Exam 2: Renal, Lower Urinary, and Prostate Cancer DSA

Question 1

List some benign and malignant renal tumors

Answer 1

• Benign tumors of the kidney including
  
  • oncocytoma
  • angiomyolipoma
  • renal papillary adenoma
• Malignant tumors of the kidney including
  
  • renal cell carcinoma
    
    • clear cell
    • papillary
    • chromophobe
  • Wilms tumor (nephroblastoma)
  • urothelial carcinomas of the renal pelvis

Question 2

Tumor type?

Key info?

Answer 2

• Oncocytoma
  
  • Arise from intercalated cells of collecting ducts
  • ~10% (5-15%) of renal tumors.
• Pathogenesis
  
  • associated with genetic changes
  • loss of chromosomes 1, 14, and 7.
• Gross
  
  • Large size
  • tan-brown to mahogany color
  • central stellate scar.
  • Can be multiple with familiar cases.
• Microscopic
  
  • Abundant mitochondria in finely granular cytoplasm.

Question 3

type of tumor?

Answer 3

• Oncocytoma
• Note the central scar (gross) and the tumor cells (microscopic) with the eosinophilic, finely granular cytoplasm.
• (a)
  
  • circumscribed tumour with central area of scarring
• (b)
  
  • conglomerate islands of cells separated by a pale-staining myxoid stroma

Question 4

type of tumor?

Answer 4

• Oncocytoma
• Note this EM of oncocytoma shows abundant mitochondria, a characteristic finding.
• Electron microscopic
  
  • The cytoplasm of the tumor cells is characteristically filled with mitochondria, many of which have stacked cristae.

Question 5

Tumor type?

Key info?

Answer 5

• Angiomyolipoma
  
  • Benign
• Composed of
  
  • blood vessels
  • smooth muscle, spindle cells
  • adipose tissue from perivascular epithelioid cells.
• Occurs in 25-50% patients with tuberous sclerosis
  
  • TS
    
    • hamartomatous lesions of brain (“tubers”)
    • skin abnormalities
    • benign tumors of heart and other organs
  • Loss-of-function mutations
    
    • in TSC1 or TSC2 tumor suppressor genes
• Susceptible to spontaneous hemorrhage

Question 6

Renal Cell Papillary Adenoma

Key info?

Answer 6

• Renal Cell Papillary Adenoma
  
  • Common finding at autopsy
  • Frequently papillary.
    
    • clear cell and chromophobe lesions should not be termed adenomas.
• Gross
  
  • small (usually <0.5 cm) cortical lesions
  • pale, yellow, well-circumscribed
• Microscopic
  
  • Indistinguishable from low-grade papillary renal cell carcinoma
  • Cuboidal or low columnar cells in papillary formations
• Natural history
  
  • consider as potentially malignant.

Question 7

Renal Cell Carcinoma

Key info?

Answer 7

• Renal Cell Carcinoma
  
  • Malignant Tumor
    
    • Can metastasize and invade.
• Most common primary cancer of the kidney (85%)
  
  • Occurs in 6th to 7th decade
  • and males > females (3:1)
• Etiology/Risk factor
  
  • Tobacco is most significant.
  • Obesity
  • HTN
  • unopposed estrogen therapy
  • toxic/industrial exposures
    
    • including cadmium and heavy metals, asbestos, petroleum products.
  • Genetics
    
    • Von Hippel-Landau (VHL) gene
      
      • familial and sporadic clear cell tumors
    • MET proto-oncogene
      
      • hereditary papillary tumors
    • Chromophobe carcinoma
      
      • multiple chromosome losses and extreme hypodiploidy
    • Others

Question 8

Tumor type?

Key info?

Answer 8

Renal Cell Carcinoma – Clear Cell Carcinoma

• Most common type
• Morphology
  
  • clear cytoplasm and non-papillary
• Can be hereditary/familial, but vast majority are sporadic.
  
  • Von Hippel-Lindau syndrome
    
    • includes cerebellar hemangioblastoma, retinal angiomas, cysts in pancreas/liver/kidney, and pheochromocytomas in addition to renal cell carcinoma.
  • Familial cases involve loss of inherited 3p (3p25.3) with VHL gene.
    
