Kidney Cancer: Epidemiology and Pathogenesis

Epidemiology

Many databases include upper tract urothelial carcinoma with kidney cancer and therefore independent incidence of kidney cancer cannot be assessed

• GLOBOCAN includes ICD-9 C65 - "Malignant neoplasm of renal pelvis" with kidney cancer

Incidence

• Incidence has been increasing due to (2):

1. Increased use of diagnostic imaging
   • Greatest increase has been in small, clinically localized renal amsses which now represent > 40% of incident tumours.
2. Increased prevalence of risk factors (e.g. obesity), see below

• Worldwide
  • Incidence rates are higher in developed countries
    • Likely due to increased use of diagnostic imaging
• US[1]
  • Includes renal pelvis cancers
  • Estimated incidence 2023: 81,800 (2022: 79,000)
• Canada[2]
  • Includes renal pelvis cancers
  • Estimated incidence 2020: 7,500
    • 10th most commonly diagnosed cancer in Canada

Mortality

• US[3]
  • Includes renal pelvis cancers
  • Estimated mortality 2022: 13,920 (2021: 13,780[4])

• 5-year relative survival (survival relative to population without disease) based on disease stage at diagnosis[5]:
  • Localized: 93%
  • Regional: 70%
  • Distant: 13%
  • All stages: 75%
• Most lethal of all GU malignancies
  • 5-year relative survival all stages for[6]:
    • Prostate cancer: 98%
    • Bladder: 77%
• Survival has been increasing (≈1% year since 2004)

Gender

• Incidence M:F 1.75:1[7]
  • Overall mortality worse in males

Age

• Typical presentation between age 50-70; median age at diagnosis: 64
  • RCC in children and young adults is more likely to be symptomatic, locally advanced, high grade, and of unfavorable histologic subtypes.
    • Children and young adults may respond better to surgical therapy and aggressive approach and formal lymphadenectomy has been recommended at the time of radical nephrectomy

Race

• More common in Blacks, American Indian, and Alaska Native populations than Whites

Risk Factors

Acquired

• Majority of cases are believed to be sporadic
• Established risk factors (5):
  1. Obesity
     • Accounts for ≈30% of incident cases
     • Obese patients are more likely to develop RCC but these tumours are more likely to be low-grade, early stage tumours
  2. Smoking
     • Accounts for ≈20% of incident cases
  3. Hypertension
  4. Familial syndromes
     • Accounts for ≈4-6% of incident cases[8]
  5. Chronic renal failure
     • Controversial; however, patients on maintenance dialysis also are reported to have an increased risk
       • It has been suggested to delay screening for kidney cancer in patients on dialysis and without other major comorbidities until the 3rd year on dialysis.
• Other risk factors (5):
  1. Family history of renal malignancy (without familial syndrome)
  2. Exposure to chlorinated solvents
  3. Retroperitoneal radiation
  4. Diet
     • Moderate alcohol intake, consumption of fruits and (cruciferous) vegetables, and a diet rich in fatty fish are believed to reduce the risk of RCC
  5. Acquired cystic renal disease
• No increased risk of RCC in patients with autosomal dominant polycystic kidney disease

Inherited

Familial Renal Cell Carcinoma Syndromes

• All are autosomal dominant
• Account for ≈4-6% of cases of RCC overall

Syndrome	Gene	Clinical Manifestations
Von Hippel-Lindau (VHL)	VHL	HIPPPEEL CNS and/or retinal Hemangioblastomas ccRCC (Increased risk) and renal cysts Pheochromocytoma Paraganglioma Pancreatic neuroendocrine tumours and cysts Epididymal cystadenoma Ear Endolymphatic sac tumour Broad Ligament tumours
Hereditary Papillary Renal Carcinoma (HPRCC)	c-MET	Type 1 papillary RCC
Hereditary Leiomyomatosis and RCC (HLRCC)*	Fumarate hydratase	Type 2 papillary or collecting duct RCC Cutaneous leioyomyomas Uterine leiyomyomas
Birt-Hogg-Dube (BHD)	Folliculin	Skin fibrofolliculomas Pulmonary cysts, spontaneous pneumothoraces Variety of renal tumours (including chromophobe RCC, oncocytoma, hybrid oncocytic/chromophobe tumors, clear cell RCC (rare), renal cysts)
Succinate Dehydrogenase RCC*	SDHB/C/D (encoding subunits of the Krebs cycle enzyme succinate dehydrogenase)	Variety of renal tumours (clear cell RCC, chromophobe RCC, type 2 papillary RCC, oncocytoma) Adrenal pheochromocytoma/paraganglioma
Tuberous Sclerosis Complex (TSC)	TSC1/2	Skin (adenoma subaceum, shagreen spots) Variety of renal tumours (increased predisposition for ccRCC, AMLs, renal cysts, polycystic kidney disease, oncycytoma) Retinal hamartomas CNS lesions (including tubers) Seizures Intellectual disability Cardiac lesions Teeth/gum lesions Bone cysts Pulmonary lymphangiomyomatosis
Cowden/PTEN Syndrome Associated RCC	PTEN	Mucocutaneous lesions Facial trichilemmomas Papillomatous papules Variety of renal tumours (ccRCC, type 1 papillary RCC, chromophobe RCC) Malignancies in other organ systems (breast, thyroid)
BAP-1 tumour predisposition syndrome[9]	BAP1	ccRCC Uveal melanoma Malignant mesothelioma Cutaneous melanoma Melanocytic tumours Basal cell carcinoma
*Renal cancers associated with these syndromes are typically more aggressive

