American Urological Association - Renal Mass and Localized Renal Cancer: AUA Guideline

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Renal Mass and Localized Renal Cancer: AUA Guideline

Published 2017

Follow-up for Clinically Localized Renal Neoplasms

Renal Mass and Localized Renal Cancer: AUA Guideline focuses on the evaluation and management of clinically localized renal masses suspicious for renal cell carcinoma (RCC). Dignosis, patient counseling, and renal biopsy are covered in addition to various management strategies, including partial and radical nephrectomy, thermal ablation, and active surveillance.

Unabridged version of this Guideline [pdf]
Algorithm associated with this Guideline [pdf]
Presentation from the 2017 AUA Annual Meeting [pdf]

Panel Members

Steven Campbell, MD; Robert G. Uzzo, MD; Mohamad E. Allaf, MD; Eric B. Bass, MD, MPH; Jeffrey A. Cadeddu, MD; Anthony Chang, MD; Peter E. Clark, MD; Philip M. Pierorazio, MD; Brian J. Davis, MD, PhD; Ithaar H. Derweesh, MD; Leo Giambarresi, PhD; Debra A. Gervais, MD; Susie L. Hu, MD; Brian R. Lane, MD, PhD; Bradley C. Leibovich, MD, FACS

Executive Summary

Purpose

This AUA Guideline focuses primarily on the evaluation and management of clinically localized sporadic renal masses suspicious for renal cell carcinoma (RCC) in adults, including solid enhancing renal tumors and Bosniak 3 and 4 complex cystic renal masses. Some patients with clinically localized renal masses may present with findings suggesting aggressive tumor biology or may be upstaged on exploration or final pathology. Management considerations pertinent to the urologist in such patients will also be addressed. Practice patterns regarding such tumors vary considerably. The literature regarding evaluation and management has been rapidly evolving. Notable examples include controversies about the role of renal mass biopsy and concerns about overutilization of radical nephrectomy.  Please also refer to the associated Renal Mass and Localized Renal Cancer treatment algorithm.

Methodology

The systematic review utilized in the creation of this guideline was completed in part through the Agency for Healthcare Research and Quality (AHRQ) and through additional supplementation that further addressed additional key questions and more recently published literature. A research librarian experienced in conducting literature searches for comparative effectiveness reviews searched in MEDLINE®, Embase®, the Cochrane Library, the Database of Abstracts of Reviews of Effects, the Health Technology Assessment Database, and the UK National Health Service Economic Evaluation database to capture both published and gray literature published from January 1, 1997 through May 1, 2015. A supplemental search was conducted adding additional literature published through August 2015, and a final update search was conducted through July 2016. When sufficient evidence existed, the body of evidence for a particular treatment was assigned a strength rating of A (high), B (moderate) or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions.

Guideline Statements

Evaluation and Diagnosis

  1. In patients with a solid or complex cystic renal mass, physicians should obtain high quality, multiphase, cross-sectional abdominal imaging to optimally characterize and clinically stage the renal mass. Characterization of the renal mass should include assessment of tumor complexity, degree of contrast enhancement (where applicable), and presence or absence of fat. (Clinical Principle)
  2. In patients with suspected renal malignancy, physicians should obtain comprehensive metabolic panel, complete blood count, and urinalysis. Metastatic evaluation should include chest imaging to evaluate for possible thoracic metastases. (Clinical Principle)
  3. For patients with a solid or complex cystic renal mass, physicians should assign CKD stage based on GFR and degree of proteinuria. (Expert Opinion)

Counseling

  1. In patients with a solid or Bosniak 3/4 complex cystic renal mass, a urologist should lead the counseling process and should consider all management strategies. A multidisciplinary team should be included when necessary. (Expert Opinion)
  2. Physicians should provide counseling that includes current perspectives about tumor biology and a patient-specific risk assessment inclusive of sex, tumor size/complexity, histology (when obtained), and imaging characteristics.  For cT1a tumors, the low oncologic risk of many small renal masses should be reviewed. (Clinical Principle)
  3. During counseling of patients with a solid or Bosniak 3/4 complex cystic renal mass, physicians must review the most common and serious urologic and non-urologic morbidities of each treatment pathway and the importance of patient age, comorbidities/frailty, and life expectancy.   (Clinical Principle)
  4. Physicians should review the importance of renal functional recovery related to renal mass management, including the risk of progressive CKD, potential short- or long-term need for renal replacement therapy, and long-term overall survival considerations. (Clinical Principle)
  5. Physicians should consider referral to nephrology in patients with a high risk of CKD progression. Such patients may include those with eGFR less than 45 ml/min/1.73m2, confirmed proteinuria, diabetics with preexisting CKD,  or whenever eGFR is expected to be less than 30 ml/min/1.73m2after intervention. (Expert Opinion)
  6. Physicians should recommend genetic counseling for all patients ≤ 46 years of age with renal malignancy and consider genetic counseling for patients with multifocal or bilateral renal masses, or if personal or family history suggests a familial renal neoplastic syndrome. (Expert Opinion)

Renal Mass Biopsy (RMB)

  1. Renal mass biopsy should be considered when a mass is suspected to be hematologic, metastatic, inflammatory, or infectious. (Clinical Principle)
  2. In the setting of a solid renal mass, RMB is not required for: 1) young or healthy patients who are unwilling to accept the uncertainties associated with RMB; or 2) older or frail patients who will be managed conservatively independent of RMB findings. (Expert Opinion)
  3. When considering the utility of RMB, patients should be counseled regarding rationale, positive and negative predictive values, potential risks and non-diagnostic rates of RMB. (Clinical Principle)
  4. For patients with a solid renal mass who elect RMB, multiple core biopsies are preferred over fine needle aspiration. (Moderate Recommendation; Evidence Level: Grade C)

Management

Partial Nephrectomy (PN) and Nephron-Sparing Approaches

  1. Physicians should prioritize PN for the management of the cT1a renal mass when intervention is indicated. In this setting, PN minimizes the risk of CKD or CKD progression and is associated with favorable oncologic outcomes, including excellent local control. (Moderate Recommendation; Evidence Level: Grade B)
  2. Physicians should prioritize nephron-sparing approaches for patients with solid or Bosniak 3/4 complex cystic renal masses and an anatomic or functionally solitary kidney, bilateral tumors, known familial RCC, preexisting CKD, or proteinuria. (Moderate Recommendation; Evidence Level: Grade C)
  3. Physicians should consider nephron-sparing approaches for patients with solid or Bosniak 3/4 complex cystic renal masses who are young, have multifocal masses, or comorbidities that are likely to impact renal function in the future, such as moderate to severe hypertension, diabetes mellitus, recurrent urolithiasis, or morbid obesity.  (Conditional Recommendation; Evidence Level: Grade C)
  4. In patients who elect PN, physicians should prioritize preservation of renal function through efforts to optimize nephron mass preservation and avoidance of prolonged warm ischemia. (Expert Opinion) 
  5. For patients undergoing PN, negative surgical margins should be a priority. The extent of normal parenchyma removed should be determined by surgeon discretion taking into account the clinical situation, tumor characteristics including growth pattern, and interface with normal tissue. Tumor enucleation should be considered in patients with familial RCC, multifocal disease, or severe CKD to optimize parenchymal mass preservation. (Expert Opinion) 

Radical Nephrectomy (RN)

