Kidney Cancer: Pathology

Classification of renal masses

2016 WHO Classification of renal neoplasms[1]

(abbreviated)

Renal cell tumours (16) Clear cell renal cell carcinoma Multilocular cystic renal neoplasm of low malignant potential Papillary renal cell carcinoma Hereditary leiomyomatosis and renal cell carcinoma associated renal cell carcinoma Chromophobe renal cell carcinoma Collecting duct carcinoma Renal medullary carcinoma MiT family translocation renal cell carcinomas Succinate dehydrogenase deficient renal cell carcinoma Mucinous tubular and spindle cell carcinoma Tubulocystic renal cell carcinoma Acquired cystic disease associated renal cell carcinoma Clear cell papillary renal cell carcinoma Renal cell carcinoma, unclassified Papillary adenoma Oncocytoma Metanephric tumors Metanephric adenoma Metanephric adenofibroma Metanephric stromal tumor Nephroblastic and cystic tumors occurring mainly in children Nephrogenic rests Nephroblastoma Cystic partially differentiated nephroblastoma Pediatric cystic nephroma

Mesenchymal tumors occurring mainly in children Clear cell sarcoma Rhabdoid tumor Congenital mesoblastic nephroma Ossifying renal tumor of infancy Mesenchymal tumors occurring mainly in adults Leiomyosarcoma (including renal vein leiomyosarcoma) Angiosarcoma Rhabdomyosarcoma Osteosarcoma Synovial sarcoma Ewing sarcoma Angiomyolipoma Epithelioid angiomyolipoma Leiomyoma Hemangioma Lymphangioma Hemangioblastoma Juxtaglomerular cell tumor Renomedullary interstitial cell tumor Schwannoma Solitary fibrous tumor Mixed epithelial and stromal tumor family Adult cystic nephroma Mixed epithelial and stromal tumor Neuroendocrine tumors Well differentiated neuroendocrine tumor Large cell neuroendocrine carcinoma Small cell neuroendocrine carcinoma Paraganglioma Miscellaneous tumors Renal hematopoietic neoplasms Germ cell tumors Metastatic tumors Tumor-like lesions Xanthogranulomatous pyelonephritis IgG4 related disease

There are additional described entities not currently in WHO

Classification by malignant vs. benign vs. inflammatory

Malignant Renal cell carcinoma (RCC) Clear cell RCC Multilocular cystic renal neoplasm of low malignant potential Papillary RCC Hereditary leiomyomatosis RCC Chromophobe RCC Collecting duct carcinoma Renal medullary carcinoma MiT Family translocation carcinomas Succinate dehydrogenase (SDH) deficient RCC Mucinous tubular and spindle cell carcinoma Tubulocystic RCC Acquired cystic disease associated RCC Clear cell papillary RCC RCC, unclassified Urothelium-based cancers Urothelial carcinoma Squamous cell carcinoma Adenocarcinoma Sarcomas Leiomyosarcoma Liposarcoma Angiosarcoma Hemangiopericytoma Malignant fibrous histiocytoma Synovial sarcoma Osteogenic sarcoma Clear cell sarcoma Rhabdomyosarcoma Wilms tumor Primitive neuroectodermal tumor Carcinoid tumor Lymphoma/leukemia Metastasis Invasion by adjacent neoplasm

Benign Cystic lesions Simple cyst Hemorrhagic cyst Solid lesions Angiomyolipoma Oncocytoma Renal adenoma Metanephric adenoma Cystic nephroma Mixed epithelial-stromal tumor Reninoma (juxtaglomerular cell tumor) Leiomyoma Fibroma Hemangioma Vascular lesions Renal artery aneurysm Arteriovenous malformation Pseudotumor Inflammatory Abscess Focal pyelonephritis Xanthogranulomatous pyelonephritis Infected renal cyst Tuberculosis Rheumatic granuloma

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)

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 Rates of disease-specific (recurrence, metastasis, or death due disease) events following nephrectomy:[3] 5 years: 3.7% 10 years: 6.4% Features associated with disease-specific events (4):[4] Tumour size Small-vessel invasion Sarcomatoid features Microscopic necrosis pT stage or nodal metastasis tended to show some association, without reaching statistical significance	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
  • 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

1. What the prognosis of ccRCC relative to chromophobe and papillary RCC? Which papillary RCC subtype is associated with better prognosis relative to the other?
2. Patients with ESRD or acquired renal cystic disease are more likely to develop with type of RCC?
3. Which RCC histology stains for Hale colloidal iron?
4. Which RCC histologies arise from the proximal tubule vs. collecting duct?
5. What are the clinical manifestations of VHL?
6. What gene is mutated and what are the clinical manifestations of HRPCC, HLPCC, Burt-Hogg-Dube, Tuberous Sclerosis Complex?
7. Explain the pathway of VHL and HIF and role in RCC pathophysiology

Answers

1. 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
2. Patients with ESRD or acquired renal cystic disease are more likely to develop with type of RCC?
   • Papillary
3. Which RCC histology stains for Hale colloidal iron?
   • Chromophobe
4. Which RCC histologies arise from the proximal tubule vs. collecting duct?
   1. Proximal tubule:
      1. Clear cell
      2. Papillary
   2. Collecting duct
      1. Chromophobe
      2. Collecting duct
      3. Medullary
5. What are the clinical manifestations of VHL?
   1. Hemangioblastoma
   2. Increased risk of ccRCC
   3. Paraganglioma
   4. Pheochromocyoma
   5. Pancreatic cysts and neuroendocrine tumours
   6. Ear endolymphatic tumour
   7. Epididymal cysts
   8. Ligament, broad tumours
6. 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
7. 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

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.