    • Other genes are inactivated by somatic mutation or hypermethylation. Lack of VHL protein stabilizes hypoxia-inducible factor (HIF-1). HIF-1 activates genes such as VEGF (angiogenesis), MYC complex; epigenetic processes are also affected.
• Gross
  
  • Usually unilateral and solitary
  • bright yellow-grey white , cortical, sharply-defined.
  • Invasion of renal vein can occur.
• Microscopic
  
  • Clear/granular cytoplasm containing glycogen and lipids.
  • Cystic and solid areas may be seen.
  • Wide range of atypicality.

Question 9

Tumor type?

Key info?

Answer 9

Renal Cell Carcinoma – Papillary Carcinoma

• 10-15% of renal cell cancers
• Tumors are frequently multifocal (more than clear cell)
• Better prognosis than clear cell
• Familial and Sporadic forms
  
  • Not associated with 3p deletions
  • Most common
    
    • Trisomies 7 and 17 and loss of Y chromosome in males.
    • Chromosome 7 has MET gene
      
      • a proto-oncogene that codes the tyrosine kinase receptor for hepatocyte growth factor, which influences growth, cell mobility and morphogenetic differentiation.
• Gross
  
  • frequently multifocal
  • hemorrhagic
  • and cystic
• Microscopic
  
  • cuboidal or low columnar cells
  • arranged in papillary formations.
  • Foamy macrophages (interstitial foam cells) are present throughout the tumor.

Question 10

Tumor type?

Key info?

Answer 10

Renal Cell Carcinoma – Chromophobe Renal Carcinoma

• 5% of renal cell cancers
• Cytogenetic
  
  • multiple chromosome losses and extreme hypodiploidy
• Thought to arise form intercalated cells of collecting ducts.
• Excellent prognosis (vs. clear cell and papillary)
• Hereditary forms occur
  
  • Birt-Hogg-Dube (BHD) syndrome
    
    • a hereditary disease with risk for bilateral, multifocal chromophobe RCC
    • is caused by mutations in folliculin.
    • This features skin, pulmonary, and renal tumors with a wide variety of histologic subtypes. Hereditary forms are more apt to be bilateral.
• Gross
  
  • frequently multifocal
  • hemorrhagic
  • and cystic
• Microscopic
  
  • Pale eosinophilic cells that often have halos around nuclei.
  • Tumor cells are arranged in solid sheets with a concentration of the largest cells around blood vessels.

Question 11

Urothelial Tumors

Answer 11

• 5-10% of primary renal tumors
  
  • benign papillomas to malignant urothelial carcinomas.
  • Similar tumors also occur in the ureters and urinary bladder.
• These were known in the past as transitional cell carcinomas.
• Ureter and bladder tumors become clinically apparent early
  
  • due to hematuria.
• They may also block the urinary outflow
  
  • and result in hydronephrosis.
• Pathogenesis/Risk factors for urothelial tumors include
  
  • cigarette smoking (most important)
  • exposure to aryl amines
  • schistosomiasis (squamous carcinoma)
  • long-term analgesic or cyclophosphamide use,
  • chronic inflammation
  • and irradiation.
  • Heavy caffeine use may be associated with a small increase in incidence.
• Acquired genetic alterations include
  
  • one pathway with mutations in
    
    • gain-of-function FGFR3 and RAS
      
      • low-grade lesions
    • loss-of-function p53 and RB
      
      • in progression to high-grade lesions.
  • Another more aggressive pathway includes p53 and loss of chromosome 9 and acquisition of other genetic abnormalities.

Question 12

Urothelial Carcinoma - Bladder

Answer 12

• In bladder, men > women.
• Lesions can be papillary
  
  • with noninvasive papillomas progressing to invasive papillary carcinoma.
• Lesion can also be flat (carcinoma in situ)
  
  • with progression to flat invasive carcinoma
• Other types of carcinoma may occur.
  
  • Squamous
    
    • Schistosomiasis
  • Adenocarcinoma
    
    • Urachal remnants or with extensive intestinal metaplasia
  • Small cell carcinoma
• Prognosis depends on grading and staging
  
  • Recurrence, progression, and mortality are higher with higher grade and stage.

Question 13

Type of tumor?

