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Renal cell carcinoma - common

Clear cell


Behtash G. Nezami, M.D.
Gregory MacLennan, M.D.

Last author update: 2 May 2024
Last staff update: 25 June 2024

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PubMed search: Clear cell renal cell carcinoma

Behtash G. Nezami, M.D.
Gregory MacLennan, M.D.
Page views in 2024 to date: 146,666
Table of Contents
Definition / general | Essential features | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Frozen section description | Frozen section images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Cytology images | Positive stains | Negative stains | Electron microscopy description | Molecular / cytogenetics description | Molecular / cytogenetics images | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2
Cite this page: Nezami BG, MacLennan G. Clear cell. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/kidneytumormalignantrccclear.html. Accessed December 15th, 2024.
Definition / general
  • Most common renal epithelial tumor, accounting for ~2% of all malignancies, typically with clear cytoplasm and a compact nested or acinar growth pattern, intersected by delicate vasculature and with characteristic alterations to chromosome 3p involving VHL (von Hippel-Lindau) gene inactivation
Essential features
  • Cortical mass with golden yellow variegated cut surface, with diverse architecture, primarily solid and nested
  • Clear or granular eosinophilic cytoplasm and prominent but delicate capillary network
  • > 95% sporadic, mostly single mass, in the sixth to seventh decade, commonly harboring VHL gene inactivation located on the short arm of chromosome 3 (3p25)
  • Small percentage of tumors are familial, mostly VHL disease with multiple bilateral tumors and earlier onset
  • Characteristic immunohistochemical profile: positive for PAX8, CAIX (box-like) and CD10; generally negative for AMACR (35% positive), CK7 (15% positive) and CD117 (2% positive)
ICD coding
  • ICD-O: 8310/3 - clear cell renal cell carcinoma
Epidemiology
Sites
  • Kidney, typically solitary cortical mass in sporadic tumors
  • Multiple tumors may represent familial syndromes but retrograde venous extension from the dominant sporadic tumor is also possible
  • Renal sinus invasion is the most common pathway of spread, often accompanied by invasion of the renal vein or its segmental branches, leading to a higher risk of distant metastasis
  • Metastases
Pathophysiology
  • Suggested to arise in epithelial cells lining the proximal convoluted tubule (EBioMedicine 2023;92:104596, Annu Rev Pathol 2015;10:263)
  • Loss of the VHL protein function by a 2 step process in 50 - 82% of somatic clear cell renal cell carcinomas (ccRCC) leading to deletion, unbalanced translocation or biallelic alteration in VHL (von Hippel-Lindau) tumor suppressor gene (3p25-26)
  • First event of 3p loss, usually by chromothripsis, occurs in childhood or adolescence in a few hundred cells (Cell 2018;173:611)
  • Second allele undergoes somatic mutation or epigenetic inactivation through hypermethylation
  • VHL protein loss leads to accumulation of hypoxia inducible transcription factor alpha (HIF1α)
  • HIF1α accumulation drives transcription of hypoxia associated genes, including VEGF, PDFGβ, GLUT1, TGFα, CAIX, EPO and metalloproteinases (Surg Pathol Clin 2009;2:199)
  • Other driver mutations are present in smaller percentages (see Molecular / cytogenetics description)
Etiology
Clinical features
  • Most commonly: anemia, gross hematuria, flank pain and mass
  • Weight loss and fever in late stages
  • Classic triad of flank mass, pain and hematuria present in < 10% of cases (Urol Oncol 2002;7:135)
Diagnosis
  • 60 - 80% found incidentally on radiologic imaging
  • Nephrectomy or partial nephrectomy; definitive diagnosis may be possible by needle biopsy
Radiology description
  • Computed tomography (CT): exophytic with mixed enhancement and heterogeneous appearance (due to internal necrosis, cystic change or hemorrhage)
  • Bosniak classification (category I to IV) for renal cysts guides the management by approximating the risk of malignancy
  • Magnetic resonance imaging (MRI): similar accuracy to CT, heterogeneous in T1 and hyperintense (bright) T2 when use of contrast materials is contraindicated
  • In metastatic cases, MRI and positron emission tomography (PET / CT) are the preferred methods
  • Ultrasonography: useful for incidental detection of renal masses
  • Reference: Radiology 2013;267:444
Radiology images

Images hosted on other servers:
Left sided clear cell renal cell carcinoma (CT scan)   Left sided clear cell renal cell carcinoma (CT scan)

Left sided mass (CT scan)

