Clear cell RCC is the most common and well-studied histological variant of RCC, accounting for about 75 % of all the cases of RCC . Clear cell RCC may be sporadic or may occur in inherited forms in association with von Hippel–Lindau (VHL) syndrome, in which individuals are also at risk of developing tumors in the cerebellum, spine, retina, inner ear, pancreas, adrenal glands, and the epididymis [17]. In patients with VHL syndrome, tumors in the kidney may increase to 600 [18], hence nephron sparing surgery is generally preferred. Given that the risk of metastasis is very low in small tumors, surgical exploration and resection are recommended once the lesions have reached the size of ≥ 3 cm. Although it was discovered in the setting of hereditary clear cell RCC, the VHL gene is an early driver of sporadic RCC as well. The loss of VHL function by mutation or promoter DNA methylation can be identified in most cases of sporadic clear cell RCC [17, 19, 20].

The VHL gene is a tumor suppressor gene located on the short arm of chromosome 3 (3p). The downstream effect of either VHL mutation or methylation is the accumulation of hypoxia inducible factor (HIF) and the subsequent increased downstream transcription of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and transforming growth factor-α (TGF-α) [21]. This ultimately leads to the increased angiogenesis and tumor cell proliferation. This mechanism or pathway is targeted by the newer systemic therapies for kidney cancer as discussed later in this chapter (Fig. 9.3) .

Papillary type 1 RCC accounts for approximately 5 % of all kidney cancers . The genetic abnormality associated with this histologic variant of RCC is activation of c-MET, an oncogene located on chromosome 7. Papillary renal tumors often demonstrate gains of chromosomes 3, 7, and 17, resulting in the increased activity of c-MET. Individuals with hereditary papillary RCC (very rare) tend to develop multiple, and often bilateral, multifocal tumors. With the goal of renal preservation and excellent oncological outcome, these tumors are managed surgically by partial nephrectomy [21−24].

Papillary type 2 RCC is an aggressive form of kidney cancer accounting for about 10 % of all RCCs . It can be found in both sporadic cases as well as in the context of hereditary leiomyomatosis RCC (HLRCC) syndrome. Along with kidney cancer, HLRCC is characterized by the associated findings of cutaneous leiomyomas and uterine fibroids. The syndrome results from an inactivating mutation in fumarate hydratase, a Krebs cycle enzyme. Given the aggressive nature of this variant of RCC, total/radical nephrectomy is generally recommended [21, 22, 25].

Chromophobe RCC and oncocytoma , each accounting about 5 % of RCC, are associated with Birt–Hogg–Dube (BHD) syndrome, either as a single entity or in combination (hybrid forms). In addition to developing renal tumors, which are often multifocal and bilateral, individuals with BHD syndrome are prone to developing fibrofolliculomas and pulmonary cysts. The genetic defect in BHD syndrome is a loss of function of the BHD gene on chromosome 17 (17p11.2), which functions as a tumor suppressor gene [21, 26]. Chromophobe RCC has been shown to have equivalent or even better cancer-specific survival outcomes when compared with clear cell or papillary RCC [27, 28].

The NCCN guidelines recommend radical nephrectomy (RN; surgical removal of the entire kidney and Gerota’s fascia +/− removal of the ipsilateral adrenal gland) in patients with kidney tumor measuring > 10 cm in its largest diameter or in patients with multiple kidney tumors in the same kidney but without genetic predispositions as described above . This treatment option is based on evidence that suggests a high risk of recurrence following surgery. However, as described below, the evidence is inconclusive as to the superiority of radical nephrectomy over partial nephrectomy in terms of renal functional or oncological outcomes [36−38].

Partial nephrectomy (PN) (also termed nephron sparing surgery (NSS)) is the goldstandard for the treatment of patients with small renal masses (SRMs) (≤ 4 cm or T1a), although it is increasingly utilized for T1b tumors (4–7 cm, confined to the kidneys) [32]. This can be done via a traditional open incision, a laparoscopic approach with or without the assistance of a robotic system, and has been shown to be safely performed, even in old patients [39]. Variations in technique that include clamping the hilar vessels during tumor extirpation (goal clamp time ≤ 30 min), selective clamping of renal vessels (zero ischemia) [40, 41], and without clamping of hilar vessels (off-clamp) [42] even for complex or hilar [43] renal tumors have been described. Reducing or eliminating warm ischemia (time in which a tissue or an organ remains at body temperature after its blood supply has been cut off before it is perfused or cooled) is thought to reduce damage to nephrons from ischemia and the release of damage-inducing free radicals.

The goal of a partial nephrectomy is to spare residual normal nephrons, thus preserving renal function, particularly in patients who at the time of diagnosis have some form of CKD. However, studies evaluating renal functional outcomes following partial nephrectomy have reported conflicting results. van Poppel et al. [37], in a randomized trial comparing partial versus radical nephrectomy for low-stage renal tumors, reported a 10-year overall survival rates of 81.1 % for radical nephrectomy and 75.7 % for nephron-sparing surgery (superiority p-value = 0.03). On the other hand, Tan et al. [38], in a retrospective analysis of Medicare beneficiaries with T1a tumors, reported a significantly improved overall survival with partial nephrectomy when compared with radical nephrectomy, albeit with the caveat of unknown confounders regarding other risk factors .

