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Kidney Cancer: Pathology: Difference between revisions

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*** '''<span style="color:#ff0000">More common with papillary histology and familial RCC</span>'''
*** '''<span style="color:#ff0000">More common with papillary histology and familial RCC</span>'''
*** '''<span style="color:#ff0000">Microsatellite analysis suggests a clonal origin for most multifocal RCC</span>'''
*** '''<span style="color:#ff0000">Microsatellite analysis suggests a clonal origin for most multifocal RCC</span>'''
== Familial RCC Syndromes ==
* '''<span style="color:#ff0000">All are autosomal dominant</span>'''
* '''Account for ≈4-6% of cases of RCC overall'''
{| 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>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>'''
|-
|'''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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