Skeletal metastasis in renal cell carcinoma: A review

Masood Umer, Yasir Mohib, Muhammed Atif, Muhammad Nazim, Masood Umer, Yasir Mohib, Muhammed Atif, Muhammad Nazim

Abstract

Background: Renal cell carcinoma account for 3% of all cancers, with peak incidence between 60 and 70 years of age predominantly affecting male population. Renal carcinoma is the most common malignancy of kidney constitutes for 80-90% of renal neoplasm with an overall 45% five years survival rate. Majority are diagnosed incidentally during investigation for other disease process of abdomen. Classical triad of gross hematuria, pain and palpable mass in abdomen is rare accounting to only 6-10%. Treatment of early stages of disease i.e. localized disease is partial or radical nephrectomy. Most common metastasis in RCC occurs to lung, followed by bone involvement in 20-35%, lymph nodes, liver, adrenal gland and brain. In metastatic disease median survival rate of patient is about eight months with 50% mortality rate within first year of life, five years survival rate is 10%. Skeletal metastasis are very destructive in patients with renal cell carcinoma compromising bone integrity leading to skeletal related events including pains, impending fractures, nerve compressions, hypercalcemia and even pathological fractures which may require surgical interventions and other therapy. In addition to skeletal complications, presence of bone metastases in RCC has negative impact on progression free survival and overall survival of patients treated with systemic therapies.

Objective: In this review we discuss pathophysiology of tumor metastasis, diagnosis, management and Case examples of metastatic renal cell carcinoma.

Conclusion: Incidence of metastatic renal carcinoma is increasing. Overall prognosis of patient with advanced RCC is poor, emphasizing the importance of early detection and prompt treatment of primary lesion in its early stage. Advancement in targeted therapy in recent decades had made some improvement in treatment of SREs and has helped in improving patent's quality of life but still we are in need of further improvement in treatment modalities to cure disease thereby decreasing morbidity and mortality.

Keywords: Impending fracture; Metastasis; Nephrectomy; Pathological fracture; Renal cell carcinoma.

Figures

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Case No 3.

