Better effect of sorafenib on the rhabdoid component of a clear cell renal cell carcinoma owing to its higher level of vascular endothelial growth factor‐A production

Sir: Antiangiogenic treatment of clear cell renal cell carcinoma (cc-RCC) targeting different steps of the tyrosine kinase (TK) cascade has brought a revolutionary change in the management of metastatic disease. These agents affect the blood flow around or to a tumour by blocking the effects of vascular endothelial growth factor (VEGF)-A in the TK cascade. The smallmolecule TK inhibitors sorafenib and sunitinib target VEGF receptor 2 and platelet-derived growth factor receptor and prevent downstream signalling. These agents are also used in experimental settings in adjuvant and neo-adjuvant therapy regimens to increase progression-free disease survival or downsize tumours in patients with locally extensive or metastatic cc-RCC. cc-RCC is the most common malignancy of the kidney. cc-RCC with rhabdoid features is an aggressive variant of ccRCC, and accounts for approximately 5% of adult RCC cases. The rhabdoid component is defined on the basis of morphological features, and its presence is related to high histological Fuhrman grade and advanced pathological stage. The rhabdoid and nonrhabdoid components in composite tumours have been shown to carry the same genetic aberrations, suggesting that these histologically distinct patterns arise from the same malignant precursor cell. Here, we present a patient in whom histological changes in a primary cc-RCC with rhabdoid features after 1 week of neo-adjuvant treatment with sorafenib were observed. The rhabdoid component of the tumour was more sensitive to sorafenib treatment. A 59-year-old woman with rheumatoid arthritis, hypertension and depression was diagnosed with a mass suspicious for cc-RCC in the upper pole of the left kidney. Clinical staging studies showed no metastases. The patient was referred to our university hospital for laparoscopic nephrectomy. At admission, she was enrolled in a clinical trial (http://www.clinicaltrials. gov/ct2/show/ NCT00602862) involving 1 week of neoadjuvant sorafenib (oral, 400 mg twice-daily) treatment. The time between cessation of medication and surgery was 60 h. The gross pathology specimen showed a centrally located nodular tumour of diameter 60 mm that extended into the perirenal fat tissue. The tumour was yellow–white with extensive necrosis and focal cystic changes. Histologically, the tumour was composed of a rhabdoid component with higher nuclear grade (grade 4) and a clear cell component (Figure 1A,B respectively). Treatment effects differed remarkably between the rhabdoid component and the non-rhabdoid cc-RCC component. In the rhabdoid component, extensive necrosis was observed, which we propose is secondary to prominent damage to the tumour vasculature. Loss of endothelial function was frequently observed, as shown by detachment of the endothelial cells, fibrinoid necrosis, thrombus formation, and obliteration of the vascular lumen. The perivascular tumour tissue showed ischaemic necrosis with mixed inflammatory cells (Figure 1C). The non-rhabdoid cc-RCC component sometimes showed perivascular hyalinization, which can be attributed to degeneration of the perivascular tumour tissue. The remaining perivascular vital tumour tissue showed clear cytoplasm, a lower nuclear grade, and shrinking of nuclei (Figure 1D). Immunohistochemical anti-VEGF-A staining showed stronger staining of the rhabdoid component than of the clear cell component (Figures 1E,F respectively). In a control group of five cc-RCCs with rhabdoid features, randomly chosen from our pathology archive, we could not detect blood vessel ⁄ endothelial damage. In 5 ⁄ 5 tumours, dispersed areas of necrosis could be observed in the rhabdoid components, which stands in contrast to the extensive necrosis observed in the current case. In 4 ⁄ 5 tumours, the rhabdoid component also showed stronger staining with anti-VEGF-A antibody than the ccRCC component (not shown). Our combined results suggest that the more aggressive rhabdoid component in ccRCC with rhabdoid features produces more VEGF-A and is therefore more susceptible to inhibition of VEGF-A effects by TK inhibitors. These findings indicate that the success of antiangiogenic therapy might be predicted on the basis of histological features of the tumour, but this should be verified in a larger patient population.