Renal Cell Carcinoma

Renal cell carcinoma (RCC) is a tumor that arises from the lining of the renal tubular system within the renal cortex. Renal cell carcinoma is responsible for 80%–85% of all primary renal neoplasms. Most RCCs arise sporadically, but smoking, hypertension, and obesity are linked to its development. The disease usually presents asymptomatically. When symptoms finally arise, the tumor has already grown significantly and/or spread to other tissues. The classic clinical triad of RCC is flank pain, hematuria, and a palpable abdominal renal mass, but this triad appears in only about 9% of cases. Affected individuals also commonly present with fever and/or anemia. Renal cell carcinoma is usually diagnosed via CT scan of the abdomen and pelvis. Localized cases of RCC are commonly treated and cured with surgery, and advanced cases are treated with a combination of immunotherapy and/or molecular targeted therapy. The long-term prognosis for locally advanced or metastatic RCC is often poor.

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Renal cell carcinoma (RCC), also called hypernephroma and renal cell adenocarcinoma, is a type of cancer that originates from the lining of the small tubules of the renal cortex.


  • Accounts for 80%–85% of all primary renal neoplasms
  • Incidence is highest in North America and the Czech Republic:
    • In North America, RCC is responsible for 76,000 new cases and 14,000 deaths each year.
    • In the United States, the incidence is highest in the White, Black, Hispanic, and American Indian populations and lowest in the Asian American and Pacific Islander populations.
  • Approximately twice as common in men as in women
  • Incidence is highest in the 6th to 8th decade of life, with a median age of 64.


  • Most cases of RCC occur sporadically.
  • Only 4% of cases are associated with a genetic component.
  • Risk factors:
    • Smoking (associated with a higher incidence and more advanced disease)
    • Hypertension
    • Obesity (risk increases with ↑ BMI)
    • CKD, especially individuals with cystic disease of the kidney acquired through dialysis
    • Occupational exposure (e.g., cadmium, asbestos, petroleum by-products)
    • Prolonged ingestion of analgesic combinations (e.g., aspirin, NSAIDs, and acetaminophen)
    • Genetics: several hereditary diseases have been associated with RCC:
      • Inherited polycystic disease 
      • Von Hippel-Lindau syndrome (approximately 40% of patients develop RCC)
      • Tuberous sclerosis (approximately 5% of patients develop RCC)
      • Hereditary leiomyomatosis and renal cancer syndrome (HLRCC)
      • Hereditary papillary renal cell carcinoma (HPRCC)
    • Cytotoxic chemotherapy
    • Chronic hepatitis C infection
    • Kidney stones

Pathologic Classification

The difference between benign and malignant masses in the kidney is determined by histologic criteria. According to the morphology, growth pattern, cell of origin, and histochemical and molecular basis, RCCs are classified into several types:

  • Clear cell (most common) 
  • Papillary
  • Chromophobe 
  • Oncocytic 
  • Collecting duct (very rare)
  • Translocation RCC (very rare)

Clear cell carcinoma

  • Incidence: 75%–85% of all renal tumors
  • Etiology: 
    • Most commonly sporadic
    • Genetic mutations:
      • Deletion of 3p
      • Gain of 5q
      • Monosomy or partial loss of 14q
    • Genetic pathway alterations:
      • VHL gene
      • PBRM1 gene
      • BAP1 gene
      • Inactivation of histone-modifying genes
      • Ubiquitin-mediated proteolysis pathway
      • Abnormalities in cellular division (Ras, p53)
  • Pathology/histologic appearance:
    • Arises from clear cells in the proximal tubular epithelium
    • Mostly well differentiated
    • Large areas of gray-white necrosis and foci of hemorrhagic discoloration
    • Can have a trabecular or tubular growth pattern with cells of rounded or polygonal shape and granular or clear cytoplasm
    • May show cystic and/or solid areas
    • May show cellular atypia
  • Prognosis:
    • Depends on the stage at diagnosis
    • Poor prognosis with higher nuclear grade and/or sarcomatoid pattern
Renal clear cell carcinoma with sheet-like, solid clear cells

Renal clear cell carcinoma:
The tumor consists of sheet-like, solid clear cells. H&E × 100

Image: “Pathological images from patient” by Chen S, Jin B, Xu L, Fu G, Meng H, Liu B, Li J, Xia D. License: CC BY 4.0, cropped by Lecturio.

