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Clear Cell Renal Cell Carcinoma

Definition

  • Carcinoma of the kidney composed predominantly of nests and sheets of clear cells

Alternate/Historical Names

  • Conventional type renal cell carcinoma
  • One of several different neoplasms previously diagnosed as granular cell renal cell carcinoma (some cases)

Diagnostic Criteria

  • Grossly circumscribed mass
    • Frequently hemorrhagic and necrotic
    • Soft yellow areas frequent, alternating with fibrous to mucoid areas
      • May appear necrotic but frequently are viable
    • Multifocal in about 5% of cases
  • Sheets and nests of cells surrounded by extensive capillary network
  • Predominantly composed of clear cells
    • Higher grade tumors often lose clear cell cytoplasm but may still have underlying recognizable low grade clear cell areas
    • Frequent granular eosinophilic areas
      • Rarely predominant
      • If extensively granular and eosinophilic, consider oncocytoma
    • Sharp cell borders
    • Cytoplasm contains lipid and glycogen
    • Features reported in rare cases
      • Rhabdoid cells in 5% of cases (Gokden 2000)
        • Abundant eccentric cytoplasm containing large eosinophilic inclusions
        • Eccentric large round nuclei, may be multinucleate
        • Keratin, EMA, vimentin positive
        • 25% of cases with rhabdoid areas have sarcomatoid areas
      • Eosinophilic 5-7 mm hyaline globules (Jagirdar 1985)
      • Basophilic inclusions
      • Myospherulosis (Chau 2000)
      • Coarse brown granular pigment (one case, Kamishima 1995, Fukuda 1997)
      • Melanin (one case, Lei 2001)
  • Nuclei range from round and regular at low grade to pleomorphic at high grade
    • Nuclear features and nucleolar size incorporated into grading
  • Dysplasia of adjacent non-carcinomatous tubules has been reported
  • Multiple and/or familial clear cell carcinomas may be seen in von Hippel Lindau syndrome

John P Higgins MD
Robert V Rouse MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting/updates: 1/24/11, 8/8/11

Supplemental studies

Immunohistology

Low MW keratin pos
CK7 neg or focal
High MW keratin neg
EMA pos
CD10 pos
PAX2 >90%
PAX8 >95%
See also markers in table below

Immunohistologic markers useful for distinguishing major types of renal cell carcinoma
  CA-IX Vim CD117 AMACR Racemase PN15 /PNRA/ gp200 CK7
Clear Cell 100% >85% <5% 15-25% 85% neg or focal
Papillary 50 >90 <20 >80 >85 20-80%
Chromophobe 0 0 >80 <15 0-45 >70% strong
Oncocytoma 0 0 >90 <15 0 neg to scattered
CA-IX = Carbonic Anhydrase IX; Vim = Vimentin; Clone PN15 anti-gp200 is sold as Renal Cell Carcinoma Marker, a unfortunately chosen, non-specific name

