A Case of Metastatic Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome-Associated Renal Cell Carcinoma Treated with a Sequence of Axitinib and Nivolumab Following Cytoreductive Nephrectomy

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Ichiro Yonese
Masaya Ito
Kosuke Takemura
Takao Kamai
Fumitaka Koga


Metastatic Hereditary Leiomyomatosis, Renal Cell Cancer Syndrome, Renal Cell Carcinoma, Cytoreductive Nephrectomy, Axitinib, Nivolumab


Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) associated renal cell carcinoma (RCC) is an aggressive form of type 2 papillary RCC caused by deficiency of the fumarate hydratase gene. For patients with metastatic disease, no standard treatment has been established with dismal prognosis. We report a case of metastatic HLRCC-associated RCC in a 65-year-old Japanese male whose clinical features mimicked advanced renal pelvic cancer. A durable response was achieved with a sequence of axitinib and nivolumab after cytoreductive and diagnostic nephrectomy. Their potential therapeutic roles in the management of metastatic HLRCC-associated RCC have been discussed based on its molecular and biological backgrounds.

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1. Tomlinson IPM, Alam NA, Rowan AJ, Barclay E, Jaeger EEM, Kelsell D, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet. 2002;30(4):406–10. http://dx.doi. org/10.1038/ng849
2. Linehan WM, Spellman PT, Ricketts CJ, Creighton CJ, Fei SS, Davis C, et al. Comprehensive molecular characterization of papillary renal-cell carcinoma. N Engl J Med. 2016;374(2):135– 45. http://dx.doi.org/10.1056/NEJMoa1505917
3. Forde C, Lim DHK, Alwan Y, Burghel G, Butland L, Cleaver R, et al. Hereditary leiomyomatosis and renal cell cancer: Clinical, molecular, and screening features in a cohort of 185 affected individuals. Eur Urol Oncol. 2019. http://dx.doi.org/10.1016/j. euo.2019.11.002
4. Menko FH, Maher ER, Schmidt LS, Middelton LA, Aittomaki  K, Tomlinson I, et al. Hereditary leiomyomatosis and renal cell cancer (HLRCC): Renal cancer risk, surveillance and treatment. Fam Cancer. 2014;13(4):637–44. http://dx.doi. org/10.1007/s10689-014-9735-2
5. Méjean A, Ravaud A, Thezenas S, Colas S, Beauval JB, Bensalah K, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. 2018;379(5):417–27. http://dx.doi.org/10.1056/NEJMoa1803675
6. Bex A, Mulders P, Jewett M, Wagstaff J, van Thienen JV, Blank CU, et al. Comparison of immediate vs deferred cytore-ductive nephrectomy in patients with synchronous metastatic renal cell carcinoma receiving sunitinib: The SURTIME randomized clinical trial. JAMA Oncol. 2019;5(2):164–70. http:// dx.doi.org/10.1001/jamaoncol.2018.5543
7. Graham J, Wells JC, Donskov F, Lee JL, Fraccon A, Pasini F, et al. Cytoreductive nephrectomy in metastatic papillary renal cell carcinoma: Results from the international metastatic renal cell carcinoma database consortium. Eur Urol Oncol. 2019;2(6):643–8. http://dx.doi.org/10.1016/j.euo.2019.03.007
8. Isaacs JS, Jung YJ, Mole DR, Lee S, Torres-Cabala C, Chung  YL, et al. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: Novel role of fumarate in regulation of HIF stability. Cancer Cell. 2005;8(2):143– 53. http://dx.doi.org/10.1016/j.ccr.2005.06.017
9. Ooi A, Wong JC, Petillo D, Roossien D, Perrier-Trudova V, Whitten D, et al. An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell
carcinoma. Cancer Cell. 2011;20(4):511–23. http://dx.doi. org/10.1016/j.ccr.2011.08.024
10. Linehan WM, Rouault TA. Molecular pathways: Fumarate hydratase-deficient kidney cancer-targeting the Warburg effect in cancer. Clin Cancer Res. 2013;19(13):3345–52. http://dx.doi. org/10.1158/1078-0432.CCR-13-0304
11. Guo X, Chen H, Fu H, Wu H. Hereditary leiomyomatosis and renal cell carcinoma syndrome combined with adrenocortical carcinoma on 18F-FDG PET/CT. Clin Nucl Med. 2017;42(9):692–4. http://dx.doi.org/10.1097/ RLU.0000000000001760
