Kidney Cancer: Pathology
Classification of renal masses
2016 WHO Classification of renal neoplasms[1]
(abbreviated)
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There are additional described entities not currently in WHO
Classification by malignant vs. benign vs. inflammatory
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Renal cell carcinoma (RCC)
- Most common (>90%) non-metastatic malignant histology of kidney tumours
- Most common benign tumours of the kidney include oncocytoma and angiomyolipoma (AML).
- Most common renal tumour in pregnancy[2]
- All RCCs are adenocarcinomas
- Most are derived from renal tubular epithelial cells of the proximal convoluted tubule
- Exceptions include chromophobe, collecting duct, and medullary RCC (see below)
- Most are derived from renal tubular epithelial cells of the proximal convoluted tubule
Subtypes
Histology | Characteristics | Familial form and genetic factors |
Clear cell RCC (ccRCC)
(70-80%, most common) |
Originates from proximal tubule
Prognosis generally worse compared to papillary or chromophobe Responds to systemic therapy |
von Hippel-Lindau disease
Chromosome 3p deletions (VHL inactivation by mutation or promoter hypermethylation occurs in 70-90% of clear cell renal tumors) |
Multilocular cystic
ccRCC (uncommon) |
Almost uniformly benign clinical behavior | Identical to ccRCC |
Papillary RCC
(10-15%, 2nd most common) |
Originates from proximal tubule
Commonly multifocal Common in ESRD and acquired renal cystic disease Type 1: good prognosis Type 2: worse prognosis Grade may be of greater prognostic significance than type 1 vs. 2 Current systemic therapies are ineffective against papillary RCC 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
Type 2: Hereditary leiomyomatosis and RCC syndrome (HLRCC) Trisomy of chromosomes 7 and 17 and loss of the Y chromosome. |
Chromophobe RCC
(3-5%) |
Originates from intercalated cells of distal tubule/collecting duct
Stains positive for Hale colloidal iron Generally good prognosis, compared to clear cell and papillary
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Commonly seen Birt-Hogg-Dubé syndrome; most cases are sporadic |
Collecting duct carcinoma (<1%) | Originates from collecting duct
Stains positive with Ulex europaeus lectin Poor prognosis; most reported cases have been high grade, advanced stage, and unresponsive to conventional therapies May share features in common with urothelial carcinoma; advanced collecting duct carcinoma may respond to cisplatin or gemcitabine-based chemotherapy |
Unknown
Multiple chromosomal losses |
Renal medullary carcinoma (rare) | Originates from collecting duct
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 |
Unclassified RCC
(1%-3%) |
Origin not defined
Poor prognosis, most are poorly differentiated and are associated with a highly aggressive biologic behavior |
Unknown |
RCC associated with Xp11.2
translocations/TFE3 gene fusions (rare) |
Occurs in children and young adults; 40% of pediatric RCC
Prognosis similar to ccRCC |
Various mutations involving chromosome Xp11.2
resulting in TFE3 gene fusion |
Post-neuroblastoma
RCC (rare) |
Occurs exclusively in children with prior neuroblastoma | Unknown |
Mucinous tubular and spindle cell (rare) | Favorable prognosis | Unknown |
Other histologic features
- Sarcomatoid differentiation
- Found in 1-5% of RCCs
- Not a distinct histologic subtype of RCC, most commonly in association with ccRCC and chromophobe RCC
- Associated with worse prognosis; multimodal approaches should be considered
- Cystic degeneration
- Found in 10-25% of RCCs
- Associated with better prognosis compared with purely solid RCC
- Laterality and focality
- Most sporadic RCCs are unilateral and unifocal
- Bilateral involvement
- Occurs in 2-4% of sporadic RCCs
- More common in patients with familial forms of RCC (e.g. von Hippel-Lindau disease).
- Can be synchronous or asynchronous
- If synchronous, likely an independent growth
- If asynchronous, likely a metastasis
- Occurs in 2-4% of sporadic RCCs
- Multifocality
- Occurs in 10-20% of cases
- More common with papillary histology and familial RCC
- Microsatellite analysis suggests a clonal origin for most multifocal RCC
Grade
- Based primarily on nuclear size, shape, and presence of predominant nucleoli
- Fuhrman Grading system
- Described in 1982
- International Society of Urological Pathology (ISUP) Grading system
- Proposed in 2012, updated in 2016
- Incorporates aspects of the Fuhrman Grading system but includes more objective criteria for nuclear characteristics.
- 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.
- In general, higher grade is associated with larger tumor size and more aggressive tumors.
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?
- Patients with ESRD or acquired renal cystic disease are more likely to develop with type of RCC?
- Which RCC histology stains for Hale colloidal iron?
- 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
- What the prognosis of ccRCC relative to chromophobe and papillary RCC? Which papillary RCC subtype is associated with better prognosis relative to the other?
- Prognosis of ccRCC is worse than chromophobe and papillary RCC
- Type II papillary RCC has worse prognosis than type I
- Patients with ESRD or acquired renal cystic disease are more likely to develop with type of RCC?
- Papillary
- Which RCC histology stains for Hale colloidal iron?
- Chromophobe
- Which RCC histologies arise from the proximal tubule vs. collecting duct?
- Proximal tubule:
- Clear cell
- Papillary
- Collecting duct
- Chromophobe
- Collecting duct
- Medullary
- Proximal tubule:
- 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
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.