Best Practices Recommendations in the Application of Immunohistochemistry in the Kidney Tumors: Report From the International Society of Urologic Pathology Consensus Conference

Primary renal neoplasms comprise multiple distinct entities, some of which are well understood and others that are not. It is not uncommon for some of these entities to have overlapping morphologic features. Their clinical behavior is varied, ranging from highly malignant to benign, and metastatic renal cell carcinoma oftentimes enters into the differential diagnosis of tumors of unknown primary. In this age of personalized medicine, identifying biomarkers that can better predict clinical outcome and response to therapy is a pressing need. In 2013 the International Society of Urological Pathology held a meeting in which best practices recommendations on the use of immunohistochemical markers in urologic malignancies were discussed. In this review we make recommendations regarding immunohistochemical markers that are best suited to aid in establishing a diagnosis of renal primary, panels of antibodies that are most useful in classifying renal tumors, and the current status of prognostic and predictive biomarkers. Although no prognostic or predictive marker and set of markers have yet to be validated, ongoing research suggests that this fact is likely to change in the near future.

[1]  J. Cheville,et al.  Loss of BAP1 protein expression is an independent marker of poor prognosis in patients with low‐risk clear cell renal cell carcinoma , 2014, Cancer.

[2]  P. Argani,et al.  Comprehensive profile of GATA binding protein 3 immunohistochemical expression in primary and metastatic renal neoplasms. , 2014, Human pathology.

[3]  Markku Miettinen,et al.  GATA3: A Multispecific But Potentially Useful Marker in Surgical Pathology A Systematic Analysis of 2500 Epithelial and Nonepithelial Tumors , 2014, The American journal of surgical pathology.

[4]  Y. Lotan,et al.  Prognostic role of cell cycle and proliferative biomarkers in patients with clear cell renal cell carcinoma. , 2013, The Journal of urology.

[5]  B. Delahunt,et al.  Renal Tumors: Diagnostic and Prognostic Biomarkers , 2013, The American journal of surgical pathology.

[6]  Lars Egevad,et al.  The International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia , 2013, The American journal of surgical pathology.

[7]  The Cancer Genome Atlas Research Network COMPREHENSIVE MOLECULAR CHARACTERIZATION OF CLEAR CELL RENAL CELL CARCINOMA , 2013, Nature.

[8]  Han Liu,et al.  Clinical and pathologic impact of select chromatin-modulating tumor suppressors in clear cell renal cell carcinoma. , 2013, European urology.

[9]  D. Grignon,et al.  Clear cell papillary renal cell carcinoma: differential diagnosis and extended immunohistochemical profile , 2013, Modern Pathology.

[10]  C. Sander,et al.  Adverse Outcomes in Clear Cell Renal Cell Carcinoma with Mutations of 3p21 Epigenetic Regulators BAP1 and SETD2: A Report by MSKCC and the KIRC TCGA Research Network , 2013, Clinical Cancer Research.

[11]  A. Ziober,et al.  Malignant tumors with clear cell morphology: a comparative immunohistochemical study with renal cell carcinoma antibody, Pax8, steroidogenic factor 1, and brachyury. , 2013, Annals of diagnostic pathology.

[12]  W. Linehan,et al.  Renal Medullary Carcinoma: Molecular, Immunohistochemistry, and Morphologic Correlation , 2013, The American journal of surgical pathology.

[13]  A. Ziober,et al.  Role of carbonic anhydrase IX, α-methylacyl coenzyme a racemase, cytokeratin 7, and galectin-3 in the evaluation of renal neoplasms: a tissue microarray immunohistochemical study. , 2013, Annals of diagnostic pathology.

[14]  P. Kapur,et al.  Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation. , 2013, The Lancet. Oncology.

[15]  H. Moch,et al.  Loss of PBRM1 expression is associated with renal cell carcinoma progression , 2013, International journal of cancer.

[16]  T. Choueiri,et al.  Biomarkers: the next therapeutic hurdle in metastatic renal cell carcinoma , 2012, British Journal of Cancer.