  1. Physicians should consider RN for patients with a solid or Bosniak 3/4 complex cystic renal mass where increased oncologic potential is suggested by tumor size, RMB, and/or imaging characteristics and in whom active treatment is planned. (Conditional Recommendation; Evidence Level: Grade B) In this setting, RN is preferred if all of the following criteria are met: 1) high tumor complexity and PN would be challenging even in experienced hands; 2) no preexisting CKD or proteinuria; and 3) normal contralateral kidney and new baseline eGFR will likely be greater than 45 ml/min/1.73m2. (Expert Opinion)

Surgical Principles

  1. For patients who are undergoing surgical excision of a renal mass with clinically concerning regional lymphadenopathy, physicians should perform a lymph node dissection for staging purposes. (Expert Opinion)
  2. For patients who are undergoing surgical excision of a renal mass, physicians should perform adrenalectomy if imaging and/or intraoperative findings suggest metastasis or direct invasion of the adrenal gland. (Clinical Principle)
  3. In patients undergoing surgical excision of a renal mass, a minimally invasive approach should be considered when it would not compromise oncologic, functional and perioperative outcomes. (Expert Opinion)
  4. Pathologic evaluation of the adjacent renal parenchyma should be performed after PN or RN to assess for possible intrinsic renal disease, particularly for patients with CKD or risk factors for developing CKD. (Clinical Principle)

Thermal Ablation (TA)

  1. Physicians should consider thermal ablation (TA) as an alternate approach for the management of cT1a renal masses <3 cm in size.  For patients who elect TA, a percutaneous technique is preferred over a surgical approach whenever feasible to minimize morbidity. (Conditional Recommendation; Evidence Level: Grade C)
  2. Both radiofrequency ablation and cryoablation are options for patients who elect thermal ablation. (Conditional Recommendation; Evidence Level: Grade C)
  3. A renal mass biopsy should be performed prior to ablation to provide pathologic diagnosis and guide subsequent surveillance. (Expert Opinion)
  4. Counseling about thermal ablation should include information regarding an increased likelihood of tumor persistence or local recurrence after primary thermal ablation relative to surgical extirpation, which may be addressed with repeat ablation if further intervention is elected. (Strong Recommendation; Evidence Level: Grade B)

Active Surveillance (AS)

  1. For patients with small solid or Bosniak 3/4 complex cystic renal masses, especially those <2cm, AS is an option for initial management. (Conditional Recommendation; Evidence Level: Grade C)
  2. For patients with a solid or Bosniak 3/4 complex cystic renal mass, physicians should prioritize active surveillance/expectant management when the anticipated risk of intervention or competing risks of death outweigh the potential oncologic benefits of active treatment. (Clinical Principle)
  3. For patients with a solid or Bosniak 3/4 complex cystic renal mass in whom the risk/benefit analysis for treatment is equivocal and who prefer AS, physicians should repeat imaging in 3-6 months to assess for interval growth and may consider RMB for additional risk stratification. (Expert Opinion)
  4. For patients with a solid or Bosniak 3/4 complex cystic renal mass in whom the anticipated oncologic benefits of intervention outweigh the risks of treatment and competing risks of death, physicians should recommend active treatment. In this setting, AS with potential for delayed intervention may be pursued only if the patient understands and is willing to accept the associated oncologic risk. (Moderate Recommendation; Evidence Level: Grade C)

Introduction

Purpose

This AUA Guideline focuses primarily on the evaluation and management of clinically localized sporadic renal masses suspicious for renal cell carcinoma (RCC) in adults, including solid enhancing renal tumors and Bosniak 3 and 4 complex cystic renal masses.  Some patients with clinically localized renal masses may present with findings suggesting aggressive tumor biology or may be upstaged on exploration or final pathology.  Management considerations pertinent to the urologist in such patients will also be addressed.  Practice patterns regarding such tumors vary considerably. The literature regarding evaluation and management has been rapidly evolving. Notable examples include controversies about the role of renal mass biopsy and concerns about overutilization of radical nephrectomy.

Methodology

Systematic Review. The systematic review utilized in the creation of this guideline was completed in part through the Agency for Healthcare Research and Quality (AHRQ) and through additional supplementation that further addressed additional key questions and more recently published literature. A research librarian experienced in conducting literature searches for comparative effectiveness reviews searched in MEDLINE®, Embase ®, the Cochrane Library, the Database of Abstracts of Reviews of Effects, the Health Technology Assessment Database, and the UK National Health Service Economic Evaluation database to capture both published and gray literature published from January 1, 1997 through May 1, 2015. A supplemental search was conducted adding additional literature published through August 2015, and a final update search was conducted through July 2016.

Assessment of Risk-of-Bias of Individual Studies. Paired investigators independently screened search results to assess eligibility. Investigators abstracted data sequentially and assessed risk of bias independently. Investigators graded the strength of evidence as a group. Citations were screened independently by two reviewers using predefined eligibility criteria. One reviewer completed data abstraction and a second reviewer checked abstraction for accuracy. Two reviewers independently assessed risk of bias for individual studies. The Cochrane Collaboration’s tool was used for assessing the risk of bias of randomized controlled trials (RCTs).1 For nonrandomized studies of treatment interventions, the reviewers used the Cochrane Risk of Bias Assessment Tool for Non-Randomized Studies of Interventions (ACROBAT-NRSI). For diagnostic studies, we used the quality assessment tool for diagnostic accuracy studies (QUADAS -2).2 Differences between reviewers were resolved through consensus. 

Determination of Evidence Strength. The categorization of evidence strength is conceptually distinct from the quality of individual studies. Evidence strength refers to the body of evidence available for a particular question and includes not only individual study quality but consideration of study design, consistency of findings across studies, adequacy of sample sizes, and generalizability of samples, settings, and treatments for the purposes of the guideline. The AUA categorizes body of evidence strength as Grade A (well-conducted and highly-generalizable RCTs or exceptionally strong observational studies with consistent findings), Grade B (RCTs with some weaknesses of procedure or generalizability or moderately strong observational studies with consistent findings), or Grade C (RCTs with serious deficiencies of procedure or generalizability or extremely small sample sizes or observational studies that are inconsistent, have small sample sizes, or have other problems that potentially confound interpretation of data). By definition, Grade A evidence is evidence about which the Panel has a high level of certainty, Grade B evidence is evidence about which the Panel has a moderate level of certainty, and Grade C evidence is evidence about which the Panel has a low level of certainty.3

AUA Nomenclature: Linking Statement Type to Evidence Strength. The AUA nomenclature system explicitly links statement type to body of evidence strength, level of certainty, magnitude of benefit or risk/burdens, and the Panel’s judgment regarding the balance between benefits and risks/burdens (Table 1). Strong Recommendations are directive statements that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be undertaken because net benefit or net harm is substantial. Moderate Recommendations are directive statements that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be undertaken because net benefit or net harm is moderate. Conditional Recommendations are non-directive statements used when the evidence indicates that there is no apparent net benefit or harm or when the balance between benefits and risks/burden is unclear. All three statement types may be supported by any body of evidence strength grade. Body of evidence strength Grade A in support of a Strong or Moderate Recommendation indicates that the statement can be applied to most patients in most circumstances and that future research is unlikely to change confidence. Body of evidence strength Grade B in support of a Strong or Moderate Recommendation indicates that the statement can be applied to most patients in most circumstances but that better evidence could change confidence. Body of evidence strength Grade C in support of a Strong or Moderate Recommendation indicates that the statement can be applied to most patients in most circumstances but that better evidence is likely to change confidence. Body of evidence strength Grade C is only rarely used in support of a Strong Recommendation. Conditional Recommendations can also be supported by any evidence strength. When body of evidence strength is Grade A, the statement indicates that benefits and risks/burdens appear balanced, the best action depends on patient circumstances, and future research is unlikely to change confidence. When body of evidence strength Grade B is used, benefits and risks/burdens appear balanced, the best action also depends on individual patient circumstances and better evidence could change confidence. When body of evidence strength Grade C is used, there is uncertainty regarding the balance between benefits and risks/burdens, alternative strategies may be equally reasonable, and better evidence is likely to change confidence.