Prognostic factors
  • 5 year survival: 50 - 70% after nephrectomy, 10% in metastatic disease
  • Survival difference is mostly due to differences in TNM stage and nuclear grade, regardless of the histologic type of the RCC (J Clin Oncol 2005;23:2763, Eur Urol 2005;48:593)
  • Worse prognosis within the same stage: higher histologic grade, sarcomatoid and rhabdoid differentiation and > 10% coagulative tumor necrosis (Pathology 2021;53:120, Am J Surg Pathol 2013;37:311, Pathology 2015;47:34)
  • Worse prognosis than papillary and chromophobe RCC
  • Better prognosis with only VHL loss or PBRM1 mutation, poor prognosis with multiple driver gene mutations or loss of 4p, 9p or 14q
  • BAP1 mutated ccRCCs have distinct morphologic and immunophenotypic features associated with more aggressive behavior than typical VHL only mutated ccRCC (Am J Clin Pathol 2021;155:718)
  • PBRM1 is mutually exclusive to BAP1 mutation and is associated with improved response to immunotherapy
  • TNM staging: the most accurate predictor (see Kidney tumor staging)
    • pT1 and pT2: limited to the kidney, classified based on size
      • T1a (≤ 4 cm)
      • T1b (> 4 cm to 7 cm)
      • T2a (> 7 cm to 10 cm)
      • T2b (> 10 cm)
    • pT3: regional spread beyond kidney parenchyma
      • pT3a: regional extrarenal spread into perinephric fat, renal sinus fat, involvement of the renal vein or segmental veins or invasion of the pelvicalyceal system
      • pT3b: extension into the inferior vena cava below the diaphragm
      • pT3c: tumor extension into the inferior vena cava above the diaphragm or invasion of the vena cava wall
    • pT4: distant spread, beyond Gerota fascia, including contiguous extension into the ipsilateral adrenal gland
  • Histologic grading
    • WHO / ISUP grading system: 4 tiers, uses nucleolar prominence; used for clear cell and papillary renal cell carcinoma (chromophobe RCC not graded)
      • G4: extreme nuclear pleomorphism, multinucleated giant cells or rhabdoid or sarcomatoid differentiation
      • G3: nucleoli are conspicuous and eosinophilic at 100x magnification
      • G2: nucleoli are conspicuous and eosinophilic at 400x magnification (but not prominent at 100x magnification)
      • G1: nucleoli are absent or inconspicuous and basophilic at 400x magnification (Urology 2014;83:969)
  • > 50% granular eosinophilic features may predict poor response to IL2 therapy (J Immunother 2005;28:488)
  • Clear cell RCCs with > 40% eosinophilic component may have worse clinical outcome (Mod Pathol 2015;28:S217)
Case reports
Treatment
  • Choice of treatment depends on the stage, overall patient health and other individualized factors
  • Surgical resection of stages 1 - 3 can be curative but up to 33% will recur
  • Partial nephrectomy for smaller and localized tumors; radical nephrectomy for tumors larger than 4 cm and centrally located tumors
  • Cryotherapy and radiofrequency ablation for unresectable tumors or some small tumors
  • Systemic chemotherapy has limited efficacy
  • Immunotherapy with checkpoint inhibitors has a 15 - 20% response rate: monoclonal antibodies against PD-1 (nivolumab and pembrolizumab), PDL1 (avelumab and atezolizumab) and CTLA4 (ipilimumab) (J Natl Compr Canc Netw 2019;17:587)
  • Inhibitors of mammalian target of rapamycin (mTOR) pathways (such as temsirolimus)
  • Tyrosine kinase inhibitors targeting VEGFR (including lenvatinib, axitinib and sunitinib), PDGFR or multitargeted (sorafenib, tivozanib, cabozantinib, lenvatinib and pazopanib) (Surg Pathol Clin 2009;2:199, Semin Oncol 2006;33:588)
  • Hypoxia inducible factor 2 alpha (HIF2α) inhibitor belzutifan for certain types of VHL disease associated tumors
  • Immune checkpoint inhibitors have shown significant response in ccRCC with sarcomatoid and rhabdoid features
  • Combined tyrosine kinase inhibitors and checkpoint inhibitors received Food and Drug Administration (FDA) approval for advanced RCCs (J Natl Compr Canc Netw 2022;20:71)
  • IL2 therapy: used less frequently
Gross description
  • Typically unilateral and unicentric renal cortical mass (average size: 7 cm)
  • Typically well circumscribed by a pseudocapsule and expansile pushing margin protruding from the renal cortex
  • Variegated solid and cystic with areas of fibrosis (gray) and recent or old hemorrhage (brown); necrosis and cystic changes are common
  • Golden yellow color due to high lipid content
  • Higher grade tumors may not be yellow due to less lipid and glycogen content
  • Soft fleshy areas may reflect sarcomatoid differentiation
  • Frequent involvement of renal vein and renal sinus
  • Bilateral and multicentric masses are features of hereditary disease
  • Notes on tumor staging
    • Tumors larger than 7 cm almost always invade renal sinus fat; if no invasion is seen in larger tumors, an additional gross review is warranted (Pathology 2021;53:120)
    • Capsular invasion
      • Disrupted and irregular advancement of tumor into the perirenal adipose tissue and loss of the smooth convex outer contour
      • Smooth bulging tumor covered by the cancer pseudocapsule is not considered perirenal fat involvement
      • Tumor cell should touch fat or extend irregular tongues into perinephric tissues, with or without desmoplasia (J Kidney Cancer VHL 2014;1:26)
    • Renal sinus invasion
      • Most common route of extrarenal spread
      • Usually happens before capsular invasion
      • Unlike renal capsule, the renal sinus is not delineated from the renal parenchyma by a fibrous capsule
      • Not regarded as true invasion if tumor is separated from sinus structures by a rim of renal parenchyma
      • Regarded as sinus invasion if tumor bulges into the renal sinus fat clearly beyond renal parenchyma, even if covered by loose connective tissue (J Kidney Cancer VHL 2014;1:26)
      • Tumor surrounding large lymphovascular structures is a sign of sinus fat invasion (Am J Surg Pathol 2004;28:1594, Am J Surg Pathol 2000;24:451)
    • Vascular invasion
      • May show as tumor nodules in renal sinus
      • In partially obliterate vessels, a single layer of endothelial lining overlying the tumor does not preclude vascular invasion
      • Small vein involvement usually implies large vein involvement
      • Renal sinus invasion usually implies renal vein invasion, cautious examination is warranted (J Urol 2005;174:1199)
Gross images

