosomal dominant inheritance, with two genes identified: TSC1, located on 9q34, and TSC2, located on 16p13.3. It affects 1 in 6000 people and is usually diagnosed at birth. This syndrome encompasses multiple organ systems, including dermatologic, cardiac, pulmonary, and renal. Skins lesions include facial angiofibromas, periungual fibroma, shagreen patches, and hypopigmented macules. Patients also develop cardiac rhabdomyomas, pulmonary lymphangioleiomyomatosis, retinal hamartomas, subependymal nodules, and giant cell astrocytomas. The renal manifestations include bilateral and multifocal AMLs and, less commonly, clear cell renal carcinoma. In contrast to spontaneous AML, AML in this setting can be associated with a low risk of occult RCC (1%). The TSC1 and TSC2 gene products inhibit activation of mTOR signaling, a major promoter of protein synthesis and cell growth.

Hereditary papillary renal cell carcinoma, inherited as an autosomal dominant trait, is caused by mutations in the MET proto-oncogene on chromosomal band 7q31–34. It is characterized primarily by bilateral, multifocal papillary type I RCC. These tumors are not aggressive and rarely metastasize. Age at onset is around the fifth decade. The MET oncogene encodes a membrane tyrosine kinase that, in HPRCC, harbors an activating mutation in the kinase domain. Hyperactivation of the MET oncoprotein leads to upregulation of several intracellular signaling pathways involving Akt, Rac, and MAP kinase.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a disease of autosomal dominant inheritance. The gene for this disorder localizes to chromosomal band 1q42.3–43 and has been identified as FH. Age at onset is between the third and fourth decades of life. The syndrome consists of cutaneous leiomyomas, uterine leiomyomas (fibroids), and papillary type II RCC tumors with high metastatic potential, even when small in size. Unlike the VHL patients, in whom delay in surgical treatment is usually the rule until the largest tumor reaches 3 cm, there should be no delay in treatment of solid renal lesions in these patients, because the disease is aggressive and metastasizes quickly. Cystic lesions in these patients should be followed with close surveillance and early surgical intervention for any radiographic development of a potentially solid component. Thirty percent of patients have solitary and unilateral renal tumors.

The FH gene functions as a tumor suppressor, with loss of the second allele detected in kidney tumors. The wild-type gene encodes an enzyme in the Krebs cycle catalyzing fumarate conversion into malate. Loss of the FH enzyme leads to accumulation of fumarate, which has been suggested to promote carcinogenesis through indirect stabilization of transcription factors HIFα and NRF2.

Distinct from HPRCC and HLRCC, Malchoff and colleagues have described a three-generation family with five cases of papillary thyroid carcinoma and two cases with papillary renal neoplasia. With the use of linkage analysis, these investigators demonstrated that the fPTC/PRN phenotype was linked to 1q21. They characterized a distinct inherited tumor syndrome that may establish a link between papillary RCC and familial papillary thyroid carcinoma.

Hereditary renal cell cancer associated with melanoma has also been described . The TFE3 gene mutated in sporadic RCC is one of four members of the MiT family of transcription factors; although TFE3 mutations have not been identified in hereditary RCC syndromes, the related MiT member, MiTF, was shown to have a specific amino acid substitution associated with hereditary RCC tumors associated with melanoma. This substitution confers hyperactivation of MiTF transcriptional activity by preventing its SUMOylation and degradation. Histologic features of these MiTF renal cancers are yet to be characterized.

Diagnosis of Renal Cell Carcinoma

As the use of imaging methods has become more widespread, the frequency of incidental detection of RCC has increased. Patients with RCC typically have a mass involving the kidney that is suggestive of the diagnosis. Nephrectomy is the most effective therapy for RCC that is confined to the kidney and should be used both diagnostically and therapeutically in most patients who are suitable surgical candidates. However, in certain clinical settings, percutaneous biopsy of a renal mass should be considered. In a retrospective study of 115 consecutive percutaneous biopsies performed on renal masses in 113 patients, investigators found percutaneous biopsy to be of high sensitivity in three clinical groups: patients with a known malignancy ( n = 55), patients with no known malignancy and suspected unresectable tumor ( n = 36), and nonsurgical patients with a mass suspected to be a resectable RCC ( n = 8). Percutaneous biopsy of renal masses appears to be safe, carrying only a minimal risk of tumor spread. Urologists should consider increasing the indications for renal biopsy of small renal masses that appear to be RCC, especially in elderly and surgically unfit patients. Percutaneous biopsy also may allow better selection of renal tumors for active surveillance and minimally invasive ablative therapies. However, there are certain histologic subtypes that cannot be easily distinguished with percutaneous biopsy. Oncocytoma, for instance, can be diagnosed only by resection, as rarely clear cell carcinoma may harbor regions of oncocytic cells, which are indistinguishable from oncocytoma with a single-needle core. In cases in which oncocytoma may be suspected (e.g., in a patient with prior multifocal oncocytomas in the contralateral kidney), several staged biopsies of the mass can be performed to increase the confidence in the diagnosis. An RCC is unlikely to have three separate biopsies all positive for oncocytic cells but without any clear cell components. Finally, initial therapy for mRCC may potentially be stratified by histologic subtype and, in the future, molecular characteristics.

