Kidney tumor
Adult renal cell carcinoma - common
Clear cell


Topic Completed: 20 April 2021

Minor changes: 20 April 2021

Copyright: 2003-2021, PathologyOutlines.com, Inc.

PubMed search: Clear cell renal cell carcinoma[title] kidney tumor review[ptyp]

Behtash G. Nezami, M.D.
Gregory MacLennan, M.D.
Page views in 2020: 57,665
Page views in 2021 to date: 26,179
Cite this page: Nezami BG, MacLennan G. Clear cell. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/kidneytumormalignantrccclear.html. Accessed May 11th, 2021.
Definition / general
  • Most common renal epithelial tumor, 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
  • Diverse architecture, primarily solid and nested
  • Clear or granular eosinophilic cytoplasm and prominent but delicate capillary network
  • Common molecular signature of VHL gene inactivation located on the short arm of chromosome 3 (3p25)
  • > 95% sporadic, mostly single mass, sixth to seventh decade
  • Small percentage familial, mostly VHL disease with multiple bilateral tumors with earlier onset
  • Characteristic immunohistochemical profile:
    • Positive for PAX8, CAIX (box-like), CD10
    • Negative for AMACR, CK7, CD117
ICD coding
  • ICD-O: 8310/3 - Clear cell renal cell carcinoma
Epidemiology
  • ~2% of all malignancies
  • 65 - 70% of all renal cell carcinomas
  • Most occur after age 40, predominantly in sixth and seventh decade
  • M > F = 1.5:1
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
  • Metastases:
    • Hematogenous more common: lung (most common), bone, liver, pleura, CNS, head and neck (J Urol 2008;179:474)
    • Lymphatic less common: hilar, aortic, caval and thoracic lymph nodes
    • Extension into the renal sinus the most common pathway of spread, usually involving extension within the renal vein
Pathophysiology
  • Arises in epithelial cells lining the proximal convoluted tubule
  • Loss of the VHL protein function, usually by deletion or unbalanced translocation, resulting in loss of 3p12-26
  • 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, metalloproteinases and erythropoietin (Surg Pathol Clin 2009;2:199)
Etiology
  • Risk factors: smoking, obesity, hypertension, long term dialysis (particularly in acquired adult cystic kidney disease) and family history of kidney cancer
  • Familial tumors: mostly von Hippel-Lindau disease (germline mutation of the VHL gene), less common in families segregating constitutional chromosome 3 translocations
  • Reference: Genet Couns 2003;14:149
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%
  • Reference: 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
  • CT: exophytic with mixed enhancement and heterogeneous appearance (due to internal necrosis, cystic change or hemorrhage)
  • MRI: similar accuracy to CT, heterogeneous in T1 and hyperintense T2
  • Ultrasonography: useful for incidental detection of renal masses
  • Reference: Radiology 2013;267:444
Prognostic factors
  • TNM staging: the most accurate predictor (see kidney tumor staging)
    • pT1 and pT2: limited to kidney, based on size (T1a ≤ 4cm < T1b ≤ 7cm < T2a ≤ 10cm < T2b)
    • pT3: regional spread
    • pT4: distant spread, beyond Gerota fascia
  • Worse prognosis within the same stage: higher histologic grade, sarcomatoid and rhabdoid differentiation
  • Coagulative tumor necrosis (> 10%) associated with shorter overall survival (Am J Surg Pathol 2013;37:1490, Am J Surg Pathol 2013;37:311, Pathology 2015;47:34)
  • 5 year survival: 50 - 70% after nephrectomy, 10% in metastatic disease
  • Clear cell RCC has worse prognosis than papillary and chromophobe RCC
  • Histologic grading:
    • WHO / ISUP grading system: 4 tiers, uses nucleolar prominence; used for clear cell and papillary renal cell carcinoma (chromophobe RCC not graded):
      • G1: nucleoli absent or inconspicuous and basophilic at 400x magnification
      • G2: nucleoli conspicuous and eosinophilic at 400x magnification and visible but not prominent at 100x magnification
      • G3: nucleoli are conspicuous and eosinophilic at 100x magnification
      • G4: extreme nuclear pleomorphism, multinucleated giant cells or rhabdoid or sarcomatoid differentiation (Urology 2014;83:969)
Case reports
Treatment
  • Surgical resection of stages 1 - 3 can be curative but up to 33% will recur
  • Systemic chemotherapy has limited efficacy
  • Immunotherapy with checkpoint inhibitors has 15 - 20% response rate: monoclonal antibodies against PD1 (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 PDGFR (sunitinib and sorafenib) and VEGF receptor (axitinib, sunitinib, pazopanib and bevacizumab) (Semin Oncol 2006;33:588, Surg Pathol Clin 2009;2:199)
  • 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 reflex sarcomatoid differentiation
  • Frequent involvement of renal vein and renal sinus
  • Bilateral and multicentric masses are features of hereditary disease
Gross images

Contributed by Gregory T. MacLennan, M.D.

Involving Gerota fascia

Confined T1b

Multifocal

In renal vein

In renal pelvis and vein

Variegated cut surface


Microscopic (histologic) description
  • Typically compact nests and sheets of cells with clear cytoplasm and distinct membrane
  • Tumor cells ~2x normal epithelial tubule cell
  • 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
  • Stroma: nondescript, no desmoplastic reaction (unlike collecting duct carcinoma or urothelial carcinoma) with little inflammatory response
  • Fibromyxoid stroma, calcification or ossification may be present
  • High grade feature:
    • Rhabdoid differentiation: large, high grade malignant cells with abundant homogeneous eosinophilic cytoplasm and eccentric nucleus globular eosinophilic intracytoplasmic inclusions
    • Sarcomatoid differentiation: may happen in any RCC subtype (Am J Surg Pathol 2004;28:435)
  • 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
Microscopic (histologic) images

Contributed by Gregory T. MacLennan, M.D.

