Renal cell carcinoma

Last updated: May 27, 2022

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Renal cell carcinoma (RCC), which originates from the renal tubular epithelium, is the most common renal malignancy in adults. Most cases are sporadic, but some hereditary disorders are also associated with the development of RCC. Major risk factors for RCC include smoking, acquired cystic disease of the kidney, nephrolithiasis, and long-term acetaminophen use. In the majority of cases, RCC is diagnosed following an incidental finding on imaging, and most patients are asymptomatic. Rarely, patients may present with the classic triad of flank pain, hematuria, and a palpable abdominal mass. Patients may also present with anemia, weight loss, and/or paraneoplastic manifestations such as hypercalcemia and hypertension. The primary imaging modality is an abdominal ultrasound, or CT or MRI with contrast. Most RCC tumors are resistant to radiotherapy and classical chemotherapeutic agents. Surgical resection is first-line treatment in nonmetastatic disease, and immunotherapy and targeted therapy, e.g., vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors, are used in metastatic RCC. Patients with early-stage RCC with tumor growth limited to the kidney have a very good prognosis.

Epidemiological data refers to the US, unless otherwise specified.

Overview

  • Most renal cell carcinomas (RCCs) occur sporadically.
  • Approx. 4% of renal cell carcinomas are associated with hereditary factors.
  • Both forms show structural alterations of the short arm of chromosome 3 (3p) and subsequent alterations of the VHL gene.

Risk factors for sporadic RCC [2][3]

Hereditary renal cell carcinomas [3]

Hereditary renal cell carcinomas are autosomal dominant and tend to affect patients at a younger age than sporadic renal cell carcinomas.

  • Overview
    • Usually asymptomatic in the early stages
    • Patients become symptomatic when the tumor has reached a large size (usually > 10 cm) and/or if metastases are present.
  • Constitutional symptoms
  • Symptoms caused by primary tumor
  • Symptoms of local spread and metastatic disease: see “Complications” below

The classical triad of renal cell carcinoma consists of hematuria, flank pain, and a palpable flank mass. However, only 10–15% of patients present with all three components of the triad and > 25% present with one or more atypical symptoms related to paraneoplastic syndromes and/or disseminated disease. [5]

TNM classification (8th Edition, 2017)

Overview of TNM classification
TNM Tissue invasion
T1
T2
T3
T4
N0
N1
M0
M1

AJCC staging (8th Edition, 2017)

Overview of AJCC stages
AJCC stage TNM
Stage I
  • T1; N0
Stage II
  • T2; N0
Stage III
  • T1 or T2; N1
  • T3; N0 or N1
Stage IV
  • T4; Any N; M0
  • Any T; Any N; M1

Approach [6][7]

Most renal masses are detected incidentally on imaging performed for another indication or to evaluate nonspecific symptoms.

  • Obtain additional imaging in patients with an indeterminate mass. [8]
    • Preferred: CT or MRI abdomen (with IV contrast)
    • Alternative: ultrasound abdomen (with IV contrast)
  • Pursue workup based on imaging findings (e.g., repeat imaging for Bosniak IIF cystic mass).

Hematuria may be the initial presentation of RCC. Patients ≥ 35 years of age with asymptomatic microhematuria, and all patients with gross hematuria in the absence of a UTI, should be referred to urology. [7]

Imaging

  • Overview: Most renal masses are detected incidentally on imaging performed for another indication or to evaluate nonspecific symptoms.
  • Indications
    • Characterization of lesions (e.g., size, regular or irregular walls).
    • Identification of lymph node and/or renal vein involvement. [9][10]
  • Modalities and characteristic findings: Abdominal CT, MRI, or ultrasound (with IV contrast) are first-line modalities. ; [6][8]
    • CT abdomen (with IV contrast; multiphase renal protocol)
      • Lesion(s) with thickened irregular walls, calcification, and variable enhancement [10][11][12]
      • Distorted renal outline
    • MRI abdomen (with IV contrast; multiphase renal protocol) [8][9]
      • May be preferred for the assessment of small lesions (< 1.5 cm) and Bosniak IIF or III cystic renal masses
      • Can provide additional information on IVC invasion if findings are unclear on a CT scan [9]
    • Ultrasound abdomen (with IV contrast)
      • Preferred study in patients with contraindications to iodinated contrast for CT and gadolinium-based contrast for MRI.
      • Can identify renal lesion(s) with variable echogenicity [10]
Workup based on imaging findings [6][7][10]
Findings Next steps
  • Follow-up is usually not required, see also “Renal cysts.” [13]
  • Repeat imaging at 6 and 12 months, then yearly for a total of 5 years.
  • Refer to urology if there is any change in appearance or > 3 mm growth per year.
  • Bosniak III or IV cystic mass
  • Solid mass > 1 cm with no fat
  • Obtain CBC, BMP, and urinalysis. [14]
  • Refer to urology for consideration of further investigations (e.g., staging, biopsy).

Metastatic evaluation

These may be considered in consultation with a urologist.

  • CT or MRI chest (with IV contrast): indicated in patients with large tumors [15][16]
  • Bone scan: may be indicated in patients with bone pain and/or ALP [9]
  • CT or MRI head: indicated in patients with neurological signs or symptoms [15]
  • Other modalities: Metastases may be an incidental finding on initial imaging, e.g., abdominal ultrasound.