Staging Systems for Renal Cell Carcinoma

The tumor-node-metastasis (TNM) system is a dynamic staging method that continually changes on the basis of new evidence from clinical studies ( Table 79.2 ). This staging system is a method of stratifying patients with cancer and is based on data from large multicenter studies with large numbers of patients and a good level of evidence. Despite continual revisions to the methodology to incorporate new clinical evidence, however, the optimal RCC patient stratification using the TNM staging system remains controversial, and further revisions probably will be needed. Revision of the TNM staging system for RCC is likely to result in the simultaneous update of the integrated prognostic systems currently used with this traditional method of staging.

Table 79.2

Tumor-Node-Metastasis (TNM) Staging System for Renal Cell Carcinoma

From Ficarra V, Galfano A, Mancini M, et al. TNM staging system for renal-cell carcinoma: current status and future perspectives. Lancet Oncol. 2007;8:554–558.

Staging	Classification	1987	1997	2002	2010
Tumor	T1	Tumor ≤2.5 cm, limited to kidney	Tumor ≤7 cm, limited to kidney	NA	Tumor ≤7 cm, limited to kidney
	T1a	NA	NA	Tumor ≤4 cm, limited to kidney	Tumor ≤4 cm, limited to kidney
	T1b	NA	NA	Tumor >4 cm and ≤7 cm, limited to kidney	Tumor >4 cm and ≤7 cm, limited to kidney
	T2	Tumor >2.5 cm, limited to kidney	Tumor >7 cm, limited to kidney	Tumor >7 cm, limited to kidney	Tumor >7 cm, limited to kidney
	T2a	NA	NA	NA	Tumor >7 cm and ≤10 cm, limited to kidney
	T2b	NA	NA	NA	Tumor >10 cm, limited to kidney
	T3	Tumor extends into major veins or invades adrenal or perinephric tissues, but not beyond Gerota fascia	Tumor extends into major veins or invades adrenal or perinephric tissues, but not beyond Gerota fascia	Tumor extends into major veins or invades adrenal or perinephric tissues, but not beyond Gerota fascia	Tumor extends into major veins or invades adrenal or perinephric tissues, but not beyond Gerota fascia
	T3a	Perinephric or adrenal extension	Perinephric or adrenal extension	Perinephric or sinus fat or adrenal extension	Renal vein, perinephric, or renal sinus fat extension
	T3b	Renal vein involvement	Renal vein or vena cava involvement below diaphragm	Renal vein or vena cava involvement below diaphragm	IVC involvement below diaphragm
	T3c	Vena cava involvement below diaphragm	Vena cava involvement above diaphragm	Vena cava involvement above diaphragm	IVC involvement above diaphragm
	T4	Outside Gerota fascia	Outside Gerota fascia	Outside Gerota fascia	Outside Gerota fascia
	T4a	Vena cava involvement above diaphragm	NA	NA	NA
	T4b	NA	NA	NA	NA
Node	Nx	Regional lymph nodes cannot be assessed	Regional lymph nodes cannot be assessed	Regional lymph nodes cannot be assessed	Regional lymph nodes cannot be assessed
	N0	No regional lymph node metastasis	No regional lymph node metastasis	No regional lymph node metastasis	No regional lymph node metastasis
	N1	Metastases in one lymph node ≤2 cm in greatest dimension	Metastases in one regional lymph node	Metastases in one regional lymph node	Metastasis in regional lymph node(s)
	N2	Metastases in one lymph node >2 cm, but not >5 cm in greatest dimension	Metastases in more than one regional lymph node	Metastases in more than one regional lymph node	NA
	N3	Metastases in one lymph node >5 cm in greatest dimension	NA	NA	NA
Metastasis	Mx	Distant metastasis cannot be assessed	Distant metastasis cannot be assessed	Distant metastasis cannot be assessed	Distant metastasis cannot be assessed
	M0	No distant metastases	No distant metastases	No distant metastases	No distant metastases
	M1	Distant metastases	Distant metastases	Distant metastases	Distant metastases

IVC, Inferior vena cava; NA, not applicable.