References

    1. Ferlay J., Bray F., Pisani P., Parkin D. IARCPress; Lyon: 2004. Cancer Incidence, Mortality and Prevalence Worldwide. IARC Cancer Base No. 5.
    1. Patard J.J., Rodriguez A., Rioux-Leclercq N., Guille F., Lobel B. Prognostic significance of the mode of detection in renal tumours. BJU Int. 2002;90(4):358–363.
    1. Patard J.J., Leray E., Rodriguez A., Rioux-Leclercq N., Guille F., Lobel B. Correlation between symptom graduation, tumor characteristics and survival in renal cell carcinoma. Eur. Urol. 2003;44(2):226–232.
    1. McNichols D.W., Segura J.W., DeWeerd J.H. Renal cell carcinoma: long-term survival and late recurrence. J. Urol. 1981;126(1):17–23.
    1. Miyao N., Naito S., Ozono S., Shinohara N., Masumori N., Igarashi T. Late recurrence of renal cell carcinoma: retrospective and collaborative study of the Japanese Society of Renal Cancer. Urology. 2011;77(2):379–384.
    1. Kozlowski J.M. Management of distant solitary recurrence in the patient with renal cancer. Contralateral kidney and other sites. The Urol. Clin. North Am. 1994;21(4):601–624.
    1. Rini B.I. Stabilization of disease in patients with metastatic renal cell carcinoma using sorafenib. Nat. Clin. Pract. Oncol. 2006;3(11):602–603.
    1. Motzer R.J., Bacik J., Mazumdar M. Prognostic factors for survival of patients with stage IV renal cell carcinoma. Clin. Canc. Res. 2004;10(18) 6302S–3S.
    1. Beuselinck B., Oudard S., Rixe O., Wolter P., Blesius A., Ayllon J. Negative impact of bone metastasis on outcome in clear-cell renal cell carcinoma treated with sunitinib. Ann. Oncol. 2010;22(4):794–800.
    1. Patil S., Figlin R., Hutson T., Michaelson M., Négrier S., Kim S. Prognostic factors for progression-free and overall survival with sunitinib targeted therapy and with cytokine as first-line therapy in patients with metastatic renal cell carcinoma. Ann. Oncol. 2010;22(2):295–300.
    1. Swanson D.A., Orovan W.L., Johnson D.E., Giacco G. Osseous metastases secondary to renal cell carcinoma. Urology. 1981;18(6):556–561.
    1. Santoni M., Conti A., Procopio G., Porta C., Ibrahim T., Barni S. Bone metastases in patients with metastatic renal cell carcinoma: are they always associated with poor prognosis? J. Exp. Clin. Canc. Res. 2015;34(1):10.
    1. Kume H., Kakutani S., Yamada Y., Shinohara M., Tominaga T., Suzuki M. Prognostic factors for renal cell carcinoma with bone metastasis: who are the long-term survivors? J. Urol. 2011;185(5):1611–1614.
    1. Hofbauer L.C., Khosla S., Dunstan C.R., Lacey D.L., Boyle W.J., Riggs B.L. The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. J. Bone Miner. Res. Off. J. Am. Soc. Bone Miner. Res. 2000;15(1):2–12.
    1. Mikami S., Katsube K., Oya M., Ishida M., Kosaka T., Mizuno R. Increased RANKL expression is related to tumour migration and metastasis of renal cell carcinomas. J. Pathol. 2009;218(4):530–539.
    1. Hauschka P.V., Mavrakos A.E., Iafrati M.D., Doleman S.E., Klagsbrun M. Growth factors in bone matrix. Isolation of multiple types by affinity chromatography on heparin-Sepharose. J. Biol. Chem. 1986;261(27):12665–12674.
    1. Kominsky S.L., Doucet M., Brady K., Weber K.L. TGF-beta promotes the establishment of renal cell carcinoma bone metastasis. J. Bone Miner. Res. Off. J. Am. Soc. Bone Miner. Res. 2007;22(1):37–44.
    1. Weber K., Doucet M., Kominsky S. Renal cell carcinoma bone metastasis–elucidating the molecular targets. Canc. Metastasis Rev. 2007;26(3–4):691–704.
    1. Joeckel E., Haber T., Prawitt D., Junker K., Hampel C., Thuroff J.W. High calcium concentration in bones promotes bone metastasis in renal cell carcinomas expressing calcium-sensing receptor. Mol. Canc. 2014;13:42.
    1. Massfelder T., Lang H., Schordan E., Lindner V., Rothhut S., Welsch S. Parathyroid hormone-related protein is an essential growth factor for human clear cell renal carcinoma and a target for the von Hippel-Lindau tumor suppressor gene. Canc. Res. 2004;64(1):180–188.
    1. Talon I., Lindner V., Sourbier C., Schordan E., Rothhut S., Barthelmebs M. Antitumor effect of parathyroid hormone-related protein neutralizing antibody in human renal cell carcinoma in vitro and in vivo. Carcinogenesis. 2006;27(1):73–83.