Where gaps in the evidence existed, the Panel provides guidance in the form of Clinical Principles or Expert Opinion with consensus achieved using a modified Delphi technique if differences of opinion emerged.4 A Clinical Principle is a statement about a component of clinical care that is widely agreed upon by urologists or other clinicians for which there may or may not be evidence in the medical literature. Expert Opinion refers to a statement, achieved by consensus of the Panel, that is based on members' clinical training, experience, knowledge, and judgment for which there is no evidence. 

Table 1: AUA Nomenclature Linking Statement Type to Level of Certainty, Magnitude of Benefit or Risk/Burden, and Body of Evidence Strength

 

Evidence Strength A

(High Certainty)

Evidence Strength B

(Moderate Certainty)

Evidence Strength C

(Low Certainty)

Strong Recommendation

 

(Net benefit or harm substantial)

Benefits > Risks/Burdens (or vice versa)

Net benefit (or net harm) is substantial

Applies to most patients in most circumstances and future research is unlikely to change confidence

Benefits > Risks/Burdens (or vice versa)

Net benefit (or net harm) is substantial

Applies to most patients in most circumstances but better evidence could change confidence

 

Benefits > Risks/Burdens (or vice versa)

Net benefit (or net harm) appears substantial

Applies to most patients in most circumstances but better evidence is likely to change confidence

(rarely used to support a Strong Recommendation)

Moderate Recommendation

 

(Net benefit or harm moderate)

Benefits > Risks/Burdens (or vice versa)

Net benefit (or net harm) is moderate

Applies to most patients in most circumstances and future research is unlikely to change confidence

Benefits > Risks/Burdens (or vice versa)

Net benefit (or net harm) is moderate

Applies to most patients in most circumstances but better evidence could change confidence

Benefits > Risks/Burdens (or vice versa)

Net benefit (or net harm) appears moderate

Applies to most patients in most circumstances but better evidence is likely to change confidence

Conditional Recommendation

 

(No apparent net benefit or harm)

Benefits = Risks/Burdens

Best action depends on individual patient circumstances

Future research unlikely to change confidence

Benefits = Risks/Burdens

Best action appears to depend on individual patient circumstances

Better evidence could change confidence

Balance between Benefits & Risks/Burdens unclear

Alternative strategies may be equally reasonable

Better evidence likely to change confidence

Clinical Principle

A statement about a component of clinical care that is widely agreed upon by urologists or other clinicians for which there may or may not be evidence in the medical literature

Expert Opinion

A statement, achieved by consensus of the Panel, that is based on members' clinical training, experience, knowledge, and judgment for which there is no evidence

Process. The Renal Mass and Localized Renal Cancer Panel was created in 2014 by the American Urological Association Education and Research, Inc. (AUA). The Practice Guidelines Committee (PGC) of the AUA selected the Panel Chair who in turn appointed the Vice Chair.  In a collaborative process, additional Panel members, including additional members of the College of American Pathologists (CAP), Society of Urologic Oncology (SUO), American College of Radiology (ACR), American Society of Nephrology (ASN), Endourological Society, and Society of Interventional Radiology (SIR) with specific expertise in this area, were then nominated and approved by the PGC. The AUA conducted a thorough peer review process. The draft guidelines document was distributed to 124 peer reviewers, 54 of which submitted comments. The Panel reviewed and discussed all submitted comments and revised the draft as needed. Once finalized, the guideline was submitted for approval to the PGC and Science and Quality Council (S&Q). Then it was submitted to the AUA and College of American Pathologists (CAP), Society of Urologic Oncology (SUO), American College of Radiology (ACR), American Society of Nephrology (ASN), Endourological Society, and Society of Interventional Radiology (SIR) Board of Directors for final approval. Panel members received no remuneration for their work.

Background

Renal masses are a biologically heterogeneous group of tumors ranging from benign masses to cancers that can be indolent or aggressive.5,6 The true incidence of renal masses (including benign masses) is unknown.  However, benign masses comprise approximately 15-20 percent of surgically resected tumors < 4 cm and allow estimations of incidence based on kidney cancer statistics.5,7,8 The vast majority (greater than 90%) of kidney cancers in the United States are renal cortical tumors known as renal cell carcinoma (RCC). 

Epidemiology: United States

It is estimated there will be over 62,000 new cases of kidney cancer in the United States in 2016.9 The incidence of kidney cancer has been increasing steadily since the 1970’s in part due to more prevalent use of axial imaging (CT and MRI).10 In the United States, over the past decade, the incidence of kidney cancer continues to increase but at a much smaller increment, approximately 1% per year.  The greatest increase in incidence has been in small, clinically localized renal masses which now represent at least 40 percent of incident tumors.11,12 

The overall survival rate for all stages of renal cancer is approximately 74%, leaving an estimated 400,000 kidney cancer survivors in the United States in 2013.9 However, approximately 14,000 men and women will die of kidney cancer in 2016. The mortality from kidney cancer has been steadily decreasing, approximately 1% per year, since 2004.13,14 Reasons for this decrease are multifactorial. 

Kidney cancer is more common in men than women, and more common in African Americans, American Indian and Alaska Native populations than Caucasians.15 The median age at diagnosis is 64 years old, although kidney cancer can present at any age.16 

Epidemiology: Global and International Considerations

Over 300,000 men and women are diagnosed with kidney cancer around the world each year and approximately 150,000 patients will die of disease.17 The incidence of kidney cancer varies dramatically around the world with the developed countries having the highest rates.18 Incidence rates have increased in both sexes and are most notable in the elderly population (greater than 75 years of age). Mortality rates have been stable in most countries but have been decreasing by 1 to 3 percent in Western and Northern Europe, the United States, and Australia. The improved mortality globally and in the US is attributed to decreased smoking rates, improved therapies, and access to medical care. The decrease in mortality has been faster in women than in men and overall mortality rates remain higher in men than women. 

Etiology

There are a number of established and putative risk factors for RCC. Smoking is a well-established risk factor, accounting for 20 percent of incident cases and increasing the risk of RCC by 50 percent in men and 20 percent in women.19,20 Obesity is associated with 30% of incident cases of RCC and each 5 kg/m2 increase in body mass index increases the risk of RCC by 24 percent in men and 34 percent in women.20-22 Interestingly, an “obesity paradox” exists in kidney cancer – where obese patients are more likely to develop RCC, but these tumors are more likely to be low-grade, early stage tumors.22-24  Hypertension is also associated with increased risk of RCC.20,25,26 The role of chronic kidney disease (CKD) as a risk factor is controversial; however patients on maintenance dialysis are also reported to have an increased risk of RCC.27 The data regarding environmental and occupational exposures are inconsistent with the exception of chlorinated solvents.20,28

Moderate alcohol intake,29,30 consumption of fruits and (cruciferous) vegetables,31,32 and a diet rich in fatty fish33 are believed to reduce the risk of RCC. Other studies suggest that non-steroidal anti-inflammatory agents and dietary factors do not play a role in the etiology of RCC.20,34 

