Diagnostic and Interventional Imaging (2015) 96, 393—395
LETTER / Genito-urinary imaging Multicystic kidney disease: A complication of crizotinib Keywords: Cyst; Kidney; Iatrogenic; Chemotherapy Crizotinib is a promising anti-cancer drug acting as a c-MET, ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) inhibitor, approved for treatment of stage IV ALK rearranged non-small cell lung cancer (NSCLC). Recently, crizotinib was associated with a reduction of eGFR (estimated Glomerular Filtration Rate), but the mechanism is still unclear [1]. Tubular toxicity was described as a cause of renal insufficiency [2]. In the crizotinib package leaflet, under ‘‘common side effects’’, it is mentioned that renal cysts appear in 1 to 10 out of 100 patients. This case report’s main objective is to illustrate this side effect and try to explain the mechanism behind the cyst formation. Methods We systematically reviewed and compared baseline studies (ultrasounds and CT scans) and studies after treatment in the 7 patients treated with crizotinib at our institution last year. Results Seven patients were treated with crizotinib at our institution last year. The appearance of bilateral renal cysts
under crizotinib therapy were observed in one patient, 6 months after the beginning of therapy. These cysts were classified as Bosniak II lesions: ovoid in shape, anechoic without internal echoes, smooth clearly demarcated walls, acoustic enhancement behind cyst on ultrasound (Fig. 1), near-water density lesion, without septa or calcification or enhancing soft tissue areas (Fig. 2). Some cysts showed minimal wall thickening with no contrast enhancement. eGFR remained stable for this patient during the whole follow-up. The cyst size fluctuated over time while doses of crizotinib were modified (Fig. 3). Because the patient had a recent history of breast cancer with liver and brain metastasis, ultrasound-guided biopsy was performed on the cysts and confirmed the inflammatory nature of the fluid (‘‘inflammatory macrophages, lymphocytes and neutrophils without epithelial or other suspect cell’’). Discussion Crizotinib is an inhibitor of c-MET. c-MET activation is linked to cyst formation and some authors suggest that inhibition of c-MET can be used for polycystic kidney disease treatment [3]. Recently, the specific suppression of c-MET in the kidney was associated with an increased risk for acute renal insufficiency. It was associated with an increase in apoptosis, inflammation and macrophage infiltration [4]. These mechanisms all play a role in cyst formation. In addition, c-MET is known to play a critical role in tubulogenesis. Absence of c-MET signaling in kidney cells culture leads to formation of cyst-like structure in vitro [5]. So, cyst formation could be
Figure 1. Ultrasonography (coronal and axial view): typical cyst, which is ovoid, anechoic without internal echoes, smooth clearly demarcated walls and acoustic enhancement behind cyst. http://dx.doi.org/10.1016/j.diii.2014.11.017 2211-5684/© 2014 Éditions franc ¸aises de radiologie. Published by Elsevier Masson SAS. All rights reserved.
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Figure 2. CT scan with contrast: near-water density lesion, without septa or calcification or enhancing soft tissue areas, but a minimal wall thickening with no contrast enhancement.
Figure 3.
Cyst size fluctuated over time, while doses of crizotinib were changed (08.13 baseline CT scan, 10.13, 01.13 and 07.13 scans).