    1. Xie C., Li Y., Li Q., Chen Y., Yao J., Yin G. Increased insulin mRNA binding Protein-3 expression correlates with vascular enhancement of renal cell carcinoma by intravenous contrast-CT and is associated with bone metastasis. J. Bone Oncol. 2015;4(3):69–76.
    1. Satcher R.L., Pan T., Cheng C.J., Lee Y.C., Lin S.C., Yu G. Cadherin-11 in renal cell carcinoma bone metastasis. PLoS One. 2014;9(2)
    1. Haber T., Jockel E., Roos F.C., Junker K., Prawitt D., Hampel C. Bone metastasis in renal cell carcinoma is preprogrammed in the primary tumor and caused by AKT and integrin alpha5 signaling. J. Urol. 2015;194(2):539–546.
    1. Wotschofsky Z., Liep J., Meyer H.A., Jung M., Wagner I., Disch A.C. Identification of metastamirs as metastasis-associated microRNAs in clear cell renal cell carcinomas. Int. J. Biol. Sci. 2012;8(10):1363–1374.
    1. Mukai S., Yorita K., Kawagoe Y., Katayama Y., Nakahara K., Kamibeppu T. Matriptase and MET are prominently expressed at the site of bone metastasis in renal cell carcinoma: immunohistochemical analysis. Hum. Cell. 2015;28(1):44–50.
    1. Sohaib S., Cook G., Allen S., Hughes M., Eisen T., Gore M. Comparison of whole-body MRI and bone scintigraphy in the detection of bone metastases in renal cancer. British J. Radiol. 2014
    1. Wood S.L., Brown J.E. Skeletal metastasis in renal cell carcinoma: current and future management options. Canc. Treat Rev. 2012;38(4):284–291.
    1. Zekri J., Ahmed N., Coleman R.E., Hancock B.W. The skeletal metastatic complications of renal cell carcinoma. Int. J. Oncol. 2001;19(2):379–382.
    1. Dhillon S., Lyseng-Williamson K.A. Zoledronic acid : a review of its use in the management of bone metastases of malignancy. Drugs. 2008;68(4):507–534.
    1. Rosen L.S., Gordon D., Tchekmedyian S., Yanagihara R., Hirsh V., Krzakowski M. Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial–the zoledronic acid lung cancer and other solid tumors study group. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2003;21(16):3150–3157.
    1. Kohno N., Aogi K., Minami H., Nakamura S., Asaga T., Iino Y. Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: a randomized, placebo-controlled trial. J. Clin. Oncol. 2005;23(15):3314–3321.
    1. Saad F., Gleason D.M., Murray R., Tchekmedyian S., Venner P., Lacombe L. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J. Nat. Cancer Inst. 2004;96(11):879–882.
    1. Rosen L.S., Gordon D., Tchekmedyian N.S., Yanagihara R., Hirsh V., Krzakowski M. Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors. Cancer. 2004;100(12):2613–2621.
    1. Costa L., Major P.P. Effect of bisphosphonates on pain and quality of life in patients with bone metastases. Nat. Clin. Pract. Oncol. 2009;6(3):163–174.
    1. Ullén A., Schwarz S., Lennartsson L., Kälkner K.-M., Sandström P., Costa F. Zoledronic acid induces caspase-dependent apoptosis in renal cancer cell lines. Scand. J. Urol. Nephrol. 2009;43(2):98–103.
    1. Broom R.J., Hinder V., Sharples K., Proctor J., Duffey S., Pollard S. Everolimus and zoledronic acid in patients with renal cell carcinoma with bone metastases: a randomized first-line phase II trial. Clin. Genitourin. Canc. 2015;13(1):50–58.
    1. Alcaraz A., Gonzalez-Lopez R., Morote J., de la Piedra C., Meseguer C., Esteban E. Biochemical markers of bone turnover and clinical outcome in patients with renal cell and bladder carcinoma with bone metastases following treatment with zoledronic acid: the TUGAMO study. British J. cancer. 2013;109(1):121–130.
    1. Keizman D., Ish-Shalom M., Maimon N., Gottfried M. Are bisphosphonates an indispensable tool in the era of targeted therapy for renal cell carcinoma and bone metastases? World J. Urol. 2014;32(1):39–45.
    1. McKay R.R., Lin X., Perkins J.J., Heng D.Y., Simantov R., Choueiri T.K. Prognostic significance of bone metastases and bisphosphonate therapy in patients with renal cell carcinoma. Eur. Urol. 2014;66(3):502–509.
    1. Munns C.F., Rajab M.H., Hong J., Briody J., Hogler W., McQuade M. Acute phase response and mineral status following low dose intravenous zoledronic acid in children. Bone. 2007;41(3):366–370.
