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Xp11 / TFE3 Translocation Carcinoma of the Kidney

Definition

  • Renal carcinoma comprising a large fraction of renal carcinomas occurring in young patients and associated with translocations involving the TFE3 gene at chromosome Xp11.2

Alternate/Historical Names

  • Juvenile renal cell carcinoma

Diagnostic Criteria

  • Most cases reported in children and young adults, mean age 25 years
    • Under-recognized in adults
      • Two studies find an incidence of 1-5% in adults (Zhong, Sukov)
      • If possible, fresh tumor tissue should be sent for cytogenetics in all renal tumor patients under 40 years of age and in older patients in which an unusual tumor is discovered at frozen section
  • Composed of cells with abundant to voluminous cytoplasm
    • Clear to granular eosinophilic cytoplasm
    • Sharp cell borders
  • Pleomorphic and polymorphic growth patterns
    • Frequent papillary, pseudopapillary, alveolar and nested patterns
    • Clusters of small cells centered on hyaline cores may be seen
      • Collections of small cells should suggest a t(6;11) carcinoma
    • Patterns and cells may vary according to the precise translocation involved
  • Large vesicular nuclei
    • Prominent round nucleoli
    • Mitotic figures frequent
  • Features frequently present
    • Psammoma bodies may be abundant
    • Intracytoplasmic hyaline droplets
  • Melanocytic variant has been reported
  • Presence of Xp11 translocation by classical cytogenetics, PCR or FISH
    • Demonstration may not be required in every case
    • TFE3 immunohistochemistry may be less reliable than reported in the literature with numerous false positives
    • Lack of, or minimal, cytokeratin and EMA expression may be the most helpful immunophenotypic findings

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

Original posting: January 24, 2011
Last update: 6/17/12

Supplemental studies

Immunohistology

Keratin weak to neg
EMA, CK7 neg
AMACR/racemase/P504S pos
CD10 pos
CD117 neg
TFE3 or TFEB

pos
MelanA, HMB45 neg-90% pos, frequently weak
  • Rare melanocytic variants are HMB45, MelanA pos, MiTF and actin negative
  • TFE3 immunohistochemistry may be less reliable than reported in the literature with numerous false positives
  • Lack of, or minimal, cytokeratin and EMA expression may be the most helpful immunophenotypic findings

Molecular Genetic Study

  • Classical cytogenetics, PCR and FISH can demonstrate translocations involving Xp11

Differential Diagnosis

  • Translocation carcinoma should be considered in the following situations
    • Any clear or papillary renal carcinoma in a patient under 35
    • Any carcinoma combining papillary with clear cell features
    • Any carcinoma with nests of cells with voluminous cytoplasm
    • Any carcinoma with large numbers of psammoma bodies
  • Immunohistochemistry can be useful in such cases
  • FISH or PCR may be required to make the diagnosis

Immunohistochemistry for the differential diagnosis of renal translocation carcinomas
  CD10 Racemase CK7 EMA CD117
Translocation Ca >90% >90% neg neg neg
Clear Cell Ca >90% 0-20% neg >90% neg
Papillary Ca >90% >90% >90% >90% neg
Chromophobe Ca neg neg >90% >90% >90%
Nuclear staining for TFE3 and/or TFEB (if available) appears to be sensitive and specific for translocation carcinoma

Xp11 Translocation Renal Cell Carcinoma Clear Cell Tubulopapillary Renal Cell Carcinoma
Frequently occurs under age 20 Mean age 60
Typically high grade nuclear features Low grade nuclear features
Voluminous cytoplasm Moderate amount of clear cytoplasm
TPE3 immunostain or FISH positive in >80% Lacks Xp11 translocations
CK7 and other keratins negative to weak, CD10 pos, Racemase/AMACR pos CK7 strong pos, CD10 neg, Racemase/AMACR neg

Grading / Staging

Grading

  • Use Fuhrman grading, but significance is unclear (see below)
    • Most cases grade 3

Staging

  • Use TNM for renal cell carcinoma

  • 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.

