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Clear cell renal cell carcinoma (view source)

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#redirect [[Kidney_tumours#Clear_cell_renal_cell_carcinoma]]
{{ Infobox diagnosis
| Name      = {{PAGENAME}}
| Image      = Clear cell renal cell carcinoma - 2 -- high mag.jpg
| Width      =
| Caption    = Clear cell renal cell carcinoma. [[H&E stain]].
| Synonyms  = conventional renal cell carcinoma
| Micro      = solid or [[trabecular]] pattern, polygonal cells usually with clear cytoplasm (may be eosinophilic - esp. in high grade tumours), central nucleus, delicate branching vasculature (chicken wire-like), +/-hyaline bodies
| Subtypes  =
| LMDDx      = [[chromophobe renal cell carcinoma]], [[clear cell papillary renal cell tumour]], [[Xp11.2 translocation carcinoma]], [[ELOC-mutated renal cell carcinoma]], [[renal cell carcinoma with fibromyomatous stroma]], [[benign clear cell clusters of the kidney]], [[alveolar soft part sarcoma]], [[adrenocortical carcinoma]], [[hemangioblastoma of the kidney]]
| Stains    = PAS +ve, PAS-D -ve, [[Hale's colloidal iron stain]] -ve
| IHC        = [[CA9]] +ve, CK7 -ve, CK20 -ve, TFE3 -ve, PAX8 +ve, vimentin +ve
| EM        =
| Molecular  =
| IF        =
| Gross      = golden/yellow colour, +/-hemorrhagic, +/-cystic, +/-[[necrosis]]
| Grossing  = [[total nephrectomy for tumour grossing]], [[partial nephrectomy grossing]]
| Staging    = [[kidney cancer staging]]
| Site      = [[kidney]] - see [[kidney tumours]]
| Assdx      =
| Syndromes  = [[von Hippel-Lindau syndrome]], familial clear cell renal cell carcinoma
| Clinicalhx =
| Signs      = +/-hematuria, +/-abdominal mass
| Symptoms  =
| Prevalence = common
| Bloodwork  =
| Rads      = renal mass
| Endoscopy  =
| Prognosis  = good-to-poor - dependent on stage and grade
| Other      =
| ClinDDx    = other [[renal tumours]]
| Tx        = surgery, targeted therapies, other drugs
}}
'''Clear cell renal cell carcinoma''', abbreviated '''CCRCC''', is the most common type of [[renal cell carcinoma]].
 
It is also known as '''conventional renal cell carcinoma''' (abbreviated '''CRCC''').
 
==General==
*Most common subtype of [[RCC]].
*May be associated with [[Von Hippel-Lindau syndrome]].
*Familial clear cell renal cell carcinoma<ref name=pmid23972705>{{Cite journal  | last1 = Keefe | first1 = SM. | last2 = Nathanson | first2 = KL. | last3 = Rathmell | first3 = WK. | title = The molecular biology of renal cell carcinoma. | journal = Semin Oncol | volume = 40 | issue = 4 | pages = 421-8 | month = Aug | year = 2013 | doi = 10.1053/j.seminoncol.2013.05.006 | PMID = 23972705 }}</ref> - usually VHL gene mutation.<ref name=pmid17205537>{{Cite journal  | last1 = Foster | first1 = RE. | last2 = Abdulrahman | first2 = M. | last3 = Morris | first3 = MR. | last4 = Prigmore | first4 = E. | last5 = Gribble | first5 = S. | last6 = Ng | first6 = B. | last7 = Gentle | first7 = D. | last8 = Ready | first8 = S. | last9 = Weston | first9 = PM. | title = Characterization of a 3;6 translocation associated with renal cell carcinoma. | journal = Genes Chromosomes Cancer | volume = 46 | issue = 4 | pages = 311-7 | month = Apr | year = 2007 | doi = 10.1002/gcc.20403 | PMID = 17205537 }}</ref>
**VHL gene not mutated in all cases.<ref name=pmid10807693>{{Cite journal  | last1 = Woodward | first1 = ER. | last2 = Clifford | first2 = SC. | last3 = Astuti | first3 = D. | last4 = Affara | first4 = NA. | last5 = Maher | first5 = ER. | title = Familial clear cell renal cell carcinoma (FCRC): clinical features and mutation analysis of the VHL, MET, and CUL2 candidate genes. | journal = J Med Genet | volume = 37 | issue = 5 | pages = 348-53 | month = May | year = 2000 | doi =  | PMID = 10807693 }}</ref>
 