    1. Ayllon J., Launay-Vacher V., Medioni J., Cros C., Spano J.P., Oudard S. Osteonecrosis of the jaw under bisphosphonate and antiangiogenic therapies: cumulative toxicity profile? Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2009;20(3):600–601.
    1. Hasegawa Y., Mita K., Matsubara A., Ohdan H. Multidisciplinary treatment including sorafenib stabilized the bone metastases of renal cell carcinoma in an immunosuppressed renal transplant recipient. Int. J. Clin. Oncol. 2009;14(5):465–467.
    1. Brunello A., Saia G., Bedogni A., Scaglione D., Basso U. Worsening of osteonecrosis of the jaw during treatment with sunitinib in a patient with metastatic renal cell carcinoma. Bone. 2009;44(1):173–175.
    1. Weitzman R., Sauter N., Eriksen E.F., Tarassoff P.G., Lacerna L.V., Dias R. Critical review: updated recommendations for the prevention, diagnosis, and treatment of osteonecrosis of the jaw in cancer patients—may 2006. Crit. Rev. Oncol. Hematol. 2007;62(2):148–152.
    1. Henry D.H., Costa L., Goldwasser F., Hirsh V., Hungria V., Prausova J. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J. Clin. Oncol. 2011;29(9):1125–1132.
    1. Lipton A., Fizazi K., Stopeck A.T., Henry D.H., Brown J.E., Yardley D.A. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur. J. cancer (Oxford, England : 1990) 2012;48(16):3082–3092.
    1. Stopeck A.T., Lipton A., Body J.J., Steger G.G., Tonkin K., de Boer R.H. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2010;28(35):5132–5139.
    1. Henry D.H., Costa L., Goldwasser F., Hirsh V., Hungria V., Prausova J. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2011;29(9):1125–1132.
    1. Patard J.-J., Rioux-Leclercq N., Fergelot P. Understanding the importance of smart drugs in renal cell carcinoma. Eur. Urol. 2006;49(4):633–643.
    1. Coppin C., Porzsolt F., Awa A., Kumpf J., Coldman A., Wilt T. Immunotherapy for advanced renal cell cancer. Cochrane Database Syst. Rev. 2004;1
    1. Jiang Y., Zhang W., Kondo K., Klco J.M., Martin T.B.S., Dufault M.R. Gene expression profiling in a renal cell carcinoma cell line: dissecting VHL and hypoxia-dependent pathways. Mol. Canc. Res. 2003;1(6):453–462.
    1. Motzer R.J., Hutson T.E., Tomczak P., Michaelson M.D., Bukowski R.M., Oudard S. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J. Clin. Oncol. 2009;27(22):3584–3590.
    1. Maita S., Yuasa T., Tsuchiya N., Mitobe Y., Narita S., Horikawa Y. Antitumor effect of sunitinib against skeletal metastatic renal cell carcinoma through inhibition of osteoclast function. Int. J. Canc. 2012;130(3):677–684.
    1. Karaca H., Lale A., Dikilitas M., Ozkan M., Er O. Recovery of paraneoplastic hypercalcemia by sunitinib treatment for renal cell carcinoma: a case report and review of the literature. Med. Oncol. 2010;27(3):1023–1026.
    1. Żołnierek J., Nurzyński P., Langiewicz P., Oborska S., Waśko-Grabowska A., Kuszatal E. Efficacy of targeted therapy in patients with renal cell carcinoma with pre-existing or new bone metastases. J. Canc. Res. Clin. Oncol. 2010;136(3):371–378.
    1. Lu X., Gu W., Zhang H., Zhu Y., Shi G., Ye D. Oligometastatic state predicts a favorable outcome for renal cell carcinoma patients with bone metastasis under the treatment of Sunitinib. Oncotarget. 2016;7(18):26879.
    1. Escudier B., Eisen T., Stadler W.M., Szczylik C., Oudard S., Siebels M. Sorafenib in advanced clear-cell renal-cell carcinoma. N. Engl. J. Med. 2007;356(2):125–134.
    1. Sternberg C.N., Davis I.D., Mardiak J., Szczylik C., Lee E., Wagstaff J. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J. Clin. Oncol. 2010;28(6):1061–1068.
    1. Escudier B., Pluzanska A., Koralewski P., Ravaud A., Bracarda S., Szczylik C. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2008;370(9605):2103–2111.
    1. Hudes G., Carducci M., Tomczak P., Dutcher J., Figlin R., Kapoor A. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N. Engl. J. Med. 2007;356(22):2271–2281.
    1. Motzer R.J., Escudier B., Oudard S., Hutson T.E., Porta C., Bracarda S. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372(9637):449–456.
