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== Classification of renal masses ==
== Classification of renal masses ==


=== 2016 WHO Classification of renal neoplasms (abbreviated)[https://pubmed.ncbi.nlm.nih.gov/26935559/] ===
=== 2016 WHO Classification of renal neoplasms[https://pubmed.ncbi.nlm.nih.gov/26935559/] ===
(abbreviated)
{| class="wikitable"
{| class="wikitable"
|
|
* '''Renal cell tumours (16)'''
* '''<span style="color:#ff0000">Renal cell tumours (16)</span>'''
** Clear cell renal cell carcinoma
** Clear cell renal cell carcinoma
** Multilocular cystic renal neoplasm of low malignant potential
** Multilocular cystic renal neoplasm of low malignant potential
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** Metanephric adenofibroma
** Metanephric adenofibroma
** Metanephric stromal tumor
** Metanephric stromal tumor
.


* '''Nephroblastic and cystic tumors occurring mainly in children'''
* '''Nephroblastic and cystic tumors occurring mainly in children'''
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** Pediatric cystic nephroma
** Pediatric cystic nephroma
|
|
* Mesenchymal tumors occurring mainly in children
* '''Mesenchymal tumors occurring mainly in children'''
** Clear cell sarcoma
** Clear cell sarcoma
** Rhabdoid tumor
** Rhabdoid tumor
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** Ossifying renal tumor of infancy
** Ossifying renal tumor of infancy


* Mesenchymal tumors occurring mainly in adults
* '''Mesenchymal tumors occurring mainly in adults'''
** Leiomyosarcoma (including renal vein leiomyosarcoma)
** Leiomyosarcoma (including renal vein leiomyosarcoma)
** Angiosarcoma
** Angiosarcoma
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** Mixed epithelial and stromal tumor
** Mixed epithelial and stromal tumor


* Neuroendocrine tumors
* '''Neuroendocrine tumors'''
** Well differentiated neuroendocrine tumor
** Well differentiated neuroendocrine tumor
** Large cell neuroendocrine carcinoma
** Large cell neuroendocrine carcinoma
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** Paraganglioma
** Paraganglioma


* Renal hematopoietic neoplasms
* '''Miscellaneous tumors'''
 
**Renal hematopoietic neoplasms
* Germ cell tumors
**Germ cell tumors
* Metastatic tumors
* '''Metastatic tumors'''
* Tumor-like lesions
* '''Tumor-like lesions'''
** Xanthogranulomatous pyelonephritis
** Xanthogranulomatous pyelonephritis
** IgG4 related disease
** IgG4 related disease
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There are additional described entities not currently in WHO
There are additional described entities not currently in WHO


=== '''Classification by malignant vs. benign vs. inflammatory''' ===
=== Classification by malignant vs. benign vs. inflammatory ===
{| class="wikitable"
{| class="wikitable"
|
|
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== Renal cell carcinoma (RCC) ==
== Renal cell carcinoma (RCC) ==


* '''Most common (>90%) non-metastatic malignant histology of kidney tumours'''
* '''<span style="color:#ff0000">Most common (>90%) non-metastatic malignant histology of kidney tumours</span>'''
** Most common benign tumours of the kidney include oncocytoma and angiomyolipoma (AML).
** Most common benign tumours of the kidney include oncocytoma and angiomyolipoma (AML).
* '''Most common renal tumour in pregnancy'''§
* '''<span style="color:#ff0000">Most common renal tumour in pregnancy[https://pubmed.ncbi.nlm.nih.gov/3756780/]</span>'''
* '''All RCCs are adenocarcinomas'''
* '''<span style="color:#ff0000">All RCCs are adenocarcinomas</span>'''
** '''Most are derived from renal tubular epithelial cells of the proximal convoluted tubule'''
** '''<span style="color:#ff0000">Most are derived from</span> renal tubular epithelial cells <span style="color:#ff0000">of the proximal convoluted tubule</span>'''
*** Exceptions include chromophobe, collecting duct, and medullary RCC (see below)
*** Exceptions include chromophobe, collecting duct, and medullary RCC (see below)


