Cross-sectional imaging, ideally with a dedicated triphasic renal CT scan, plays a primary role in the diagnosis of renal masses , and has changed the landscape of RCC as outlined above. It facilitates proper detection and characterization of renal masses, and provides essential information for clinical staging and surgical planning. In general, any mass that enhances with intravenous (IV) administration of contrast material on CT by more than 15 Hounsfield Units should be considered RCC until proven otherwise. However, within this group of enhancing renal tumors will be a variety of benign neoplasms including oncocytomas and angiomyolipomas. Most angiomyolipomas are readily identified due to distinctive areas with Housefield units (HU) lower than − 20, reflecting high fat content, although about 10 % are fat poor and impossible to differentiate from RCC based on imaging alone. Avidly enhancing tumors are most commonly clear cell RCC, while hypoenhancing tumors are more likely to correlate with papillary or chromophobe histology [5]. Clear cell RCC also associates with necrosis and retroperitoneal collateral circulation that can be observed on magnetic resonance imaging (MRI). Recent reports demonstrate that papillary RCC are typically hypointense on T2-weighted imaging, whereas clear cell RCC tends to be iso- to hyperintense in this phase. Interestingly, oncocytomas often demonstrate strong contrast enhancement, and can be very difficult to differentiate from RCC based on imaging alone. Other important imaging characteristics such as morphology (well circumscribed vs. infiltrative) and focality (bilaterality and multicentricity) can also provide clues with respect to potential histologic subtypes and familial versus sporadic etiology, as discussed above.

Renal mass biopsy and molecular imaging have been studied in an attempt to provide a more accurate preoperative diagnosis and to allow for more rational and intelligent patient counseling. The main concern has traditionally related to a high incidence of false negative biopsies, but this is much less common in the modern era, representing < 1 % of cases in most recent series [6]. Nevertheless, differentiation between oncocytoma and the eosinophilic variants of RCC can still be problematic with the limited material provided by a biopsy, and the implications of the diagnosis of “oncocytic neoplasm” have not been adequately defined. Most centers now pursue renal mass biopsy on a utility-based approach, as follows. Young healthy patients who are unwilling to accept the uncertainty of surveillance even if the biopsy is negative, and frail, elderly patients who will be managed conservatively even if the biopsy is positive, should not be exposed to the risk of renal mass biopsy. In contrast, patients who could be considered for a variety of treatment modalities ranging from surgical excision to active surveillance may benefit from further risk stratification. If the biopsy demonstrates a clear cell RCC, surgery would be prioritized, while a diagnosis of oncocytoma or even “oncocytic neoplasm” would encourage a less aggressive approach. Molecular imaging with radioactive antibodies to carbonic anhydrase IX (CA-IX), which is expressed primarily in clear cell RCC, may play a similar role in the future. Renal mass biopsy is also now beginning to play an important role for patients with advanced RCC. Clear cell tumors in particular are most likely to respond to immunotherapy and targeted agents, which can help guide management decisions in this challenging patient population.

Treatment of RCC has evolved considerably in the last decade, and is best discussed based upon disease categorization, as outlined in Table 27.2 . Localized disease includes stages T1-2 tumors without nodal involvement and with a negative metastatic profile. Most smaller tumors (≤ 4.0 cm) in this group have limited oncologic potential, with 20 % benign, and only 20 % harboring potentially aggressive features such as high nuclear grade or locally invasive phenotype. Most agree now that radical nephrectomy represents therapeutic overkill for these patients, often leading to chronic kidney disease and its potential adverse sequelae. Partial nephrectomy is considered the reference standard for this population and is typically associated with the local control in 98–99 % of cases. Partial nephrectomy should always be prioritized when preservation of renal function is at a premium and for multicentric and familial tumors . Thermal ablation provides local control in about 90 % of such patients and often can be administered percutaneously thus minimizing potential morbidity. Active surveillance should be prioritized for patients with limited life expectancy or extensive comorbidities in whom the risk of intervention outweighs the oncologic risk . Most such tumors grow slowly (about 3–4 mm/year) and the risk of metastatic spread within a few years appears to be low (1–2 %) presuming sensible patient selection. However, some series contain a subgroup of patients with rapidly growing tumors that appear to have more aggressive tumor biology, underscoring the importance of patient selection and the potential risks of active surveillance. For instance, in the Volpe series [6] eight out of 32 masses (25 %) doubled in volume within 12 months, and 11 masses (34 %) reached at threshold of 4 cm diameter, most with a rapid doubling time. Infiltrative tumors almost always correlate with aggressive histologic subtypes and should be managed accordingly, even if relatively small. Oncologic potential increases in proportion with tumor size, and most T2 tumors (> 7.0 cm) are best managed with radical nephrectomy unless preservation of the renal function is of primary importance .