    1. Nishino M., Jagannathan J.P., Ramaiya N.H., Van den Abbeele A.D. Revised RECIST guideline version 1.1: what oncologists want to know and what radiologists need to know. Am. J. Roentgenol. 2010;195(2):281–289.
    1. Szendrői A., Dinya E., Kardos M., Szász A.M., Németh Z., Áts K. Prognostic factors and survival of renal clear cell carcinoma patients with bone metastases. Pathol. Oncol. Res. 2010;16(1):29–38.
    1. Takahashi A., Sasaki H., Kim S.J., Tobisu K-i, Kakizoe T., Tsukamoto T. Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis. Canc. Res. 1994;54(15):4233–4237.
    1. Chatziioannou A., Johnson M., Pneumaticos S., Lawrence D., Carrasco C.H. Preoperative embolization of bone metastases from renal cell carcinoma. Eur. Radiol. 2000;10(4):593–596.
    1. Giberti C., Oneto F., Martorana G., Rovida S., Carmignani G. Radical nephrectomy for renal cell carcinoma: long-term results and prognostic factors on a series of 328 cases. Eur. Urol. 1997;31(1):40–48.
    1. Kavolius J., Mastorakos D., Pavlovich C., Russo P., Burt M., Brady M.S. Resection of metastatic renal cell carcinoma. J. Clin. Oncol. 1998;16(6):2261–2266.
    1. Hardman P., Robb J., Kerr G., Rodger A., MacFarlane A. The value of internal fixation and radiotherapy in the management of upper and lower limb bone metastases. Clin. Oncol. 1992;4(4):244–248.
    1. Damron T.A., Morgan H., Prakash D., Grant W., Aronowitz J., Heiner J. Critical evaluation of Mirels' rating system for impending pathologic fractures. Clin. Orthop. Relat. Res. 2003;415:S201–S207.
    1. Mirels H. The classic: metastatic disease in long bones a proposed scoring system for diagnosing impending pathologic fractures. Clin. Orthop. Relat. Res. 2003;415:S4–S13.
    1. Ward W.G., Holsenbeck S., Dorey F.J., Spang J., Howe D. Metastatic disease of the femur: surgical treatment. Clin. Orthop. Relat. Res. 2003;415:S230–S244.
    1. Marcove R.C., Sadrieh J., Huvos A.G., Grabstald H. Cryosurgery in the treatment of solitary or multiple bone metastases from renal cell carcinoma. J. Urol. 1972;108(4):540–547.
    1. Bickels J., Dadia S., Lidar Z. Surgical management of metastatic bone disease. JBJS. 2009;91(6):1503–1516.
    1. Jacofsky D.J., Haidukewych G.J. Management of pathologic fractures of the proximal femur: state of the art. J. Orthop. Trauma. 2004;18(7):459–469.
    1. Yamada Y., Bilsky M.H., Lovelock D.M., Venkatraman E.S., Toner S., Johnson J. High-dose, single-fraction image-guided intensity-modulated radiotherapy for metastatic spinal lesions. Int. J. Radiat. Oncol. Biol. Phys. 2008;71(2):484–490.
    1. Basile A., Giuliano G., Scuderi V., Motta S., Crisafi R., Coppolino F. Cementoplasty in the management of painful extraspinal bone metastases: our experience. La Radiologia medica. 2008;113(7):1018–1028.
    1. Reichel L.M., Pohar S., Heiner J., Buzaianu E.M., Damron T.A. Radiotherapy to bone has utility in multifocal metastatic renal carcinoma. Clin. Orthop. Relat. Res. 2007;459:133–138.
    1. Fizazi K., Lipton A., Mariette X., Body J.J., Rahim Y., Gralow J.R. Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2009;27(10):1564–1571.
    1. Gangi A., Kastler B., Klinkert A., Dietemann J.L. Injection of alcohol into bone metastases under CT guidance. J. Comput. Assist. Tomogr. 1994;18(6):932–935.
    1. Callstrom M.R., Atwell T.D., Charboneau J.W., Farrell M.A., Goetz M.P., Rubin J. Painful metastases involving bone: percutaneous image-guided cryoablation–prospective trial interim analysis. Radiology. 2006;241(2):572–580.
    1. Simon C.J., Dupuy D.E., Mayo-Smith W.W. vol. 25. Publication of the Radiological Society of North America, Inc.; 2005. pp. S69–S83. (Microwave Ablation: Principles and Applications. Radiographics : a Review). Suppl 1.
    1. Toyota N., Naito A., Kakizawa H., Hieda M., Hirai N., Tachikake T. Radiofrequency ablation therapy combined with cementoplasty for painful bone metastases: initial experience. Cardiovas. Intervent. Radiol. 2005;28(5):578–583.
    1. Woodward E., Jagdev S., McParland L., Clark K., Gregory W., Newsham A. Skeletal complications and survival in renal cancer patients with bone metastases. Bone. 2011;48(1):160–166.

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