Letter linked to the tubular toxicity of crizotinib and/or the critical role of c-MET function in tubulogenesis. Our report emphasizes that the use of crizotinib can lead to renal cysts formation. Future works should determine if the appearance of kidney cysts is predictive of kidney dysfunction. A close monitoring of kidney function and morphology is therefore mandatory in patients treated with crizotinib. Comparison with baseline exams is important because renal cysts, a common imaging finding in adults, are sometimes not mentioned in the final radiology report. This side effect should be known, so that these cysts are not confused with cystic metastasis or primary renal tumour and avoid useless investigations. Conclusion Renal cysts may occur in patients treated with crizotinib. A thorough understanding of baseline imaging studies is essential for diagnosis. The clinical significance of cyst formation must be studied. It could reflect an optimal inhibition of cMET that could predict a better outcome for patients treated with this drug. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Brosnan EM, Weickhardt AJ, Lu X, Maxon DA, Barón AE, Chonchol M, et al. Drug-induced reduction in estimated glomerular filtration rate in patients with ALK-positive non-small cell lung cancer treated with the ALK inhibitor crizotinib. Cancer 2013, http://dx.doi.org/10.1002/cncr.28478. [2] Gastaud L, Ambrosetti D, Otto J, Marquette CH, Coutts M, Hofman P, et al. Acute kidney injury following crizotinib
395 administration for non-small-cell lung carcinoma. Lung Cancer 2013;82(2):362—4, http://dx.doi.org/10.1016/j.lungcan. 2013.08.007. [3] Qin S, Taglienti M, Nauli SM, Contrino L, Takakura A, Zhou J, et al. Failure to ubiquitinate c-MET leads to hyperactivation of mTOR signaling in a mouse model of autosomal dominant polycystic kidney disease. J Clin Invest 2010;120(10):3617—28, http://dx.doi.org/10.1172/JCI41531 [Epub 2010 Sep 13]. [4] Zhou D, Tan RJ, Lin L, Zhou L, Liu Y. Activation of hepatocyte growth factor receptor, c-MET, in renal tubules is required for renoprotection after acute kidney injury. Kidney Int 2013;84(3):509—20, http://dx.doi.org/10.1038/ki.2013.102 [Epub 2013 May 29]. [5] Prat M, Crepaldi T, Pennacchietti S, Bussolino F, Comoglio PM. Agonistic monoclonal antibodies against the Met receptor dissect the biological responses to HGF. J Cell Sci 1998;111(Pt 2):237—47.
P. Souteyrand a,b,∗ , S. Burtey c,d , F. Barlesi e a
APHM, Conception, Service d’Imagerie Médicale, 13005 Marseille, France b Aix-Marseille University, LIIE—Laboratoire d’Imagerie Interventionnelle Expérimentale, EA 4264, 13005 Marseille, France c Aix-Marseille University, UMRS-1076, VRCM, Marseille, France d Centre de néphrologie et transplantation rénale, APHM, Marseille, France e Aix-Marseille University, APHM, Multidisciplinary Oncology and Therapeutic Innovations department and Inserm U911 CRO2, Marseille, France ∗ Corresponding author. Department of Radiology, Hospital Conception, 147, boulevard Baille, 13005 Marseille, France. E-mail address: [email protected] (P. Souteyrand)
LETTER / Genito-urinary imaging Multicystic kidney disease: A complication of crizotinib Keywords: Cyst; Kidney; Iatrogenic; Chemotherapy Crizotinib is a promising anti-cancer drug acting as a c-MET, ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) inhibitor, approved for treatment of stage IV ALK rearranged non-small cell lung cancer (NSCLC). Recently, crizotinib was associated with a reduction of eGFR (estimated Glomerular Filtration Rate), but the mechanism is still unclear [1]. Tubular toxicity was described as a cause of renal insufficiency [2]. In the crizotinib package leaflet, under ‘‘common side effects’’, it is mentioned that renal cysts appear in 1 to 10 out of 100 patients. This case report’s main objective is to illustrate this side effect and try to explain the mechanism behind the cyst formation. Methods We systematically reviewed and compared baseline studies (ultrasounds and CT scans) and studies after treatment in the 7 patients treated with crizotinib at our institution last year. Results Seven patients were treated with crizotinib at our institution last year. The appearance of bilateral renal cysts
under crizotinib therapy were observed in one patient, 6 months after the beginning of therapy. These cysts were classified as Bosniak II lesions: ovoid in shape, anechoic without internal echoes, smooth clearly demarcated walls, acoustic enhancement behind cyst on ultrasound (Fig. 1), near-water density lesion, without septa or calcification or enhancing soft tissue areas (Fig. 2). Some cysts showed minimal wall thickening with no contrast enhancement. eGFR remained stable for this patient during the whole follow-up. The cyst size fluctuated over time while doses of crizotinib were modified (Fig. 3). Because the patient had a recent history of breast cancer with liver and brain metastasis, ultrasound-guided biopsy was performed on the cysts and confirmed the inflammatory nature of the fluid (‘‘inflammatory macrophages, lymphocytes and neutrophils without epithelial or other suspect cell’’). Discussion Crizotinib is an inhibitor of c-MET. c-MET activation is linked to cyst formation and some authors suggest that inhibition of c-MET can be used for polycystic kidney disease treatment [3]. Recently, the specific suppression of c-MET in the kidney was associated with an increased risk for acute renal insufficiency. It was associated with an increase in apoptosis, inflammation and macrophage infiltration [4]. These mechanisms all play a role in cyst formation. In addition, c-MET is known to play a critical role in tubulogenesis. Absence of c-MET signaling in kidney cells culture leads to formation of cyst-like structure in vitro [5]. So, cyst formation could be
Figure 1. Ultrasonography (coronal and axial view): typical cyst, which is ovoid, anechoic without internal echoes, smooth clearly demarcated walls and acoustic enhancement behind cyst. http://dx.doi.org/10.1016/j.diii.2014.11.017 2211-5684/© 2014 Éditions franc ¸aises de radiologie. Published by Elsevier Masson SAS. All rights reserved.