Papillary carcinoma

  • Incidence: 10%–15%
  • Etiology: 
    • Most commonly sporadic
    • MET gene mutations
    • FH gene mutation
  • Pathology/histologic appearance: 
    • Can arise from the proximal or distal convoluted tubules
    • Can be multifocal and/or bilateral
    • Usually hemorrhagic and cystic, especially if large
    • Made of cuboidal or low columnar cells that are arranged in papillary formations.
    • Interstitial foam cells and psammoma bodies may be present.
  • Prognosis: 
    • Type 1 papillary RCC has a favorable prognosis.
    • Type 2 papillary RCC has a poor prognosis.
Histology of papillary renal cell carcinoma

H&E-stained specimen showing characteristic histology of papillary renal cell carcinoma

Image: “Hematoxylin and Eosin staining of the tumor tissue showing characteristic histology of papillary renal cell carcinoma” by Alanee S, Dynda DI, Hemmer P, Schwartz B. License: CC BY 4.0

Chromophobe carcinoma

  • Incidence: 5%–10%
  • Etiology: 
    • Hypodiploid number of chromosomes
    • Up-regulated KIT oncogene
    • Up-regulated TERT gene
  • Pathology/histologic appearance: 
    • Arises from intercalated cells of the collecting ducts
    • Made up of pale, eosinophilic cells arranged in solid sheets around blood vessels
    • Perinuclear halos can be seen
  • Prognosis: 
    • Favorable prognosis (more than clear cell RCC)
    • Possibly due to presentation at an earlier stage
Sarcomatoid chromophobe renal cell carcinoma

Sarcomatoid chromophobe renal cell carcinoma

Image: “ Microphotograph showing sarcomatoid renal cell carcinoma” by Chakrabarti I, Giri A, Majumdar K, Anuradha DE. License: CC BY 2.0

Oncocytic carcinoma/oncocytomas

  • Incidence: 3%–7%
  • Etiology: 
    • Tuberous sclerosis
    • Birt-Hogg-Dubé syndrome
  • Pathology/histologic appearance: 
    • Arises from intercalated cells of the collecting ducts
    • Composed of oncocytes, well-differentiated neoplastic cells that have a very eosinophilic cytoplasm due to numerous mitochondria.
  • Prognosis: 
    • Favorable prognosis
    • Behave as benign tumors
    • Rarely invasive or metastatic
High-grade oncocytic renal tumor

High-grade oncocytic renal tumor

Image: “High-grade oncocytic renal tumour — high mag” by Nephron. License: CC BY-SA 4.0

Collecting or Bellini duct tumors

  • Incidence: very rare
  • Etiology: usually due to genetic abnormalities
  • Pathology/histologic appearance: 
    • Composed of irregular channels 
    • Epithelium is very atypical, with a hobnail pattern.
  • Prognosis: 
    • Poor
    • Commonly associated with metastatic and/or advanced disease
Collecting duct carcinoma

H&E-stained tissue sections demonstrating collecting duct carcinoma

Image: “Hematoxylin and eosin staining of tissue sections from the nephrectomy specimens demonstrating collecting duct carcinoma” by Tazi EM, Essadi I, Tazi MF, Ahellal Y, M’rabti H, Errihani H. License: CC BY 2.0

Translocation renal cell carcinoma

  • Incidence: 
    • Very rare
    • Occurs at a younger age and predominantly in women
  • Etiology: 
    • Due to a fusion of the TFE3, TFEB, or MITF genes to a number of other genes, including ASPSCR1, PRCC, SFPQ, and NONO
    • Presents in children with previous chemotherapy, autoimmune disorders, or bone marrow transplant conditioning
  • Prognosis: 
    • Much worse prognosis than most other types of RCC because symptoms develop at a later stage
    • Resistant to targeted therapies
Translocation renal cell carcinoma

