Editing Kidney Cancer: Epidemiology and Pathogenesis

[[Category:Kidney Cancer]]

== Epidemiology ==
Many databases include upper tract urothelial carcinoma with kidney cancer and therefore independent incidence of kidney cancer cannot be assessed
* [https://pubmed.ncbi.nlm.nih.gov/33538338/ GLOBOCAN] includes ICD-9 C65 - "Malignant neoplasm of renal pelvis" with kidney cancer
=== Incidence ===

* Incidence has been increasing due to (2):
# Increased use of diagnostic imaging
#* Greatest increase has been in small, clinically localized renal amsses which now represent > 40% of incident tumours.
# 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'''[https://acsjournals.onlinelibrary.wiley.com/doi/full/10.3322/caac.21763]
** Includes renal pelvis cancers
** '''Estimated incidence 2023: 81,800''' (2022: 79,000)
* '''Canada'''[https://pubmed.ncbi.nlm.nih.gov/32122974/]
** Includes renal pelvis cancers
** Estimated incidence 2020: 7,500
*** 10th most commonly diagnosed cancer in Canada

=== Mortality ===
* '''US'''[https://pubmed.ncbi.nlm.nih.gov/35020204/]
** Includes renal pelvis cancers
** '''Estimated mortality 2022: 13,920''' (2021: 13,780[https://pubmed.ncbi.nlm.nih.gov/33433946/])

* 5-year relative survival (survival relative to population without disease) based on disease stage at diagnosis[https://pubmed.ncbi.nlm.nih.gov/33433946/]:
** Localized: 93%
** Regional: 70%
** Distant: 13%
** All stages: 75%
* '''Most lethal of all GU malignancies'''
** 5-year relative survival all stages for[https://pubmed.ncbi.nlm.nih.gov/33433946/]:
*** Prostate cancer: 98%
*** Bladder: 77%
* Survival has been increasing (≈1% year since 2004)

=== <span style="color:#ff0000">Gender</span> ===
* '''<span style="color:#ff0000">Incidence M:F 1.75:1[https://pubmed.ncbi.nlm.nih.gov/35020204/]</span>'''
** '''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

== Pathogenesis ==

=== Risk Factors ===

==== Acquired ====

*'''Majority of cases are believed to be sporadic'''
* '''<span style="color:#ff0000">Established risk factors (4):'''
*# '''<span style="color:#ff0000">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
*# '''<span style="color:#ff0000">Smoking'''
*#* Accounts for ≈20% of incident cases
*# '''<span style="color:#ff0000">Hypertension'''
*# '''<span style="color:#ff0000">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):'''
*# '''Family history of renal malignancy (without familial syndrome)'''
*# '''Exposure to chlorinated solvents'''
*# '''Retroperitoneal radiation'''
*# '''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'''
*# '''Acquired cystic renal disease'''
* '''No increased risk of RCC in patients with autosomal dominant polycystic kidney disease'''