Hereditary and Familial Renal Cell Carcinoma

Family history is associated with an increased risk of RCC and a number of familial RCC syndromes are now well-established, accounting for approximately 4-6% of cases of RCC overall.35  These syndromes include von Hippel-Lindau (VHL), hereditary papillary renal carcinoma (HPRC), Birt Hogg-Dubé (BHD), hereditary leiomyomatosis RCC (HLRCC), succinate dehydrogenase deficiency RCC, tuberous sclerosis, and PTEN hamartoma tumor syndrome (Cowden syndrome). Most of these syndromes have associated tumors or benign findings in other organ systems.  RCC in these syndromes tends to be earlier in onset and multifocal and management should prioritize nephron-sparing approaches, including tumor enucleation when feasible to optimize preservation of parenchymal mass. For most of these syndromes, tumors can be observed if less than 3 cm as the risk of metastases remains low in this setting.36 HLRCC and succinate dehydrogenase deficiency RCC are the exception as tumors in these syndromes are often very aggressive and a proactive approach to evaluation and management should be pursued. Genetic counseling should also be strongly recommended for patients suspected of having familial RCC, as it may allow for more intensive evaluation of the patient for RCC and associated manifestations and identification of blood relatives that may be at syndromic risk.

Major Pathological Subtypes

Renal tumors are classified based on cell of origin and morphologic appearance with renal adenocarcinoma (RCC) being the most common malignant tumor. Major sub-classifications of RCC include clear cell, papillary, chromophobe, collecting duct and unclassified RCC.37 A number of uncommon or rare subtypes exist including but not limited to acquired cystic disease-associated RCC, clear cell (tubulo) papillary, and renal medullary carcinoma, which is an aggressive variant typically seen in patients with sickle cell trait.  The most common benign tumors of the kidney include oncocytoma and angiomyolipoma (AML). An abbreviated version of the 2016 World Health Organization classification of renal neoplasms is detailed in Table 2.38  

TABLE 2. Modified 2016 World Health Organization classification of renal neoplasms with focus on adult neoplasms.38

Renal cell tumors

Clear cell RCC

Multilocular cystic renal neoplasm of low malignant potential

Papillary RCC

Hereditary leiomyomatosis RCC

Chromophobe RCC

Collecting duct carcinoma

Renal medullary carcinoma

MiT Family translocation carcinomas

Succinate dehydrogenase (SDH) deficient RCC

Mucinous tubular and spindle cell carcinoma

Tubulocystic RCC

Acquired cystic disease associated RCC

Clear cell papillary RCC

RCC, unclassified

Benign renal tumors

Papillary adenoma

Oncocytoma

Angiomyolipoma

Metanephric adenoma and other metanephric tumors

Adult cystic nephroma

Mixed epithelial stromal tumors

Juxtaglomerular cell tumor

Mesenchymal tumors

Leiomyosarcoma (including renal vein) and other sarcomas

Leiomyoma and other benign mesenchymal tumors

Others

Adult Wilms tumor

Primitive neuroectodermal tumor

Metastatic tumors, lymphoma, leukemia

Presentation & Diagnosis

Presentation

The “classic triad” of symptoms associated with a malignant renal mass include hematuria, flank pain and abdominal mass. Symptoms associated with RCC are often a result of local tumor growth, hemorrhage, paraneoplastic symptoms, or metastatic disease and are uncommon in patients with clinically localized disease. In fact, less than 5 percent of patients in contemporary series present with these symptoms and greater than 50 percent of renal masses are diagnosed incidentally during an evaluation for unrelated signs or symptoms.39,40

Diagnosis

Physical examination has a limited role in the diagnosis of clinically localized disease. However, physical examination may have value in distinguishing the signs and symptoms of advanced disease. For instance, paraneoplastic syndromes (i.e. hypertension, polycythemia, hypercalcemia) are present in approximately 10-20 percent of patients with metastatic RCC.41,42 Importantly, physical examination of patients with localized disease may occasionally reveal unsuspected adenopathy, varicocele or medical conditions that influence management decisions including body habitus, prior abdominal scars, stigmata of CKD, etc. In addition, careful physical examination may also reveal findings suggestive of familial disease, such as dermatologic lesions.

Laboratory Evaluation

There are no biomarkers or routine laboratory tests used to diagnose renal malignancies. As such, laboratory tests are useful in the assessment of renal function (glomerular filtration rate) and for completeness of metastatic evaluation. Routine laboratory tests for renal mass evaluation include complete metabolic panel, complete blood count, and urinalysis.

Imaging Techniques

Pre and post contrast-enhanced axial imaging, either computed tomography (CT) or magnetic resonance imaging (MRI), is the ideal imaging technique for the diagnosis and staging of clinically localized renal masses. Masses initially diagnosed by ultrasound or intravenous pyelography should be confirmed with pre/post contrast-enhanced imaging. Depending on tumor size, 20 to 30 percent of clinically localized renal masses may be benign.5,8 Patient and tumor characteristics can indicate populations more or less likely to harbor benign or malignant disease. For instance, women with smaller tumors have a higher likelihood of having benign tumors.7,43,44 However, with the exception of fat-containing AML, none of the current imaging modalities can reliably distinguish between benign and malignant tumors or between indolent and aggressive tumor biology.

Contrast-enhanced abdominal imaging (CT or MRI) best characterizes the mass, provides information regarding renal morphology (of the affected and unaffected kidney), assesses extrarenal tumor spread (venous invasion or regional lymphadenopathy) and evaluates the adrenal glands and other abdominal organs for visceral metastases. Patients with CKD and GFR less than 45 ml/min/1.73m2 should receive contrast with caution as iodinated contrast agents can transiently or permanently affect glomerular filtration rate (contrast induced nephropathy)45 and gadolinium-based MRI contrast agents can lead to nephrogenic systemic fibrosis – a devastating and potentially fatal condition.46 Non-contrast CT, MRI (with diffusion weighted images) and US (with Doppler) can be used to characterize renal masses in patients who cannot receive intravenous contrast.

In general, solid renal masses that enhance greater than 15-20 HU with intravenous contrast and do not exhibit fat density should be considered suspicious for RCC. Approximately 5% of AML’s are fat poor and difficult to identify on imaging. Fat poor AML’s often demonstrate suggestive features such as high attenuation on unenhanced CT, homogeneous enhancement on CT, or hypointensity on T2-weighted MR, but the diagnosis remains difficult. Complex cystic renal masses that have thickened irregular walls or septa in which measurable enhancement is present are classified as Bosniak 3. Approximately 50% of such lesions prove to be malignant on final pathology. Bosniak 4 complex cystic lesions are very suspicious for malignancy as they contain enhancing nodular soft tissue components and about 75-90% of such lesions prove to be RCC on final pathology. This guideline focuses primarily on the evaluation and management of clinically localized sporadic renal masses suspicious for renal cell carcinoma (RCC) in adults, including solid enhancing renal tumors and Bosniak 3 and 4 cystic renal masses.

In patients with RCC or suspicion of RCC, complete staging is typically finalized with chest radiography (x-ray) or chest CT. Chest CT scan should be obtained selectively, primarily for patients with pulmonary symptoms or abnormal chest x-ray, or for patients with high-risk disease.47,48 Bone scans should be reserved primarily for patients with bone pain or elevated alkaline phosphatase and brain imaging for those with neurologic symptoms.49-51 Importantly, positron emission tomography (PET) scan has no role in the routine evaluation or staging of RCC. 

