Stewart Fleming

 stewart-flemingTumours of kidney and urinary tract – update on WHO classification, IHC and molecular morphology
Presentation (PDF)

The early 1990s saw a paradigm shift in the pathology of renal cell carcinoma (RCC) with the incorporation of our understanding of the molecular basis of tumour formation into the histopathological classification.  This thinking has continued in first the Heidelberg and subsequently WHO classifications of renal tumours1. The basis for this approach has been the observed remarkable correlation between genotype and morphology of renal carcinoma. The most common form of RCC is clear cell and these are almost always associated with functional loss of the Von Hippel Lindau protein by mutation and loss of wild type allele2.  This change leads via hypoxia inducible factors (HIFs) to a ‘pseudohypoxic’ phenotype with expression of VEGF and EGFR3.  We can measure the VHL loss directly by genotyping or indirectly by demonstrating the expression of hypoxia markers VEGF and carbonic anhydrase 9. Recently described RCC forms include fumarate hydratase mutation in the Herditary Leiomyomatosis4 and RCC syndrome (HLRCC) and succinate dehydrogenase B mutation in the SDH deficient RCC5. These lead to accumulation of fumarate and succinate which also lead to activation of the pseudohypoxic state through a mechanism of inhibition of the hydroxylation of the HIFs6.  These molecular data have informed the latest version of the WHO Classification of renal and urinary tract neoplasms.  The evidence for the importance of these molecular changes and the pathology of RCC including use of molecular techniques in diagnostic will be discussed.


  1. Kovacs G, Akhtar M, Beckwith BJ, et al. The Heidelberg classification of renal cell tumours. J Pathol 1997; 183(2): 131-3.

  2. Foster K, Prowse A, van den Berg A, et al. Somatic mutations of the von Hippel-Lindau disease tumour suppressor gene in non-familial clear cell renal carcinoma. Hum Mol Genet 1994; 3(12): 2169-73.

  3. Cockman ME, Masson N, Mole DR, et al. Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J Biol Chem 2000; 275(33): 25733-41.

  4. Alam NA, Rowan AJ, Wortham NC, et al. Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency. Hum Mol Genet 2003; 12(11): 1241-52.

  5. Housley SL, Lindsay RS, Young B, et al. Renal carcinoma with giant mitochondria associated with germ-line mutation and somatic loss of the succinate dehydrogenase B gene. Histopathology 2010; 56(3): 405-8.

  6. Ratcliffe PJ. Fumarate hydratase deficiency and cancer: activation of hypoxia signaling? Cancer Cell 2007; 11(4): 303-5.


Stewart Fleming is a medical graduate of the University of Glasgow.  He completed his residency training in Glasgow and was then appointed Lecturer at the University of Southampton and in 1988 Senior Lecturer in Edinburgh University.  His doctoral thesis involved investigating the development of Wilms’ tumour and led to the discovery of WT1 and its role in kidney and genital tract biology.  He has researched the genetics and pathology of renal tumours for 30 years including the discovery of VHL mutations in clear cell carcinoma, and the first descriptions of collecting duct carcinoma, succinate dehydrogenase deficient renal cancer and the pathology of fumarate hydratase mutations in HLRCC.  He has published over 150 papers on the pathology of the kidney and renal cancer and his work is cited more than 250 times per annum. He is the Professor of Pathology in the University of Dundee since 2000.