Treatment:
*Surgery.
*Various drugs.
*Targeted therapies.
**[[Tyrosine kinase inhibitors]] (e.g. [[sunitinib]], sorafenib).<ref name=pmid25467013>{{Cite journal  | last1 = Elaidi | first1 = R. | last2 = Harbaoui | first2 = A. | last3 = Beuselinck | first3 = B. | last4 = Eymard | first4 = JC. | last5 = Bamias | first5 = A. | last6 = De Guillebon | first6 = E. | last7 = Porta | first7 = C. | last8 = Vano | first8 = Y. | last9 = Linassier | first9 = C. | title = Outcomes from second-line therapy in long-term responders to first-line tyrosine kinase inhibitor in clear-cell metastatic renal cell carcinoma. | journal = Ann Oncol | volume = 26 | issue = 2 | pages = 378-85 | month = Feb | year = 2015 | doi = 10.1093/annonc/mdu552 | PMID = 25467013 }}</ref><ref name=pmid21484781>{{Cite journal  | last1 = Verma | first1 = J. | last2 = Jonasch | first2 = E. | last3 = Allen | first3 = P. | last4 = Tannir | first4 = N. | last5 = Mahajan | first5 = A. | title = Impact of tyrosine kinase inhibitors on the incidence of brain metastasis in metastatic renal cell carcinoma. | journal = Cancer | volume = 117 | issue = 21 | pages = 4958-65 | month = Nov | year = 2011 | doi = 10.1002/cncr.26138 | PMID = 21484781 }}</ref>
**Anti-VEGF antibodies (e.g. bevacizumab).<ref name=pmid21330923>{{Cite journal  | last1 = Singer | first1 = EA. | last2 = Gupta | first2 = GN. | last3 = Srinivasan | first3 = R. | title = Update on targeted therapies for clear cell renal cell carcinoma. | journal = Curr Opin Oncol | volume = 23 | issue = 3 | pages = 283-9 | month = May | year = 2011 | doi = 10.1097/CCO.0b013e32834479c0 | PMID = 21330923 }}</ref>
 
==Gross==
Features:
*Golden/yellow colour.
*+/-Haemorrhage (common).
*+/-Necrosis (common in large tumours).
*+/-Calcification.
*+/-Cysts.
*Usually unifocal. ‡
 
Note:
*‡ Approximately 4% of CCRCCs are multifocal (based on a set of 5378 patients).<ref name=pmid22502873>{{Cite journal  | last1 = Siracusano | first1 = S. | last2 = Novara | first2 = G. | last3 = Antonelli | first3 = A. | last4 = Artibani | first4 = W. | last5 = Bertini | first5 = R. | last6 = Carini | first6 = M. | last7 = Carmignani | first7 = G. | last8 = Ciciliato | first8 = S. | last9 = Cunico | first9 = SC. | title = Prognostic role of tumour multifocality in renal cell carcinoma. | journal = BJU Int | volume = 110 | issue = 11 Pt B | pages = E443-8 | month = Dec | year = 2012 | doi = 10.1111/j.1464-410X.2012.11121.x | PMID = 22502873 }}</ref>
 
===Image===
<gallery>
Image:Renal cell carcinoma.jpg | CCRCC. (WC/euthman)
</gallery>
 
==Microscopic==
Features:<ref name=Ref_PBoD1017-8>{{Ref PBoD|1017-8}}</ref>
*Clear cytoplasm.
**May have eosinophilic cytoplasm (in high-grade tumours) - usually focal.
*Delicate branching vasculature - '''key feature'''.
**Often called "chicken wire-like" vasculature.
*Solid or [[trabecular]] pattern.
*Polygonal cells.
*Central nucleus.
*+/-[[Renal cell carcinoma with rhabdoid morphology|Rhabdoid cells]]:
**Eccentric nucleus.
**Abundant eosinophilic cytoplasm.
 
Notes:
*Cytoplasm may be eosinophilic.<ref name=Ref_WMSP291>{{Ref WMSP|291}}</ref>
**This change is typically focal - other areas have a classic appearance.
**Chicken wire-like vasculature present - helps distinguish from other tumours.
*[[Hyaline bodies]] common.<ref>AFIP Renal Tumours Book.</ref>
**Not common in papillary RCC.
*Clear cytoplasm - due to lipid content.
*[[Necrosis]] is independent predictor of outcome - if present in a significant quantity:<ref name=pmid25474516>{{Cite journal  | last1 = Renshaw | first1 = AA. | last2 = Cheville | first2 = JC. | title = Quantitative tumour necrosis is an independent predictor of overall survival in clear cell renal cell carcinoma. | journal = Pathology | volume = 47 | issue = 1 | pages = 34-7 | month = Jan | year = 2015 | doi = 10.1097/PAT.0000000000000193 | PMID = 25474516 }}</ref>
**>30% is significant for pT3a tumours.
**>20% is significant for pT1-2 pN0 tumours.
 
