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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 or "soap bubble"
      • Prominent, distinct cell membrane
    • Eosinophilic (variant) cells have moderate amount of finely granular eosinophilic cytoplasm
      • Prominent perinuclear clearing
        • Peripheral condensation of cytoplasm accentuates cell membrane
    • Nuclei vary from round, regular to koilocytoid
      • Koilocytoid nuclei have wrinkled nuclear membrane, coarse chromatin
      • Frequently binucleate
    • 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
  • 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
    • 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

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, 7/17/11

Supplemental studies

Immunohistology

CK7 >70%
EMA >90
CD10 0-73
High molecular weight keratin 0
PAX2 0-80
PAX8 >80
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 >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 deletions involving chromosomes 1, 2, 6, 10, 13, 17, 21
    • Not commonly used for diagnosis

Hale colloidal iron stain diffusely positive in cell cytoplasm

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

  • Fuhrman and modified Fuhrman grading schemes do not apply to chromophobe carcinoma (Delahunt)
  • Paner et al. have proposed a grading scheme
    • Grade I
      • No nuclear crowding and anaplasia (see definitions below)
    • Grade 2 requires both criteria below:
      • Nuclear crowding
        • High geographic nuclear/cytoplasmic density detectable at 10x objective
        • Some nuclei in direct contact with each other when assessed at 40x objective
      • Nuclear pleomorphism
        • Size variation of ≥3-fold and
        • Distinct nuclear chromatin irregularities
          • Not smudged nuclear atypia of degenerate foci
    • Grade 3 requires either
      • Nuclear polylobation and tumor giant cells, or
      • Sarcomatoid change
    • At least two distinct areas required to have above features to determine the grade
      • Otherwise, use next lower grade
  • A large study (Przybycin 2011) does not find grading to predict behavior
    • Following features found to be predictive of adverse outcome
      • Angiolymphatic invasion
      • Microscopic necrosis
      • Tumor size (>7cm)
      • Sarcomatoid differentiation

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)
  • Critical/controversial points in staging of RCC include:
    • pT3a is defined as extension into perirenal fat
      • This requires actual 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.

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
  • 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.
  • 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.
  • Quiroga-Garza G, Khurana H, Shen S, Ayala AG, Ro JY. Sarcomatoid chromophobe renal cell carcinoma with heterologous sarcomatoid elements. A case report and review of the literature. Arch Pathol Lab Med. 2009 Nov;133(11):1857-60.
  • Petersson F, Gatalica Z, Grossmann P, Perez Montiel MD, Alvarado Cabrero I, Bulimbasic S, Swatek A, Straka L, Tichy T, Hora M, Kuroda N, Legendre B, Michal M, Hes O. Sporadic hybrid oncocytic/chromophobe tumor of the kidney: a clinicopathologic, histomorphologic, immunohistochemical, ultrastructural, and molecular cytogenetic study of 14 cases. Virchows Arch. 2010 Apr;456(4):355-65.
  • Katzman PJ, Schwartz JI. Chromophobe renal cell carcinoma in a child: case report and review of the literature. Pediatr Dev Pathol. 2007 Mar-Apr;10(2):125-8.
  • Parada DD, Peña KB. Chromophobe renal cell carcinoma with neuroendocrine differentiation. APMIS. 2008 Sep;116(9):859-65.
  • Przybycin CG, Cronin AM, Darvishian F, Gopalan A, Al-Ahmadie HA, Fine SW, Chen YB, Bernstein M, Russo P, Reuter VE, Tickoo SK. Chromophobe renal cell carcinoma: a clinicopathologic study of 203 tumors in 200 patients with primary resection at a single institution. Am J Surg Pathol. 2011 Jul;35(7):962-70.
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