Contributed by Gregory T. MacLennan, M.D. and Behtash Nezami, M.D.
Involving Gerota fascia

Involving Gerota fascia (pT4)

Confined T1b

Confined T1b

Multifocal

Multifocal

In renal vein

In renal vein


invading sinus fat and pelvicalyceal system

Invading sinus fat and pelvicalyceal system

Variegated cut surface

Variegated cut surface

Cystic changes

Cystic changes

Frozen section description
  • Limited application in determining the subtype of renal cell carcinoma
  • Sometimes important to distinguish urothelial carcinoma from RCC
  • Characteristic findings on microscopy include clear cell cytoplasm, highly dense vascularization (chicken wire) and nested growth pattern
  • Sometimes only naked abnormal nuclei are present
Frozen section images

Contributed by Behtash Nezami, M.D.
Nests of large cells

Nests of large cells

Nested architecture and atypical cells

Nested architecture and atypical cells

Microscopic (histologic) description
  • Typically compact nests and sheets of cells with clear cytoplasm and distinct membrane
  • Granular eosinophilic cytoplasm observed in high grade tumors or near areas of hemorrhage or necrosis
  • Network of arborizing small, thin walled vessels (important diagnostic feature for cases with granular eosinophilic cytoplasm)
  • Architectural patterns: solid, alveolar (nested), acinar (tubular), microcystic (containing extravasated red blood cells or eosinophilic fluid) and occasionally macrocystic
  • Focal papillary architecture may be seen but prominent papillary formation raises the possibility of other subtypes (clear cell papillary renal cell tumor, TFE3 rearranged, TFEB altered, ELOC mutated RCC)
  • Stroma: nondescript, no desmoplastic reaction (unlike collecting duct carcinoma or urothelial carcinoma) with little inflammatory response
  • High grade features
    • Rhabdoid differentiation: large, high grade malignant cells with abundant homogeneous eosinophilic cytoplasm, eccentric nuclei and globular eosinophilic intracytoplasmic inclusions
    • Sarcomatoid differentiation: may happen in any RCC subtype (Am J Surg Pathol 2004;28:435)
    • Tumor necrosis
  • Uncommon histologic variations (unknown prognostic significance): cystic, pseudopapillary, heterotopic bone formation, intracellular and extracellular hyaline globules, basophilic cytoplasmic inclusions, abundant multinucleated giant cells, sarcoid-like granulomas or myospherulosis features (Hum Pathol 2014;45:735, Am J Clin Pathol 2023;160:603, Histopathology 2022;80:922)
  • BAP1 mutated ccRCC frequently shows papillary architecture, eosinophilic cytoplasm and cytoplasmic globules (Am J Clin Pathol 2021;155:718)
  • Practically, the lower grade areas of tumor with classic ccRCC histology are most helpful for diagnosis
  • Higher grade tumors can demonstrate overlapping features with other RCC types
Microscopic (histologic) images

