Renal Cell Carcinoma: Diagnosis and Management Richard E. Gray, DO, and Gabriel T. Harris, MD, Uniformed Services University of the Health Sciences, Bethesda, Maryland Kidney cancer is one of the 10 most common cancers in the United States with 90% being attributed to renal cell carci- noma. Men, especially black men, are more likely to be affected than women. Renal masses, either cystic or solid, are best detected with contrast-enhanced, triple-phase computed tomography. Renal tumors are often detected incidentally during a computed tomography scan of the abdomen or chest that was ordered for unrelated symptoms. Hematuria serves as a warning sign that necessitates further evaluation and imaging leading to a diagnosis and treatment plan. Treatment options include active surveillance, ablation, nephron-sparing tumor excision, nephrectomy, and systemic treatment. Predictors of a poor prognosis include poor functional status and metastasis. In recent years new therapies have improved the prognosis for patients with metastatic disease. The family physician should be aware of risk factors (e.g., hypertension, tobacco use, exposure to trichloroethylene, familial syndromes) and lifestyle and dietary modifications that may reduce risk. (Am Fam Physician. 2019; 99(3): 179-184. Copyright © 2019 American Academy of Family Physicians.) Kidney cancer is one of the 10 most common cancers in most commonly encountered by mechanics, dry cleaners, the United States.1 Renal cell carcinoma accounts for 90% of oil processors, polyvinyl chloride manufacturers, and low- all kidney cancers.2 Death attributed to renal cell carcinoma nicotine tobacco producers.8 accounted for 2% of all cancer deaths or approximately There are 10 familial syndromes that confer greater risk 14,000 persons in 2016.1,2 Men are diagnosed with renal cell of developing renal cell carcinoma.11 The most common carcinoma at almost twice the rate of women, and there is a of these is von Hippel-Lindau disease which leads to the greater prevalence in black men.3 Most cases are diagnosed development of clear cell renal cell carcinoma through the between 60 and 70 years of age.1,2 activation of vascular endothelial growth factor (VEGF).11 Renal cell carcinoma is classified in three major histolog- Approximately 60% of sporadic clear cell renal cell carcino- ical subtypes: clear cell (75%), papillary (15% to 20%), and mas follow the same pathogenesis. This discovery has led to chromophobe (5%).4 Disease-specific survival is worst with the development of new therapies that inhibit VEGF recep- clear cell renal cell carcinoma as it tends to be discovered at tors and are being used to treat heritable and sporadic cases a more advanced stage.5 of clear cell renal cell carcinoma.11,12 Risk Factors Screening and Prevention Risk factors for renal cell carcinoma include hypertension, Screening for renal cell carcinoma is not recommended, except tobacco use, obesity, and acquired cystic kidney disease in the setting of a known heritable syndrome associated with in the setting of end-stage renal disease.1,3,6 Occupational the development of renal cell carcinoma.1 The management exposure to trichloroethylene can lead to the develop- of hypertension and obesity, and the avoidance of tobacco ment of renal cell carcinoma and increased mortality from use are the only established methods of primary prevention.8 renal cell carcinoma.5,7-9 The International Agency for Evidence from prospective and observational studies suggest Research on Cancer labels trichloroethylene as carcino- that consuming fatty fish (relative risk [RR] = 0.56;​​ 95% con- genic to humans and specifically associates it with renal fidence interval [CI], 0.35 to 0.91), three or more servings of cancer.10 Occupational exposure to trichloroethylene is fruits and vegetables (RR = 0.68;​​ 95% CI, 0.54 to 0.87), and one alcoholic beverage daily (RR = 0.76;​​ 95% CI, 0.68 to 0.85) 5,13-15 See related editorial on page 145. may reduce the risk of developing renal cell carcinoma. CME This clinical content conforms to AAFP criteria for con- tinuing medical education (CME). See CME Quiz on page 157. Clinical Presentation Author disclosure: No relevant financial affiliations. More than 50% of patients with renal cell carcinoma are asymptomatic and diagnosed incidentally during Downloaded from the American Family Physician website at www.aafp.org/afp. Copyright © 2018 American Academy of Family Physicians. For the private, noncom- Downloaded from the American Family Physician website at www.aafp.org/afp. Copyright © 2018 American Academy of Family Physicians. For the private, noncom- ◆ 179 mercial use of one individual user of the website. All other rights reserved. Contact [email protected] for