Renal Cell Carcinoma

Aka: Renal Cell Carcinoma, Renal Cell Cancer, Kidney Cancer, Renal Cancer, Renal Cell Adenocarcinoma, Clear Cell Adenocarcinoma of Kidney, Papillary Adenocarcinoma of Kidney, Chromophobe Adenocarcinoma of Kidney

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II. Epidemiology

  1. Incidence
    1. Worldwide (2012): 337,860 new cases (9th most common cancer)
    2. U.S. (2013): 65,150 new cases (13,680 deaths)
  2. Demographics
    1. Most common in developed countries (partly due to incidental diagnosis on imaging)
    2. Male gender (twice as common as in women)
    3. Black men are affected more often than white men
    4. Diagnosis peaks at ages 60-70 years old

III. Risk Factors

  1. Tobacco Use (RR>2)
    1. Risks increases with pack year exposure
  2. Obesity (esp. women)
    1. Risk increases linearly with body weight
  3. Occupation chemical exposure
    1. Trichloroethylene
      1. Mechanics
      2. Dry cleaners
      3. Polyvinyl chloride manufacturers
      4. Low NicotineTobacco production
      5. Oil processing
    2. Benzene
    3. Cadmium
    4. Benzidine
    5. Coal Tar, soot, pitch, creosote or asphalt
    6. Herbicides and Pesticides
    7. Mineral, cutting or lubricating oil
    8. Mustard Gas
    9. Pesticides
    10. Vinyl Chloride
    11. Hu (2002) Occup Med 52(3):157-64 [PubMed]
  4. Hereditary conditions
    1. Von Hippel-Lindau syndrome (via Vascular Endothelial Growth Factor)
    2. Hereditary papillary renal carcinoma
    3. Birt-Hogg-Dube syndrome
    4. Hereditary renal carcinoma
  5. Other possible risks
    1. NSAIDs
    2. Tuberous sclerosis
    3. Long-term renal Dialysis and Renal Transplant (via acquired cystic disease of the Kidney)
    4. Hypertension

IV. Types: Kidney Cancers

  1. Common: Tubule derived cancers (Renal Cell Carcinomas, >90% of all Kidney Cancer)
    1. Clear Cell Adenocarcinoma (75%)
      1. Clear cytoplasm in clustered cells within dense endothelial tissue
      2. Von Hippel-Lindau (VHL) tumor suppressor gene defect is associated in >60% of sporadic cases
      3. Typically diagnosed at later stage and is associated with worse prognosis
    2. Papillary Adenocarcinoma (15-20%)
      1. Basophilic cytoplasm with foamy histiocytes
      2. Papillary Type 1
        1. Associated familial syndromes: MET proto-oncogene mutation
      3. Papillary Type 2
        1. Associated familial syndromes: HLRCC syndrome (with hereditary leiomyomatosis)
    3. Chromophobe Adenocarcinoma of Kidney (5%)
      1. Empty cytoplasm and perinuclear clearing
      2. Lowest metastasis risk
      3. Associated with Chromosome loss including whole Chromosome loss (1, 2, 6, 10, 13, 17, 21)
      4. Associated familial syndromes: Birt-Hogg-Dube Syndrome
  2. Rare (<5%): Non-tubule derived cancers (non-RCC Kidney Cancers)
    1. Collecting duct carcinoma
    2. Renal Medullary carcinoma
      1. Associated with Hemoglobinopathy (esp. Sickle Cell Trait)
    3. Urethelial carcinoma
      1. Variant of transitional cell carcinoma

V. Presentations

  1. Asymptomatic at time of diagnosis in 50% of cases (incidental finding on imaging)
  2. Classic presentation (Gross Hematuria, Flank Pain, palpable abdominal mass)
    1. Has become an uncommon presentation in U.S.
    2. Associated with advanced disease at time of diagnosis
  3. Paraneoplastic disease (20%)
    1. Hypertension
    2. Hypercalcemia
    3. Polycythemia
  4. Metastases
    1. Fever
    2. Weight loss
    3. Adenopathy
    4. Bone pain

VI. Symptoms

  1. Hematuria (40%)
  2. Flank Pain (40%)
  3. Weight loss (33%)
  4. Fever (20%)
  5. Hypertension (20%)
  6. Night Sweats
  7. Malaise

VII. Signs

  1. Palpable flank mass or abdominal mass (25%)
  2. Varicocele (esp. isolated right sided or non-reducing bilateral)
    1. , Right Varicocele drains directly to right renal vein
  3. Bilateral Lower Extremity Edema
    1. May be caused by inferior vena cava obstruction

VIII. Labs

  1. Urinalysis with microscopic exam
    1. See Microscopic Hematuria for evaluation protocol

IX. Imaging

  1. Triple-phase CT Urography
    1. Evaluation of persistent Microscopic Hematuria
  2. MRI Abdomen with and without contrast
    1. Consider if CT Urography is contraindicated