==== Inherited ====

===== Familial Renal Cell Carcinoma Syndromes =====
*'''<span style="color:#ff0000">All are autosomal dominant</span>'''
*'''<span style="color:#ff0000">Accounts for ≈4-6% of incident cases[https://pubmed.ncbi.nlm.nih.gov/34115547/]'''
{| class="wikitable"
|'''<span style="color:#ff0000">Syndrome</span>'''
|'''<span style="color:#ff0000">Gene</span>'''
|'''<span style="color:#ff0000">Clinical Manifestations</span>'''
|-
|'''<span style="color:#ff0000">Von Hippel-Lindau (VHL)</span>'''
|'''<span style="color:#ff0000">VHL</span>'''
|'''<span style="color:#0000ff">HIPPPEEL</span>'''
#'''<span style="color:#ff0000">CNS and/or retinal </span><span style="color:#0000ff">H</span><span style="color:#ff0000">emangioblastomas</span>'''
#'''<span style="color:#ff0000">ccRCC (</span><span style="color:#0000ff">I</span><span style="color:#ff0000">ncreased risk) and renal cysts</span>'''
#'''<span style="color:#0000ff">P</span><span style="color:#ff0000">heochromocytoma</span>'''
#'''<span style="color:#0000ff">P</span><span style="color:#ff0000">araganglioma</span>'''
#'''<span style="color:#0000ff">P</span><span style="color:#ff0000">ancreatic neuroendocrine tumours and cysts</span>'''
#'''<span style="color:#0000ff">E</span><span style="color:#ff0000">pididymal cystadenoma</span>'''
#'''<span style="color:#ff0000">Ear </span><span style="color:#0000ff">E</span><span style="color:#ff0000">ndolymphatic sac tumour</span>'''
#'''<span style="color:#ff0000">Broad </span><span style="color:#0000ff">L</span><span style="color:#ff0000">igament tumours</span>'''
|-
|'''<span style="color:#ff0000">Hereditary Papillary Renal Carcinoma (HPRCC)</span>'''
|'''''<span style="color:#ff0000">c-MET</span>'''''
|
#'''<span style="color:#ff0000">Type 1 papillary RCC</span>'''
|-
|'''<span style="color:#ff0000">Hereditary Leiomyomatosis and RCC (HLRCC)*</span>'''
|'''<span style="color:#ff0000">Fumarate hydratase</span>'''
|
#'''<span style="color:#ff0000">Type 2 papillary or collecting duct RCC</span>'''
#'''<span style="color:#ff0000">Cutaneous leioyomyomas</span>'''
#'''<span style="color:#ff0000">Uterine leiyomyomas</span>'''
|-
|'''<span style="color:#ff0000">Birt-Hogg-Dube (BHD)</span>'''
|'''<span style="color:#ff0000">Folliculin</span>'''
|
#'''<span style="color:#ff0000">Skin fibrofolliculomas</span>'''
#'''<span style="color:#ff0000">Pulmonary cysts, spontaneous pneumothoraces</span>'''
#'''<span style="color:#ff0000">Variety of renal tumours (including chromophobe RCC, oncocytoma, hybrid oncocytic/chromophobe tumors,</span> clear cell RCC (rare), renal cysts)'''
|-
|'''<span style="color:#ff0000">Succinate Dehydrogenase RCC*</span>'''
|'''''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)'''
#'''<span style="color:#ff0000">Adrenal pheochromocytoma/paraganglioma</span>'''
|-
|'''<span style="color:#ff0000">Tuberous Sclerosis Complex (TSC)</span>'''
|'''''<span style="color:#ff0000">TSC1/2</span>'''''
|
#'''<span style="color:#ff0000">Skin (adenoma subaceum, shagreen spots)</span>'''
#'''<span style="color:#ff0000">Variety of renal tumours (increased predisposition for ccRCC, AMLs,</span> renal cysts, polycystic kidney disease, oncycytoma)'''
#'''<span style="color:#ff0000">Retinal hamartomas</span>'''
#'''<span style="color:#ff0000">CNS lesions (including tubers)</span>'''
#'''<span style="color:#ff0000">Seizures</span>'''
#'''<span style="color:#ff0000">Intellectual disability</span>'''
#'''<span style="color:#ff0000">Cardiac lesions</span>'''
#'''<span style="color:#ff0000">Teeth/gum lesions</span>'''
#'''<span style="color:#ff0000">Bone cysts</span>'''
#'''<span style="color:#ff0000">Pulmonary lymphangiomyomatosis</span>'''
|-
|'''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)'''
|-
|'''<span style="color:#ff0000">BAP-1 tumour predisposition syndrome[https://www.ncbi.nlm.nih.gov/books/NBK390611/]</span>'''
|'''<span style="color:#ff0000">BAP1</span>'''
|
*'''<span style="color:#ff0000">ccRCC</span>'''
*'''<span style="color:#ff0000">Uveal melanoma</span>'''
*'''Malignant mesothelioma'''
*'''Cutaneous melanoma'''
*'''Melanocytic tumours'''
*'''Basal cell carcinoma'''
|-
| colspan="3" |'''<span style="color:#ff0000">*Renal cancers associated with these syndromes are typically more aggressive</span>'''
|}

====== <span style="color:#ff0000">Von Hippel-Lindau Disease</span> ======
*Incidence 1:30,000-1:40,000
*'''<span style="color:#ff0000">RCC develops in 35-70% of VHL patients</span> and is''' '''distinctive for early age (median 40) of onset and bilateral and multifocal involvement'''
*'''<span style="color:#ff0000">Mutation: VHL</span>'''
**'''VHL is a tumor suppressor gene,''' for both familial and sporadic ccRCC, at '''chromosome 3'''p25-26
***'''<span style="color:#ff0000">VHL mutation is most common genetic mutation in sporadic RCC[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3483538/]</span>'''
**Under normal conditions, the '''<span style="color:#ff0000">VHL complex targets hypoxia-inducible factors (HIF) for degradation</span>''', keeping levels of HIF low. HIF regulates response to hypoxia, starvation, and other stresses
**'''<span style="color:#ff0000">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.
*'''<span style="color:#ff0000">Pheochromocytoma manifestations of VHL are restricted to certain families (type 2 VHL)</span>'''
*'''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
*'''<span style="color:#ff0000">RCC is most common cause of death in VHL patients</span>'''

====== <span style="color:#ff0000">Hereditary Papillary Renal Cell Carcinoma (HPRCC)</span> ======
*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 <span style="color:#ff0000">constitutive activation of the receptor for hepatocyte growth factor</span>'''

====== <span style="color:#ff0000">Hereditary leiomyomatosis and RCC syndrome (HLRCC)</span> ======
*'''<span style="color:#ff0000">Almost all individuals with this syndrome will develop cutaneous leiomyomas and uterine fibroids (if female),</span>''' 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''' '''<span style="color:#ff0000">more aggressive</span>'''; therefore, '''prompt surgical management is indicated'''

====== Tuberous Sclerosis Complex (TSC) ======
*Classic triad:
*#Seizures
*#Adenoma sebaceum
*#Intellectual disability
**May not be present due to variable penetrance of the TSC mutation
*'''50% of patients with TSC develop AMLs'''
== Questions ==

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

== Answers ==

# What proportion of RCCs are familial?
#* ≈4-6%
#What are the clinical manifestations of VHL?
##Hemangioblastoma
##Increased risk of ccRCC
##Paraganglioma
##Pheochromocyoma
##Pancreatic cysts and neuroendocrine tumours
##Ear endolymphatic tumour
##Epididymal cysts
##Ligament, broad tumours
#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
#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
#What are the established risk factors for RCC?
## Obesity
## Hypertension
## Smoking
## Acquired cystic disease
## Familial syndrome

== Next Chapter: [[Kidney Cancer: Pathology and Familial Syndromes|Pathology]] ==

== 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.