Locally advanced RCC is still primarily a surgical disease and complete surgical excision should always be prioritized. Careful preoperative planning and a comprehensive surgical approach are required, often incorporating an extensive retroperitoneal lymph node dissection and/or IVC thrombectomy. Even with resection to R0 status, most such patients are at high risk for disease recurrence and adjuvant systemic therapy trials, currently utilizing targeted agents, should be considered. Neoadjuvant approaches using tyrosine kinase inhibitors (TKIs) have recently been reported for patients with unresectable locally advanced disease related to proximity to vital structures and other complexities. These studies have demonstrated downsizing that can facilitate surgical resection in some patients, but such favorable responses appear to be limited to patients with clear cell histology. In a neoadjuvant sunitinib study, median downsizing for patients with clear cell RCC ( n = 22) was 28 %, and 59 % were able to proceed with surgical resection. In contrast, no substantial responses were observed in patients with nonclear cell histology ( n = 8), and surgical resection was not possible in this subgroup [7]. It is important to emphasize that the neoadjuvant approach remains investigational .

Targeted therapies have revolutionized the management of patients with metastatic RCC, but there is still an important role for surgery in this challenging patient population. Cytoreductive nephrectomy was shown to provide a greater than 6-month prolongation of survival in phase III trials where interferon was the systemic therapy of choice, and most believe that this procedure is still indicated in this era. The precise role of debulking nephrectomy for nonclear cell RCC is less certain as the clinical trials of debulking nephrectomy were limited to the clear cell population. The best candidates are patients with limited metastatic burden, good performance status, and reasonable cardiopulmonary status. A small proportion, certainly < 5 %, of patients with metastatic RCC have solitary or oligometastases and can be considered for metastasectomy, which can provide durable cancer-free status in about 30 % of patients in this fortunate category. Beyond this, systemic therapy must be considered [8] .

Targeted therapies include bevacizumab which sequesters the vascular endothelial growth factor (VEGF) ligand, TKIs such as sunitinib, sorafenib, pazopanib, and axitinib that target the VEGF receptor, and the mammalian target of rapamycin (mTOR) inhibitors, temsirolimus, and everolimus. These agents provide prolonged progression-free survival when compared to placebo or interferon-alpha, and collectively have extended overall survival for metastatic RCC. As such, they have displaced immunotherapy for the management of patients with metastatic RCC. One exception is high dose IL-2, which is still the only agent that provides a realistic chance (3–5 %) for a durable complete remission. Ideal candidates for high dose IL-2 include patients with excellent performance status and clear cell RCC because the treatment can be rather toxic, and responses have been limited almost exclusively to patients with this histologic subtype .

Each targeted agent now has an established niche for the management of patients with metastatic RCC based on randomized, prospective clinical trials. For instance, sunitinib, pazopanib and a combination of bevacizumab and interferon are now typically chosen for patients with treatment-naïve metastatic RCC, while temsirolimus is often prioritized for patients with poor prognostic features. Axitinib and everolimus are positioned for patients who have failed TKIs, based upon established treatment algorithms. In general, patients with clear cell RCC appear to respond best to targeted therapies based upon the inherent biology of clear cell RCC which results in VEGF overproduction. A reference standard for patients with nonclear cell metastatic RCC is not established at this point in time, and clinical trials are a priority .