Kidney tumor

• Emerging subtype of renal cell carcinoma (RCC) with abundant eosinophilic cytoplasm and solid / cystic growth, not yet recognized in the 2013 International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia or the updated 2016 World Health Organization (WHO) renal tumor classification (Am J Surg Pathol 2013;37:1469, Eur Urol 2016;70:93)

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• Typically display indolent behavior
• May rarely be locally aggressive or metastasize
  • Lymph node (Histopathology 2018;72:1066)
  • Liver (Histopathology 2018;72:588)
  • Lung (Histopathology 2018;72:588)
  • Bone (Hum Pathol 2018;80:65)

• 33 and 65 year old women with loss of function mutations in TSC2 (Am J Surg Pathol 2018;42:911)
• 69 year old woman with metastasis to renal hilar lymph node (Histopathology 2018;72:1066)

Case series:

• 4 cases (3 women, 1 man; ages 27 - 50) including 1 with bone metastases and 1 with locally aggressive disease (Hum Pathol 2018;80:65)
• 6 cases (all women; ages 42 - 66), all with deleterious mutations in either TSC1 or TSC2 (biallelic alterations in 2 cases) (Am J Surg Pathol 2018;42:1166)
• 10 cases (all women; ages 32 - 85) including 1 case with multifocal disease (Am J Surg Pathol 2017;41:1299)
• 10 cases (6 women, 4 men; ages 14 - 35) including 4 cases with multifocal lesions (1 bilateral), 1 case with metastatic disease to the liver and lung and 1 case with history of sickle cell trait (Histopathology 2018;72:588)
• 16 cases, all solitary sporadic neoplasms with indolent behavior occurring in women (ages 31 - 75) (Am J Surg Pathol 2016;40:60)