References for general IPOX of major types of RCC

  • Truong LD, Shen SS. Immunohistochemical diagnosis of renal neoplasms. Arch Pathol Lab Med. 2011 Jan;135(1):92-109.
  • Allory Y, Bazille C, Vieillefond A, Molinié V, Cochand-Priollet B, Cussenot O, Callard P, Sibony M. Profiling and classification tree applied to renal epithelial tumours. Histopathology. 2008 Jan;52(2):158-66.
  • Molinié V, Balaton A, Rotman S, Mansouri D, De Pinieux I, Homsi T, Guillou L. Alpha-methyl CoA racemase expression in renal cell carcinomas. Hum Pathol. 2006 Jun;37(6):698-703.
  • Paner GP, Srigley JR, Radhakrishnan A, Cohen C, Skinnider BF, Tickoo SK, Young AN, Amin MB. Immunohistochemical analysis of mucinous tubular and spindle cell carcinoma and papillary renal cell carcinoma of the kidney: significant immunophenotypic overlap warrants diagnostic caution. Am J Surg Pathol. 2006 Jan;30(1):13-9.
  • Liu L, Qian J, Singh H, Meiers I, Zhou X, Bostwick DG. Immunohistochemical analysis of chromophobe renal cell carcinoma, renal oncocytoma, and clear cell carcinoma: an optimal and practical panel for differential diagnosis. Arch Pathol Lab Med. 2007 Aug;131(8):1290-7.
  • Memeo L, Jhang J, Assaad AM, McKiernan JM, Murty VV, Hibshoosh H, Tong GX, Mansukhani MM. Immunohistochemical analysis for cytokeratin 7, KIT, and PAX2: value in the differential diagnosis of chromophobe cell carcinoma. Am J Clin Pathol. 2007 Feb;127(2):225-9.
  • Avery AK, Beckstead J, Renshaw AA, Corless CL. Use of antibodies to RCC and CD10 in the differential diagnosis of renal neoplasms. Am J Surg Pathol. 200 Feb;24(2):203-10.
  • Wang HY, Mills SE. KIT and RCC are useful in distinguishing chromophobe renal cell carcinoma from the granular variant of clear cell renal cell carcinoma. Am J Surg Pathol. 2005 May;29(5):640-6.
  • McGregor DK, Khurana KK, Cao C, Tsao CC, Ayala G, Krishnan B, Ro JY, Lechago J, Truong LD. Diagnosing primary and metastatic renal cell carcinoma: the use of the monoclonal antibody 'Renal Cell Carcinoma Marker'. Am J Surg Pathol. 2001 Dec;25(12):1485-92.
  • Yoshida SO, Imam A. Monoclonal antibody to a proximal nephrogenic renal antigen: immunohistochemical analysis of formalin-fixed, paraffin-embedded human renal cell carcinomas. Cancer Res. 1989 Apr 1;49(7):1802-9.

Genetic Study

  • Most show 3p deletions
    • Not commonly used for diagnosis, but generally taken as definitional for research purposes

Differential Diagnosis

Conventional Clear Cell Renal Cell Carcinoma Chromophobe Renal Cell Carcinoma
Sheets and nests of clear cells with prominent surrounding vascular network Rigid cell membranes, central nuclei with surrounding nuclear clearing
CD117/KIT neg CD117/KIT pos
Vimentin, Carbonic Anhydrase IX generally pos Vimentin, Carbonic Anhydrase IX negative
Hale colloidal iron negative Hale colloidal iron positive

Conventional Clear Cell Renal Cell Carcinoma, Granular Variant Renal Oncocytoma
Nearly always has clear cell areas Clear cells only in focal, hyalinized scar areas
Prominent surrounding capillary network Surrounding stroma hypocellular
Carbonic anhydrase IX, AMACR/racemase, vimentin usually pos Carbonic anhydrase IX, AMACR/racemase, vimentin usually neg
cKIT/CD117 usually neg cKIT/CD117 usually pos

Conventional Clear Cell Renal Cell Carcinoma Clear Cell Tubulopapillary Renal Cell Carcinoma
Sheets and clusters of cells with extensive vascular network Nearly all have branched tubules and anastomosing ribbons
Solid areas have clusters more than two cells wide Solid areas usually formed by compressed tubules, each only two cells wide
May have high grade nuclear features, vascular invasion and necrosis Low grade nuclear features, no invasion or necrosis
Cysts frequently due to degeneration, lined in areas by multiple layers of cells Uniformly lined by single layer of cells
Clear cytoplasm apical or diffuse, non-localized Frequent regular basal clearing, resembling interval endometrium
Usually CK7 neg, CD10 pos CK7 pos, CD10 neg to focal

Conventional Clear Cell Renal Cell Carcinoma Multilocular Cystic Renal Cell Carcinoma
Both cystic and solid areas No solid areas
Nodules of clear cells are expansile and/or invasive Nests of clear cells are not expansile or invasive
May be low or high grade Must be low grade (1 or 2)