DDx:
*[[Chromophobe renal cell carcinoma]].
**Chromophobe: "translucent" (NOT quite clear), reticulated, Hale's colloidal iron stain+, CK7+ (cell membrane).
*[[Clear cell papillary renal cell tumour]].
*[[ELOC-mutated renal cell carcinoma]].
*[[Xp11.2 translocation carcinoma]].
*[[Adrenocortical carcinoma]] (ACC).
**EMA -ve, CKs mostly -ve, inhibin +ve (neg. in RCC).<ref name=Ref_GUP285>{{Ref GUP|285}}</ref>
*[[Alveolar soft part sarcoma]].
*[[Adrenal gland]], normal cortex - wispy, vacuolated.
*[[Epithelioid angiomyolipoma]].
*[[Benign clear cell clusters of the kidney]].
*[[Renal cell carcinoma with fibromyomatous stroma]].
*[[Hemangioblastoma of the kidney]] - especially in [[von Hippel-Lindau disease]].
**S-100 +ve, inhibin +ve, PAX-8+ve, EMA -ve, CA9 -ve.
 
===Images===
====Case 1====
<gallery>
Image: Clear cell renal cell carcinoma - 2 -- intermed mag.jpg | CCRCC - intermed. mag. (WC)
Image: Clear cell renal cell carcinoma - 2 -- high mag.jpg | CCRCC - high mag. (WC)
Image: Clear cell renal cell carcinoma - 2 -- very high mag.jpg | CCRCC - very high mag. (WC)
</gallery>
====Case 2====
<gallery>
Image: Clear cell renal cell carcinoma -- intermed mag.jpg | CCRCC - intermed. mag. (WC)
Image: Clear cell renal cell carcinoma -- high mag.jpg | CCRCC - high mag. (WC)
Image: Clear cell renal cell carcinoma -- very high mag.jpg | CCRCC - very high mag. (WC)
</gallery>
====Case 3====
<gallery>
Image:Clear_cell_renal_cell_carcinoma_intermed_mag.jpg | CRCC - intermed. mag. (WC/Nephron)
Image:Clear_cell_renal_cell_carcinoma_high_mag.jpg | CRCC - high mag. (WC/Nephron)
</gallery>
 
==Stains==
*PAS +ve.
*PAS-D -ve.<ref>{{cite journal |authors=Kolečková M, Tichý T, Melichar B, Veverková L, Hes O, Kolek V, Kolář Z |title=Metastatic Clear Cell Renal Carcinoma Without Evidence of a Primary Renal Tumour Mimicking Advanced Stage of Malignant Lung Tumour |journal=Klin Onkol |volume=32 |issue=Supplementum1 |pages=154–156 |date=2019 |pmid=31064187 |doi= |url=}}</ref><ref>{{cite journal |authors=Liu S, Liu H, Weng B, Hou S |title=Case report: Tongue metastasis as an initial sign of clear cell renal cell carcinoma and its prognosis |journal=Front Oncol |volume=14 |issue= |pages=1473211 |date=2024 |pmid=39931206 |pmc=11807832 |doi=10.3389/fonc.2024.1473211 |url=}}</ref>
*Hale's colloidal iron -ve.
**+ve in [[chromophobe RCC]].
 
Note:
*''[[Hale's colloidal iron]]'' does not stain iron... it stains hemosiderin.<ref>Latta. 27 January 2009.</ref>
 
