Kidney tumor
Adult renal cell carcinoma - common
Clear cell

Topic Completed: 1 October 2016

Minor changes: 8 February 2021

Copyright: 2003-2021,, Inc.

PubMed Search: Clear cell renal cell carcinoma[title]

Nicole K. Andeen, M.D.
Maria Tretiakova, M.D., Ph.D.
Page views in 2020: 57,665
Page views in 2021 to date: 10,494
Cite this page: Andeen NK, Tretiakova M. Clear cell. website. Accessed February 27th, 2021.
Definition / general
  • Morphologically heterogeneous group of renal carcinomas with clear or eosinophilic cytoplasm, characteristic vasculature and common molecular signature of VHL inactivation
Essential features
  • Architecturally and cytologically diverse: solid, alveolar, acinar, cystic growth patterns of cells with clear or eosinophilic cytoplasm
  • Characteristic network of small, thin walled, "chicken wire" vasculature
  • Inactivation of VHL and upregulation of hypoxia inducible factor (HIF) (WHO 2016)
  • Also called conventional / classic type
  • Historical names: hypernephroma, Grawitz tumor
  • 65 - 70% of adult renal cancers (WHO 2016)
  • When VHL gene is inactivated, the VHL protein complex cannot degrade HIF-1-alpha, a transcription factor
  • This drives transcription of hypoxia associated genes including VEGF, PDGF and GLUT1 (WHO 2016)
  • Proposed origin of tumor cells: proximal convoluted tubule
Clinical features
  • 60 - 80% are found incidentally on imaging
  • Metastases often hematogenous via renal veins: lung, liver, bone, soft tissue, adrenal
  • Risk factors: adult polycystic disease, smoking, obesity in women, hypertension, von Hippel-Lindau (VHL) disease, tuberous sclerosis (but not via VHL mutations, Mod Pathol 2002;15:205)
  • Both papillary and chromophobe have a better prognosis than clear cell RCC (Urology 2014;83:969)

von Hippel-Lindau disease:
  • Autosomal dominant syndrome with hemangioblastomas of retina and cerebellum, cysts of pancreas, liver and kidney, clear cell tumors of other sites, papillary cystadenoma of epididymis, pheochromocytoma
  • Associated with bilateral or multiple renal cell carcinomas in 50% (eMedicine - Imaging in Von Hippel-Lindau Syndrome)
Prognostic factors
  • Grading for Clear Cell RCC: Fuhrman classification is a 3 tiered system in which nuclear size, shape and nucleolar prominence are assessed simultaneously to assign a grade (see nuclear grading)
  • An ISUP Grading System based on nucleolar prominence appears to be a more powerful prognostic discriminator and has been recommended as a substitute (Urology 2014;83:969):
    • Grade 1: nucleoli inconspicuous or absent at 400× (objective magnification 40×)
    • Grade 2: nucleoli prominent at 400×
    • Grade 3: nucleoli prominent at 100× magnification
    • Grade 4: extreme nuclear pleomorphism, multinucleated giant cells, sarcomatoid and / or rhabdoid change

  • Histology: Sarcomatoid and rhabdoid differentiation have higher rates of tumor recurrence and metastasis and should be reported (Urology 2014;83:969)
    • Presence of rhabdoid differentiation should be reported
    • Sarcomatoid differentiation should be reported; the % area of sarcomatoid component should be reported

  • Necrosis: Coagulative tumor necrosis has an independent prognostic significance and should be reported, including the amount of necrosis present as a percentage (Am J Surg Pathol 2013;37:311, Am J Surg Pathol 2013;37:1490, Pathology 2015;47:34)
Case reports