Renal Mass Biopsy

Renal mass biopsy (RMB) currently has an adjunctive role in the diagnosis and risk stratification of patients with renal masses suspicious for renal cancer. Biopsy, or fine needle aspiration, was traditionally reserved for patients suspected of having metastasis of another primary to the kidney, abscess, or lymphoma, or when needed to establish a pathologic diagnosis of RCC in occasional patients presenting with disseminated metastases or unresectable primary tumors. The role of RMB for clinically localized RCC has evolved considerably over the past few decades with considerable variance in practice patterns.

Tumor Characteristics

Staging

Kidney cancer is staged both clinically and pathologically using the staging system outlined by the American Joint Committee on Cancer (AJCC), also known as the tumor node metastases (TNM) classification.52 The AJCC TNM Staging System for Kidney Cancer is detailed in Table 3. Stage I and II tumors include cancers of any size that are confined to the kidney. This guideline statement identifies patients with renal masses suspicious for clinical stage I and II RCC, recognizing that a certain number of patients will be upstaged. Stage III tumors are either locally invasive (T3) or have involved lymph nodes (N1). Stage IV tumors have spread beyond the kidney into adjacent organs by direct invasion (T4) or distant metastases (M1). Prognosis is best predicted by stage with cancer-specific survival rates that approximate 85-90% for clinically localized (Stage I and II) RCC. 

Table 3. The AJCC TNM Staging System for Kidney Cancer.38 Primary Tumor (T), Regional Lymph Nodes (N) and Distant Metastases (M) are detailed in Table 3A; The Anatomic Stage/Prognostic Groups are detailed in Table 3B.

Table 3A

Primary Tumor (T)

TX

Primary tumor cannot be assessed.

T0

No evidence of primary tumor.

T1

Tumor ≤7 cm in greatest dimension, limited to the kidney.

T1a

Tumor ≤4 cm in greatest dimension, limited to the kidney.

T1b

Tumor >4 cm but not >7 cm in greatest dimension, limited to the kidney.

T2

Tumor >7 cm in greatest dimension, limited to the kidney.

T2a

Tumor >7 cm but ≤10 cm in greatest dimension, limited to the kidney.

T2b

Tumor >10 cm, limited to the kidney.

T3

Tumor extends into major veins or perinephric tissues but not into the ipsilateral adrenal gland and not beyond Gerota fascia.

T3a

Tumor extends into the renal vein or its segmental branches, or invades the pelvicaliceal system, or invades perirenal and/or renal sinus fat but not beyond Gerota fascia.

T3b

Tumor grossly extends into the vena cava below the diaphragm.

T3c

Tumor grossly extends into the vena cava above the diaphragm or invades the wall of the vena cava.

T4

Tumor invades beyond Gerota fascia (including contiguous extension into the ipsilateral adrenal gland).

Regional Lymph Nodes (N)

NX

Regional lymph nodes cannot be assessed.

N0

No regional lymph node metastasis.

N1

Metastases in regional lymph node(s).

Distant Metastasis (M)

M0

No distant metastasis.

M1

Distant metastasis.


Table 3B

Stage

T

N

M

I

T1

N0

M0

II

T2

N0

M0

III

T1 or T2

N1

M0

T3

N0 or N1

M0

IV

T4

Any N

M0

Any T

Any N

M1

Grading

Historically, a number of grading systems existed and evolved to describe tumor differentiation, cytologic aggressiveness, and prognosis of RCC based on nuclear size and irregularity. In 1982, the Fuhrman Grading system was described and became the most widely used grading system for RCC.53 In 2012, the International Society of Urological Pathology (ISUP) Grading System for Renal Cell Carcinoma was proposed.54 The ISUP Grading System incorporates aspects of the Fuhrman Grading system but includes more objective criteria for nuclear characteristics. In addition, sarcomatoid and rhabdoid tumors, tumors with giant cells, and tumors with extreme nuclear pleomorphism are included within grade 4 tumors; chromophobe RCC is no longer graded in the ISUP system. In general, higher grade is associated with larger tumor size and more aggressive tumors.55,56

Other Prognostic Indicators and Nomograms

Other factors for prognostic consideration include tumor size, necrosis, microvascular invasion, sarcomatoid features, collecting system invasion, patient symptoms, signs of paraneoplastic syndromes, and performance status. Tumor size is important for risk stratification regarding the likelihood of malignancy and more aggressive pathology.5-8, 44 Other tumor characteristics including tumor necrosis, microvascular invasion, and collecting system invasion have not been reliably demonstrated to influence prognosis beyond the current staging and grading systems. However, a number of prognostic systems including the UCLA Integrated Staging System (UISS),57,58 Stage, Size, Grade and Necrosis (SSIGN) score,59-61and other nomograms62,63 incorporate a variety of pathological and patient characteristics to provide an enhanced prediction of prognosis. 

Other Clinical and Biological Indicators

A number of molecular studies and markers have been proposed for diagnostic and prognostic purposes in RCC. The recent Agency for Healthcare Research and Quality (AHRQ) Systematic Review identified a number of biomarkers and laboratory tests that may have diagnostic or prognostic utility in the renal cancer literature.64 However, these studies were often univariable in design and therefore excluded from analysis due to a failure to include clinical variables or suboptimal methodology to validate the ultimate value of the tests. Therefore, the AHRQ report identified clinical and biological indicators as a major research gap in the renal cancer literature.65

Of note, urine aquaporin-1 and perilipin-2 were identified as emerging biomarkers with potential for the diagnosis of RCC.66,67 Carbonic anhydrase-9 (CAIX) expression is governed by the transcription factor hypoxia-inducible factor-1α (HIF-1α), a well-known component of the von Hippel-Lindau (VHL) pathway of clear cell RCC.68 While CAIX expression on primary tumors is a prognostic factor, especially in patients with metastatic RCC, high and homogenous levels of CAIX expression prevent risk stratification and clinical utility beyond the established clinical predictors of aggressive, clear cell RCC.69 Serum tests including C-reactive protein and platelet count may have prognostic roles, but further investigation is needed. New imaging modalities, including molecular imaging techniques using CAIX70-72 or 99m technetium-sestamibi73 single photon emission computed tomography, may help to better differentiate between malignant and benign pathology.  However, most markers and imaging modalities in this domain are best characterized as investigational.

Overview of Treatment Alternatives

A number of strategies exist for the management of sporadic renal masses suspicious for clinically localized renal cancer. Four strategies are considered standards of care and include active surveillance, radical nephrectomy, partial nephrectomy, and thermal ablation. 

Active Surveillance (AS)

A growing body of literature exists regarding active surveillance (AS) for patients with clinically localized small renal masses (cT1a, ≤4cm). A number of retrospective studies and meta-analyses evaluate the safety of AS and quote the risk of metastatic progression while on AS to be less than 2 percent in well selected patients over the initial 3 years of AS.74-76 Two large prospective AS programs have been initiated that follow patients with serial imaging, and both report slow growth rates and extremely low rates of metastatic progression, albeit with relatively short follow-up.77-79 Both programs screen patients with an initial metastatic evaluation including serum laboratory evaluation and chest imaging. Patients are then evaluated every 3-6 months for two years and with extended imaging intervals beyond that. Rates of biopsy are variable with one group utilizing RMB in greater than 50 percent of the cohort and the other using biopsy in less than 10 percent of its patients. Further data with longer follow-up from these cohorts will help to inform the utility of AS in the small renal mass population, and should allow for more intelligent patient selection for AS. Of note, the Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) Registry prospectively catalogues a contemporaneous cohort of patients undergoing AS and primary intervention and will offer data regarding comparative effectiveness.79

Radical Nephrectomy (RN)

RN was the mainstay of therapy for all renal masses for many decades. Historically, RN included the removal of the entire kidney including Gerota's/Zuckerkandel's fascia, regional lymph nodes and the adrenal gland. RN can be performed through an open incision or via minimally-invasive approaches (laparoscopic or robotic). Cancer-specific survival associated with RN is excellent however recent controversies regarding RN include its negative impact on renal function and overutilization for the management of stage I, especially T1a, tumors.

