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Clear Cell Tubulopapillary Renal Cell Carcinoma

Definition

  • CK7 positive, CD10 and Racemase negative clear cell carcinoma with tubulopapillary patterns

Alternate/Historical Names

  • Clear cell papillary and cystic renal cell carcinoma
  • Clear cell papillary renal cell carcinoma
  • Clear cell papillary renal cell carcinoma of end stage kidneys
  • Renal angiomyoadenomatous tumor
  • Sporadic renal cell carcinoma with diffuse CK7 reactivity

Diagnostic Criteria

  • Most tumors exhibit mixtures of tubular, cystic and papillary patterns
    • Branching tubules and anastomosing ribbons
      • Lumens may contain eosinophilic secretion
      • Lumens may be compressed by sclerosis
      • Nuclei typically uniformly separated from base of cell by clear cytoplasm (pseudoendometrial appearance)
    • Multicystic with variably sized cysts
      • Frequent intracystic papillae
    • Papillae ranging from coarse to fine
      • No foamy macrophages or psammoma bodies
  • All patterns lined by a single layer of cuboidal cells
    • Scant eosinophilic or moderate clear cytoplasm
    • Frequently subnuclear clearing
  • Low grade and stage
    • Fuhrman grade 1 or 2
    • Over 95% pT1a
      • No vascular or renal sinus invasion
    • May be multifocal
  • Frequent prominent partial to complete capsule
    • Most cases have at least focal smooth muscle in capsule
    • Occasional cases have at least focal smooth muscle in the tumor stroma
  • Immunophenotype CK7 strong positive, CD10 negative to focal, Racemase negative
  • Small solid foci of clear cells reminiscent of conventional clear cell renal cell carcinoma may be seen
    • These may be formed by compressed aggregates of tubules
    • There is no immunohistochemical or genetic evidence that they are precursors of conventional carcinoma
  • May be seen in sporadic patients and in those with end stage renal disease (Tickoo)
  • Relationship to clear cell renal cell carcinoma with angioleiomyomatous stroma is not clear (Kuhn; Shannon; Mai 2010)
    • Reported cases are CK7+ but CD10+ also (small numbers tested)
    • Three cases studied with FISH show chromosome 3 abnormalities consistent with conventional clear cell RCC (Shannon)

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: 11/11/11

Supplemental studies

Immunohistology

CK7, EMA, carbonic anhydrase IX (CA9) 100% strong pos
CD10 neg to focal (<10% of cells)
AMACR/racemase/P504S neg
TFE3

neg

Genetic Studies

  • While not typically used for diagnosis, clear cell tubulopapillary carcinomas are distinct from both conventional clear cell and papillary carcinomas

Differential Diagnosis

Papillary Renal Cell Carcinoma Clear Cell Tubulopapillary Renal Cell Carcinoma
Clear cell cytoplasm, if present, is focal Widespread clear cell cytoplasm, frequently subnuclear/basal
Frequently has foamy macrophages, psammoma bodies, stromal hemosiderin Lacks foamy macrophages, psammoma bodies, stromal hemosiderin
May have high grade nuclear features and necrosis Low grade nuclear features, no necrosis
CD10 pos, Racemase/AMACR pos CD10 neg, Racemase/AMACR neg

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

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

Multilocular Cystic Renal Cell Carcinoma Clear Cell Tubulopapillary Renal Cell Carcinoma
No tubules, ribbons or papillae Nearly all have branched tubules, anastomosing ribbons and papillae
Clear cytoplasm apical or diffuse, non-localized Frequent regular basal clearing, resembling interval endometrium
Nests of clear cells in septa Nests of clear cells if present are formed by compressed tubules, each of which is only two cells wide
CK7 neg, CD10 pos CK7 pos, CD10 neg to focal

Grading / Staging

Grading

  • All reported cases are Fuhrman grade 1 or 2 (see below)

Staging

  • Use TNM for renal cell carcinoma
    • 95% are pT1a

  • 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 about 60
      • Range 26-85
    • No aggressive behavior or metastases reported
    • May be associated with end stage renal disease
      • Same appearance and indolent behavior

    Classification / Lists

    Renal epithelial neoplasms

    Bibliography

    • Aydin H, Chen L, Cheng L, Vaziri S, He H, Ganapathi R, Delahunt B, Magi-Galluzzi C, Zhou M. Clear cell tubulopapillary renal cell carcinoma: a study of 36 distinctive low-grade epithelial tumors of the kidney. Am J Surg Pathol. 2010 Nov;34(11):1608-21.
    • Srigley JR, Delahunt B. Uncommon and recently described renal carcinomas. Mod Pathol. 2009 Jun;22 Suppl 2:S2-S23.
    • Kuhn E, De Anda J, Manoni S, Netto G, Rosai J. Renal cell carcinoma associated with prominent angioleiomyoma-like proliferation: Report of 5 cases and review of the literature. Am J Surg Pathol. 2006 Nov;30(11):1372-81.
    • Shannon BA, Cohen RJ, Segal A, Baker EG, Murch AR. Clear cell renal cel carcinoma with smooth muscle stroma. Hum Pathol. 2009 Mar;40(3):425-9. Epub 2008 Sep 11.
    • Mai KT, Faraji H, Desantis D, Robertson SJ, Belanger EC, Levac J. Renal cell carcinoma with mixed features of papillary and clear cell cytomorphology: a fluorescent in situ hybridization study. Virchows Arch. 2010 Jan;456(1):77-84.
    • Mai KT, Kohler DM, Belanger EC, Robertson SJ, Wang D. Sporadic clear cell renal cell carcinoma with diffuse cytokeratin 7 immunoreactivity. Pathology. 2008 Aug;40(5):481-6.
    • Michal M, Hes O, Nemcova J, Sima R, Kuroda N, Bulimbasic S, Franco M, Sakaida N, Danis D, Kazakov DV, Ohe C, Hora M. Renal angiomyoadenomatous tumor: morphologic, immunohistochemical, and molecular genetic study of a distinct entity. Virchows Arch. 2009 Jan;454(1):89-99.
    • Tickoo SK, dePeralta-Venturina MN, Harik LR, Worcester HD, Salama ME, Young AN, Moch H, Amin MB. Spectrum of epithelial neoplasms in end-stage renal disease: an experience from 66 tumor-bearing kidneys with emphasis on histologic patterns distinct from those in sporadic adult renal neoplasia. Am J Surg Pathol. 2006 Feb;30(2):141-53.
    • Gobbo S, Eble JN, Grignon DJ, Martignoni G, MacLennan GT, Shah RB, Zhang S, Brunelli M, Cheng L. Clear cell papillary renal cell carcinoma: a distinct histopathologic and molecular genetic entity. Am J Surg Pathol. 2008 Aug;32(8):1239-45.
    • Adam J, Couturier J, Molinié V, Vieillefond A, Sibony M. Clear-cell papillary renal cell carcinoma: 24 cases of a distinct low-grade renal tumour and a comparative genomic hybridization array study of seven cases. Histopathology. 2011 Jun;58(7):1064-71.
    • Rohan SM, Xiao Y, Liang Y, Dudas ME, Al-Ahmadie HA, Fine SW, Gopalan A, Reuter VE, Rosenblum MK, Russo P, Tickoo SK. Clear-cell papillary renal cell carcinoma: molecular and immunohistochemical analysis with emphasis on the von Hippel-Lindau gene and hypoxia-inducible factor pathway-related proteins. Mod Pathol. 2011 Sep;24(9):1207-20.
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