Contributed by Gregory T. MacLennan, M.D., Behtash Nezami, M.D., Nicole K. Andeen, M.D. and Maria Tretiakova, M.D., Ph.D.
Sinusoidal vasculature

Sinusoidal vasculature

Micro and macrocysts

Micro and macrocysts

with renal capsule invasion

With renal capsule invasion

ISUP grade 1   ISUP grade 1

ISUP grade 1

ISUP grade 2

ISUP grade 2


ISUP grade 3

ISUP grade 3

ISUP grade 4

ISUP grade 4

In renal vein

In renal vein

In perirenal fat   In perirenal fat

In perirenal fat

Sarcomatoid

Sarcomatoid


Sarcomatoid

Sarcomatoid

Rhabdoid differentiation

Rhabdoid differentiation

Rhabdoid and sarcomatoid areas

Rhabdoid and sarcomatoid areas

Necrosis   Necrosis

Necrosis

heterotopic bone formation

Heterotopic bone formation


Clear cell RCC could have areas of eosinophilic cytoplasm mimicking other RCC sybtypes   Clear cell RCC could have areas of eosinophilic cytoplasm mimicking other RCC sybtypes   Clear cell RCC could have areas of eosinophilic cytoplasm mimicking other RCC sybtypes   Clear cell RCC could have areas of eosinophilic cytoplasm mimicking other RCC sybtypes   Clear cell RCC could have areas of eosinophilic cytoplasm mimicking other RCC sybtypes   Clear cell RCC could have areas of eosinophilic cytoplasm mimicking other RCC sybtypes

Clear cell RCC could have areas of eosinophilic cytoplasm mimicking other RCC sybtypes


intramural granulomatous reaction

Intramural granulomatous reaction

Involving pelvicalyceal system (pT3a)   Involving pelvicalyceal system (pT3a)

Involving pelvicalyceal system (pT3a)

CD10 IHC staining

CD10 IHC staining

CAIX IHC staining

CAIX IHC staining

Sarcomatoid, pancytokeratin

Sarcomatoid, pancytokeratin

Virtual slides

Images hosted on other servers:
Clear cell renal cell carcinoma   Clear cell renal cell carcinoma

Clear cell renal cell carcinoma

Cytology description
  • Cohesive nests of fairly uniform cells with pale cytoplasm, mixed with stromal components and capillaries
  • Numerous single cells
  • Well defined cell membranes, round central or eccentric nuclei
  • Prominent nucleoli in high grade
  • Intranuclear vacuoles are common
  • Pale, vacuolated or granular cytoplasm
  • Background with blood and necrosis is frequent
Cytology images