==IHC==
*CD10 +ve.
*Vimentin +ve.
*CK7 -ve.
**Strong CK7 staining is more in keeping with [[clear cell papillary renal cell carcinoma]]<ref name=pmid26457355>{{Cite journal  | last1 = Williamson | first1 = SR. | last2 = Gupta | first2 = NS. | last3 = Eble | first3 = JN. | last4 = Rogers | first4 = CG. | last5 = Michalowski | first5 = S. | last6 = Zhang | first6 = S. | last7 = Wang | first7 = M. | last8 = Grignon | first8 = DJ. | last9 = Cheng | first9 = L. | title = Clear Cell Renal Cell Carcinoma With Borderline Features of Clear Cell Papillary Renal Cell Carcinoma: Combined Morphologic, Immunohistochemical, and Cytogenetic Analysis. | journal = Am J Surg Pathol | volume = 39 | issue = 11 | pages = 1502-10 | month = Nov | year = 2015 | doi = 10.1097/PAS.0000000000000514 | PMID = 26457355 }}</ref> or the evolving entity of [[TCEB1-mutated renal cell carcinoma]]. 
*CK20 -ve.
*Glut-1 >85% of CCRCC (membranous pattern).<ref name=pmid17638658>{{Cite journal  | last1 = Ozcan | first1 = A. | last2 = Shen | first2 = SS. | last3 = Zhai | first3 = QJ. | last4 = Truong | first4 = LD. | title = Expression of GLUT1 in primary renal tumors: morphologic and biologic implications. | journal = Am J Clin Pathol | volume = 128 | issue = 2 | pages = 245-54 | month = Aug | year = 2007 | doi = 10.1309/HV6NJVRQKK4QHM9F | PMID = 17638658 }}</ref>
*E-cadherin +ve - usually weak, often -ve in higher stage tumours.<ref name=pmid23939157>{{Cite journal  | last1 = Hu | first1 = H. | last2 = Chen | first2 = JW. | last3 = Xu | first3 = KX. | last4 = Wang | first4 = D. | last5 = Wang | first5 = Y. | last6 = Wang | first6 = GW. | last7 = Zhang | first7 = SY. | last8 = Wang | first8 = XF. | title = [Expressions of CMTM8 and E-cadherin in primary and metastatic clear cell renal cell carcinoma]. | journal = Beijing Da Xue Xue Bao | volume = 45 | issue = 4 | pages = 537-41 | month = Aug | year = 2013 | doi =  | PMID = 23939157 }}</ref>
*CAIX (also CA9) +ve.
 
A panel to confirm the diagnosis:
*CK7 (-ve), CD10 (+ve), PAX8 (+ve), vimentin (+ve).
 
===CCRCC versus [[chromophobe RCC]]===
ISUP recommends:<ref name=pmid25025364 >{{cite journal |author=Amin MB, Epstein JI, Ulbright TM, ''et al.'' |title=Best practices recommendations in the application of immunohistochemistry in urologic pathology: report from the international society of urological pathology consensus conference |journal=Am. J. Surg. Pathol. |volume=38 |issue=8 |pages=1017–22 |year=2014 |month=August |pmid=25025364 |doi=10.1097/PAS.0000000000000254 |url=}}</ref>
*CD117 -ve (+ve in ChRCC).
**Aguilar-León ''et al.'' found ~8% of CCRCC are CD117 +ve.<ref name=pmid25643775>{{Cite journal  | last1 = Aguilar-León | first1 = D. | last2 = Del Ángel-Millán | first2 = G. | last3 = Zepeda-Quiroz | first3 = I. | last4 = Soria-Céspedes | first4 = D. | title = [Immunohistochemical Expression of CD117 (c-kit) in 75 Renal Cell Tumors]. | journal = Gac Med Mex | volume = 150 Suppl 2 | issue =  | pages = 156-60 | month = Dec | year = 2014 | doi =  | PMID = 25643775 }}</ref>
**Liu ''et al.'' found ~80% of ChRCC are CD117 +ve.<ref name=pmid17683191/>
*CA9 ([[carbonic anhydrase 9]]) +ve (membranous).<ref name=pmid21677535>{{cite journal |author=Al-Ahmadie HA, Alden D, Fine SW, ''et al.'' |title=Role of immunohistochemistry in the evaluation of needle core biopsies in adult renal cortical tumors: an ex vivo study |journal=Am. J. Surg. Pathol. |volume=35 |issue=7 |pages=949–61 |year=2011 |month=July |pmid=21677535 |doi=10.1097/PAS.0b013e31821e25cd |url=}}</ref>
*[[CK7]] -ve (+ve in ChRCC).
 
May also be useful:
*Vimentin +ve.
**-ve in ChRCC.<ref name=pmid17683191>{{Cite journal  | last1 = Liu | first1 = L. | last2 = Qian | first2 = J. | last3 = Singh | first3 = H. | last4 = Meiers | first4 = I. | last5 = Zhou | first5 = X. | last6 = Bostwick | first6 = DG. | title = Immunohistochemical analysis of chromophobe renal cell carcinoma, renal oncocytoma, and clear cell carcinoma: an optimal and practical panel for differential diagnosis. | journal = Arch Pathol Lab Med | volume = 131 | issue = 8 | pages = 1290-7 | month = Aug | year = 2007 | doi = 10.1043/1543-2165(2007)131[1290:IAOCRC]2.0.CO;2 | PMID = 17683191 }}</ref>
 
===CCRCC versus [[CCPRCC]]===
[[ISUP]] recommends:<ref name=pmid25025364/>
*CA9 +ve (strong membranous).
*CK7 -ve.
**Usually +ve in [[clear cell papillary renal cell carcinoma]].
*AMACR -ve.
 