Conventional Clear Cell Renal Cell Carcinoma Renal Adenoma
No size cutoff for clear cell tumors Papillary lesion ≤0.5 cm, clear cells not permitted
May be high or low grade Must be no higher than grade 2
CK7, AMACR/racemase/P504S neg to focal CK7, AMACR/racemase/P504S pos

Grading / Staging

Grading

  • Most commonly cited grading scheme is that of Fuhrman
    • Requires simultaneous assessment of three features: nuclear size, shape and nucleoli
      • Nuclear size may be subject to fixation variables and difficult to measure
      • No provision for cases with discrepant grade features
      • Poor interobserver agreement
  • We and others find a simplified version based primarily on nucleolar prominence to be more practical
    • This approach has been shown to have predictive value for clear cell and papillary carcinomas (Lohse; Sika-Paotonu; Delahunt)
    • Grade based on worst high powered field
    • Does not apply to chromophobe carcinoma or oncocytomas
    • Is provisionally applied to various other types and variants of RCC but has not been validated
      • Complete Fuhrman grading has not been validated on other types either
    Simplified Fuhrman Grading
  • Grade 1 Small, round, dark lymphocyte-like nuclei with without visible nucleoli
    Grade 2 Inconspicuous nucleoli, visible only at 200-400X (nuclei usually small and uniform with open, finely granular chromatin)
    Grade 3 Prominent nucleoli, easily visible at 100X (nuclei usually mildly to moderately pleomorphic)
    Grade 4 Markedly pleomorphic, bizarre nuclei, giant cells, multiple nucleoli
    • Sarcomatoid differentiation may be seen in many types of renal carcinomas (de Peralta-Venturina; Cheville)
      • It no longer refers to a type of carcinoma
      • It is considered an adverse prognostic factor
        • Prognosis may be worse than simple grade 4 carcinoma
      • Defined as a spindle cell component measuring at least one low power (40x) field with either
        • Adjacent carcinoma, or
        • Evidence of epithelial differentiation in the spindle cells
      • Spindle cells usually show moderate to marked atypia
        • Frequent patterns include fibrosarcoma, malignant fibrous histiocytoma, rhabdomyosarcoma
        • Occasional cases have low grade atypia in spindle component
        • No clinical significance to type of differentation or degree of atypia
      • May arise in setting of many types of carcinoma
        • Clear cell RCC (reported 5-8% incidence of sarcomatoid foci, in our experience it is less frequent)
        • Papillary RCC (2-3% incidence)
        • Chromophobe RCC (9% incidence)
        • Collecting duct carcinoma (39% incidence)

    Bibliography (for Grading)