X. Staging: TNM System

  1. T Primary Tumor Staging
    1. TX
      1. Primary tumor not able to be assessed
    2. T0
      1. No evidence of primary tumor
    3. T1
      1. Tumor size <=7 cm in greatest dimension
      2. Tumor limited to Kidney
      3. T1a
        1. Tumor size 4 cm or less in greatest dimension
      4. T1b
        1. Tumor size 4-7 cm in greatest dimension
    4. T2
      1. Tumor size >7 cm in greatest dimension
      2. Tumor limited to Kidney
      3. T2a
        1. Tumor size 7-10 cm or less in greatest dimension
      4. T2b
        1. Tumor size >10 cm in greatest dimension
    5. T3
      1. Tumor local spread
        1. No growth into Gerota’s fascia (surrounding Kidney)
      2. T3a
        1. Growth into major vein or fatty tissue around Kidney
      3. T3b
        1. Growth into abdominal vena cava
      4. T3c
        1. Growth into chest vena cava or the vena cava wall
    6. T4
      1. Tumor spread into Gerota’s fascia (surrounding Kidney)
      2. Tumor spread may also occur into Adrenal Gland
  2. N (Node)
    1. NX
      1. Nodes not able to be assessed
    2. N0
      1. No local Lymph Node spread
    3. N1
      1. Local Lymph Node spread
  3. M (Metastasis)
    1. M0
      1. No spread to distant Lymph Nodes or organs
    2. M1
      1. Distant metastasis
      2. Spread to distant Lymph Nodes or organs (esp. lungs, bone, liver, brain)
  4. References
    1. NCI: Renal Cell Cancer Staging
      1. http://www.cancer.gov/types/kidney/hp/kidney-treatment-pdq#section/_7

XI. Staging: Grouping (AJCC)

  1. Stage 1: T1, N0, M0
    1. Tumor <=7 cm affecting a single Kidney without Lymph Node involvement or metastases
  2. Stage 2: T2, N0, M0
    1. Tumor >=7 cm affecting a single Kidney without Lymph Node involvement or metastases
  3. Stage 3
    1. T3, N0, M0
      1. Tumor growth into major vein or tissue around Kidney but not into Adrenal Gland or Gerota’s fascia
    2. T1-T3, N1, M0
      1. Tumor growth of any size, affecting single Kidney, without involving Gerota’s fascia
      2. Local Lymph Node involvement, but no distant Lymph Node involvement or metastases
  4. Stage 4
    1. T4, N0-1, M0
      1. Tumor growth into Gerota’s fascia (or into Adrenal Gland)
      2. Local Lymph Node involvement may occur
      3. No spread to distant Lymph Nodes or organs
    2. T1-4, N0-1, M1:
      1. Spread to distant Lymph Nodes or organs

XII. Management: Localized Disease

  1. Background
    1. Localized Disease accounts for 75% of RCC presentations
    2. Indicated if no distant metastasis
  2. Partial or radical nephrectomy (gold standard)
    1. Radical nephrectomy indications
      1. Solid mass >3 cm
      2. Complex cystic mass
      3. Normal contralateral Kidney
      4. Partial nephrectomy challenging
    2. Partial nephrectomy (if anatomically feasible) offers similar outcomes to radical nephrectomy
      1. Jonasch (2012) Mol Cancer Res 10:859-80 [PubMed]
    3. Laparoscopic and robotic techniques are typically utilized for partial nephrectomy
      1. Higher rate of conversion to radical nephrectomy with laparoscopy (10%) than robotic (1%)
      2. Long (2012) Eur Urol 61:1257-62 [PubMed]
    4. Ablation (radiofrequency, microwave, cryoablation, stereotactic)
      1. Renal Mass biopsy (multiple core) prior to ablation for histologic diagnosis and surveillance guidance
      2. Used for small Renal Masses in those unable to undergo partial nephrectomy
      3. Limited evidence
    5. Active Surveillance
      1. Indicated in Renal Mass <2 cm in reduced Life Expectancy and high risk of surgical complication
      2. Renal Mass biopsy (multiple core) for histologic diagnosis and surveillance guidance
      3. Repeat imaging every 3-6 months
    6. Lymph Node dissection
      1. Controversial in localized disease (typically individualized based on risks and surgical findings)
      2. Indicated for staging in concerning Regional Lymphadenopathy
    7. Adrenalectomy
      1. Adrenal invasion is suspected
  3. Other measures
    1. No adjuvant Chemotherapy has been found effective as of 2015

XIII. Management: Metastatic Disease (30% of cases at Renal Cell Carcinoma diagnosis)

  1. Cytoreductive nephrectomy (tumor debulking) AND
  2. Chemotherapy: Cytokines
    1. Cytokines double the median survival time from 10-15 months to >24 months
    2. Agents (VEGF Inhibitors, Tyrosine Kinase Inhibitors, Immunotherapy)
      1. VEGF Receptor Blockers (e.g. Sunitinib, Pazopanib)
      2. mTOR Inhibitors (e.g. Everolimus, Temsirolimus)
      3. Immunotherapy Agents (Bevacizumab)

XIV. Prevention

  1. Tobacco Cessation
  2. Hypertension Management
  3. Obesity Management
  4. Other factors that may reduce Renal Cell Carcinoma risk
    1. Fatty fish intake
    2. Increased fruit and vegetable intake (3 or more servings per day)
    3. One Alcoholic beverage daily

XV. Prognosis

  1. Stage 1 RCC: 81-95% five year survival
  2. Stage 2 RCC: 74-80% five year survival
  3. Stage 3 RCC: 53-60% five year survival
  4. Stage 4 RCC: 8-10% five year survival

XVI. Resources

  1. Emedicine: Renal Cell Carcinoma
    1. http://emedicine.medscape.com/article/281340-clinical#showall
  2. NIH Kidney Cancer
    1. http://www.cancer.gov/types/kidney/hp

XVII. References

  1. Gray (2019) Am Fam Physician 99(3): 179-84 [PubMed]
  2. Jonasch (2014) BMJ 349:g4797 +PMID:25385470 [PubMed]

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