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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> |
| | |
| == 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><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</span>.
| |
| **** 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 == | | == Questions == |
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