    • Murphy WM, Grignon DJ, Perlman EJ. Tumors of the Kidney, Bladder and Related Urinary Structures, Atlas of Tumor Pathology, AFIP Fourth Series, Fascicle 1, 2004
    • Delahunt B. Advances and controversies in grading and staging of renal cell carcinoma. Mod Pathol. 2009 Jun;22 Suppl 2:S24-36.
    • Delahunt B, Sika-Paotonu D, Bethwaite PB, William Jordan T, Magi-Galluzzi C, Zhou M, Samaratunga H, Srigley JR. Grading of clear cell renal cell carcinoma should be based on nucleolar prominence. Am J Surg Pathol. 2011 Aug;35(8):1134-9.
    • Delahunt B, Bethwaite PB, Nacey JN. Outcome prediction for renal cell carcinoma: evaluation of prognostic factors for tumours divided according to histological subtype. Pathology. 2007 Oct;39(5):459-65.
    • Lohse CM, Blute ML, Zincke H, Weaver AL, Cheville JC. Comparison of standardized and nonstandardized nuclear grade of renal cell carcinoma to predict outcome among 2,042 patients. Am J Clin Pathol. 2002 Dec;118(6):877-86.
    • de Peralta-Venturina M, Moch H, Amin M, Tamboli P, Hailemariam S, Mihatsch M, Javidan J, Stricker H, Ro JY, Amin MB. Sarcomatoid differentiation in renal cell carcinoma: a study of 101 cases. Am J Surg Pathol. 2001 Mar;25(3):275-84.
    • Cheville JC, Lohse CM, Zincke H, Weaver AL, Leibovich BC, Frank I, Blute ML. Sarcomatoid renal cell carcinoma: an examination of underlying histologic subtype and an analysis of associations with patient outcome. Am J Surg Pathol. 2004 Apr;28(4):435-41.
    • Sika-Paotonu D, Bethwaite PB, McCredie MR, William Jordan T, Delahunt B. Nucleolar grade but not Fuhrman grade is applicable to papillary renal cell carcinoma. Am J Surg Pathol. 2006 Sep;30(9):1091-6.
    • Delahunt B, Sika-Paotonu D, Bethwaite PB, McCredie MR, Martignoni G, Eble JN, Jordan TW. Fuhrman grading is not appropriate for chromophobe renal cell carcinoma. Am J Surg Pathol. 2007 Jun;31(6):957-60..
    • Paner GP, Amin MB, Alvarado-Cabrero I, Young AN, Stricker HJ, Moch H, Lyles RH. A novel tumor grading scheme for chromophobe renal cell carcinoma: prognostic utility and comparison with Fuhrman nuclear grade. Am J Surg Pathol. 2010 Sep;34(9):1233-40.
    • Fuhrman SA, Lasky LC, Limas C. Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol. 1982 Oct;6(7):655-63.

    Staging

    • Use TNM staging for all renal carcinomas at present
      • Remember that it is based predominantly on clear cell carcinomas
      • It has not been validated as applicable to other types of carcinoma (see Herrmann for an example)
        • Note that oncocytomas can infiltrate fat and exhibit vascular invasion without affecting prognosis (Perez-Odonez)
    • Critical/controversial points in staging of RCC include:
      • pT3a is defined as extension into perirenal fat
        • This requires actual touching of fat, preferably infiltration into and between fat cells
          • It does not include bulging tumor with stretched, thin capsule that appears to touch fat
        • Classically has been considered fat peripheral to the cortical capsule
          • It appears that renal sinus (peripelvic) fat should be considered equivalent
            • The renal sinus must be examined grossly and appropriately sampled
      • pT3 requires gross involvement of renal vein and or vena cava
        • This requires an adequate gross examination
        • Retraction of vascular wall around a lumenal tumor thrombus may falsely suggest a positive margin
          • Positive vascular margin requires involvement of the vessel wall at the margin
      • Direct (contiguous) invasion of the adrenal gland (pT4) should be distinguished from discontiguous (metastatic) involvement (pM1)

    Bibliography (for Staging)

    • Murphy WM, Grignon DJ, Perlman EJ. Tumors of the Kidney, Bladder and Related Urinary Structures, Atlas of Tumor Pathology, AFIP Fourth Series, Fascicle 1, 2004
    • Delahunt B. Advances and controversies in grading and staging of renal cell carcinoma. Mod Pathol. 2009 Jun;22 Suppl 2:S24-36.
    • Bonsib SM. The renal sinus is the principal invasive pathway: a prospective study of 100 renal cell carcinomas. Am J Surg Pathol. 2004 Dec;28(12):1594-600.
    • Bonsib SM. Renal veins and venous extension in clear cell renal cell carcinoma. Mod Pathol. 2007 Jan;20(1):44-53.
    • Bonsib SM. T2 clear cell renal cell carcinoma is a rare entity: a study of 120 clear cell renal cell carcinomas. J Urol. 2005 Oct;174(4 Pt 1):1199-202; discussion 1202.
    • Herrmann E, Trojan L, Becker F, Wülfing C, Schrader AJ, Barth P, Stöckle M, Hammerschmied CG, Staehler M, Stief C, Haferkamp A, Hohenfellner M, Legal W, Wullich B, Bolenz C, Klein T, Noldus J, Bierer S, Hertle L, Brenner W, Roos F, Michel MS, Walter B, Wieland W, Gerss J, Otto W, Hartmann A. Prognostic factors of papillary renal cell carcinoma: results from a multi-institutional series after pathological review. J Urol. 2010 Feb;183(2):460-6.
    • Trpkov K, Grignon DJ, Bonsib SM, Amin MB, Billis A, Lopez-Beltran A, Samaratunga H, Tamboli P, Delahunt B, Egevad L, Montironi R, Srigley JR; members of the ISUP Renal Tumor Panel. Handling and staging of renal cell carcinoma: the International Society of Urological Pathology Consensus (ISUP) conference recommendations. Am J Surg Pathol. 2013 Oct;37(10):1505-17.

