Renal Oncocytoma

Definition

• Benign neoplasm of the kidney composed of cells with mitochondria rich eosinophilic cytoplasm

Diagnostic Criteria

• Strictly defined, oncocytoma is benign
  • In the past, some cases of clear cell carcinoma and chromophobe carcinoma have been included in series of oncocytomas
    • Such cases probably explain the rare examples of metastatic oncocytoma
• Pathologic findings must fall within the following range of criteria
  • Grossly circumscribed but not encapsulated
    • Usually dark (mahogany) brown
      • Frequent central scar
    • No gross necrosis
  • Tight nests and alveoli surrounded by myxoid or hyalinized hypocellular stroma
    • Round balls of cells appearing to float in the stroma
    • Nests may form central lumen or multiple lumens
      • Nests may show central hyalinization
    • This pattern is nearly always present and usually predominates
    • Tubulocystic areas may also be present
      • Closely packed tubules and cysts with scant stroma
      • Usually mixed with nest pattern (above)
      • Exclusively or pronounced cystic growth suggests tubulocystic carcinoma, which is composed of cells reminiscent of oncocytoma
    • Solid areas may be formed by densely packed tight nests and alveoli
      • Nests retain their circumscribed pattern
        • Individually surrounded by reticulin, even in areas of collapse
      • Invariably merge with floating nests as above
  • Nearly all cells have prominent granular eosinophilic cytoplasm
    • Due to presence of numerous mitochondria
    • Foci of smaller cells with scant eosinophilic cytoplasm, hyperchromatic nuclei and high N:C ratio may be present
      • Should merge with conventional eosinophilic cells
      • Have been termed "oncoblasts"
      • Rare cases have been described in which these small cell predominate (Hes 2001, Petersson 2011)
        • Diagnosis should be made with great caution in such cases
    • Clear cytoplasm seen only in rare cells trapped in hyaline scarred areas
      • No peripheral ballooning of clear cells
    • No perinuclear clearing in eosinophilic cells
    • Extracellular eosinophilic round hyaline bodies may be seen within the nests (Guarino)
  • Round regular nuclei throughout
    • Frequently have dispersed chromatin and prominent central nucleolus
    • Mitotic figures are infrequent and never atypical
    • Intranuclear vacuoles may be seen
    • Foci of degenerative atypia may be present
      • Pleomorphic, hyperchromatic nuclei with smudged chromatin
        • Occasionally multinucleated or polylobated
      • Not associated with mitotic activity
      • Typically clustered, not diffuse
• Must not have any of the following features
  • Grossly visible or substantial microscopic necrosis
    • Focal microscopic necrosis is permitted
  • Sheet-like growth pattern
  • Prominent or well-developed papillary architecture, even if focal
    • Minimal short, degenerate appearing papillae are permitted
  • Significant clear cell population
    • Only focal clear cells in hyalinized scar area are permitted
  • Spindled/sarcomatoid change
  • Easily found mitotic activity
    • Any atypical mitotic figures
• Following features are permitted if above criteria (positive and negative) are fulfilled
  • Minimal microscopic necrosis
  • Infrequent mitotic figures
  • Rare, focal psammoma bodies and foam cells
  • Invasion of renal parenchyma (surrounded normal tubules)
    • Must not have desmoplastic response
  • Invasion of perirenal fat
    • Must not have desmoplastic response
  • Microscopic vascular and/or gross renal vein invasion (Hes 2008)
  • Pseudorosettes with PASd positive globule in center (Petersson 2011)
• Extensive sampling is required to confirm this diagnosis
  • At least 1 section per cm diameter

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, 11/27/11

Supplemental studies

Immunohistology

Extracellular hyaline bodies positive for collagen type I and IV, laminin and heparan sulfate

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

• Frequent loss of Y or chromosome 1
• No consistent loss of 3p or trisomy 7/17
  • Not commonly used for diagnosis

Differential Diagnosis

• Chromophobe carcinoma
• Clear cell renal cell carcinoma
• Papillary oncocytoma
• Tubulocystic renal cell carcinoma
• Neuroblastoma associated renal cell carcinoma

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

Conventional Clear Cell Renal Cell Carcinoma, Granular Variant	Renal Oncocytoma
Nearly always has clear cell areas	Clear cells only in focal, hyalinized scar areas
Prominent surrounding capillary network	Surrounding stroma hypocellular
Carbonic anhydrase IX, AMACR/racemase, vimentin usually pos	Carbonic anhydrase IX, AMACR/racemase, vimentin usually neg
cKIT/CD117 usually neg	cKIT/CD117 usually pos