  • Resection, IL2 therapy, targeted therapy
Gross description
  • Orange / yellow, circumscribed, hemorrhagic, necrotic, solid and cystic
  • Unifocal or multifocal
  • Frequent involvement of renal vein and renal sinus
  • Soft fleshy areas may herald sarcomatous component
  • Bilateral in 1% (usually with von Hippel-Lindau or tuberous sclerosis)
Staging / staging classifications
  • See also Staging topic
  • Perinephric fat invasion: either the tumor touching the fat or extending as irregular tongues into the perinephric tissue, with or without desmoplasia
  • Renal sinus invasion: when the tumor is in direct contact with the sinus fat or the loose connective tissue of the sinus, clearly beyond the renal parenchyma or if it involves any endothelium lined spaces within the renal sinus
    • If uncertain, at least 3 blocks of the tumor renal sinus interface should be submitted
  • Renal vein margin: margin is positive only when adherent tumor is visible microscopically at the actual margin
    • If it is submitted separately as “caval thrombus”, take 2 or more sections to look for adherent caval wall tissue
  • Uninvolved renal parenchyma: should be sampled, distant from tumor, for underlying tumor
  • Lymph nodes: should be sought, but are found in < 10% of radical nephrectomy specimens
  • Am J Surg Pathol 2013;37:1505
Gross images

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Clear cell renal cell carcinoma

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With leiomyosarcoma of renal vein

Microscopic (histologic) description
  • Compact, alveolar, tubulocystic or rarely papillary architecture of cells with clear cytoplasm (from lipid / glycogen), distinct but delicate cell boundaries; cell size is 2x normal epithelial tubule cell
  • Characteristic network of small, thin walled, "chicken wire" vasculature
  • May have angioleiomyomatous features (Am J Surg Pathol 2006;30:1372), smooth muscle stroma (Hum Pathol 2009;40:425), myospherulosis (Arch Pathol Lab Med 2000;124:1476), overlapping morphologic features of papillary carcinoma (Arch Pathol Lab Med 2003;127:1176)
  • Some tumors may have pseudopapillary architecture due to high grade changes and loss of cell cohesion (Am J Surg Pathol 2008;32:1780)
  • See Prognosis section for Grading, Histology subtypes and Necrosis
Microscopic (histologic) images

Contributed by Nicole K. Andeen, M.D. and Maria Tretiakova, M.D.
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Clear cell RCC entrapping glomeruli

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Clear cell RCC 10×

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Clear cell RCC grade 1

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Clear cell RCC grade 2

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Clear cell RCC grade 2 (right) and 4 (left)

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Clear cell RCC grade 3

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Clear cell RCC grade 4

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Clear cell RCC in fat

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Clear cell RCC renal sinus invasion

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Clear cell RCC metastasis to thyroid

Contributed by Gabriel B.W. Lerner, MS4, case #461

Clear cell RCC metastatic to the thyroid

CD10, 400x

RCC, 400x

Cytology images

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Atypical cells

Positive stains
Negative stains
IHC panels
 Hale  KIT  CK7  S100A1  VIM  CAIX  AMACR  SDH  TFE3
 Chromophobe RCC   +++   +++   +++   -   -   -   -   +++   - 
 Clear cell RCC   -   -   -   -   +++   +++   -   +++   - 
 Oncocytoma   -   +++   rare   +++   -   -   -   +++   - 
 Papillary RCC   -   -   +++   -   +++   -   +++   +++   - 
 Translocation RCC   -   -   -   -   -   -   ++   +++   +++ 
 SDH deficient RCC   -   -   -   -   -   -   -   -   - 