Partial Nephrectomy (PN)

PN is widely accepted as a nephron-sparing approach to the management of clinically localized RCC. Initially underutilized and predominantly performed in large academic centers,80,81 the management of clinically localized renal masses by PN has expanded with implementation of guideline statements and the expansion of robotic technology.82,83 PN can be performed through an open incision or via a minimally invasive approach, although the robotic approach has largely supplanted laparoscopic surgery as the preferred minimally invasive approach.84 The benefit of PN lies in the potential to preserve renal function but this is counterbalanced by an increased risk of urologic complications, although most are manageable and typically associated with good outcomes. Recent controversies surround modifiable and non-modifiable factors during surgery to improve renal functional outcomes, including parenchymal volume preservation, warm versus cold ischemia, and duration of ischemia.

Thermal Ablation (TA)

TA techniques were developed in an effort to improve patient procedural tolerance and reduce the potential for complications from PN, while still preserving function. A multitude of techniques/technologies have been investigated to ablate renal tumors, however radiofrequency ablation (RFA) and cryoablation have been most widely investigated and integrated into clinical practice. While the superiority of RFA or cryoablation remains controversial, it is generally accepted that oncologic outcomes are similar for both approaches.85-87 TA has traditionally been performed through a variety of approaches, including open, laparoscopic, and percutaneous. Concerns with the TA literature included relatively limited follow-up, lack of pre and post treatment biopsy to define malignancy and efficacy, and increased local recurrence rates relative to surgical excision. The latter require a longer period of surveillance (5 years) with cross-sectional imaging to monitor for late local recurrences. 

Investigational Modalities

Other technologies including high intensity focused ultrasound, radiosurgery, microwave therapy, pulsed cavitational ultrasound, and laser thermal therapy remain investigational at this time.

Evaluation & Diagnosis

Guideline Statement 1

In patients with a solid or complex cystic renal mass, physicians should obtain high quality, multiphase, cross-sectional abdominal imaging to optimally characterize and clinically stage the renal mass. Characterization of the renal mass should include assessment of tumor complexity, degree of contrast enhancement (where applicable), and presence or absence of fat. (Clinical Principle)

Discussion


Guideline Statement 2

In patients with suspected renal malignancy, physicians should obtain comprehensive metabolic panel, complete blood count, and urinalysis. Metastatic evaluation should include chest imaging to evaluate for possible thoracic metastases. (Clinical Principle) 

Discussion


Guideline Statement 3

For patients with a solid or complex cystic renal mass, physicians should assign CKD stage based on GFR and degree of proteinuria. (Expert Opinion)

Discussion


Counseling

Guideline Statement 4

In patients with a solid or Bosniak 3/4 complex cystic renal mass, a urologist should lead the counseling process and should consider all management strategies. A multidisciplinary team should be included when necessary. (Expert Opinion)

Discussion


Guideline Statement 5

Physicians should provide counseling that includes current perspectives about tumor biology and a patient-specific risk assessment inclusive of sex, tumor size/complexity, histology (when obtained), and imaging characteristics.  For cT1a tumors, the low oncologic risk of many small renal masses should be reviewed. (Clinical Principle)

Discussion


Guideline Statement 6

During counseling of patients with a solid or Bosniak 3/4 complex cystic renal mass, physicians must review the most common and serious urologic and non-urologic morbidities of each treatment pathway and the importance of patient age, comorbidities/frailty, and life expectancy. (Clinical Principle)

Discussion


Guideline Statement 7

Physicians should review the importance of renal functional recovery related to renal mass management, including the risk of progressive CKD, potential short- or long-term need for renal replacement therapy, and long-term overall survival considerations. (Clinical Principle)

Discussion


Guideline Statement 8

Physicians should consider referral to nephrology in patients with a high risk of CKD progression. Such patients may include those with eGFR less than 45 ml/min/1.73m2, confirmed proteinuria, diabetics with preexisting CKD,  or whenever eGFR is expected to be less than 30 ml/min/1.73m2 after intervention. (Expert Opinion)

Discussion


Guideline Statement 9

Physicians should recommend genetic counseling for all patients ≤ 46 years of age with renal malignancy and consider genetic counseling for patients with multifocal or bilateral renal masses, or if personal or family history suggests a familial renal neoplastic syndrome. (Expert Opinion)

Discussion


Renal Mass Biopsy

Guideline Statement 10

Renal mass biopsy should be considered when a mass is suspected to be hematologic, metastatic, inflammatory, or infectious. (Clinical Principle)

Discussion


Guideline Statement 11

In the setting of a solid renal mass, RMB is not required for: 1) young or healthy patients who are unwilling to accept the uncertainties associated with RMB; or 2) older or frail patients who will be managed conservatively independent of RMB findings. (Expert Opinion)

Discussion


Guideline Statement 12

When considering the utility of RMB, patients should be counseled regarding rationale, positive and negative predictive values, potential risks and non-diagnostic rates of RMB. (Clinical Principle)

Discussion


Guideline Statement 13

For patients with a solid renal mass who elect RMB, multiple core biopsies are preferred over fine needle aspiration. (Moderate Recommendation; Evidence Level: Grade C)

Discussion


Management

Partial Nephrectomy (PN) and Nephron-Sparing Approaches

Guideline Statement 14

Physicians should prioritize PN for the management of the cT1a renal mass when intervention is indicated. In this setting, PN minimizes the risk of CKD or CKD progression and is associated with favorable oncologic outcomes, including excellent local control. (Moderate Recommendation; Evidence Level: Grade B)

Discussion


Guideline Statement 15

Physicians should prioritize nephron-sparing approaches for patients with solid or Bosniak 3/4 complex cystic renal masses and an anatomic or functionally solitary kidney, bilateral tumors, known familial RCC, preexisting CKD, or proteinuria. (Moderate Recommendation; Evidence Level: Grade C)

Discussion


Guideline Statement 16

Physicians should consider nephron-sparing approaches for patients with solid or Bosniak 3/4 complex cystic renal masses who are young, have multifocal masses, or comorbidities that are likely to impact renal function in the future, such as moderate to severe hypertension, diabetes mellitus, recurrent urolithiasis, or morbid obesity. (Conditional Recommendation; Evidence Level: Grade C)

Discussion


Guideline Statement 17

In patients who elect PN, physicians should prioritize preservation of renal function through efforts to optimize nephron mass preservation and avoidance of prolonged warm ischemia. (Expert Opinion) 

Discussion


Guideline Statement 18

For patients undergoing PN, negative surgical margins should be a priority. The extent of normal parenchyma removed should be determined by surgeon discretion taking into account the clinical situation, tumor characteristics including growth pattern, and interface with normal tissue. Tumor enucleation should be considered in patients with familial RCC, multifocal disease, or severe CKD to optimize parenchymal mass preservation. (Expert Opinion)

Discussion


Radical Nephrectomy (RN)