Von Hippel-Lindau Disease

• Incidence 1:30,000-1:40,000
• RCC develops in 35-70% of VHL patients and is distinctive for early age (median 40) of onset and bilateral and multifocal involvement
• Mutation: VHL
  • VHL is a tumor suppressor gene, for both familial and sporadic ccRCC, at chromosome 3p25-26
    • VHL mutation is most common genetic mutation in sporadic RCC[10]
  • Under normal conditions, the VHL complex targets hypoxia-inducible factors (HIF) for degradation, keeping levels of HIF low. HIF regulates response to hypoxia, starvation, and other stresses
  • In the absence of VHL, HIF accumulates and leads to overexpression of vascular endothelial growth factor (VEGF), the primary angiogenic growth factor in RCC, contributing to the neovascularity associated with ccRCC.
    • Production of erythropoietin (EPO) is closely associated with circulating oxygen levels. During conditions of hypoxia, hypoxia-inducible factor-1-alpha (HIF-1-a) is upregulated increasing EPO transcription. HIF-1-a is then rapidly degraded by proteases upon restoration of normal oxygen tension.
• Pheochromocytoma manifestations of VHL are restricted to certain families (type 2 VHL)
• Patients suspected of having VHL, or the appropriate relatives of those with documented disease, should strongly consider genetic evaluation.
  • Patients with germline mutations of the VHL gene can be offered screening to identify major manifestations of VHL at a pre-symptomatic phase
• RCC is most common cause of death in VHL patients

Hereditary Papillary Renal Cell Carcinoma (HPRCC)

• Tumours tend to be less aggressive than their sporadic counterparts
• Most of the mutations in HPRCC have been found in the tyrosine kinase domain of met and lead to constitutive activation of the receptor for hepatocyte growth factor

Hereditary leiomyomatosis and RCC syndrome (HLRCC)

• Almost all individuals with this syndrome will develop cutaneous leiomyomas and uterine fibroids (if female), usually manifesting at the age of 20-35 years.
  • A high proportion of women have had a hysterectomy for fibroids before formal diagnosis of HLRCC.
• Only a minority (20%) of HLRCC patients develop RCC
  • Penetrance for RCC in HLRCC is lower than for the cutaneous and uterine manifestations
• Unlike other familial syndromes, tumours with this syndrome tend to be unilateral, solitary, and more aggressive; therefore, prompt surgical management is indicated

Tuberous Sclerosis Complex (TSC)

• Classic triad:
  1. Seizures
  2. Adenoma sebaceum
  3. Intellectual disability
  • May not be present due to variable penetrance of the TSC mutation
• 50% of patients with TSC develop AMLs

Questions

1. What proportion of RCCs are familial?
2. What are the clinical manifestations of VHL?
3. What gene is mutated and what are the clinical manifestations of HRPCC, HLPCC, Burt-Hogg-Dube, Tuberous Sclerosis Complex?
4. Explain the pathway of VHL and HIF and role in RCC pathophysiology
5. What are the risk factors for RCC?

Answers

1. What proportion of RCCs are familial?
   • ≈4-6%
2. What are the clinical manifestations of VHL?
   1. Hemangioblastoma
   2. Increased risk of ccRCC
   3. Paraganglioma
   4. Pheochromocyoma
   5. Pancreatic cysts and neuroendocrine tumours
   6. Ear endolymphatic tumour
   7. Epididymal cysts
   8. Ligament, broad tumours
3. What gene is mutated and what are the clinical manifestations of HRPCC, HLPCC, Burt-Hogg-Dube, Tuberous Sclerosis Complex?
   • HRPCC: c-met; clinical manifestations: type I papillary RCC
   • HLPCC: fumarate hydratase; clinical manifestations; type II papillary RCC, cutaneous leiyomyoma and uterine leiyomyoma
   • Burt-Hogg-Dube: folliculin; clinical manifestations: pneumothorax, pulmonary cysts, skin fibrofolliculuomas, chromophobe RCC and other renal tumours
   • Tuberous sclerosis complex: TSC1 and TSC2; clinical manifestations: adenoma subaceum, shagreen spots, AMLs, ccRCC, retinal hamartomas, CNS lesions, epilepsy, mental retardation, cardiac lesions, teeth lesions, gum lesions, bone cysts, pulmonary lymphangiomyomatosis
4. Explain the pathway of VHL and HIF and role in RCC pathophysiology
   • Under normal conditions, VHL targets hypoxia-induced factor (HIF) for degradation. In the absence of VHL due to mutation, HIF accumulates resulting in increased expression of VEGF, the primary angiogenic growth factor for RCC
5. What are the established risk factors for RCC?
   1. Obesity
   2. Hypertension
   3. Smoking
   4. Acquired cystic disease
   5. Familial syndrome

References

• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 57
• Campbell, Steven C., et al. "Renal Mass and Localized Renal Cancer: Evaluation, Management, and Follow-Up: AUA Guideline Part I." The Journal of urology (2021): 10-1097.