=== '''Subtypes''' ===
=== <span style="color:#ff0000">Subtypes</span> ===
{| class="wikitable"
{| class="wikitable"
|'''Histology'''
|'''<span style="color:#ff0000">Histology</span>'''
|'''Characteristics'''
|'''<span style="color:#ff0000">Characteristics</span>'''
|'''Familial form and genetic factors'''
|'''<span style="color:#ff0000">Familial form and genetic factors</span>'''
|-
|-
|'''Clear cell RCC (ccRCC)'''
|'''<span style="color:#ff0000">Clear cell RCC (ccRCC)</span>'''


'''(70-80%, most common)'''
'''<span style="color:#ff0000">(70-80%, most common)</span>'''
|'''Originates from proximal tubule'''
|'''<span style="color:#ff0000">Originates from proximal tubule</span>'''


'''Prognosis generally worse compared to papillary or chromophobe'''
'''<span style="color:#ff0000">Prognosis generally worse compared to papillary or chromophobe</span>'''


'''Responds to systemic therapy'''
'''Responds to systemic therapy'''
|'''von Hippel-Lindau disease'''
|'''<span style="color:#ff0000">von Hippel-Lindau disease</span>'''


'''Chromosome 3p deletions''' (VHL inactivation by mutation or promoter hypermethylation occurs in 70-90% of clear cell renal tumors)
'''Chromosome 3p deletions''' (VHL inactivation by mutation or promoter hypermethylation occurs in 70-90% of clear cell renal tumors)
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|'''Identical to ccRCC'''
|'''Identical to ccRCC'''
|-
|-
|'''Papillary RCC'''
|'''<span style="color:#ff0000">Papillary RCC</span>'''


'''(10-15%, 2nd most common)'''
'''<span style="color:#ff0000">(10-15%, 2nd most common)</span>'''
|'''Originates from proximal tubule'''
|'''<span style="color:#ff0000">Originates from proximal tubule</span>'''


'''Commonly multifocal'''
'''<span style="color:#ff0000">Commonly multifocal</span>'''


'''Common in ESRD and acquired renal cystic disease'''
'''<span style="color:#ff0000">Common in ESRD and acquired renal cystic disease</span>'''


'''Type 1: good prognosis'''
'''<span style="color:#ff0000">Type 1: good prognosis</span>'''


'''Type 2: worse prognosis'''
'''<span style="color:#ff0000">Type 2: worse prognosis</span>'''


'''Grade may be of greater prognostic significance than type 1 vs. 2'''
'''Grade may be of greater prognostic significance than type 1 vs. 2'''


'''Current systemic therapies are ineffective against papillary RCC'''
'''<span style="color:#ff0000">Current systemic therapies are ineffective against papillary RCC</span>'''


Papillary adenomas are small (≤5mm) tumours that resemble papillary RCC under the microscope, are often well encapsulated and low grade, commonly found at autopsy, possess many of the same genetic alterations found in larger papillary RCCs, but are benign neoplasms
Papillary adenomas are small (≤5mm) tumours that resemble papillary RCC under the microscope, are often well encapsulated and low grade, commonly found at autopsy, possess many of the same genetic alterations found in larger papillary RCCs, but are benign neoplasms
|'''Type 1: Hereditary papillary RCC (HPRCC) syndrome'''
|'''<span style="color:#ff0000">Type 1: Hereditary papillary RCC (HPRCC) syndrome</span>'''


'''Type 2: Hereditary leiomyomatosis and RCC syndrome (HLRCC)'''
'''<span style="color:#ff0000">Type 2: Hereditary leiomyomatosis and RCC syndrome (HLRCC)</span>'''


'''Trisomy of chromosomes 7 and 17 and loss of the Y chromosome.'''
'''Trisomy of chromosomes 7 and 17 and loss of the Y chromosome.'''
|-
|-
|'''Chromophobe RCC'''
|'''<span style="color:#ff0000">Chromophobe RCC</span>'''


