Differential diagnosis of renal tumors with clear cytoplasm: clinical relevance of renal tumor subclassification in the era of targeted therapies and personalized medicine

Arch Pathol Lab Med. 2013 Apr;137(4):467-80. doi: 10.5858/arpa.2012-0085-RA.


Context: The World Health Organization classification of renal tumors synthesizes morphologic, immunohistochemical, and molecular findings to define more than 40 tumor types. Of these, clear cell (conventional) renal cell carcinoma is the most common malignant tumor in adults and-with the exception of some rare tumors-the most deadly. The diagnosis of clear cell renal cell carcinoma on morphologic grounds alone is generally straightforward, but challenging cases are not infrequent. A misdiagnosis of clear cell renal cell carcinoma has clinical consequences, particularly in the current era of targeted therapies.

Objective: To highlight morphologic mimics of clear cell renal cell carcinoma and provide strategies to help differentiate clear cell renal cell carcinoma from other renal tumors and lesions. The role of the pathologist in guiding treatment for renal malignancies will be emphasized to stress the importance of proper tumor classification in patient management.

Data sources: Published literature and personal experience.

Conclusions: In challenging cases, submission of additional tissue is often an inexpensive and effective way to facilitate a correct diagnosis. If immunohistochemical stains are to be used, it is best to use a panel of markers, as no one marker is specific for a given renal tumor subtype. Selection of limited markers, based on a specific differential diagnosis, can be as useful as a large panel in reaching a definitive diagnosis. For renal tumors, both the presence and absence of immunoreactivity and the pattern of labeling (membranous, cytoplasmic, diffuse, focal) are important when interpreting the results of immunohistochemical stains.

Publication types

  • Review

MeSH terms

  • Adenocarcinoma, Papillary / diagnosis*
  • Adenoma, Oxyphilic / diagnosis*
  • Adrenal Cortex Neoplasms / diagnosis*
  • Angiomyolipoma / diagnosis*
  • Biomarkers, Tumor / metabolism
  • Carcinoma, Renal Cell / classification
  • Carcinoma, Renal Cell / diagnosis*
  • Carcinoma, Renal Cell / drug therapy
  • Carcinoma, Renal Cell / metabolism
  • Diagnosis, Differential
  • Epithelioid Cells / pathology
  • Genetic Markers
  • Humans
  • Kidney Neoplasms / classification
  • Kidney Neoplasms / diagnosis*
  • Kidney Neoplasms / drug therapy
  • Kidney Neoplasms / metabolism
  • Molecular Targeted Therapy
  • Precision Medicine
  • Translocation, Genetic
  • World Health Organization


  • Biomarkers, Tumor
  • Genetic Markers