In the most recent (2010), seventh edition of the American Joint Committee on Cancer (AJCC) staging manual for RCC, T2 lesions are now subclassified as T2a (>7 cm up to 10 cm) and T2b (>10 cm), and ipsilateral adrenal involvement is now staged based on type of invasion: T4 if contiguous, M1 if not contiguous. In addition, renal vein involvement is reclassified as T3a, and nodal involvement is simplified to either N0 or N1, with the N2 stage dropped. In the previous (2002) edition of the manual, the key change was the subdivision of T1 lesions into T1a and T1b. The rationale was based on evidence from studies of patients undergoing partial nephrectomy, a procedure commonly used for tumors that are 4 cm or smaller. It has been reported that patients who undergo partial nephrectomy for RCC tumors smaller than 4 cm have equivalent survival to those undergoing radical nephrectomy. In a separate study of 485 patients undergoing nephron-sparing surgery for RCC with a mean follow-up period of 47 months, patients were divided into four groups based on the size of the primary. Patients in group 1 (tumors <2.5 cm in diameter) and those in group 2 (tumors 2.5–4.0 cm) had equivalent survival, although survival was significantly greater for groups 1 and 2 than for group 3 (tumors 4–7 cm) and group 4 (tumors >7 cm). These findings were similar to those previously published in a separate series of 394 patients.

Prognostic Factors for Renal Cell Carcinoma

Although TNM stage, Fuhrman grade, and Eastern Cooperative Oncology Group (ECOG) Performance Status are the most widely recognized prognostic factors in RCC, research continues to determine strong and easily available prognostic parameters that may help to classify patients into groups with different risks for death from renal cancer. The prognosis for patients with RCC is dependent primarily on disease stage. Patients with histopathologic stage pT1 or pT2 (organ confined) disease have the best prognosis, with 5-year cancer-specific survival rates after nephrectomy ranging from 71% to 97%. For patients with locally advanced tumors, 5-year cancer-specific survival rates after nephrectomy decrease by 20% to 53%, and once RCC has metastasized, the 5-year survival rate is less than 10%.

Numerous models exist to predict disease recurrence after nephrectomy for all histologic types and specifically for clear cell RCC. The natural history and risk group stratification have also been evaluated in those with newly diagnosed mRCC and in patients with previously treated metastatic disease. Currently, RCC histologic subtypes are classified according to the Union for International Cancer Control (UICC) and AJCC recommendations. These recommendations are based on the Heidelberg classification system, which categorizes RCCs as clear cell, papillary, chromophobe, collecting duct, and unclassified RCC subtypes. Studies have suggested that stratification by histologic subtype could lend prognostic value.

The University of California at Los Angeles (UCLA) Integrated Staging System (UISS) was developed for the purpose of improving the prognostic accuracy of the 1997 TNM staging system by incorporating clinical variables. To confirm the ability of the UISS to stratify patients with localized and mRCC into risk groups, an international multicenter study was conducted. A total of 4202 patients from eight academic centers were classified according to the UISS. The UISS stratified both localized and mRCC cases into three different risk groups. For localized RCC, the 5-year survival rates were 92%, 67%, and 44% for low-, intermediate-, and high-risk groups, respectively. A trend toward a higher risk of death was observed in all centers for increasing UISS risk category. For mRCC, the 3-year survival rates were 37%, 23%, and 12% for low-, intermediate-, and high-risk groups, respectively. In six of eight centers, a trend toward a higher risk of death was observed for increasing UISS risk category. A greater variability in survival rates among centers was observed for high-risk patients. These results suggest that the UISS is an accurate predictor of survival for patients with localized RCC, applicable to external databases. Although the UISS may be useful for patients with mRCC, it may be less accurate in this subset of patients because of the heterogeneity of patients and treatments.