Guideline Statement 19

Physicians should consider RN for patients with a solid or Bosniak 3/4 complex cystic renal mass where increased oncologic potential is suggested by tumor size, RMB, and/or imaging characteristics and in whom active treatment is planned. (Conditional Recommendation; Evidence Level: Grade B) In this setting, RN is preferred if all of the following criteria are met: 1) high tumor complexity and PN would be challenging even in experienced hands; 2) no preexisting CKD or proteinuria; and 3) normal contralateral kidney and new baseline eGFR will likely be greater than 45 ml/min/1.73m2. (Expert Opinion)

Discussion


Surgical Principles

Guideline Statement 20

For patients who are undergoing surgical excision of a renal mass with clinically concerning regional lymphadenopathy, physicians should perform a lymph node dissection for staging purposes. (Expert Opinion)

Discussion


Guideline Statement 21

For patients who are undergoing surgical excision of a renal mass, physicians should perform adrenalectomy if imaging and/or intraoperative findings suggest metastasis or direct invasion of the adrenal gland. (Clinical Principle)

Discussion


Guideline Statement 22

In patients undergoing surgical excision of a renal mass, a minimally invasive approach should be considered when it would not compromise oncologic, functional and perioperative outcomes. (Expert Opinion)

Discussion


Guideline Statement 23

Pathologic evaluation of the adjacent renal parenchyma should be performed after PN or RN to assess for possible intrinsic renal disease, particularly for patients with CKD or risk factors for developing CKD. (Clinical Principle)

Discussion


Thermal Ablation (TA)

Guideline Statement 24

Physicians should consider thermal ablation (TA) as an alternate approach for the management of cT1a renal masses <3 cm in size. For patients who elect TA, a percutaneous technique is preferred over a surgical approach whenever feasible to minimize morbidity. (Conditional Recommendation; Evidence Level: Grade C)

Discussion


Guideline Statement 25

Both radiofrequency ablation and cryoablation are options for patients who elect thermal ablation. (Conditional Recommendation; Evidence Level: Grade C)

Discussion


Guideline Statement 26

A renal mass biopsy should be performed prior to ablation to provide pathologic diagnosis and guide subsequent surveillance. (Expert Opinion) 

Discussion


Guideline Statement 27

Counseling about thermal ablation should include information regarding an increased likelihood of tumor persistence or local recurrence after primary thermal ablation relative to surgical extirpation, which may be addressed with repeat ablation if further intervention is elected. (Strong Recommendation; Evidence Level: Grade B)

Discussion


Active Surveillance

The decision to embark on a course of active surveillance (AS) rather than treatment in the setting of a localized renal mass presumed to be a renal cancer requires thoughtful consideration by both the patient and the physician. In making the decision, an objective baseline evaluation of patient, tumor, and treatment-related factors should be undertaken (Figure 6). This should include formal decision-making tools whenever possible leading to a well communicated risk-benefit analysis unique to the individual patient’s circumstances.99,267-270 The shared decision-making process should be consistent with the patient’s inherent preferences and tolerance of uncertainty. 271

Figure 6. Algorithm for active surveillance or expectant management of localized renal masses suspicious for malignancy

Renal Mass and Localized Renal Cancer Figure 6
Hi-Res Version of the AS-Algorithm [pdf]

High level data regarding the frequency and preferred imaging modalities for renal mass surveillance are lacking. Therefore at the time of the initial baseline assessment and during subsequent re-assessments, the clinician should estimate how to best achieve the goals of (1) preventing stage progression, (2) maintaining renal function and (3) avoiding the potential risks of treatment when it is unlikely to provide an oncologic or survival benefit. At the onset of AS, the clinician should request and evaluate prior abdominal imaging that may demonstrate the existence of the renal mass at an earlier time point to assess growth rate or changes in clinical stage. Next, patients placed on a program of non-intervention should be considered for either AS or expectant management (observation or watchful waiting) (Figure 6).

Active surveillance (AS) is most appropriate for patients in whom the anticipated net benefit of AS is modest to significant when compared to treatment. Excluded from this track are patients who are reasonable candidates for intervention if tumor size, infiltrative appearance, interval growth, or RMB suggest the potential for cancer progression, unless they are willing to accept the associated increase in oncologic risk (see statement 31 below). Patients with no prior imaging should have surveillance imaging initially every 3 to 6 months to assess for interval growth, substantial radiographic changes in the character of the lesion, or the presence of rare occult synchronous metastases in the setting of a small renal mass. The preferred modality is not well established in the literature but initial imaging should preferably consist of contrast-enhanced cross sectional imaging. Subsequent imaging may include the same or when appropriate an abdominal ultrasound can be substituted. Abdominal US (as opposed to retroperitoneal US), may have the additional benefit of a survey of the intraabdominal organs for progression. Differences in tumor dimension measurements between these different modalities may be significant and should be interpreted with caution when making treatment decisions.79 RMB can be considered for additional risk stratification for patients on AS. 

It is recognized that not all patients on AS will require the same intensity of surveillance as their tradeoffs, risk calculations and personal objectives may differ. Some patients may therefore require more intensive AS while others require less intensive AS. The decision as to the frequency and imaging modality must therefore be customized and informed by robust communication focusing on goals, risks and triggers for intervention.

Expectant management (observation) is appropriate in patients in whom treatment poses an unacceptably higher risk than surveillance. In this setting, yearly abdominal US including images of the retroperitoneal and intraperitoneal organs can be performed to screen for stage progression which may trigger systemic therapy in the appropriately selected patient. 

Regardless of the intensity of surveillance, chest imaging with plain radiography (CXR) is warranted annually or if intervention triggers are encountered or symptoms arise. These recommendations are consistent with recently published AUA guidelines for follow-up for clinically localized renal neoplasms.272 The intensity of surveillance can be attenuated if the renal mass exhibits slow growth kinetics, is noted to be radiographically stable or if the patient’s medical condition deteriorates. In cases such as this, patients can cross over between AS and expected management (observation) based on changing risk profiles, performance status, absolute tumor size, tumor growth kinetics, stage progression or other recalibration triggers for possible intervention.273,274 While no level 1 data exist that define these triggers precisely, they should generally be based on changes in tumor-based risk (absolute size > 3cm, median growth rate in excess of 5mm/year, or stage migration) or patient-based risks (co-morbidities) with continual objective reassessments to include the use of RMB when appropriate.273,274 Published data demonstrate that in most instances, judicious delayed intervention for localized stage I renal masses remains effective.273-275

The key to successful AS of a localized renal mass remains thoughtful and recurrent reassessments and robust communication in partnership with the patient and his/her care givers. Prospective trials, ideally randomized, of AS versus treatment, with improved reporting and more extended follow-up, should be prioritized to provide higher quality data about oncologic, functional and survival outcomes.

Guideline Statement 28

For patients with small solid or Bosniak 3/4 complex cystic renal masses, especially those <2cm, AS is an option for initial management. (Conditional Recommendation; Evidence Level: Grade C)

Discussion


Guideline Statement 29

For patients with a solid or Bosniak 3/4 complex cystic renal mass, physicians should prioritize active surveillance/expectant management when the anticipated risk of intervention or competing risks of death outweigh the potential oncologic benefits of active treatment. (Clinical Principle)

Discussion


Guideline Statement 30

For patients with a solid or Bosniak 3/4 complex cystic renal mass in whom the risk/benefit analysis for treatment is equivocal and who prefer AS, physicians should repeat imaging in 3-6 months to assess for interval growth and may consider RMB for additional risk stratification. (Expert Opinion)

Discussion


Guideline Statement 31

For patients with a solid or Bosniak 3/4 complex cystic renal mass in whom the anticipated oncologic benefits of intervention outweigh the risks of treatment and competing risks of death, physicians should recommend active treatment. In this setting, AS with potential for delayed intervention may be pursued only if the patient understands and is willing to accept the associated oncologic risk. (Moderate Recommendation; Evidence Level: Grade C)

Discussion


Future Direction

The most promising routes to advance the field in localized renal cancer include (1) clinical trials, (2) collaborative quality initiatives, (3) novel diagnostics/biomarkers, and (4) improved technologies and systemic therapies. Each of these requires an unrelenting commitment to continuous clinical improvement and scientific investigation.