With respect to renal functional outcomes, the European Organization for Research and Treatment of Cancer (EORTC) conducted a randomized trial by comparing nephron-sparing surgery versus radical nephrectomy. After a median follow-up of 6.7 years, Scosyrev et al. [44] reported a significant reduction in the incidence of moderate renal dysfunction (eGFR < 60 mL/min; 64.7 % for NSS versus 85.7 % for RN, respectively). Although not statistically significant, NSS was associated with a reduced incidence of advanced kidney disease (eGFR < 30 mL/min; 6.3 % and 10.0 %, respectively). However, the incidence of kidney failure (eGFR < 15 mL/min) was essentially identical between NSS and RN (1.6 % versus 1.5 %, respectively), and the impact of NSS on renal functional outcomes did not translate into an improved overall survival in this trial [44].

On the other hand, a study of a community-based population evaluating the impact of medical renal disease, demonstrated the risk of death to increase as GFR decreases below 60 mL/min, with hazard ratios ranging from 1.2 (with an eGFR of 45–59 mL/min) to 5.9 (with an eGFR of < 15 mL/min per 1.7 m² of body-surface area). An inverse relationship was also observed between eGFR and the risk of cardiovascular events and hospitalization [45]. While NSS has not been shown to improve the overall survival outcome, this study indicates the importance of prevention of chronic renal insufficiency and the need to perform nephron-sparing surgery for renal masses when possible without compromising on oncologic outcomes .

Although extirpative surgery is the mainstay of treatment of kidney tumors, percutaneous ablation is a safe and effective option and can be successfully employed in patients with multiple comorbidities who are not surgical candidates . Two modalities that have been popularized are cryoablation and radiofrequency ablation (RFA). Cryoablation involves the delivery of freezing temperatures (up to—50 °C) via probes (in a freeze-thaw cycles) to cause tissue destruction by an immediate direct cellular damaging effect and by a delayed vascular mechanism, with hypoxia-ischemia resulting from microvascular stasis during cooling [46, 47]. Alternatively, RFA involves the use of high-frequency alternating current, causing frictional heating from electrons flowing near the site of energy delivery. At temperatures 49 °C and above, cell death results from enzyme inactivation, denaturation of proteins, and irreparable damage to cellular membranes [48, 49].

In a meta-analysis comparing cryoablation and RFA, El Dib et al. [50] reported a clinical efficacy of 89 % and 90 %, respectively, for these two modalities in the management of patients with small renal masses ( ≤ 4 cm). This analysis showed no statistically significant difference in complication rates between cryoablation and RFA. While these ablation techniques may be a reasonable approach, they are limited by the paucity of long-term follow-up data and difficulty in evaluating patients for either recurrence or the presence of residual tumor following treatment [50].

Unlike some other solid organ tumors, surgical removal of the kidney in the setting of metastatic kidney cancer (cytoreductive nephrectomy) has been shown to be associated with an improved overall survival . Motzer et al. [51] identified the absence of a prior nephrectomy as one of the five prognostic factors predicting shorter overall survival in patients with advanced RCC. Cytoreductive nephrectomy was evaluated in two prospective randomized controlled trials, both demonstrating an increase in overall survival favoring surgical intervention along with interferon versus interferon alone [52, 53]. The combined analysis of these two trials demonstrated a median survival of 13.6 months for the cytoreductive nephrectomy plus interferon cohort as compared with 7.8 months for interferon alone, corresponding to a 31 % decrease in the risk of death (p = 0.002) [54].

Several mechanisms have been proposed to explain the observed survival improvement following cytoreductive nephrectomy. Although all theoretical, the proposed mechanisms include reduced tumor burden, reversal of the associated immunosuppressive milieu within the primary tumor, and reduction in the amount of circulating angiogenic factors, such as VEGF [55].

Prognostic factors have become important stratification variables in clinical trials of agents for the treatment of metastatic RCC . The behavior of metastatic RCC is quite variable and some patients with low-disease burden and favorable prognostic features after nephrectomy may be followed for evidence of progression prior to the initiation of treatment [57]. There are a few patients that may not require treatment at all in the setting of asymptomatic indolent disease in the face of competing comorbidities. Others may have rapid progression of disease. With this disease heterogeneity in mind, a review of patients treated on prior chemotherapy and immunotherapy clinical trials at Memorial Sloan-Kettering Cancer Center (MSKCC) identified five prognostic factors that could be used to stratify patients into one of three prognostic groups. The five factors identified are: a Karnofsky performance status (KPS) of less than 80 %, low hemoglobin value (less than lower limit of normal), high corrected calcium level ( > 10 mg/dL), high LDH level ( > 1.5 times the upper limit of normal), and less than 1 year from the time of nephrectomy to metastases. The presence of three or more risk factors results in the shortest overall survival and comprises the poor-risk group. Patients with one or two factors are considered intermediate-risk and the absence of any of these factors, the favorable-risk group. In the initial study, the 3-year survival rate among patients treated with cytokines was 31, 7, and 0 % for the favorable-risk, intermediate-risk, and poor-risk groups, respectively [51].

Given that the MSKCC schema was developed in the cytokine era, additional risk-stratification systems have been proposed more recently. Prior radiotherapy and the number of metastatic sites were added to the MSKCC scoring system in a model from the Cleveland Clinic [58]. Heng et al. proposed a new model for patients treated in the current era of targeted therapy from a cohort of consecutive patients that were treatment naive and had received sunitinib, sorafenib, or bevacizumab on clinical trial. Using overall survival as the endpoint, 16 potential predictive covariates were assessed in univariate and multivariate analyses. In the final analysis, four of the five predictive factors from the original MSKCC criteria remained significant. Additionally, an elevated absolute neutrophil count and an elevated platelet count (both above the upper limit of normal) were predictive of worse outcome. The authors reported 2-year overall survival probability of 75, 53, and 7 % for the favorable-risk, intermediate-risk, and poor-risk groups, respectively [59].