copyright questions and/or permission requests. Februarymercial 1,use 2019 of one Volume individual 99, user Number of the website.3 All other rightswww.aafp.org/afp reserved. Contact [email protected] for copyright questionsAmerican and/or Family permission Physician requests. RENAL CELL CARCINOMA SORT: KEY RECOMMENDATIONS FOR PRACTICE Evidence Clinical recommendation rating References Comments Patients 35 years or older who have asymptomatic microhematuria C 17 Recommendation from should have cystoscopy and imaging with multiphasic computed consensus guideline based tomography urography performed. on observational studies Refer for a urology consultation for gross hematuria without urinary C 25 Recommendation from tract infection, especially if the patient is older than 45 years. consensus guideline based on observational studies Refer for a urology consultation for any mass with Bosniak III or IV C 21 Recommendation from classification and for selected, low-risk patients with IIF classification, consensus guideline based or any solid mass greater than 1 cm. on observational studies A = consistent, good-quality patient-oriented evidence;​​ B = inconsistent or limited-quality patient-oriented evidence;​​ C = consensus, disease- oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to https:// www.aafp. org/afpsort. thoracoabdominal imaging ordered for unrelated issues.5,16 creatinine, C-reactive protein, hemoglobin, erythrocyte The history and physical examination triad of gross hema- sedimentation rate, alkaline phosphatase, and serum cal- turia, flank pain, and palpable abdominal mass is now an cium.7 Routine urine cytology is not recommended for the uncommon presentation, and is associated with advanced initial evaluation of asymptomatic microscopic hematuria.17 disease.6,12,16 Nonreducing or isolated right-sided varicocele Patients 35 years or older who have asymptomatic microhe- and bilateral lower extremity edema can also be symptoms maturia should have cystoscopy and imaging with multi- of advanced disease through occlusion of the right testicu- phasic CT urography performed.17 lar venous system that drains directly to the right renal vein. Similarly, bilateral lower extremity edema can occur from IMAGING tumor occlusion of the inferior vena cava. Approximately A contrast-enhanced, triple-phase helical CT scan that images 20% of patients present with paraneoplastic disease, mani- the urinary tract before, during, and after contrast load is the fested by hypertension, hypercalcemia, and polycythemia.5 preferred imaging study for evaluating renal masses or per- Fever, weight loss, cough, adenopathy, and bone pain may sistent microscopic hematuria.19,20 CT detects 90% of renal indicate metastatic disease. masses, identifies benign and pathologic features, and evalu- ates surrounding anatomy to detect lymphadenopathy or an Diagnosis associated thrombus. A contrast-enhanced CT scan will also CLINICAL EVALUATION identify benign masses that do not require further testing. An isolated right-sided varicocele and nonreducing bilat- The Hounsfield unit scale measures a tissue’s density eral varicocele should be evaluated with abdominal imag- or attenuation. Fat has very low attenuation (i.e., –100 to ing. Gross hematuria requires computed tomography (CT), –10 HU), and masses containing fat are almost always urography, and urology consultation for cystoscopy.17 Signs benign angiomyolipomas. Homogeneous masses with low of paraneoplastic or metastatic disease require evaluation attenuation (–10 to +20 HU) can be identified as benign, for malignancy, including chest and abdominal imaging. fluid-filled, simple cysts. Masses with attenuation greater than 20 HU, heterogeneous appearance, septations, or cal- LABORATORY EVALUATION cifications, may be malignant and require further evalua- Hematuria should be diagnosed by microscopic exam- tion21 (Figure 2). The differential diagnosis of renal masses ination that shows three or more red blood cells per is included in Table 1.22 high-powered field, not by urine dipstick alone. The urine For incompletely characterized masses or contraindica- should be without pyuria or red blood cell casts, which tions to CT, magnetic resonance imaging with and without indicates infection or glomerulonephritis, respectively. If intravenous contrast is recommended.21 asymptomatic microscopic hematuria is detected, manage- ment is recommended per American Urological Association Management guidelines (Figure 1).17,18 Benign causes should be ruled out, The management of cystic lesions should be guided by the including infection, recent vigorous exercise, menstruation, Bosniak classification system (Table 2).21 Shared decision- and instrumentation. Identified