A retrospective, single-institution review of 24 consecutive clinical trials conducted at Memorial Sloan-Kettering Cancer Center (MSKCC) using cytokines or chemotherapy for the treatment of advanced RCC ( N = 670) identified a small subgroup of patients ( n = 30) who were long-term survivors after nephrectomy and treatment with interferon-α, interleukin (IL)-2, or surgical resection of metastasis. The five most prominent negative prognostic factors that were identified with multivariate analysis included low Karnofsky Performance Status score (<80%), elevated lactate dehydrogenase (>1.5 times the upper limit of normal), low serum hemoglobin (below the lower limit of normal), high corrected serum calcium (>10 mg/dL), and absence of nephrectomy. Patients with zero risk factors were assigned a favorable-risk status; those with one or two risk factors, an intermediate-risk status; and those with three or more risk factors, a poor-risk status. All long-term survivors in this study were in either good- or intermediate-risk groups.

The natural history and risk group stratification also have been evaluated in patients with newly diagnosed mRCC. For patients diagnosed with disease recurrence, no specific risk stratification tools have been available at the time of recurrence. A retrospective study sought to evaluate the usefulness of the prognostic score suggested by Motzer and coworkers. From January 1989 to July 2005, patients with localized RCC treated with nephrectomy in whom recurrent disease subsequently developed were identified. Each patient was given a total risk score of 0 to 5, with 1 point for each of five prognostic variables (recurrence at <12 months after nephrectomy, serum calcium concentration >10 mg/dL, hemoglobin concentration less than the lower limit of normal, lactate dehydrogenase level >1.5 times the upper limit of normal, and Karnofsky performance status <80%). Patients were categorized into low- (score = 0), intermediate- (score = 1 to 2), and high-risk subgroups (score = 3 to 5). The final cohort included 118 patients, with a median survival time of 21 months from the time of recurrence. Median duration of follow-up for survivors was 27 months. Overall survival (OS) was associated with risk group category. Low-risk, intermediate-risk, and high-risk criteria were fulfilled in 34%, 50%, and 16% of patients, respectively. Median survival times for low-risk, intermediate-risk, and high-risk patients were 76, 25, and 6 months, respectively. Two-year OS rates for low-risk, intermediate-risk, and high-risk patients were 88%, 51%, and 11%, respectively. These additional data support the use of a scoring system based on objective clinical and laboratory data to achieve meaningful risk stratification for both patient counseling and clinical trial entry.

Heng and colleagues reported a novel model that validates components of the MSKCC model with the addition of platelet and neutrophil counts to establish a prognosticator algorithm for OS in patients with mRCC treated with VEGF inhibitors. In their latest report, the authors conducted an external validation and comparison with existing databases in RCC patients treated with VEGF inhibitors in the first-line setting at 13 institution members of the Consortium's database. They compared the Database Consortium model with the Cleveland Clinic Foundation, the International Kidney Cancer Working Group, the French, and the MSKCC models. A total of 1028 patients were assessed, with the majority having complete data. Median OS was 18.8 months. The previously defined prognostic factors (anemia, thrombocytosis, neutrophilia, hypercalcemia, Karnofsky Performance Status <80%, and <1 year from diagnosis to treatment) were independent predictors of reduced survival in this external validation set. The results showed that median OS was 43.2 months in the favorable-risk group (no risk factors), 22.5 months in the intermediate-risk group (one or two risk factors), and 7.8 months in the poor-risk group (three or more risk factors). The concordance index of the Database Consortium with the other models ranged between 0.636 and 0.687. Now that this Database Consortium model has been externally validated, it can be applied to stratify patients by risk in clinical trials involving anti-VEGF therapies and to counsel patients about prognosis.

Management Options for Localized Disease

The gold standard treatment for RCC localized to the kidney is surgical resection, which can be a curative treatment in this setting. Resection is performed by means of radical nephrectomy, with removal of the entire kidney and tumor en bloc, or partial nephrectomy, with removal of the tumor alone, maximizing preservation of renal function. Locally advanced tumors may require additional resection of tumor in the renal vein and vena cava and/or partial resection of surrounding organs. The operation can be performed as an open procedure or laparoscopically, the latter with or without robotic assistance, and by using either a transperitoneal or a retroperitoneal anatomic approach. Regional lymphadenectomy in the absence of lymphadenopathy remains controversial and is at present not routinely performed. In patients with significant comorbidity, advanced age, small tumor size, and/or low-risk tumor histologic type, or who are otherwise unwilling to undergo surgery, less invasive options include thermal ablation and active surveillance. However, long-term outcomes supporting the oncologic safety of these alternatives are less well established; therefore these options are currently reserved for select patients with greater operative than oncologic risk.

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