    Clinical

    • Mean age reported about 25
      • Most studies have focused on renal tumors arising in young people
      • Has been reported at all ages
        • Clearly has been under-recognized in the past in adults
    • Behavior uncertain
      • Frequently presents with metastases
      • Initial reports suggested relatively indolent behavior
      • Later reports describe more aggressive behavior, especially in adults
    • A few cases have been reported following chemotherapy for other processes

    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.
    • Srigley JR, Delahunt B. Uncommon and recently described renal carcinomas. Mod Pathol. 2009 Jun;22 Suppl 2:S2-S23.
    • Argani P, Hicks J, De Marzo AM, Albadine R, Illei PB, Ladanyi M, Reuter VE, Netto GJ. Xp11 translocation renal cell carcinoma (RCC): extended immunohistochemical profile emphasizing novel RCC markers. Am J Surg Pathol. 2010 Sep;34(9):1295-303.
    • Zhong M, De Angelo P, Osborne L, Keane-Tarchichi M, Goldfischer M, Edelmann L, Yang Y, Linehan WM, Merino MJ, Aisner S, Hameed M. Dual-color, break-apart FISH assay on paraffin-embedded tissues as an adjunct to diagnosis of Xp11 translocation renal cell carcinoma and alveolar soft part sarcoma. Am J Surg Pathol. 2010 Jun;34(6):757-66.
    • Armah HB, Parwani AV. Xp11.2 translocation renal cell carcinoma. Arch Pathol Lab Med. 2010 Jan;134(1):124-9.
    • Chang IW, Huang HY, Sung MT. Melanotic Xp11 translocation renal cancer: a case with PSF-TFE3 gene fusion and up-regulation of melanogenetic transcripts. Am J Surg Pathol. 2009 Dec;33(12):1894-901.
    • Argani P, Aulmann S, Karanjawala Z, Fraser RB, Ladanyi M, Rodriguez MM. Melanotic Xp11 translocation renal cancers: a distinctive neoplasm with overlapping features of PEComa, carcinoma, and melanoma. Am J Surg Pathol. 2009 Apr;33(4):609-19.
    • Wu A, Kunju LP, Cheng L, Shah RB. Renal cell carcinoma in children and young adults: analysis of clinicopathological, immunohistochemical and molecular characteristics with an emphasis on the spectrum of Xp11. translocation-associated and unusual clear cell subtypes. Histopathology. 2008 Nov;53(5):533-44.
    • Camparo P, Vasiliu V, Molinie V, Couturier J, Dykema KJ, Petillo D, Furge KA, Comperat EM, Lae M, Bouvier R, Boccon-Gibod L, Denoux Y, Ferlicot S, Forest E, Fromont G, Hintzy MC, Laghouati M, Sibony M, Tucker ML, Weber N, Teh BT, Vieillefond A. Renal translocation carcinomas: clinicopathologic, immunohistochemical, and gene expression profiling analysis of 31 cases with a review of the literature. Am J Surg Pathol. 2008 May;32(5):656-70.
    • Meyer PN, Clark JI, Flanigan RC, Picken MM. Xp11.2 translocation renal cell carcinoma with very aggressive course in five adults. Am J Clin Pathol. 2007 Jul;128(1):70-9.
    • Zhong M, De Angelo P, Osborne L, Paniz-Mondolfi AE, Geller M, Yang Y, Linehan WM, Merino MJ, Cordon-Cardo C, Cai D. Translocation renal cell carcinomas in adults: a single-institution experience. Am J Surg Pathol. 2012 May;36(5):654-62.
    • Sukov WR, Hodge JC, Lohse CM, Leibovich BC, Thompson RH, Pearce KE, Wiktor AE, Cheville JC. TFE3 rearrangements in adult renal cell carcinoma: clinical and pathologic features with outcome in a large series of consecutively treated patients. Am J Surg Pathol. 2012 May;36(5):663-70.
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