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Renal cell carcinoma

I. What every physician needs to know.

The term renal cell carcinoma (RCC) encompasses several histologically distinct cancers which arise from the renal tubular epithelium including clear cell (~80%), papillary, oncocytoma, chromophobe, and collecting duct. Initial presentation may include the classic triad of hematuria, abdominal pain and abdominal mass (10-20% of cases) but is increasingly common as an incidental finding on abdominal imaging. All solid masses of the kidney should be considered RCC until proven otherwise. Mutation or inactivation of the von Hippel-Lindau (VHL) gene is responsible for both hereditary and almost all sporadic clear cell RCC, and the VHL pathways are the target of most available therapies for RCC.

II. Diagnostic Confirmation: Are you sure your patient has renal cell carcinoma?

In most cases, a partial or radical nephrectomy should be done for both diagnostic and curative purposes. In the case of diagnostic uncertainty, serious comorbid conditions, and/or small renal tumors, diagnosis is sometimes made via percutaneous biopsy first.

A. History Part I: Pattern Recognition:

Solid renal mass
Hematuria
Flank pain
Flank mass
Weight loss
Anemia or polycythemia

B. History Part 2: Prevalence:

RCC accounts for approximately 3% of all cancers with peak incidence occurring between 50 and 70 years. It is more common in African Americans and has a male to female ratio of 2:1. Risk factors include smoking, obesity, hypertension acquired cystic kidney disease associated with end stage renal disease, and occupational exposures. Recent evidence also implicates chronic use of certain NSAIDs as a risk factor. Clear cell RCC is also associated with von Hippel-Lindau disease, along with pheochromocytomas and hemangioblastomas.

C. History Part 3: Competing diagnoses that can mimic renal cell carcinoma.

All solid renal masses should be considered RCC, but definitive diagnosis is made histologically usually by partial or complete nephrectomy. Other solid renal masses include:

Angiomyolipoma (appears fatty on computed tomography [CT] with an attenuation value under -20 Hounsfield units is virtually pathognomonic)
Transitional cell carcinoma (positive urine cytology, usually centrally located)
Adrenal tumors
Renal abscesses
Lymphoma
Metastasis from another primary site
Renal cysts (generally distinguishable because of their smooth appearance, lack of enhancement or septations and density of 0 Hounsfield units [equivalent to water]).

D. Physical Examination Findings.

Flank mass (in 25% of patients)
Lower extremity edema (due to inferior vena cava [IVC] involvement)
Varicoceles (in 11% of male patients due to obstruction of the gonadal vein, usually left-sided and does not decompress when lying down)

E. What diagnostic tests should be performed?

N/A

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Urinalysis – micro- or macroscopic hematuria occurs in 60% of patients
Complete blood count (CBC) – patients may have anemia of chronic inflammation (normo- or microcytic), some have erythrocytosis from paraneoplastic erythropoietin (Epo) production, and rarely some have thrombocytosis
Basic metabolic panel (BMP) – patients may have hypercalcemia due to lytic bone lesions, paraneoplastic Parathyroid hormone related protein (PTHrP) secretion, or increased prostaglandin production
Liver function tests (LFTS) – hepatic dysfunction can occur with or without (Stauffer Syndrome) metastatic disease to the liver

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Approximately half of all renal cell carcinomas are discovered incidentally on some form of abdominal imaging, but CT of the abdomen and pelvis with and without contrast is the most useful test for evaluation of the tumor and staging. Staging is important for prognosis.

Staging takes into account tumor size, local invasion, the presence or absence of nodal involvement and the presence or absence of metastatic disease. A stage I tumor is seven centimeters (cm) or less and limited to the kidney. Stage II tumors are larger than seven centimeters and still limited to the kidney. Stage III includes any size tumor with nodal involvement only OR any size tumor that has invaded locally to involve the perinephric fat and/or IVC but no lymph nodes. Stage IV tumors include those with local invasion beyond Gerota’s fascia +/- ipsilateral adrenal gland involvement OR any tumor size and metastatic disease. The most common sites of metastasis are bone, lung, liver and brain.

A CT of the chest should be performed in cases of suspected metastases. Magnetic resonance imaging (MRI) without contrast is useful in patients with contraindications to intravenous contrast or to evaluate for IVC or atrial involvement. Positron emission tomography (PET) scan should be done in patients with bone pain or elevated alkaline phosphatase.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

None

III. Default Management.

N/A

A. Immediate management.

Immediate management involves managing any life-threatening paraneoplastic syndromes or complications that are present, such as hypercalcemia, IVC/right atrial thrombus, or massive hematuria.

After managing life-threatening complications, determine staging through a complete history and physical and further imaging if necessary. Urology and oncology should be involved with decision making. Excision is appropriate therapy in surgical candidates, even in patients with locally advanced or metastatic disease (“cytoreduction”) as it may improve longevity. In localized RCC, excision is often curative. In patients with a single metastatic site, surgical resection of the primary + metastectomy may also be curative. In the case of small renal tumors (by definition, <4 cm), active surveillance may be appropriate with serial repeat abdominal imaging rather than proceeding directly to excision, particularly those renal tumors < 1 cm or <4 cm in a patient with comorbid conditions and/or short life expectancy.

Typically if surgical management is pursued, a radical nephrectomy should be performed. A partial nephrectomy may be warranted when there are simultaneous bilateral lesions, poor renal function or disease in the contralateral kidney, or the tumor is in a solitary kidney. More recently, radiofrequency and cryoablation have been utilized as nephron-sparing procedures, particularly in those with small renal tumors and in the management of hereditary RCC-predisposing syndromes such as VHL.

Radiation therapy is only used for palliation in patients who are not surgical candidates, such as for treatment of painful bony or renal fossa metastases or for brain metastases.

Locally advanced and metastatic RCC or recurrent RCC following definitive resection require systemic therapy. First line therapy for highly selected patients with good performance status and access to a center qualified to manage its complications is immunotherapy with high-dose IL-2 (interleukin-2). First-line therapy for those who are not candidates for IL-2 is a molecularly targeted anti-angiogenic (anti-vascular endothelial growth factor or anti-VEGF) agent or a programmed cell death (PD) protocol. The anti-angiogenic agents include the tyrosine kinase inhibitors sorafenib, sunitinib, pazopanib, cabozantinib, and axitinib and the monoclonal antibody bevacizumab.

Second-line therapy for those who have progressed through high-dose IL-2 is a molecularly targeted anti-angiogenic agent. Second-line therapy for those who have progressed through a first anti-angiogenic agent is either a second anti-angiogenic agent or an agent targeting the mTOR (mechanistic target of rapamycin) pathway (severolimus or temsirolimus).

Chemotherapy with drugs such as 5-fluorouracil (5-FU), capecitabine, and gemcitabine have been shown to help a small number of patients who have not responded to targeted therapy or immunotherapy.

B. Physical Examination Tips to Guide Management.

None

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Post-nephrectomy, a CBC should be monitored for possible bleeding. Blood urea nitrogen (BUN) and creatinine should be checked to monitor renal function.

D. Long-term management.

Post-operative surveillance is important as 50% of patients will experience a relapse, two-thirds of which occur in the first year. Both the American Urologic Association and National Comprehensive Cancer Network have released guidelines for surveillance of RCC, with the protocol, duration, and intervals differing according to stage but including a history and physical, laboratory testing, chest imaging (radiograph versus CT), and abdominal imaging (ultrasound, CT or MRI).

E. Common Pitfalls and Side-Effects of Management

Side effects of management vary with treatment strategy.

IV. Management with Co-Morbidities

N/A