394
Letter
Figure 2. CT scan with contrast: near-water density lesion, without septa or calcification or enhancing soft tissue areas, but a minimal wall thickening with no contrast enhancement.
Figure 3.
Cyst size fluctuated over time, while doses of crizotinib were changed (08.13 baseline CT scan, 10.13, 01.13 and 07.13 scans).
Letter linked to the tubular toxicity of crizotinib and/or the critical role of c-MET function in tubulogenesis. Our report emphasizes that the use of crizotinib can lead to renal cysts formation. Future works should determine if the appearance of kidney cysts is predictive of kidney dysfunction. A close monitoring of kidney function and morphology is therefore mandatory in patients treated with crizotinib. Comparison with baseline exams is important because renal cysts, a common imaging finding in adults, are sometimes not mentioned in the final radiology report. This side effect should be known, so that these cysts are not confused with cystic metastasis or primary renal tumour and avoid useless investigations. Conclusion Renal cysts may occur in patients treated with crizotinib. A thorough understanding of baseline imaging studies is essential for diagnosis. The clinical significance of cyst formation must be studied. It could reflect an optimal inhibition of cMET that could predict a better outcome for patients treated with this drug. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Brosnan EM, Weickhardt AJ, Lu X, Maxon DA, Barón AE, Chonchol M, et al. Drug-induced reduction in estimated glomerular filtration rate in patients with ALK-positive non-small cell lung cancer treated with the ALK inhibitor crizotinib. Cancer 2013, http://dx.doi.org/10.1002/cncr.28478. [2] Gastaud L, Ambrosetti D, Otto J, Marquette CH, Coutts M, Hofman P, et al. Acute kidney injury following crizotinib
395 administration for non-small-cell lung carcinoma. Lung Cancer 2013;82(2):362—4, http://dx.doi.org/10.1016/j.lungcan. 2013.08.007. [3] Qin S, Taglienti M, Nauli SM, Contrino L, Takakura A, Zhou J, et al. Failure to ubiquitinate c-MET leads to hyperactivation of mTOR signaling in a mouse model of autosomal dominant polycystic kidney disease. J Clin Invest 2010;120(10):3617—28, http://dx.doi.org/10.1172/JCI41531 [Epub 2010 Sep 13]. [4] Zhou D, Tan RJ, Lin L, Zhou L, Liu Y. Activation of hepatocyte growth factor receptor, c-MET, in renal tubules is required for renoprotection after acute kidney injury. Kidney Int 2013;84(3):509—20, http://dx.doi.org/10.1038/ki.2013.102 [Epub 2013 May 29]. [5] Prat M, Crepaldi T, Pennacchietti S, Bussolino F, Comoglio PM. Agonistic monoclonal antibodies against the Met receptor dissect the biological responses to HGF. J Cell Sci 1998;111(Pt 2):237—47.
P. Souteyrand a,b,∗ , S. Burtey c,d , F. Barlesi e a
APHM, Conception, Service d’Imagerie Médicale, 13005 Marseille, France b Aix-Marseille University, LIIE—Laboratoire d’Imagerie Interventionnelle Expérimentale, EA 4264, 13005 Marseille, France c Aix-Marseille University, UMRS-1076, VRCM, Marseille, France d Centre de néphrologie et transplantation rénale, APHM, Marseille, France e Aix-Marseille University, APHM, Multidisciplinary Oncology and Therapeutic Innovations department and Inserm U911 CRO2, Marseille, France ∗ Corresponding author. Department of Radiology, Hospital Conception, 147, boulevard Baille, 13005 Marseille, France. E-mail address: [email protected] (P. Souteyrand)
