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Renal Medullary Carcinoma

Definition

  • High grade renal adenocarcinoma arising in medulla of the kidney, associated with sickle cell trait

Alternate/Historical Names

  • In the past, some were included in collecting duct carcinoma
    • Distinction may be largely clinical (see Differential Diagnosis at left)

Diagnostic Criteria

  • Essentially every case associated with sickle cell trait or sickle cell disease
    • Sickled cells may be seen in adjacent vessels
    • Nearly all of African ancestry
  • Firm mass centered on the renal medulla
    • Frequently extends into renal cortex and/or pelvis
  • Infiltrating sheets or cords of cells
    • Frequent reticular/microcystic pattern
      • Spaces of varying size
      • Reminiscent of yolk sac tumor
      • May also have tubular and papillary patterns
    • Dark eosinophilic granular cytoplasm
    • Intralumenal mucin frequent
    • Extra-renal and vascular invasion frequent
  • Rhabdoid pattern may be seen
    • INI1 negative (all patterns)
  • Prominent stromal desmoplasia
    • May be collagenous or myxoid
  • High grade nuclear atypia
    • Pleomorphic vesicular nuclei with large nucleoli
    • Frequent mitotic figures
    • Frequent necrosis and hemorrhage
      • May form microabscesses
  • Renal medullary carcinoma is considered a separate entity from collecting duct carcinoma
    • Considered by some reports to be a variant of collecting duct carcinoma
    • Overlaps histopathologically with collecting duct carcinoma but is separated based on the following features
      • Occurrence in young patients
      • Association with sickle cell trait
      • Lack of INI1 expression (Cheng 2008) vs retention in 85% of collecting duct carcinoma (Elwood 2011)

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, 6/17/12, 12/29/12

Supplemental studies

Immunohistology

Low MW keratin pos
High MW keratin neg
EMA pos
Vimentin pos
CK7 variable
CEA

variable

CK20 neg
INI1 neg
  • One series reports germ cell tumor marker OCT3/4 positive in 10/14 medullary carcinomas (Rao)
    • SALL4 negative
    • Collecting duct and urothelial carcinomas negative

 

Differential Diagnosis

Urothelial Carcinoma Medullary Carcinoma of the Kidney
Adjacent usual urothelial carcinoma or carcinoma in situ frequently present Lacks urothelial components
Mean age >50 Mean age 20
No association with sickle cell Associated with sickle cell trait
OCT3/4 negative OCT3/4 69% positive

Medullary Carcinoma of the Kidney Collecting Duct Carcinoma
Frequent solid and/or reticular areas Predominantly tubular and papillary
Mean age 20-24 Mean age 50-55
Associated with sickle cell trait/disease No association with sickle cell
INI negative INI positive in 85%
OCT3/4 69% positive OCT3/4 negative
The distinction may be largely clinical as there is considerable morphologic overlap

Grading / Staging

Grading

  • Definitionally high grade (see below)

Staging

  • Use TNM
  • Nearly all present with high stage

  • 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 20-24
      • Range 5-69
    • M:F = 3:1 to 10:1
    • Virtually all patients of African ancestry with sickle cell trait or disease
    • Poor prognosis
      • 95% have metastases at presentation

    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.
    • Davis CJ Jr, Mostofi FK, Sesterhenn IA. Renal medullary carcinoma. The seventh sickle cell nephropathy. Am J Surg Pathol. 1995 Jan;19(1):1-11.
    • Watanabe IC, Billis A, Guimarães MS, Alvarenga M, de Matos AC, Cardinalli IA, Filippi RZ, de Castro MG, Suzigan S. Renal medullary carcinoma: report of seven cases from Brazil. Mod Pathol. 2007 Sep;20(9):914-20.
    • Swartz MA, Karth J, Schneider DT, Rodriguez R, Beckwith JB, Perlman EJ. Renal medullary carcinoma: clinical, pathologic, immunohistochemical, and genetic analysis with pathogenetic implications. Urology. 2002 Dec;60(6):1083-9.
    • Rao P, Tannir NM, Tamboli P. Expression of OCT3/4 in renal medullary carcinoma represents a potential diagnostic pitfall. Am J Surg Pathol. 2012 Apr;36(4):583-8.
    • Cheng JX, Tretiakova M, Gong C, Mandal S, Krausz T, Taxy JB. Renal medullary carcinoma: rhabdoid features and the absence of INI1 expression as markers of aggressive behavior. Mod Pathol. 2008 Jun;21(6):647-52.
    • Elwood H, Chaux A, Schultz L, Illei PB, Baydar DE, Billis A, Sharma R, Argani P, Epstein JI, Netto GJ. Immunohistochemical analysis of SMARCB1/INI-1 expression in collecting duct carcinoma. Urology. 2011 Aug;78(2):474.e1-5.
    • Gupta R, Billis A, Shah RB, Moch H, Osunkoya AO, Jochum W, Hes O, Bacchi CE, de Castro MG, Hansel DE, Zhou M, Vankalakunti M, Salles PG, Cabrera RA, Gown AM, Amin MB. Carcinoma of the collecting ducts of Bellini and renal medullary carcinoma: clinicopathologic analysis of 52 cases of rare aggressive subtypes of renal cell carcinoma with a focus on their interrelationship. Am J Surg Pathol. 2012 Sep;36(9):1265-78.
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