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KIDNEY CANCER: PATHOLOGY & FAMILIAL SYNDROMES

 

• Classification of renal masses
• Renal cell carcinoma
  • Subtypes
• Familial syndromes
• Grade
• Questions
• Answers

Classification of renal masses

• Abbreviated 2016 WHO Classification of renal neoplasms§:

   

  Renal cell carcinoma (RCC) tumours (14) 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

  Benign renal tumours (7) Papillary adenoma Oncocytoma Angiomyolipoma Metanephric adenoma and other metanephric tumors Adult cystic nephroma Mixed epithelial stromal tumors Juxtaglomerular cell tumor . Mesenchymal tumors Leiomyosarcoma (including renal vein) and other sarcomas Leiomyoma and other benign mesenchymal tumors . Others Adult Wilms tumor Primitive neuroectodermal tumor Metastatic tumors, lymphoma, leukemia

   

• Another classification method (malignant vs. benign vs. inflammatory):

 

Malignant Renal cell carcinoma 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§
• 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 Genrally good prognosis, compared to clear cell and papillary Rates of disease-specific (recurrence, metastasis, or death due disease) events following nephrectomy:§ 5 years: 3.7% 10 years: 6.4% Features associated with disease-specific events (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
• 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 synchrnous, 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

Familial RCC Syndromes

• All are autosomal dominant
• Account for ≈4-6% of cases of RCC overall

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
*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 3p25-26
• 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:
    1. Seizures
    2. Adenoma sebaceum
    3. Intellectual disability
    • May not be present due to variable penetrance of the TSC mutation
  • 50% of patients with TSC develop AMLs

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.

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