Kidney tumor
Adult renal cell carcinoma - common
Clear cell
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PubMed search: Clear cell renal cell carcinoma
Table of Contents
Definition / general | Essential features | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Prognostic factors | Case reports | Treatment | Gross description | Gross images | 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 | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2 | Board review style question #3 | Board review style answer #3Cite this page: Nezami BG, MacLennan G. Clear cell. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/kidneytumormalignantrccclear.html. Accessed October 2nd, 2023.
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)
- WHO / ISUP grading system: 4 tiers, uses nucleolar prominence; used for clear cell and papillary renal cell carcinoma (chromophobe RCC not graded):
Case reports
- 41, 55 and 68 year old men with clear cell RCC metastasis that significantly decreased in size or resolved with no surgical or other types of treatment (Case Rep Oncol 2020;13:1285)
- 52 year old man with a metastatic clear cell RCC to the forearm without an identifiable primary renal mass (Urol Case Rep 2019;27:100989)
- 63 year old man with 15 cm clear cell RCC with syncytial giant cells (Arch Pathol Lab Med 2004;128:1435)
- 65 year old man with a 2.4 cm tumor with nonnecrotizing sarcoidal-like granulomata (Clin Pathol 2020;13:2632010X20954215)
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
Frozen section images
Contributed by Debra L. Zynger, M.D.
Nests of large cells
Vacuolated cytoplasm
Nuclear atypia
Tumor cell are difficult to identify
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. and Debra L. Zynger, M.D.
FNA cytology
FNA high grade
Diff Quik preparation
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
- CK7: may be focally positive or patchy in high grade areas or cystic components
- 34 beta E12
- CK20 (Am J Surg Pathol 2014;38:e35)
- AMACR
- CD117
- Cathepsin K
- TFE3
- HMB45
- MelanA
- Inhibin
| | | | | | | | | | | | |
| Clear cell RCC | |||||||||||
| Papillary RCC | |||||||||||
| Clear cell papillary RCC | |||||||||||
| Chromophobe RCC | |||||||||||
| Oncocytoma | |||||||||||
| Angiomyolipoma | |||||||||||
| Collecting duct carcinoma | |||||||||||
| Tubulocystic carcinoma | |||||||||||
| Translocation RCC | |||||||||||
| MTSCC | |||||||||||
Legend:
*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
- Von Hippel-Lindau familial cancer syndrome:
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
- Papillary RCC with cytoplasmic clearing:
- Papillary architecture, lacks prominent delicate "chicken wire" vasculature
- Positive for CK7 and AMACR; negative for CAIX (opposite staining pattern to clear cell RCC) (Am J Surg Pathol 2008;32:1780)
- Multilocular cystic renal neoplasm of low malignant potential
(MCRNLMP):
- Clear cells lining the thin fibrous septa of multiple cystic spaces or within the fibrous septa
- Uncommon, usually lower grade associated with an excellent prognosis
- Absence of expansile solid nodules
- Similar IHC staining pattern to clear cell RCC but more commonly CK7 positive and less often CD10 positive (Am J Surg Pathol 2012;36:1425)
- Chromophobe RCC:
- Circumscribed mass with a homogeneous light tan cut surface
- Large cells with sharply defined hard cell border, finely reticulated cytoplasm, irregular nuclear border (raisinoid) and perinuclear halo
- Lack "chicken wire" vasculature
- Positive for CK7, E-cadherin; CD117; negative for CAIX and vimentin (opposite staining pattern to clear cell RCC) (Am J Surg Pathol 2014;38:e35)
- Oncocytoma:
- Clear cell papillary RCC:
- Low grade tumor cells with clear cytoplasm
- Well circumscribed, with variable papillary, tubular, acinar and cystic architecture
- Characteristically polarized luminal nuclear arrangement ("piano key") away from the basement membrane and cup-like CAIX positivity, rather than diffuse box-like membranous pattern in clear cell renal cell carcinoma
- Lack "chicken wire" vasculature
- Diffusely positive for CK7 and negative for CD10 (opposite staining pattern to clear cell RCC)
- Most tumors present as pT1 stage with excellent clinical outcome
- Lack foamy macrophages and necrosis (opposite to papillary RCC)
- Epithelioid angiomyolipoma (AML):
- Characteristic abnormal AML vessels and smooth muscle
- Positive for HMB45, cathepsin K
- Negative for CAIX, EMA and cytokeratins
- MiT family translocation renal cell carcinomas:
- Mostly children and young adults
- High grade nuclei and eosinophilic (not clear) cytoplasm
- Xp11 or 6p21 translocation RCC
- Positive for TFE3 or TFEB, cathepsin K, CD10, AMACR and variable focal CAIX, EMA and cytokeratins (opposite to clear cell RCC)
- Adrenal cortical carcinoma:
- Clear cell carcinoma of the ovary:
- Positive for keratin 34 beta E12 and CK7
- Clear cell carcinoma of the thyroid:
- Positive for thyroglobulin and TTF1
- PAX8 is positive in both
- Mesothelioma:
- Positive for calretinin, mesothelin and CK5/6
- Hemangioblastoma:
Board review style question #1
Which chromosomal abnormality is most often associated with clear cell renal cell carcinoma?
- Deletion of Y and trisomy 7 and 17
- Germline mutation of c-MET
- Loss of 1 copy of chromosomes 1, 2, 6, 10, 13 and 17
- Loss of chromosomes 1 and Y
- 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.
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Reference: Clear cell renal cell carcinoma
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Board review style question #2
Which of the following statements regarding clear cell renal cell carcinoma is true?
- Associated with trisomies of 7 and 17
- Minimum 10% of sarcomatoid tumor is required to make a diagnosis of sarcomatoid carcinoma
- PAX8 staining is specific for renal cell carcinomas
- Tends to be CK7 and CAIX positive
- 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.
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Board review style question #3
Which of the following intracellular contents results in typical golden yellow appearance of clear cell renal cell carcinoma?
- Hyaline globules
- Lipid
- Lysosomes
- 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.
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