ISUP grade 1

ISUP grade 2

ISUP grade 3

ISUP grade 4


Sinusoidal vasculature

Micro and macrocysts

In renal vein

In perirenal fat

Sarcomatoid


Sarcomatoid, pancytokeratin

Rhabdoid differentiation

Rhabdoid and sarcomatoid areas

Necrosis

Heterotopic bone formation

Virtual slides

Images hosted on other servers:

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 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 high grade

Positive stains
  • PAX8: ~100%, nuclear; PAX2 similar but less sensitive
  • CAIX: 75 - 100%, diffuse membranous (box-like), diminished expression in high grade regions (Am J Surg Pathol 2014;38:e35)
  • CD10 (82 - 94%, membranous) and RCC (72 - 84%, cytoplasmic and membranous): proximal tubular brush border antigens, also present in normal cells
  • Epithelial markers: AE1 / AE3, CAM 5.2, EMA
  • Vimentin (cytoplasm and membranous)
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 RCC
+
-
+ (cup-like)
+/-
-
+
+
+/-
-
-
+/-*
Chromophobe RCC
+
-/+
-
+/-
-
-
+
-
+
-
+/-
Oncocytoma
+
-/+
-
-
-
-
Focal
-
+
-/+
-
Angiomyolipoma
-
-
-/+
-
+
-/+
-
-
-
-
-
Collecting duct carcinoma
+
-
-/+
-
-
+
+/-
+
-
-
-
Tubulocystic carcinoma
+
+
+/-
+
-
+/-
-/+
-
-
+/-
-
Translocation RCC
+
+/-
-/+
+/-
+/-
+
-
-
-
+/-
-
MTSCC
+
-/+
-/+
+/-
-
+
+
-/+
-
+/-
-
Legend:
  • + = usually positive
  • - = usually negative
  • +/- = frequently positive
  • -/+ = occasionally positive

*Reference: Hum Pathol 2017;66:152
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
Molecular / cytogenetics description
  • Somatic:
    • 3p loss or biallelic alteration (mutation or hypermethylation of promoter region) in VHL tumor suppressor gene (3p25-26) in 80 - 98%
    • 3p locus harbors at least 4 other clear cell RCC tumor suppressor genes: KD-M6A (also called UTX), KDM5C (also called JARID1C), SETD2 and PBRM1 (Nature 2013;499:43)
    • Poor prognosis: allelic losses on chromosome 14q (40 - 60%), loss of 4p and 9p, loss of function mutations in the BAP1 gene; PBRM1 is also commonly mutated in clear cell RCC
    • Progression of clear cell RCC can eventually lead to polyploid karyotype and further losses or gains of genetic material
  • Familial:
    • Von Hippel-Lindau familial cancer syndrome:
      • 70% lifetime risk of developing renal tumors, autosomal dominant, early onset, 35 - 45% of patients develop bilateral multifocal clear cell RCC, as many as 1100 cysts and 600 microscopic clear cell RCCs (J Urol 2003;170:2163)
      • Patients are born with a germline defect in 1 of the 2 alleles of the VHL gene
      • Loss of the second allele results in clinical disease expression
    • Families segregating constitutional chromosome 3 translocations
Sample pathology report
  • Kidney, core needle biopsy:
    • Renal parenchyma involved by renal cell carcinoma, clear cell type (see comment)
    • Comment: Tumor cells show positive immunostaining for PAX8, CAIX and keratin CAM5.2. Scattered tumor cells show positive immunostaining for CK7.
  • Kidney, nephrectomy:
    • Renal cell carcinoma, clear cell type, ISUP grade 3, pathologic stage pT1a pNX (see cancer summary sheet)
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. Loss of chromosomes 1 and Y is observed in oncocytoma. Chromophobe RCC shows loss of 1 copy of chromosomes 1, 2, 6, 10, 13 and 17 in 85% of the tumors. Trisomy 7 and 17 and deletion of Y is associated with papillary renal cell carcinoma. Germline mutation of c-MET is seen in hereditary papillary RCC.

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. Minimum 10% of sarcomatoid tumor is required to make a diagnosis of sarcomatoid carcinoma
  3. PAX8 staining is specific for renal cell carcinomas
  4. Tends to be CK7 and CAIX positive
  5. They have worse prognosis than papillary renal cell carcinoma
Board review style answer #2
E. They have worse prognosis than papillary renal cell carcinoma. Clear cell RCC is generally CK7 negative, has worse prognosis than papillary renal cell carcinoma. PAX8 is not specific to renal tissue and is also positive in thyroid tissue. No minimum proportion of sarcomatoid tumor is required to make a diagnosis of sarcomatoid carcinoma.

Comment Here

Reference: Clear cell renal cell carcinoma
Board review style question #3
Which of the following intracellular contents results in typical golden yellow appearance of clear cell renal cell carcinoma?

  1. Hyaline globules
  2. Lipid
  3. Lysosomes
  4. Mitochondria
Board review style answer #3
B. Lipid. The golden yellow appearance of clear cell RCC is due to high lipid content of tumor cells. Abundant mitochondria are present in oncocytic tumor and chromophobe, hence the brown.

Comment Here

Reference: Clear cell renal cell carcinoma
Back to top
Image 01 Image 02