Translocation renal cell carcinoma, composed of clear cells with voluminous cytoplasm and distinct cell borders showing typical papillary architecture and hyalinized fibrous vascular cords

Image: “Translocation renal cell carcinoma” by Kmetec A, Jeruc J. License: CC BY 3.0

Clinical Presentation

Many cases present asymptomatically, leading to further progression of the diseases. Symptoms arise when the tumor has reached a significant size, invaded adjacent structures, or developed distant metastasis.

  • Classic triad of flank pain, hematuria, and palpable abdominal mass (present in only 9% of cases)
  • Other symptoms:
    • Fever
    • Weight loss
    • Muscle wasting
    • Fatigue 
    • Secondary polycythemia
    • Anemia
    • Scrotal varicocele, usually left-sided
    • Involvement of the inferior vena cava (IVC):
      • Lower-extremity edema
      • Ascites
      • Hepatic dysfunction
      • Pulmonary emboli
    • Paraneoplastic syndrome, which can lead to increased levels of the following hormones:
      • Erythropoietin
      • Parathyroid hormone-related protein
      • Gonadotropins
      • Human placental lactogen
      • Adrenocorticotropic hormone–like substance
      • Renin
      • Glucagon
      • Insulin
    • Hypercalcemia due to:
      • Lytic bone lesions
      • Parathyroid hormone-related protein
      • Elevated prostaglandins that promote bone resorption

Diagnosis and Staging


  • 1st-line: CT scan of the abdomen and pelvis to show characteristics of RCC, as opposed to a simple renal cyst:
    • Thickened, irregular or smooth wall
    • Septations
    • Enhancement after contrast injection
  • Ultrasonography may also be performed.
  • MRI used if CT and/or ultrasonography inconclusive
  • A biopsy is performed after the imaging diagnosis and must be evaluated for the extent of local invasion and metastatic disease prior to surgery.
Two illustrative cases for selection of ROI location

Two illustrative cases for selection of region of interest (ROI; approximately 1 cm in diameter):
(a) An ROI was placed in the well-enhancing part in left renal clear cell carcinoma in a 37-year-old female patient.
(b) An ROI was placed in left renal cell carcinoma in a 46-year-old female patient.

Image: “Two illustrative cases for selection of ROI location” by Scientific Reports. License: CC BY 4.0


RCCs vary greatly in the extent of disease at presentation.

  • Localized to the kidney: 65%
  • Regional (lymph nodes): 17%
  • Metastatic disease: 16%
  • Unstaged: 3%
Table: TNM staging of renal cell carcinoma
Tumor stage
T0No evidence of primary tumor
T1< 7 cm in the greatest dimension, confined to the kidney
  • 1a: < 4 cm
  • 1b: > 4 cm and < 7 cm
T2> 7 cm in the greatest dimension, confined to the kidney
  • 2a: > 7 cm and < 10 cm
  • 2b: > 10 cm
T3Extends into major veins or perinephric tissues, but not into the adrenal gland or beyond the Gerota fascia (anterior perirenal fascia)
  • 3a: invades into renal vein branches or perirenal/renal sinus fat
  • 3b: invades the subdiaphragmatic IVC
  • 3c: invades the supradiaphragmatic IVC
T4Invades beyond the Gerota fascia and/or into the adrenal gland
Regional lymph nodes
N0No metastasis to regional lymph nodes
N1Metastasis to regional lymph nodes
Distant metastasis
M0No distant metastasis
M1Metastasis to distant lymph nodes and/or organs