    Clinical

    • Predominantly seen in adults but may be seen in children
    • Classic triad of flank mass, flank pain and hematuria is rare now
      • Many cases are found incidentally during imaging directed at nearby organs
        • Many are small, leading to increase in partial nephrectomies

    Classification / Lists

    Renal epithelial neoplasms

    Bibliography

    • Murphy WM, Grignon DJ, Perlman EJ. Tumors of the Kidney, Bladder and Related Urinary Structures, Atlas of Tumor Pathology, AFIP Fourth Series, Fascicle 1, 2004
    • Eble JN, Sauter G, Epstein JI, Sesterhenn IA eds. World Health Organization Classification of Tumors. Pathology and genetics of tumors of the Urinary System and Male Genital Organs. IARC Press: Lyon 2004.
    • Störkel S, Eble JN, Adlakha K, Amin M, Blute ML, Bostwick DG, Darson M, Delahunt B, Iczkowski K. Classification of renal cell carcinoma: Workgroup No. 1. Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer. 1997 Sep 1;80(5):987-9.
    • Kovacs G, Akhtar M, Beckwith BJ, Bugert P, Cooper CS, Delahunt B, Eble JN, Fleming S, Ljungberg B, Medeiros LJ, Moch H, Reuter VE, Ritz E, Roos G, Schmidt D, Srigley JR, Störkel S, van den Berg E, Zbar B. The Heidelberg classification of renal cell tumours. J Pathol. 1997 Oct;183(2):131-3.
    • Gökden N, Nappi O, Swanson PE, Pfeifer JD, Vollmer RT, Wick MR, Humphrey PA. Renal cell carcinoma with rhabdoid features. Am J Surg Pathol. 2000 Oct;24(10):1329-38
    • Lei JY, Middleton LP, Guo XD, Duray PH, McWilliams G, Linehan WM, Merino MJ. Pigmented renal clear cell carcinoma with melanocytic differentiation. Hum Pathol. 2001 Feb;32(2):233-6.
    • Kamishima T, Fukuda T, Emura I, Tanigawa T, Naito M. Pigmented renal cell carcinoma. Am J Surg Pathol. 1995 Mar;19(3):350-6.
    • Fukuda T, Kamishima T, Emura I, Takastuka H, Suzuki T. Pigmented renal cell carcinoma: accumulation of abnormal lysosomal granules. Histopathology. 1997 Jul;31(1):38-46.
    • Mourad WA, Nestok BR, Saleh GY, Solez K, Power RF, Jewell LD. Dysplastic tubular epithelium in "normal" kidney associated with renal cell carcinoma. Am J Surg Pathol. 1994 Nov;18(11):1117-24.
    • Jagirdar J, Irie T, French SW, Patil J, Schwarz R, Paronetto F. Globular Mallory-like bodies in renal cell carcinoma: report of a case and review of cytoplasmic eosinophilic globules. Hum Pathol. 1985 Sep;16(9):949-52..
    • Chau KY, Pretorius JM, Stewart AW. Myospherulosis in renal cell carcinoma. Arch Pathol Lab Med. 2000 Oct;124(10):1476-9.
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