 The management of localized renal cancer is an area for which there is a paucity of randomized clinical trials (RCT’s). Improving the strength of evidence will require an increased commitment to clinical trial design, conduct, and funding. Although our understanding of the nature and management of this disease continues to progress, without adequate engagement and support, our treatment paradigms will likely continue to be more art than science.

 An appropriate companion to RCT’s is the development of collaborative quality initiatives (CQI’s).279 Within a CQI, participating hospitals and providers collect, share, and analyze data through clinical registries. CQI participants design and affect changes that improve outcomes of complex, highly technical areas of care. CQI registries allow for a more robust analysis of the link between processes and outcomes than can occur with retrospective single or multi-institutional studies; particularly as more sensitive and specific diagnostics/biomarkers are complemented by technologic advances. Scientific inquiry will continue to provide fundamental knowledge regarding the biological basis, inherent risks, and natural history of localized renal masses such that appropriate trade-offs can be made when considering optimal management.

Evaluation and Diagnosis

 The localized renal mass remains primarily a radiographic diagnosis. The field of tumor radiomics and molecular imaging promises to improve our ability to discriminate tumor histology, grade280,281 and ultimately gene and protein expression with prognostic implications. Concurrently, the development of more sophisticated modeling of patient demographic features as recorded in the electronic medical record, such as age, race, body mass index, comorbidities, exposure to tobacco, and other risk factors should be further studied to contextualize and individualize management options. Finally, tumor markers detected in biopsy, blood, or urine should be studied to improve prognostic models for RCC. Initial efforts based on gene expression identified multiple promising markers that may one day distinguish between subtypes of malignant and benign renal tumors.282,283 Recent work through The Cancer Genome Atlas (TCGA) to identify genomic markers for clear cell RCC284, papillary RCC285, and chromophobe RCC286 holds great clinical potential for more accurate diagnosis, prognostication, and surveillance of renal masses. The promise of measuring circulating tumor cells, or liquid tumor biopsies, for diagnosis and surveillance for recurrence and response to treatment is several years off, but could substantially transform care models.287,288

Counseling and Outcomes-based Research

 As data emerge regarding variability in treatments performed for localized renal cancer, the impact of the individual physician-patient interaction becomes more evident. The quality of patient counseling can only be improved by providing high quality data, particularly from RCT’s. Given our current state of knowledge, translation of information from research studies and guidelines into practical materials for patients is not straight-forward. The development of decision aids for informed medical-decision making is ongoing.289,290 The appropriate application of data from large registries and implementations sciences to improve processes and standardization of care is an important initiative that must move forward. Increased quality of data, including improved assessment of tumor biology and prospective trials of management options, is greatly needed to facilitate more intelligent patient counseling.

Management

 A major limitation of the literature supporting the current guidelines for management of localized renal cancer is the relatively low level of evidence. Prospective comparative trials, ideally randomized, comparing active surveillance vs. active intervention should be prioritized to provide higher quality data about oncologic and renal functional outcomes and to assess the treatment-related morbidities or limitations of each approach. With improved reporting and more extended follow-up, multi-institutional observational data will strengthen confidence in recommendations, but not nearly to the extent that clinical trials can provide.

 Prospective trials with meaningful endpoints comparing TA versus PN, incorporating standardized post-treatment surveillance as advised by AUA Guidelines,272 should be prioritized to provide higher quality data about the oncologic and functional outcomes of each modality and to assess treatment-related morbidities. Even multi-institutional comparisons of patients with similar features with 5 year or longer follow-up would be of benefit given current deficiencies in the literature.

 Comparison of extirpative treatment modalities should include prospective evaluation of PN versus RN, prioritized in patients with a normal contralateral kidney and no preexisting CKD/albuminuria, with the goal of assessing the impact of new baseline functional status on overall survival, cardiovascular health, and subsequent renal stability on a longitudinal basis. Ideally, patients with tumors with increased oncologic potential (cT1b/T2) should be prioritized for such trials.205 Regarding nephron-sparing surgery, improved data comparing the relative merits and limitations of standard PN versus tumor enucleation should be sought, ideally through prospective evaluation incorporating improved reporting, and standard assessment of surgical margins.196

 Multiple non-extirpative methods being actively investigated in the management of renal masses include stereotactic body radiation therapy (SBRT), high-intensity focused ultrasound (HIFU), microwave ablation (MWA), and laser interstitial thermal therapy (LITT). These approaches differ in their mechanisms of action, invasiveness, reported outcomes and experience. Their use should be approached systematically and with caution, and they should be considered investigational at present. SBRT, also frequently referred to as stereotactic ablative radiotherapy (SABR), has been reported in a small number of series. SBRT involves relatively intense protocols (24 to 40 Gy) over one to five fractions and a high degree of spatial precision, offering the potential to be less invasive than surgical or conventional ablative approaches.291 Despite encouraging results, the current body of evidence is limited due to small patient numbers, short follow-up and inconsistent methods of reporting outcomes.291 Thus, SBRT in the management of localized renal masses at present remains investigational and should be primarily considered for patients who are medically inoperable and are not candidates for established TA approaches. Clinical trials should be prioritized if possible (NCT02138578NCT02853162NCT01890590).

 Similarly, HIFU remains investigational in the management of renal masses, although it is currently used clinically to treat prostate cancer and uterine fibroids.292 HIFU relies on the use of a lens or focused transducer to deliver high-frequency sound waves to tissue, typically 1 to 5 MHz. HIFU may be administered in an entirely noninvasive means similar to extracorporeal lithotripsy, thus minimizing the risk of tumor seeding, urinary extravasation or hemorrhage.293 Initial clinical investigations have established the feasibility of transcutaneous HIFU; however, distinct regions of renal masses are frequently left untreated resulting in incomplete ablation.294-297

 Similar to RFA, microwave ablation (MWA) delivers electromagnetic energy through flexible probes inserted into a target lesion. MWA produces target temperatures (>60° C) more rapidly than RFA, and, thus, appears to have significant potential as an ablative modality.298 Laser Interstitial Thermal Therapy (LITT) uses optical fibers that are inserted directly into the target tissue to deliver laser light that is converted into thermal energy. The most common laser type used in LITT is a neodymium: yttrium-aluminum-garnet (Nd:YAG) laser.299 Outcomes of clinical investigations are limited due to the small number of treated patients and short follow-up.300,301 Given the limited number of published studies involving HIFU, MWA and LITT and lack of long-term follow-up, appropriate use of these modalities in the management of SRM's remains poorly defined. Larger prospective trials will be necessary to develop and assess optimal use, risks and morbidity.

Summary 

 In conclusion, improving the management of localized renal tumors will require a concerted effort among clinicians to develop higher quality evidence and facilitate more precise estimations of the relative risks and benefits of each therapeutic approach.

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