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• Tuberous sclerosis complex (TSC) associated RCC:
  • Clinical diagnosis of tuberous sclerosis complex
    • Highly penetrant autosomal dominant genetic disorder with variable expressivity
    • Infantile spasms or seizures (most frequent clinical manifestation, Arch Dis Child 2011;96:1020)
    • Updated 2012 clinical diagnostic criteria for TSC (Pediatr Neurol 2013;49:243)
      • Major features: 1) ≥ 3 angiofibromas or fibrous cephalic plaque; 2) ≥ 2 ungual fibromas; 3) ≥ 3 hypomelanotic macules; 4) shagreen patch; 5) multiple retinal hamartomas; 6) cortical dysplasias including tubers and cerebral white matter radial migration lines; 7) subependymal nodules; 8) subependymal giant cell tumor; 9) cardiac rhabdomyoma; 10) lymphangioleiomyomatosis; 11) ≥ 2 angiomyolipomas
      • Minor features: 1) "confetti" skin lesions; 2) ≥ 3 dental enamel pits; 3) ≥ 2 intraoral fibromas; 4) retinal achromic patch; 5) multiple renal cysts; 6) nonrenal hamartomas
      • Definite diagnosis: 2 major features or 1 major feature with ≥ 2 minor features
      • Possible diagnosis: either 1 major feature or ≥ 2 minor features
    • Updated 2012 genetic diagnostic criteria for TSC (Pediatr Neurol 2013;49:243)
      • Either a TSC1 or TSC2 pathogenic mutation (i.e. deleterious or loss of function) in DNA from normal tissue (definite diagnosis)
    • De novo mutations (69 - 83%, mostly TSC2) (Sci Rep 2017;7:16697, Eur J Pediatr 2002;161:393, Genet Med 2007;9:88)
  • Renal cell carcinoma in tuberous sclerosis complex (2 - 4% of patients, Kidney Int 2006;70:1777)
    • TSC2 mutations > TSC1 mutations
    • May coexist with angiomyolipoma (most common tuberous sclerosis complex renal neoplasm)
    • Bilateral or multifocal (± heterogeneous morphologies, synchronous or metachronous)
    • Concurrent renal cysts (common, background kidney)
      • Lined by cells with prominent eosinophilic cytoplasm and round nuclei with prominent nucleoli
      • Prominent cyst formation
        • May indicate autosomal dominant polycystic kidney disease
        • Corresponds to large deletion extending from TSC2 into adjacent PKD1 gene on chromosome 16p (may require alternative molecular testing for detection)
    • Various histologic types
      • Granular eosinophilic macrocystic morphology (11%): morphologically similar to sporadic eosinophilic, solid and cystic RCC (Am J Surg Pathol 2014;38:1457, Int J Surg Pathol 2010;18:409)
      • Hybrid oncocytic / chromophobe tumor (HOCT) (chromophobe-like or oncocytoma-like) (59%) (Am J Surg Pathol 2014;38:1457, Am J Surg Pathol 2014;38:895)
      • Renal angiomyoadenomatous tumor (RAT-like), RCC with angioleiomyoma-like stroma or RCC with a tubulopapillary architecture and clear cytoplasm separated by smooth muscle stroma (30%, Am J Surg Pathol 2014;38:1457, J Pathol Clin Res 2018;4:167)
      • Clear cell RCC
• RCC postneuroblastoma:
  • Prior history of neuroblastoma
  • Various subtypes
    • Oncocytoid: morphologically similar to sporadic eosinophilic, solid and cystic RCC (Am J Surg Pathol 2016;40:989, Am J Surg Pathol 2018;42:1166, Am J Surg Pathol 1999;23:772)
    • Hybrid oncocytic chromophobe tumor (HOCT)
    • Clear cell RCC
    • Papillary RCC-like
    • MiT family translocation RCC
• TSC2 or MTOR mutated sporadic RCC with eosinophilic and vacuolated cytoplasm (Am J Surg Pathol 2019;43:121):
  • 7 reported cases (Am J Surg Pathol 2019;43:121)
    • Well circumscribed, unencapsulated solitary renal mass
    • M = F
    • Mean age at presentation, 54 years
    • Nested growth pattern with dispersed single cells, extreme vacuolization and thick walled vessels
    • CK7- / CK20-
    • Cathepsin K+ in most cases
    • Inactivating mutations of TSC2 or activating mutations of MTOR
  • May be related to eosinophilic, solid and cystic RCC
• High grade oncocytic tumor (HOT) (Virchows Arch 2018;473:725):
  • 14 reported cases (Virchows Arch 2018;473:725)
    • F > M
    • Median age, 50 years (range, 25 - 73)
    • Well circumscribed and unencapsulated
    • Predominantly nested growth pattern in a background of loose fibromatous oncocytoma-like stroma
    • Entrapped nonneoplastic renal tubules and prominent thick walled vessels at the periphery
    • Voluminous, variably granular cytoplasm with large cytoplasmic vacuoles or inclusions of flocculent eosinophilic material
    • Distinct cell membranes
    • Rounded nuclear contours with conspicuous nucleoli
    • CD117+ in most cases
    • CK7 and CK20 negative to focally positive
    • Cathepsin K+ / CD10+ in most cases
    • Molecular characterization limited with no sequencing data available; possibly related to TSC2 or MTOR mutated sporadic RCC with eosinophilic and vacuolated cytoplasm (see above)
• MiT family translocation RCC:
  • Nuclear TFE3+ (using antibody to the C terminal portion of TFE3) or nuclear TFEB+, HMB45±
  • Fluorescence in situ hybridization (FISH) positive for Xp11 or t(6;11) translocation
• Epithelioid angiomyolipoma:
  • PAX8-, HMB45+, CK7-, CK20-, PanCK-
• Papillary RCC, solid variant, oncocytic type:
  • CK7+, CK20-
• SDH deficient RCC:
  • SDHB-, CK20-
• Chromophobe RCC, eosinophilic type:
  • CD117+, CK7+, CK20-
• Clear cell RCC, eosinophilic morphology:
  • CAIX+, CK20-

Which of the following immunoprofiles would support the diagnosis of this kidney lesion an eosinophilic, solid and cystic RCC and distinguish it from an epithelioid angiomyolipoma?

1. Diffusely CD117+ / diffusely CK7+ / CK20-
2. PAX8+ / CK20+ / CD117-
3. SDHB- / PAX8+ / vimentin-
4. TFE3+ / TFEB- / HMB45+

B. PAX8+ / CK20+ / CD117-. This is an eosinophilic, solid and cystic (ESC) renal cell carcinoma. ESC RCCs are consistently immunoreactive for PAX8, frequently CK20+ (74% of cases, may be focal) and usually CK7- / CD117- (may be focal but never diffuse). Epithelioid angiomyolipomas, on the other hand, are typically negative for PAX8 and CK20 and positive for CD117. Both entities would be negative for strong nuclear TFE3 and show intact SDHB expression.

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Reference: Eosinophilic, solid and cystic renal cell carcinoma

Eosinophilic, solid and cystic (ESC) renal cell carcinoma is most frequently associated with genetic alterations in which gene(s)?

1. FLCN
2. SDHB
3. TSC1 / 2
4. VHL

C. TSC1 / 2

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Reference: Eosinophilic, solid and cystic renal cell carcinoma