[17]  R. Eccles,et al.  Combined p53 and MDM2 biomarker analysis shows a unique pattern of expression associated with poor prognosis in patients with renal cell carcinoma undergoing radical nephrectomy , 2012, BJU international.

[18]  R. Shah,et al.  p63, CK7, PAX8 and INI‐1: an optimal immunohistochemical panel to distinguish poorly differentiated urothelial cell carcinoma from high‐grade tumours of the renal collecting system , 2012, Histopathology.

[19]  L. Medeiros,et al.  N-terminal PAX8 polyclonal antibody shows cross-reactivity with N-terminal region of PAX5 and is responsible for reports of PAX8 positivity in malignant lymphomas , 2012, Modern Pathology.

[20]  L. Truong,et al.  Role of Immunohistochemistry in Diagnosing Renal Neoplasms , 2012 .

[21]  P. Argani,et al.  Cathepsin K expression in the spectrum of perivascular epithelioid cell (PEC) lesions of the kidney , 2012, Modern Pathology.

[22]  Ximing J. Yang,et al.  Expression of carbonic anhydrase IX in genitourinary and adrenal tumours , 2011, Histopathology.

[23]  J. Jeruc,et al.  Typing of renal tumors by morphological and immunocytochemical evaluation of fine needle aspirates , 2011, Virchows Archiv.

[24]  M. Ladanyi,et al.  Differential expression of cathepsin K in neoplasms harboring TFE3 gene fusions , 2011, Modern Pathology.

[25]  T. Berney,et al.  Immunohistochemical assessment of Pax8 expression during pancreatic islet development and in human neuroendocrine tumors , 2011, Histochemistry and Cell Biology.

[26]  Anil V Parwani,et al.  Diffuse Expression of PAX2 and PAX8 in the Cystic Epithelium of Mixed Epithelial Stromal Tumor, Angiomyolipoma With Epithelial Cysts, and Primary Renal Synovial Sarcoma: Evidence Supporting Renal Tubular Differentiation , 2011, The American journal of surgical pathology.

[27]  M. Rosenblum,et al.  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 , 2011, Modern Pathology.

[28]  P. Argani,et al.  Immunohistochemical analysis of SMARCB1/INI-1 expression in collecting duct carcinoma. , 2011, Urology.

[29]  P. Russo,et al.  Role of Immunohistochemistry in the Evaluation of Needle Core Biopsies in Adult Renal Cortical Tumors: An Ex Vivo Study , 2011, The American journal of surgical pathology.

[30]  P. A. Futreal,et al.  Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma , 2010, Nature.

[31]  L. Truong,et al.  Immunohistochemical diagnosis of renal neoplasms. , 2011, Archives of pathology & laboratory medicine.

[32]  J. McKenney,et al.  The Utility of Pax-2 and Renal Cell Carcinoma Marker Immunohistochemistry in Distinguishing Papillary Renal Cell Carcinoma From Nonrenal Cell Neoplasms With Papillary Features , 2010, Applied immunohistochemistry & molecular morphology : AIMM.

[33]  A. Sangoi,et al.  The Use of Immunohistochemistry in the Diagnosis of Metastatic Clear Cell Renal Cell Carcinoma: A Review of PAX-8, PAX-2, hKIM-1, RCCma, and CD10 , 2010, Advances in anatomic pathology.

[34]  B. Delahunt,et al.  Clear Cell Tubulopapillary Renal Cell Carcinoma: A Study of 36 Distinctive Low-grade Epithelial Tumors of the Kidney , 2010, The American journal of surgical pathology.

[35]  S. Signoretti,et al.  Carbonic anhydrase IX and pathological features as predictors of outcome in patients with metastatic clear‐cell renal cell carcinoma receiving vascular endothelial growth factor‐targeted therapy , 2010, BJU international.

[36]  M. Ladanyi,et al.  Xp11 Translocation Renal Cell Carcinoma (RCC): Extended Immunohistochemical Profile Emphasizing Novel RCC Markers , 2010, The American journal of surgical pathology.