Contributed by Gregory T. MacLennan, M.D.
FNA cytology

FNA cytology

FNA high grade

FNA high grade

Positive stains
Negative stains

PAX8 CD10 CAIX RCC Melanocytic markers Vimentin CK7 HMWCK CD117 / KIT AMACR GATA3
Clear cell RCC + + + (box-like) + - + - - - -/+ -
Papillary RCC + + +/- + - + + - - + -
Clear cell papillary RCT + - + (cup-like) +/- - + + +/- - - +/-
Chromophobe RCC + -/+ - +/- - - + - + - +/-
Epithelioid angiomyolipoma - - -/+ - + -/+ - - - - -
Tubulocystic carcinoma + + +/- + - +/- -/+ - - +/- -
TFE3 rearranged / TFEB altered RCC + +/- -/+ +/- TFEB: +
TFE3: -/+ 		+ - - - +/- -
MTSCC + -/+ -/+ +/- - + + -/+ - +/- -
FH deficient RCC (FH loss and 2SC+) + - - - + - - - - -/+
TSC / mTOR / ELOC + + + - -/+ +/- - - +
Legend
  • + = usually positive
  • - = usually negative
  • +/- = frequently positive
  • -/+ = occasionally positive
Electron microscopy description
  • Variable cytoplasmic lipid droplets, scant organelles, microvesicles and glycogen
  • Evidence of tubular differentiation: well defined long microvilli typical of the brush border seen in normal proximal tubules
  • Numerous cell junctions
  • Eosinophilic granular cytoplasm due to increased number of large pleomorphic mitochondria
  • References: Ultrastruct Pathol 1987;11:483, Am J Surg Pathol 2000;24:1247
Molecular / cytogenetics description
  • VHL gene alteration in the majority of somatic cases
  • 3p locus also contains other tumor suppressor chromatin remodeling genes frequently associated with ccRCC: PBRM1 (in 30 - 40% of cases), BAP1 (6 - 10%) and SETD2 (7 - 11%) (Nature 2013;499:43, Clin Cancer Res 2013;19:3259, Nat Genet 2013;45:849, Nat Genet 2013;45:860)
  • Other driver alterations: mTOR pathway genes (TSC1, TSC2, MTOR, PIK3CA and PTEN), TP53, loss of 4p, 9p or 14q, mostly occurring in association with VHL alterations as subclonal drivers
  • Progression of ccRCC leads to a polyploid karyotype and further gains or losses of genetic material, contributing to disease progression and aggressiveness
  • Von Hippel-Lindau familial cancer syndrome
    • High risk of developing renal tumors
    • Patients born with a germline defect in 1 of the 2 alleles of the VHL gene
    • Loss of the second functioning allele (a second hit) leads to the development of clinical disease and tumor formation
    • Autosomal dominant inheritance pattern
    • Tends to manifest at an early age with a lifetime risk of developing renal tumors of ~70%
    • Bilateral multifocal ccRCC in 35 - 45% of patients
    • As many as 1,100 cysts and 600 microscopic ccRCC foci have been reported (J Urol 2003;170:2163)
  • Other familial syndromes (see Etiology)
Molecular / cytogenetics images

Contributed by Behtash Nezami, M.D.
genetic alterations

Genetic alterations

Sample pathology report
  • Kidney, core needle biopsy:
    • Clear cell renal cell carcinoma (see comment)
    • Comment: Tumor cells show positive immunostaining for PAX8, CAIX and keratin CAM 5.2. CK7 is negative arguing against clear cell papillary renal cell tumor.

  • Kidney, radical nephrectomy:
    • Clear cell renal cell carcinoma, WHO / ISUP grade 3, measuring 2.5 cm in greatest dimension (see comment)
    • Tumor is confined within the renal capsule.
    • All surgical margins are negative for carcinoma.
    • See cancer summary report.
    • Comment: Immunohistochemical stains are positive for PAX8, CAIX (box-like pattern) and CD10, supportive of this diagnosis.
Differential diagnosis
Board review style question #1


Which chromosomal abnormality is most often associated with clear cell renal cell carcinoma?

  1. Deletion of Y and trisomy 7 and 17
  2. Germline mutation of c-MET
  3. Loss of 1 copy of chromosomes 1, 2, 6, 10, 13 and 17
  4. Loss of chromosomes 1 and Y
  5. Loss of short arm of chromosome 3
Board review style answer #1
E. Loss of short arm of chromosome 3. Clear cell RCC is associated with losses in short arm of chromosome 3. Answer A is incorrect because trisomy 7 and 17 and deletion of Y is associated with papillary renal cell carcinoma. Answer B is incorrect because germline mutation of c-MET is seen in hereditary papillary RCC. Answer C is incorrect because chromophobe RCC shows loss of 1 copy of chromosomes 1, 2, 6, 10, 13 and 17 in 85% of the tumors. Answer D is incorrect because loss of chromosomes 1 and Y is observed in oncocytoma.

Comment Here

Reference: Clear cell renal cell carcinoma
Board review style question #2
Which of the following statements regarding clear cell renal cell carcinoma is true?

  1. Associated with trisomies of 7 and 17
  2. Has a worse prognosis than papillary renal cell carcinoma
  3. Minimum of 10% of sarcomatoid tumor is required to make a diagnosis of sarcomatoid carcinoma
  4. PAX8 staining is specific for renal cell carcinomas
  5. Tends to be CK7 and CAIX positive
Board review style answer #2
B. Has a worse prognosis than papillary renal cell carcinoma. ccRCC has a worse prognosis than papillary and chromophobe RCC. Answer A is incorrect because trisomy 7 and 17 along with loss of chromosome Y are features of papillary RCC. Answer C is incorrect because no minimum proportion of sarcomatoid tumor is required to make a diagnosis of sarcomatoid carcinoma. Answer D is incorrect because PAX8 is not specific to renal tissue and carcinomas and is also positive in thyroid tissue. Answer E is incorrect because clear cell RCC is generally CK7 negative, although weak focal staining can be seen in a small percentage.

Comment Here

Reference: Clear cell renal cell carcinoma
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