Others:
*CD10 +ve.
**Usually -ve in [[clear cell papillary renal cell carcinoma]].
 
===CCRCC versus Xp11.2 translocation carcinomas===
ISUP recommends:<ref name=pmid25025364/>
*Cathepsin K -ve.<ref name=pmid21602817>{{cite journal |author=Martignoni G, Gobbo S, Camparo P, ''et al.'' |title=Differential expression of cathepsin K in neoplasms harboring TFE3 gene fusions |journal=Mod. Pathol. |volume=24 |issue=10 |pages=1313–9 |year=2011 |month=October |pmid=21602817 |doi=10.1038/modpathol.2011.93 |url=}}</ref>
*TFE3 -ve.
*TFEB -ve.
 
==Sign out==
===Biopsy===
<pre>
Kidney Mass, Left, Core Biopsy:
- Clear cell renal cell carcinoma
- ISUP nucleolar grade 2 (based on biopsy)
- No renal parenchyma identified
 
Comment:
The quantity of tissue available at microscopy is very limited.
Immunostains confirm the morphologic impression (see microscopic).
</pre>
 
====MDA form====
<pre>
Kidney Mass, Left, Core Biopsy:
- CLEAR CELL RENAL CELL CARCINOMA, preliminary ISUP nucleolar grade 2 (see comment).
- No renal parenchyma identified.
 
Comment:
The quantity of tissue at microscopy is limited, and may not be representative
of the lesion identified radiologically.
</pre>
 
===Resection===
Note:
*The surgeon wants the diagnosis and margin status; thus, these are included in the diagnosis line with the tumour stage.
 
<pre>
Left Kidney, Radical Nephrectomy:
    - CLEAR CELL RENAL CELL CARCINOMA.
    -- Margins clear.
    -- Please see synoptic report.
</pre>
 
====Block letters====
<pre>
KIDNEY, LEFT, NEPHRECTOMY:
- CLEAR CELL RENAL CELL CARCINOMA, FUHRMAN GRADE 2, pT1a, pNx.
-- MARGINS NEGATIVE FOR MALIGNANCY.
-- PLEASE SEE TUMOUR SUMMARY.
</pre>
 
====Adrenal gland present====
<pre>
KIDNEY, RIGHT, RADICAL NEPHRECTOMY:
- CLEAR CELL RENAL CELL CARCINOMA, FUHRMAN GRADE 2, pT1a, pNx.
-- MARGINS NEGATIVE FOR MALIGNANCY.
-- PLEASE SEE TUMOUR SUMMARY.
- ADRENAL GLAND WITHIN NORMAL LIMITS.
</pre>
 
<pre>
KIDNEY, RIGHT, RADICAL NEPHRECTOMY:
- CLEAR CELL RENAL CELL CARCINOMA, FUHRMAN GRADE 3, pT1b, pNx.
-- MARGINS NEGATIVE FOR MALIGNANCY.
-- PLEASE SEE TUMOUR SUMMARY.
- ADRENAL GLAND WITHIN NORMAL LIMITS.
</pre>
 
===Micro===
The sections show a tumour with a chicken wire-like vasculature composed of clear cells with basally stratified nuclei. Hemosiderin-laden macrophages are present. Necrosis is present. Abundant hyaline globules are present. 
 
There is no perinuclear clearing.  The cytoplasm is not wispy. Papillae are not evident.
 
Rare, small nucleoli are visible with the 10x objective.  The tumour nuclei are approximately 15 micrometers.
 
====Alternate====
The sections show cohesive mildly atypical clear cells with a columnar morphology. Small cystic spaces are present. The nuclei are basal stratified. Nucleoli are not prominent. Siderophages are present. Blood is present.
 
No perinuclear halos are apparent. No papillary structures are identified. No definite renal parenchyma is seen.
 
==See also==
*[[Kidney tumours]].
*[[TCEB1-mutated renal cell carcinoma]].
*[[Renal cell carcinoma with rhabdoid morphology]].
 
==References==
{{Reflist|2}}


[[Category:Diagnosis]]
[[Category:Diagnosis]]
[[Category:Kidney tumours]]
Michael
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