'''(3-5%)'''
'''<span style="color:#ff0000">(3-5%)</span>'''
|'''Originates from''' intercalated cells of '''distal tubule/collecting duct'''
|'''<span style="color:#ff0000">Originates from</span>''' intercalated cells of '''<span style="color:#ff0000">distal tubule/collecting duct</span>'''


'''Stains positive for Hale colloidal iron'''
'''Stains positive for Hale colloidal iron'''


'''Genrally good prognosis''', compared to clear cell and papillary
'''<span style="color:#ff0000">Generally good prognosis</span>''', compared to clear cell and papillary


* Rates of disease-specific (recurrence, metastasis, or death due disease) events following nephrectomy:§
* Rates of disease-specific (recurrence, metastasis, or death due disease) events following nephrectomy:[https://pubmed.ncbi.nlm.nih.gov/21602658/]
** 5 years: 3.7%
** 5 years: 3.7%
** 10 years: 6.4%
** 10 years: 6.4%
* Features associated with disease-specific events (4):§
* Features associated with disease-specific events (4):[https://pubmed.ncbi.nlm.nih.gov/21602658/]
*# Tumour size
*# Tumour size
*# Small-vessel invasion
*# Small-vessel invasion
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*# Microscopic necrosis
*# Microscopic necrosis
** pT stage or nodal metastasis tended to show some association, without reaching statistical significance
** pT stage or nodal metastasis tended to show some association, without reaching statistical significance
|'''Commonly seen Birt-Hogg-Dubé syndrome; most cases are sporadic'''
|'''<span style="color:#ff0000">Commonly seen Birt-Hogg-Dubé syndrome;</span> most cases are sporadic'''
|-
|-
|'''Collecting duct carcinoma (<1%)'''
|'''<span style="color:#ff0000">Collecting duct carcinoma (<1%)</span>'''
|'''Originates from collecting duct'''
|'''<span style="color:#ff0000">Originates from collecting duct</span>'''


'''Stains positive with Ulex europaeus lectin'''
'''Stains positive with Ulex europaeus lectin'''
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Multiple chromosomal losses
Multiple chromosomal losses
|-
|-
|'''Renal medullary carcinoma (rare)'''
|'''<span style="color:#ff0000">Renal medullary carcinoma</span> (rare)'''
|'''Originates from collecting duct'''
|'''<span style="color:#ff0000">Originates from collecting duct</span>'''


'''Dismal prognosis'''; '''many cases are both locally advanced and metastatic at the time of diagnosis'''
'''Dismal prognosis'''; '''many cases are both locally advanced and metastatic at the time of diagnosis'''
|'''Associated with sickle cell trait (NOT disease);''' typically diagnosed in young African-Americans
|'''<span style="color:#ff0000">Associated with sickle cell trait (NOT disease);</span>''' typically diagnosed in young African-Americans
|-
|-
|'''Unclassified RCC'''
|'''Unclassified RCC'''
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|}
|}


=== '''Other histologic features''' ===
=== <span style="color:#ff0000">Other histologic features</span> ===