Laboratory studies and urinalysis

Further investigations

  • Renal mass biopsy: only required if it may alter the management or is requested by the patient. [6][23]
  • Split renal function [9]

Refer patients ≤ 46 years of age with renal malignancy and those with multifocal or bilateral renal masses or other findings suggestive of familial RCC for genetic counseling. [6]

Renal cell carcinomas are adenocarcinomas that usually arise from the epithelial cells of the proximal convoluted tubule.

Overview of the most important types of renal cell carcinoma [24][25]
Clear cell renal cell carcinoma Non-clear cell renal cell carcinomas
Papillary (chromophilic) RCC Chromophobe RCC Oncocytic RCC Collecting duct carcinoma (Bellini duct carcinoma)
Relative frequency
  • ∼ 70%
  • ∼ 10–15%
  • ∼ 5%
  • ∼ 1%
  • ∼ 1%
Cell of origin
Etiology
  • Unknown
  • Unknown
Macroscopic appearance
  • Yellow or golden due to high intracellular lipid concentration
Microscopic appearance
  • Clear cells
  • Unifocal, unilateral growth
  • Cuboidal, low columnar cells
  • Cells grow in papillary formations
  • Bilateral, multifocal growth possible
  • Originate from oncocytomas
  • Similar to chromophobic RCC, but without perinuclear halo
  • Cells occur as tumor nests
  • Hobnail pattern: irregularly arranged malignant glandular cells within a fibrous stroma
  • Medullary duct carcinoma: A variant that is associated with sickle cell disease.
Prognosis
  • Excellent prognosis
  • Aggressive tumor with a poor prognosis

Rule of 3: A mutation in the VHL (von Hippel-Lindau) gene on chromosome 3 causes RCC (renal cell carcinoma).

Malignant renal masses

All renal masses > 1 cm in size are presumed to be renal cell carcinoma and treated as such.

Benign renal masses

Angiomyolipoma [26]

Oncocytoma

Others

The differential diagnoses listed here are not exhaustive.

Approach

Surgery [6]

The following applies to patients with solid renal masses or renal cysts with Bosniak classification III or IV. The approach may be open, robotic, or laparoscopic.

  • Partial nephrectomy: Only the mass and some surrounding renal tissue are removed; the rest of the kidney is spared. [6]
    • Absolute indications: patients with a T1a renal mass , a solitary kidney, bilateral masses, familial RCC, preexisting chronic kidney disease, or proteinuria [27]
    • Relative indications: patients who are young and/or have a longer life expectancy, multifocal masses, or comorbidities that impact renal function
  • Radical nephrectomy

Medical therapy [19][28]

  • Regimens vary (e.g., axitinib combined with pembrolizumab) and are determined by risk level. [28][30]

Other

Many RCC tumors are also resistant to chemotherapy due to the expression of multidrug resistance protein 1 (MDR-1) by tumor cells. [9][32]

Complications caused by paraneoplastic syndromes

Paraneoplastic RCC: Polycythemia (EPO), Renin (hypertension), hyperCalcemia (PTHrP) and hyperCortisolism (ACTH).

Complications caused by local spread

Complications caused by metastatic disease

Reactive amyloidosis [34]

We list the most important complications. The selection is not exhaustive.

Survival of kidney cancer patients

  • Overall prognosis is determined by the anatomic extent of the disease (stage of cancer at diagnosis) and the histopathology of the tumor.
  • Targeted therapies have significantly prolonged survival time.
  • Early stage RCC with tumor growth limited to the kidney generally has a good prognosis.
5-year survival of kidney cancer patients [37]
SEER stage Description 5-year survival rate
Localized
  • 93%
Regional
  • 70%
Distant
  • 12%
All stages combined
  • Combination of all three SEER stages
  • 75%

Increased awareness and screening (e.g., ultrasound) of high-risk patients in recent years has led to earlier tumor detection and improved the prognosis of RCC.

Motzer score [38]

Overview

  • Used to determine prognosis of patients with stage IV (distant) disease
  • A point is assigned for each of the following criteria.
  • Based on the resulting score, the prognosis of the metastatic RCC patient is estimated.
  • High scores are associated with a poorer prognosis.

Instrument

Motzer score
Parameter Description
Karnofsky performance status

< 80%

< 80%: 1 point
> 80%: 0 points
Hemoglobin level

< 12.0 g/dL

< 12.0 g/dL: 1 point
> 12.0 g/dL: 0 points
< 13.5 g/dL < 13.5 g/dL: 1 point
> 13.5 g/dL: 0 points
LDH (> 1.5 times the upper normal limit) > 420 U/L > 420 U/L: 1 point
< 420 U/L: 0 point
Serum calcium > 10 mg/dL (> 2.5 mmol/L) > 10 mg/dL (> 2.5 mmol/L): 1 point
< 10 mg/dL (< 2.5 mmol/L): 0 points
Time from diagnosis to systemic treatment < 1 year < 1 year: 1 point
> 1 year: 0 points

Interpretation

Motzer score interpretation
Points Risk Median survival
0
  • Low
  • 20 months
1–2
  • Intermediate
  • 10 months
≥ 3
  • High
  • 4 months
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