[37]  L. Truong,et al.  PAX-2 Expression in Non-neoplastic, Primary Neoplastic, and Metastatic Neoplastic Tissue: A Comprehensive Immunohistochemical Study , 2010, Applied immunohistochemistry & molecular morphology : AIMM.

[38]  W. Oyen,et al.  Carbonic anhydrase IX in renal cell carcinoma: implications for prognosis, diagnosis, and therapy. , 2010, European urology.

[39]  V. Reuter,et al.  Differential diagnosis of renal tumours with clear cell histology. , 2010, Pathology.

[40]  N. Kanomata,et al.  Immunohistochemical application of S100A1 in renal oncocytoma, oncocytic papillary renal cell carcinoma, and two variants of chromophobe renal cell carcinoma , 2011, Medical Molecular Morphology.

[41]  H. Moch,et al.  Diagnostic and prognostic molecular markers for renal cell carcinoma: a critical appraisal of the current state of research and clinical applicability. , 2009, European urology.

[42]  L. Truong,et al.  PAX-2 in the diagnosis of primary renal tumors: immunohistochemical comparison with renal cell carcinoma marker antigen and kidney-specific cadherin. , 2009, American journal of clinical pathology.

[43]  A. Young,et al.  Claudin-7 and claudin-8: immunohistochemical markers for the differential diagnosis of chromophobe renal cell carcinoma and renal oncocytoma. , 2009, Human pathology.

[44]  M. Amin,et al.  Diagnostic Implications of Transcription Factor Pax 2 Protein and Transmembrane Enzyme Complex Carbonic Anhydrase IX Immunoreactivity in Adult Renal Epithelial Neoplasms , 2009, The American journal of surgical pathology.

[45]  P. Argani,et al.  Papillary Renal Cell Carcinoma With Low-grade Spindle Cell Foci: A Mimic of Mucinous Tubular and Spindle Cell Carcinoma , 2008, The American journal of surgical pathology.

[46]  F. Waldman,et al.  von Hippel-Lindau gene status and response to vascular endothelial growth factor targeted therapy for metastatic clear cell renal cell carcinoma. , 2008, The Journal of urology.

[47]  L. Qin,et al.  Carbonic Anhydrase IX Expression in Clear Cell Renal Cell Carcinoma: An Immunohistochemical Study Comparing 2 Antibodies , 2008, The American journal of surgical pathology.

[48]  David B Seligson,et al.  Hypoxia-Inducible Factor 1α in Clear Cell Renal Cell Carcinoma , 2007, Clinical Cancer Research.

[49]  S. Signoretti,et al.  Potential histologic and molecular predictors of response to temsirolimus in patients with advanced renal cell carcinoma. , 2007, Clinical genitourinary cancer.

[50]  J. Cheville,et al.  Carbonic anhydrase IX is not an independent predictor of outcome for patients with clear cell renal cell carcinoma. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[51]  J. Srigley,et al.  Expression Analysis of Kidney-specific Cadherin in a Wide Spectrum of Traditional and Newly Recognized Renal Epithelial Neoplasms: Diagnostic and Histogenetic Implications , 2007, The American journal of surgical pathology.

[52]  K. Grankvist,et al.  Prognostic impact of carbonic anhydrase IX expression in human renal cell carcinoma , 2007, BJU international.

[53]  R. Shah,et al.  Expression of Renal Cell Carcinoma Antigen (RCC) in Renal Epithelial and Nonrenal Tumors: Diagnostic Implications , 2007, Applied immunohistochemistry & molecular morphology : AIMM.

[54]  A. Scarpa,et al.  Diagnostic utility of S100A1 expression in renal cell neoplasms: an immunohistochemical and quantitative RT-PCR study , 2007, Modern Pathology.

[55]  P. Russo,et al.  Immunohistochemical expression of hypoxia inducible factor-1alpha and its downstream molecules in sarcomatoid renal cell carcinoma. , 2007, The Journal of urology.

[56]  M. Péoc'h,et al.  S100A1: a powerful marker to differentiate chromophobe renal cell carcinoma from renal oncocytoma. , 2006, Histopathology.