Answer 13

Urothelial Carcinoma - Bladder

• Image A - Papilloma
  
  • consisting of small papillary fronds lined by normal-appearing urothelium
• Image B - Low-grade papillary urothelial carcinoma
  
  • with an overall orderly appearance
  • with a thicker lining than papilloma
  • and scattered hyperchromatic nuclei and mitotic figures (arrows).
• Image C - High-grade papillary urothelial carcinoma
  
  • with marked cyto­logic atypia.
• Image D - High-grade invasive transitional cell carcinoma
  
  • at an advanced stage.
  • The aggressive multinodular neoplasm has fungated into the bladder lumen and spread over a wide area.
  • The yellow areas represent areas of ulceration and necrosis.
• Image E - Flat carcinoma in situ
  
  • with numerous cells having enlarged and pleomorphic nuclei.

Question 14

Urothelial Carcinoma - Bladder

Treatment?

Answer 14

• BCG instillation into bladder
  
  • for patients at high risk for recurrence or progression
• Transurethral resection
  
  • of small, low-grade, papillary tumors
• Radical cystectomy
  
  • for invasive, high-grade lesions
  • or lesions resistant to BCG
  • and those tumors extending into urethral/prostatic ducts
• Chemotherapy
  
  • for metastatic

Question 15

Wilms Tumor / Nephroblastoma

Answer 15

• Tumor of embryonal renal elements
• Most common primary tumor in children
  
  • peak incidence between 2 and 5 years.
  • Usually prior to 10 years of age.
• Most are unilateral.
  
  • 5-10% are bilateral
    
    • either simultaneously (synchronous)
    • or sequentially (metachronous).
    • Bilateral tumors occur earlier and suggest germline mutations.
• Pathogenesis
  
  • Most are sporadic.
  • Increased incidence with 3 groups of congenital abnormalities.
    
    1. WAGR (Wilms tumor, aniridia, genital anomalies, and mental retardation).
       
       • Deletions of 11p13
       • First hit is inherited; second hit is necessary.
       • WT1 is involved in regulation of other genes (e.g. IGF-II, E-cadherin, PDGF).
       • Most also show loss of heterozygosity at another locus on 11p (similar to area involved with BWS; see below.
    2. Denys-Drash syndrome
       
       • with gonadal dysgenesis (male pseudohermaphroditism) and early-onset nephropathy (diffuse mesangial sclerosis).
       • WT1 mutation affects DNA-biding properties.
       • Tumorgenesis requires bi-allelic inactivation of WT1
         
         • dominant negative inheritance
    3. Beckwith-Wiedemann syndrome (BWS)
       
       • has gigantism, organomegaly, macroglossia, hem hypertrophy, omphalocele, and/or abnormal large cells in adrenal cortex.
       • Associated with band 11p15.5 but exact gene has not been identified (“WT2”).
       • Often associated with imprinting.
• Beta-catenin and p53 mutations also occur (e.g. in sporadic cases)
• Nephrogenic rests are putative precursor lesions (i.e. hyperplastic to sclerotic rests)

Question 16

Type of tumor?

Answer 16

Wilms Tumor (nephroblastoma)

• Image A
  
  • Wilms tumor in the lower pole of the kidney with the characteristic tan-to-gray color and well-circumscribed margins
• Image B
  
  • tightly packed blue cells consistent with the blastemal componen
  • and interspersed primitive tubules representing the epithelial component.
• Image C
  
  • Focal anaplasia was present in other areas
  • hyperchromatic cells, pleomorphic nuclei, and abnormal mitoses.
• Image D
  
  • highly cellular areas composed of undifferentiated blastema (B
  • loose stroma (S) containing undifferentiated mesenchymal cells and immature tubules (T).
  • Note the many mitotic figures (arrows).
• Gross
  
  • usually unilateral, large, solitary at presentation
  • 10% bilateral or multicentric with higher incidence in familial tumors)
  • Soft, homogeneous, tan to gray
  • with occasional foci of hemorrhage, cyst formation or necrosis.
• Micro
  
  • Often undifferentiated and primitive
  • Attempt to recapitulate different stages of nephrogenesis
    
    • Blastemal – small blue cells
    • Stroma – fibrocytic or myxoid
    • Epithelial - abortive tubules
• 5% have anaplasia (with p53 mutations) and chemotherapy resistance