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Chromophobe Renal Cell Carcinoma

Definition

  • Carcinoma of the kidney composed predominantly of distinctive cells with prominent cell membranes and cleared cytoplasm

Alternate/Historical Names

  • Conventional type renal cell carcinoma (some cases)
  • Granular cell renal cell carcinoma (some cases)

Diagnostic Criteria

  • Generally sheet-like or broad alveolar patterns
    • Less frequently tubular or cystic
    • Vessels frequently thick walled and/or eccentrically hyalinized
  • Composed of cells with cytoplasm ranging from clear to eosinophilic
    • Clear cells (classical) have abundant clear cytoplasm
      • May be flocculent, "soap bubble" or reticular
    • Eosinophilic (variant) cells have moderate amount of finely granular eosinophilic cytoplasm
      • Prominent perinuclear clearing
        • Peripheral condensation of cytoplasm accentuates cell membrane
    • Most often mixed but may be pure of either type
      • Mixed cases frequently have a distinctive pattern
        • Eosinophilic cells occupy the center of the nest, merging with
        • Peripheral clear cells with abundant cytoplasm adjacent to the fibrovascular stromal border
  • Nuclei vary from round, regular to koilocytoid
    • Koilocytoid nuclei have wrinkled nuclear membrane, coarse chromatin
    • Frequently binucleate
  • Prominent cell borders with centrally located nuclei with perinuclear clearing result in a "plant cell appearance"
    • Reminiscent of the rigid cell walls of plant cells
  • Hale colloidal iron stain positive
    • A temperamental stain
    • Other colloidal iron stains are not equivalent
  • Chromophobe and hybrid chromophobe/oncocytoma cases may be seen in Birt Hogg Dubé syndrome
    • Often multiple and bilateral
    • Associated with germline folliculin mutations
    • Sporadic hybrid chromophobe/oncocytoma cases have been described (Petersson)
  • Sarcomatoid cases may have a variety of patterns (Viswanathan; Quiroga-Garza)
    • Poor prognosis
  • One case reported with neuroendocrine differentiation (Parada)
    • Not clear from the report that this was not a collision tumor

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

Original posting/last update: 1/24/11, 11/3/16

Supplemental studies

Immunohistology

CD117 >90%, membranous
CK7 >70%
EMA >90
CD10 0 to focal
High molecular weight keratin 0
CAIX 0
PAX8 >80
CK7 typically diffuse in classic chromophobe carcinoma, but may be patchy, focal or even negative in eosinophilic variant
Also see 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 >90 <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 deletions involving multiple chromosomes (often 1, 2, 6, 10, 13, 17, 21)
    • Not commonly used for diagnosis

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

Chromophobe Renal Cell Carcinoma Renal Oncocytoma
Diffuse, sheet like pattern Nests floating in hypocellular stroma
Perinuclear halos usually prominent No perinuclear clearing
Clear cells usually prominent, frequently peripheral in nests Clear cells only focally in hyalinized scars
CK7 usually diffuse, strong CK7 usually negative or scattered positive cells
Hale colloidal iron stain diffusely positive Hale colloidal iron stain may be apical, but not diffuse, confluent

  • This is one of the most problematic distinctions between renal neoplasms and may frequently be impossible
  • We consider a diagnosis of “oncocytic renal neoplasm” with a comment that chromophobe carcinoma cannot be completely excluded to be preferable to overdiagnosing a likely benign neoplasm as chromophobe carcinoma

Grading / Staging

Grading

  • Although this grading system has not been validated as an indicator of prognosis for other types of renal cell neoplasia (due primarily to small numbers of reported cases) the system can be used to describe the morphologic features of these tumors
    • Grade should be assigned based on the siingle high power field showing the greatest degre of nuclear pleomorphism
    • WHO/ISUP grading system for clear cell and papillary renal cell carcinomas
    • Grade 1 Nucleoli are absent or inconspicuous and basophilic at 400x magnification
      Grade 2 Nucleoli are conspicuous and eosinophilic at 400x and visible but not prominent at 100x
      Grade 3 Nucleoli are conspicuous and eosinophilic at 100x
      Grade 4 Extreme nuclear pleomorphism, multinucleate giant cells, and/or rhabdoid and/or sarcomatoid differentiation

Staging

  • Use TNM

Clinical

  • Predominantly seen in adults
    • Range 24-82, mean about 60
    • One report at 8 years of age (Katzman)
  • 8% multifocal
  • 95% 5 year survival
  • Poor survival in cases with sarcomatoid differentiation
    • Found in <2% of cases

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
  • Moch H, Humphrey PA, Ulbright TM, Reuter VE eds. World Health Organization Classification of Tumors. Pathology and genetics of tumors of the Urinary System and Male Genital Organs, 4th edition,. IARC Press: Lyon 2016..
  • 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.
  • Tickoo SK, Gopalan A. Pathologic features of renal cortical tumors. Urol Clin North Am. 2008 Nov;35(4):551-61.
  • 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.
  • 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.
  • Amin MB, Paner GP, Alvarado-Cabrero I, Young AN, Stricker HJ, Lyles RH, Moch H. Chromophobe renal cell carcinoma: histomorphologic characteristics and evaluation of conventional pathologic prognostic parameters in 145 cases. Am J Surg Pathol. 2008 Dec;32(12):1822-34.
  • 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.
  • Yusenko MV. Molecular pathology of chromophobe renal cell carcinoma: a review. Int J Urol. 2010 Jul;17(7):592-600.
  • Brunelli M, Delahunt B, Gobbo S, Tardanico R, Eccher A, Bersani S, Cossu-Rocca P, Parolini C, Balzarini P, Menestrina F, Cheng L, Eble JN, Martignoni G. Diagnostic usefulness of fluorescent cytogenetics in differentiating chromophobe renal cell carcinoma from renal oncocytoma: a validation study combining metaphase and interphase analyses. Am J Clin Pathol. 2010 Jan;133(1):116-26.
  • Mai KT, Teo I, Belanger EC, Robertson SJ, Marginean EC, Islam S. Progesterone
    receptor reactivity in renal oncocytoma and chromophobe renal cell carcinoma. Histopathology. 2008 Feb;52(3):277-82.
  • Kim SS, Choi YD, Jin XM, Cho YM, Jang JJ, Juhng SW, Choi C. Immunohistochemical stain for cytokeratin 7, S100A1 and claudin 8 is valuable in differential diagnosis of chromophobe renal cell carcinoma from renal oncocytoma. Histopathology. 2009 Apr;54(5):633-5.
  • Viswanathan S, Desai SB, Prabhu SR, Amin MB. Squamous differentiation in a sarcomatoid chromophobe renal cell carcinoma: an unusual case report with review of the literature. Arch Pathol Lab Med. 2008 Oct;132(10):1672-4.
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