[57]  K. Grankvist,et al.  Hypoxia-Inducible Factor 1α Expression in Renal Cell Carcinoma Analyzed by Tissue Microarray , 2006 .

[58]  Ximing J. Yang,et al.  Expression of kidney-specific cadherin in chromophobe renal cell carcinoma and renal oncocytoma. , 2006, American journal of clinical pathology.

[59]  V. Reuter,et al.  Alpha-methylacyl-CoA racemase as a marker in the differential diagnosis of metanephric adenoma , 2006, Modern Pathology.

[60]  J. Srigley,et al.  Immunohistochemical Analysis of Mucinous Tubular and Spindle Cell Carcinoma and Papillary Renal Cell Carcinoma of the Kidney: Significant Immunophenotypic Overlap Warrants Diagnostic Caution , 2006, The American journal of surgical pathology.

[61]  C. Magi-Galluzzi,et al.  The usefulness of immunohistochemical markers in the differential diagnosis of renal neoplasms. , 2005, Clinics in laboratory medicine.

[62]  S. Signoretti,et al.  Carbonic Anhydrase IX Expression Predicts Outcome of Interleukin 2 Therapy for Renal Cancer , 2005, Clinical Cancer Research.

[63]  S. Mills,et al.  KIT and RCC Are Useful in Distinguishing Chromophobe Renal Cell Carcinoma From the Granular Variant of Clear Cell Renal Cell Carcinoma , 2005, The American journal of surgical pathology.

[64]  Joon-Oh Park,et al.  Somatic VHL alteration and its impact on prognosis in patients with clear cell renal cell carcinoma. , 2005, Oncology reports.

[65]  M. Ladanyi,et al.  Renal Carcinomas With the t(6;11)(p21;q12): Clinicopathologic Features and Demonstration of the Specific Alpha-TFEB Gene Fusion by Immunohistochemistry, RT-PCR, and DNA PCR , 2005, The American journal of surgical pathology.

[66]  M. Ladanyi,et al.  Aberrant Nuclear Immunoreactivity for TFE3 in Neoplasms With TFE3 Gene Fusions: A Sensitive and Specific Immunohistochemical Assay , 2003, The American journal of surgical pathology.

[67]  Steve Horvath,et al.  Carbonic anhydrase IX is an independent predictor of survival in advanced renal clear cell carcinoma: implications for prognosis and therapy. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[68]  Kazuki Kobayashi,et al.  VHL tumor suppressor gene alterations associated with good prognosis in sporadic clear-cell renal carcinoma. , 2002, Journal of the National Cancer Institute.

[69]  Holger Moch,et al.  VHL mutations and their correlation with tumour cell proliferation, microvessel density, and patient prognosis in clear cell renal cell carcinoma , 2002, The Journal of pathology.

[70]  L. Truong,et al.  Diagnosing Primary and Metastatic Renal Cell Carcinoma: The Use of the Monoclonal Antibody `Renal Cell Carcinoma Marker' , 2001, The American journal of surgical pathology.

[71]  P. Chu,et al.  Paraffin-section detection of CD10 in 505 nonhematopoietic neoplasms. Frequent expression in renal cell carcinoma and endometrial stromal sarcoma. , 2000, American journal of clinical pathology.

[72]  E. Jones,et al.  Renal oncocytoma and chromophobe renal cell carcinoma. A comparison of colloidal iron staining and electron microscopy. , 1999, American journal of clinical pathology.

[73]  S. Tickoo,et al.  Discriminant nuclear features of renal oncocytoma and chromophobe renal cell carcinoma. Analysis of their potential utility in the differential diagnosis. , 1998, American journal of clinical pathology.

[74]  S. Tickoo,et al.  Colloidal iron staining in renal epithelial neoplasms, including chromophobe renal cell carcinoma: emphasis on technique and patterns of staining. , 1998, The American journal of surgical pathology.

[75]  M. Toublanc,et al.  Renal chromophobe cell carcinoma and oncocytoma. A comparative morphologic, histochemical, and immunohistochemical study of 124 cases. , 1997, Archives of pathology & laboratory medicine.