Review of succinate dehydrogenase-deficient renal cell carcinoma with focus on clinical and pathobiological aspects.

Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) was first identified in 2004 and has been integrated into the 2016 WHO classification of RCC. Succinate dehydrogenase (SDH) is an enzyme complex composed of four protein subunits (SDHA, SDHB, SDHC and SDHD). The tumor which presents this enzyme mutation accounts for 0.05 to 0.2% of all renal carcinomas. Multiple tumors may occur in approximately 30% of affected patients. SDHB-deficient RCC is the most frequent, and the tumor histologically consists of cuboidal cells with eosinophilic cytoplasm, vacuolization, flocculent intracytoplasmic inclusion and indistinct cell borders. Ultrastructurally, the tumor contains abundant mitochondria. Immunohistochemically, tumor cells are positive for SDHA, but negative for SDHB in SDHB-, SDHC- and SDHD-deficient RCCs. However, SDHA-deficient RCC shows negativity for both SDHA and SDHB. In molecular genetic analyses, a germline mutation in the SDHB, SDHC or SDHD gene (in keeping with most patients having germline mutations in an SDH gene) has been identified in patients with or without a family history of renal tumors, paraganglioma/pheochromocytoma or gastrointestinal stromal tumor. While most tumors are low grade, some tumors may behave in an aggressive fashion, particularly if they are high nuclear grade, and have coagulative necrosis or sarcomatoid differentiation.

Tubulo-interstitial involvement in lupus nephritis with emphasis on pathogenesis.

Glomerular lesions in lupus nephritis have been extensively studied in recent decades, but much less attention has been paid to the tubulo-interstitial compartment. The aim of this study was to contribute to the understanding of the pathogenesis of tubulo-interstitial lesions in lupus nephritis by analysing their incidence, character, and their associations. One hundred and ninety kidney biopsies of 190 patients fulfilling American Rheumatology Association (ARA) criteria of systemic lupus erythematosus (SLE) were examined by traditional light, immunofluorescence and electron microscopy. Interstitial inflammatory infiltration and tubulo-interstitial immune deposits concurred in 72 cases (37.9%). Their frequency was the highest in WHO class IV lupus glomerulonephritis. By multivariate analysis, the intensity of interstitial inflammatory infiltration correlated best with the percentage of renal corpuscules with extracapillary crescents and the extent of interstitial fibrosis. On immunohistochemical assessment, the inflammatory infiltrate was found to be composed of CD45RO positive T lymphocytes (191.3/mm2), CD68 positive macrophages (101.7/mm2) and CD45RA positive B lymphocytes (17.2/mm2). For all cell types the median value was higher in cases with extracapillary crescents, and did not correlate with presence and intensity of tubulo-interstitial immune deposits. Infiltration showed the tendency of periglomerular distribution, especially around glomeruli showing extracapillary proliferation and destruction of the capsular basal membrane. Rare S100 positive cells were only found in the interstitium. Tubulo-interstitial lesions estimated semiquantitatively correlated with the degree of proteinuria. Our findings suggest that tubulo-interstitial deposits do not play a major role in the pathogenesis of tubulo-interstitial lesions. The formation of interstitial cell infiltrates appears to be greatly influenced by the development of extracapillary crescents, perhaps by direct transmission of the severe inflammatory process to the adjacent interstitium. The composition of the infiltrate, including antigen presenting cells may signalize an additional involvement of cell-mediated immune mechanisms acting against so far hypothetical tubular epithelial neoantigens.