12. Hwang SH, Cho A, Yun M, Choi YD, Rha SY, Kang WJ. Prognostic value of pretreatment metabolic tumor volume and total lesion glycolysis using 18F-FDG PET/CT in patients with metastatic renal cell carcinoma treated with anti-vascular endothelial growth factor-targeted agents. Clin Nucl Med. 2017;42(5):e235–e41. http://dx.doi.org/10.1097/ RLU.0000000000001612
13. Giles RH, Choueiri TK, Heng DY, Albiges L, Hsieh JJ, Linehan WM, et al. Recommendations for the management of rare kidney cancers. Eur Urol. 2017;72(6):974–83. http://dx.doi. org/10.1016/j.eururo.2017.06.040
14. Kamai T, Abe H, Arai K, Murakami S, Sakamoto S, Kaji Y, et al. Radical nephrectomy and regional lymph node dissection for locally advanced type 2 papillary renal cell carcinoma in an at-risk individual from a family with hereditary leiomyomatosis and renal cell cancer: A case report. BMC Cancer. 2016;16:232. http://dx.doi.org/10.1186/s12885-016-2272-7
15. Park I, Shim YS, Go H, Hong BS, Lee JL. Long-term response of metastatic hereditary leiomyomatosis and renal cell carcinoma syndrome associated renal cell carcinoma to bevacizumab plus erlotinib after temsirolimus and axitinib treatment failures. BMC Urol. 2019;19(1):51. http://dx.doi.org/10.1186/ s12894-019-0484-2
16. Chahoud J, Msaouel P, Campbell MT, Bathala T, Xiao L, Gao J, et al. Nivolumab for the treatment of patients with metastatic non-clear cell renal cell carcinoma (nccRCC): A single-institutional experience and literature meta-analysis. Oncologist. 2020;25(3):252. http://dx.doi.org/10.1634/theoncologist.2019-0372
17. Koshkin VS, Barata PC, Zhang T, George DJ, Atkins MB, Kelly WJ, et al. Clinical activity of nivolumab in patients with non-clear cell renal cell carcinoma. J Immunother Cancer. 2018;6(1):9. http://dx.doi.org/10.1186/s40425-018-0319-9
18. Adrianzen Herrera DA, Fleisig SB, Gartrell BA. Impressive and durable response to nivolumab in a patient with metastatic type 2 papillary renal cell carcinoma: On-label but without evidence. Invest New Drugs. 2017;35(5):665–8. http://dx.doi.org/10.1007/ s10637-017-0469-5
19. Geynisman DM. Anti-programmed cell death protein 1 (PD-1) antibody nivolumab leads to a dramatic and rapid response in papillary renal cell carcinoma with sarcomatoid and rhabdoid features. Eur Urol. 2015;68(5):912–14. http://dx.doi. org/10.1016/j.eururo.2015.07.008
20. Ruiz-Bañobre J, Anido U, Abdulkader I, Antúnez-López J, López-López R, García-González J. Long-term response to nivolumab and acute renal failure in a patient with metastatic papillary renal cell carcinoma and a PD-L1 tumor expression increased with sunitinib therapy: A case report. Front Oncol. 2016;6:250. http://dx.doi.org/10.3389/fonc.2016.00250
21. Samstein RM, Lee CH, Shoushtari AN, Hellmann MD, Shen  R, Janjigian YY, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet. 2019;51(2):202–6. http://dx.doi.org/10.1038/ s41588-018-0312-8
22. Turajlic S, Litchfield K, Xu H, Rosenthal R, McGranahan N, Reading JL, et al. Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: A pan-cancer analysis. Lancet Oncol. 2017;18(8):1009–21. http:// dx.doi.org/10.1016/S1470-2045(17)30516-8
23. Sulkowski PL, Sundaram RK, Oeck S, Corso CD, Liu  Y, Noorbakhsh S, et al. Krebs-cycle-deficient hereditary cancer syndromes are defined by defects in homologous-recombination DNA repair. Nat Genet. 2018;50(8):1086–92. http://dx.doi. org/10.1038/s41588-018-0170-4
24. Ricketts CJ, De Cubas AA, Fan H, Smith CC, Lang M, Reznik E, et al. The Cancer genome atlas comprehensive molecular characterization of renal cell carcinoma. Cell Rep. 2018;23(1):313–26.e5.
25. Ito K, Schöder H, Teng R, Humm JL, Ni A, Wolchok JD, et al. Prognostic value of baseline metabolic tumor volume measured on. Eur J Nucl Med Mol Imaging. 2019;46(4):930–9. http://dx. doi.org/10.1007/s00259-018-4211-0
26. Guisier F, Cousse S, Jeanvoine M, Thiberville L, Salaun M. A rationale for surgical debulking to improve anti-PD1 therapy outcome in non small cell lung cancer. Sci Rep. 2019;9(1):16902.