Management and Prognosis


  • Localized, nonmetastatic disease requires surgery, which is curative in stages I–III. 
    • Partial nephrectomy
    • Radical nephrectomy
    • Enucleation
    • Thermal ablation
  • Metastatic disease: 
    • If metastasis has already developed, the disease is usually unresectable.
    • Immunotherapy with or without molecularly targeted therapy:
      • Nivolumab plus ipilimumab 
      • Pembrolizumab plus axitinib 
      • Nivolumab plus cabozantinib 
      • Molecularly targeted therapy: vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (e.g., cabozantinib, lenvatinib plus everolimus, nivolumab) 


  • Depends on:
    • Type of renal cell carcinoma
    • Extent and size of the tumor at the time of detection
  • Sarcomatoid appearance indicates poor prognosis.
  • The 5-year survival rate of patients with kidney cancer has increased in recent years because of advancements in technology allowing for the detection of more tumors incidentally and at smaller sizes:
    • Localized: 93%
    • Regional: 70%
    • Distant metastasis: 13%
    • Combined survival rate: 75%

Differential Diagnosis

  • Benign renal tumor:
    • Angiomyolipoma: appears on imaging as an enhancing mass containing macroscopic fat and no calcifications. Small angiomyolipomas with minimal fat are difficult to characterize on imaging and often require further evaluation. Associated with tuberous sclerosis, especially if bilateral. 
    • Metanephric adenoma: rare, benign lesions that are more common in women than in men. Often discovered incidentally, but can present with pain, hematuria, or a palpable mass. Can be difficult to differentiate on histology from papillary RCC or epithelial-predominant Wilms tumor.
  • Metastatic disease: cancer from another source that spreads to the kidney. Metastatic disease often presents with multiple renal lesions with borderline enhancement and widespread metastatic disease.
  • Lymphoma: hematologic malignancy that can involve the kidney. Percutaneous biopsy should be done to differentiate lymphoma from RCC. Renal involvement in hematologic malignancies is found at autopsy in about ⅓ of terminal lymphoma or leukemia patients. Renal involvement should be suspected in patients with massive retroperitoneal lymphadenopathy, splenomegaly, or lymphadenopathy elsewhere in the body or in atypical retroperitoneal regions. 
  • Renal abscess or focal pyelonephritis: a variety of infectious and inflammatory conditions can mimic RCC, including acute and chronic pyelonephritis and renal abscess. Axial imaging often shows perineal inflammatory changes. Clinical symptoms, such as chills, fever, flank pain, or pyuria aid in the diagnosis. Renal mass biopsy or aspiration with drain placement can aid in the diagnosis. Serial imaging to demonstrate the resolution of the mass may also be required after the treatment.


  1. American Cancer Society. Key statistics about kidney cancer.
  2. American Cancer Society. What is kidney cancer?
  3. National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Program. (2020). Cancer stat facts: kidney and renal pelvis cancer.
  4. Choueiri, T.K. (2020). Prognostic factors in patients with renal cell carcinoma. UpToDate. Retrieved February 17, 2021, from
  5. George, D., Jonasch, E. (2021). Systemic therapy advanced clear cell renal carcinoma. UpToDate. Retrieved February 17, 2021, from
  6. Motzer, R.J. (2018). Renal cell carcinoma. In Jameson, J., et al. (Eds.). Harrison’s Principles of Internal Medicine, 20th ed. McGraw-Hill.
  7. Pierorazio, P.M., Campbell, S.C. (2021). Diagnostic approach, differential diagnosis, and management of a small renal mass. UpToDate. Retrieved Feb 17, 2021, from
  8. Richie, J.P. (2021). Definitive surgical management of renal cell carcinoma. UpToDate. Retrieved Feb 17, 2021, from
  9. Atkins, M.B. (2020). Clinical manifestations, evaluation, and staging of renal cell carcinoma. UpToDate. Retrieved July 15, 2021, from
  10. Atkins, M.B., Choueiri, T.K. (2021). Epidemiology, pathology, and pathogenesis of renal cell carcinoma. UpToDate. Retrieved July 15, 2021, from
  11. Atkins, M.B. (2021). Overview of the treatment of renal cell carcinoma. UpToDate. Retrieved July 15, 2021, from

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