* '''Sarcomatoid differentiation'''
* '''<span style="color:#ff0000">Sarcomatoid differentiation</span>'''
** Found in 1-5% of RCCs
** Found in 1-5% of RCCs
** '''Not a distinct histologic subtype of RCC''', '''most commonly in association with ccRCC and chromophobe RCC'''
** '''Not a distinct histologic subtype of RCC''', '''<span style="color:#ff0000">most commonly in association with ccRCC and chromophobe RCC</span>'''
** '''Associated with worse prognosis; multimodal approaches should be considered'''
** '''<span style="color:#ff0000">Associated with worse prognosis;</span> multimodal approaches should be considered'''
* '''Cystic degeneration'''
* '''Cystic degeneration'''
** Found in 10-25% of RCCs
** Found in 10-25% of RCCs
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* '''Laterality and focality'''
* '''Laterality and focality'''
** '''Most sporadic RCCs are unilateral and unifocal'''
** '''<span style="color:#ff0000">Most sporadic RCCs are unilateral and unifocal</span>'''
** '''Bilateral involvement'''
** '''<span style="color:#ff0000">Bilateral involvement</span>'''
*** Occurs in 2-4% of sporadic RCCs
*** Occurs in 2-4% of sporadic RCCs
**** '''More common in patients with familial forms of RCC ('''e.g'''.''' von Hippel-Lindau disease).
**** '''More common in patients with familial forms of RCC ('''e.g'''.''' von Hippel-Lindau disease).
*** Can be synchronous or asynchronous
*** Can be synchronous or asynchronous
**** '''If synchronous, likely an independent growth'''
**** '''<span style="color:#ff0000">If synchronous, likely an independent growth</span>'''
**** '''If asynchronous, likely a metastasis'''
**** '''<span style="color:#ff0000">If asynchronous, likely a metastasis</span>'''
** '''Multifocality'''
** '''<span style="color:#ff0000">Multifocality'''
*** '''Occurs in 10-20% of cases'''
*** '''<span style="color:#ff0000">Occurs in 10-20% of cases</span>'''
*** '''More common with papillary histology and familial RCC'''
*** '''<span style="color:#ff0000">More common with papillary histology and familial RCC</span>'''
*** '''Microsatellite analysis suggests a clonal origin for most multifocal RCC'''
*** '''<span style="color:#ff0000">Microsatellite analysis suggests a clonal origin for most multifocal RCC</span>'''
 
== Familial RCC Syndromes ==
 
* '''All are autosomal dominant'''
* '''Account for ≈4-6% of cases of RCC overall'''
 
{| class="wikitable"
|'''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'''§
|'''BAP1'''
|
* '''ccRCC'''
* '''Uveal melanoma'''
* '''Malignant mesothelioma'''
* '''Cutaneous melanoma'''
* '''Melanocytic tumours'''
* '''Basal cell carcinoma'''
|-
| colspan="3" |'''*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 3'''p25-26
**** '''VHL mutation is most common genetic mutation in sporadic RCC'''§
*** 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:
**# Seizures
**# Adenoma sebaceum
**# Intellectual disability
*** May not be present due to variable penetrance of the TSC mutation
** '''50% of patients with TSC develop AMLs'''


== Grade ==
== Grade ==
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** Sarcomatoid and rhabdoid tumors, tumors with giant cells, and tumors with extreme nuclear pleomorphism are included within grade 4 tumors.
** Sarcomatoid and rhabdoid tumors, tumors with giant cells, and tumors with extreme nuclear pleomorphism are included within grade 4 tumors.
** Chromophobe RCC is no longer graded in the ISUP system.
** Chromophobe RCC is no longer graded in the ISUP system.
* In general, higher grade is associated with larger tumor size and more aggressive tumors.
* In general, higher grade is associated with larger tumor size and more aggressive tumors.</span>
 
== Questions ==
== Questions ==


# What the prognosis of ccRCC relative to chromophobe and papillary RCC? Which papillary RCC subtype is associated with better prognosis relative to the other?
# What the prognosis of ccRCC relative to chromophobe and papillary RCC? Which papillary RCC subtype is associated with better prognosis relative to the other?
# Patients with ESRD or acquired renal cystic disease are more likely to develop with type of RCC?
# Patients with ESRD or acquired renal cystic disease are more likely to develop which type of RCC?
# Which RCC histology stains for Hale colloidal iron?
# Which RCC histology stains for Hale colloidal iron?
# Which RCC histologies arise from the proximal tubule vs. collecting duct?
# Which RCC histologies arise from the proximal tubule vs. collecting duct?
# 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


== Answers ==
== Answers ==
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### Collecting duct
### Collecting duct
### Medullary
### Medullary
# 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


== Next Chapter: TNM Staging ==
== Next Chapter: [[Kidney Cancer: TNM Staging|TNM Staging]] ==


== References ==
== References ==
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