Renal Oncocytoma	Oncocytic Papillary Renal Cell Carcinoma
Solid, with minimal, poorly developed papillary change	Usually predominantly papillary
At most, rare, focal foamy macrophages	May have clusters of foamy macrophages
Necrosis is rare and only microscopic foci	May have tumor cell necrosis
AMACR/racemase/P504S usually negative	AMACR/racemase/P504S positive

Occasional oncocytic papillary renal cell carcinomas may be largely solid; the bottom three criteria are more important in such cases

Tubulocystic Carcinoma of the Kidney	Renal Oncocytoma with Cystic Features
Overwhelmingly cystic	Usually solid nests with focal cystic dilation
Fibrotic stroma	Loose hypocellular stroma
Large irregular nuclei	Large round nuclei
Consistent prominent nucleoli	Nucleoli variably present
Racemase and CD10 positive	Racemase and CD10 usually negative

Renal Oncocytoma	Neuroblastoma Associated Renal Cell Carcinoma
No history of neuroblastoma	History of neuroblastoma
Rare in children	Most in children, some in young adults
Minimal papillary component	Usually papillary

Neuroblastoma associated carcinomas are typically composed of oncocytic cells, which may pose this differential

Grading / Staging

Grading/Staging

• Neither is required as oncocytoma is benign

Clinical

• Predominantly seen in adults but may be seen in children
  • Range 10-94, median 65
• Benign if strictly defined
  • Rarely reported malignant cases in the past probably represent chromophobe or clear cell carcinoma

Classification / Lists

Renal epithelial neoplasms

• Classical types
  • Clear cell (conventional) renal cell carcinoma
  • Multilocular clear cell renal cell carcinoma
  • Papillary renal cell carcinoma
  • Chromophobe renal cell carcinoma
  • Carcinoma of collecting ducts of Bellini
  • Renal cell carcinoma unclassified
  • Oncocytoma
  • Papillary adenoma
  • (Sarcomatoid)
• Newer variants and types
  • Renal medullary carcinoma
  • Mucinous tubular and spindle cell carcinoma
  • Tubulocystic carcinoma
  • Xp11 translocation carcinoma
  • Neuroblastoma associated renal cell carcinoma
  • Renal cell carcinoma associated with end stage renal disease
  • Thyroid-like follicular carcinoma of the kidney
  • Clear cell tubulopapillary renal cell carcinoma
  • Oncocytic papillary renal cell carcinoma
• Neuroendocrine tumors
  • Carcinoid
  • Neuroendocrine carcinoma

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, Amin MB, Zarbo RJ. Colloidal iron staining in renal epithelial neoplasms, including chromophobe renal cell carcinoma: emphasis on technique and patterns of staining. Am J Surg Pathol. 1998 Apr;22(4):419-24.
  
• Amin MB, Crotty TB, Tickoo SK, Farrow GM. Renal oncocytoma: a reappraisal of morphologic features with clinicopathologic findings in 80 cases. Am J Surg Pathol. 1997 Jan;21(1):1-12.
  
• Guarino M, Zuccoli E, Garda E, Cristofori E, Pallotti F, Nebuloni M, Giordano F. Extracellular matrix globules in renal oncocytoma. Pathol Res Pract. 2001;197(4):245-52.
  
• Hes O, Michal M, Boudova L, Mukensnabl P, Kinkor Z, Miculka P. Small cell variant of renal oncocytoma--a rare and misleading type of benign renal tumor. Int J Surg Pathol. 2001 Jul;9(3):215-22.
• Hes O, Michal M, Síma R, Vanecek T, Brunelli M, Martignoni G, Kuroda N, Cabrero IA, Perez-Montiel D, Hora M, Urge T, Dvorák M, Jarosová M, Yang X. Renal oncocytoma with and without intravascular extension into the branches of renal vein have the same morphological, immunohistochemical and genetic features. Virchows Arch. 2008 Mar;452(3):285-93.
• Petersson F, Síma R, Grossmann P, Michal M, Kuroda N, Hora M, Yang X, Kinkor Z, Trivunic S, Zalud R, Sperga M, Jaunmuktane Z, Branžovský J, Ferda J, Hes O. Renal small cell oncocytoma with pseudorosettes A histomorphologic, immunohistochemical, and molecular genetic study of 10 cases. Hum Pathol. 2011 Nov;42(11):1751-60.