References: Pathol Res Pract 2015;211:303, Ann Diagn Pathol 2020;44:151448, Am J Surg Pathol 2014;38:e6, Arch Pathol Lab Med 2019;143:1455, Transl Androl Urol 2019;8:S123, Hum Pathol 2020 Jul 13 [Epub ahead of print]
Electron microscopy description
  • Abundant glycogen, well defined long microvilli similar to brush border of normal proximal tubules, numerous cell junctions
  • Variable fat, scant organelles, may have scant microvesicles
Molecular / cytogenetics description
  • Inactivation of VHL on 3p and upregulation of hypoxia inducible factor (HIF), by mutation, deletion, promotor hypermethylation or other
  • The VHL protein complex cannot degrade HIF-1-alpha, a transcription factor. This drives transcription of hypoxia associated genes including those encoding for VEGF, PDGF and GLUT1 (WHO 2016)
  • 3p locus also has at least 4 other CCRCC tumor suppressor genes: KD-M6A, KDM5C, SETD2 and PBRM1, which is part of the SWI / SNF chromatin remodeling complex (WHO 2016)
  • Also 5q21+ (70%), 14q− (41%)
  • BAP1 (role in chromatin remodeling) mutations are typically seen in high grade CCRCC and are associated with a poor outcome (WHO 2016)
Sample pathology report
  • Left kidney, partial nephrectomy:
    • Clear cell renal cell carcinoma, WHO/ISUP grade 3; see synoptic report.
    • Margins free of tumor.
  • Left renal mass, biopsy:
    • Clear cell renal cell carcinoma, WHO/ISUP grade 2 (see comment)
    • Comment: H&E stained slides reveal kidney parenchyma with a focus of infiltrative clear cell population comprised of bland looking single cells or small cohesive nests surrounded by rich capillary network. The tumor cells contain slightly eccentric nuclei with inconspicuous nucleoli visible only at high magnification. These cells are immunoreactive for CAIX, RCC and CD10, and negative for CK7 and CKIT (with positive internal controls). Taken together, the morphology and immunohistochemical profile are most consistent with conventional clear cell renal cell carcinoma.
Differential diagnosis
  • Papillary RCC with cytoplasmic clearing:
    • Papillary architecture, generally lacks “chicken wire” vasculature
    • Expresses CK7 and AMACR and is negative for CAIX
    • Clear cell RCC has opposite staining pattern (Am J Surg Pathol 2008;32:1780)
  • Chromophobe RCC:
    • Large cells with prominent “hard” cell border, “raisinoid” nuclei with perinuclear halo
    • Lacks “chicken wire” vasculature
    • Negative for CAIX and vimentin, positive for CK7 and CD117
    • Clear cell RCC has opposite staining pattern (Am J Surg Pathol 2014;38:e35)
  • Oncocytoma:
    • Nested architecture with myxoid / hyalinized stroma, cells with eosinophilic to granular cytoplasm and small round nuclei
    • Lacks “chicken wire” vasculature
    • CD117 positive, negative for vimentin and often negative for CD10
    • Clear cell RCC has opposite staining pattern (Arch Pathol Lab Med 2007;131:1290)
  • Clear cell papillary RCC:
    • More papillary architecture, low nuclear grade, generally lacks “chicken wire” vasculature
    • Has cup like CAIX positivity, rather than diffuse circumferential membranous
    • CK7 is positive in CCPRCC, but negative in clear cell RCC
  • Epithelioid angiomyolipoma (AML):
    • Characteristic abnormal AML vessels and smooth muscle
    • Expresses HMB45, Cathepsin K, but negative for CAIX, EMA and cytokeratins
  • MiT family tumors:
    • Express Cathepsin K, TFE3
    • Only variable focal CAIX, EMA and cytokeratins, unlike clear cell RCC
  • Note: clear cell renal cell carcinoma may have areas with abundant eosinophilic cytoplasm rather than clear, particularly high grade tumors; metastases are usually PAX8 and CAIX positive
Board review style question #1
Which of the following statements is true?

A. Metastases to the thyroid are a common finding
B. Most patients with thyroid metastases have no known primary
C. Melanoma is a common primary that metastasizes to the thyroid
D. PAX8 may be positive in both thyroid and renal tumors
Board review style answer #1
D. PAX8 may be positive in both thyroid and kidney tumors

Comment Here

Reference: Clear cell (conventional)
Board review style question #2

    How would you grade the above clear cell RCC using current WHO/ISUP grading system?

  1. Grade 2 because only conventional clear cell component should be graded (left side)
  2. Grade 3 as an average grade of conventional (left) and pleomorphic (right) components
  3. Grade 4 because of extreme nuclear pleomorphism (right side)
  4. Grade 4 because of rhabdoid dedifferentiation (right side)
Board review style answer #2
C. Grade 4 because of extreme nuclear pleomorphism (right side). There is no evidence of rhabdoid differentiation characterized by discohesive cells resembling rhabdomyoblasts due to eccentrically placed nuclei, prominent nucleoli and densely eosinophilic cytoplasm (Histopathology 2019;74:4).

Comment Here

Reference: Clear cell (conventional)
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