Tumor lysis syndrome: Definition, pathogenesis, clinical manifestations, etiology and risk factors
- Richard A Larson, MD
Richard A Larson, MD
- Editor-in-Chief — Hematology
- Section Editor — Leukemia
- Professor of Medicine
- University of Chicago Pritzker School of Medicine
- Ching-Hon Pui, MD
Ching-Hon Pui, MD
- Chair of the Department of Oncology
- Fahad Al-Rashid Chair of Leukemia Research
- St. Jude's Children's Hospital
- American Cancer Society Professor
- Professor of Pediatrics
- University of Tennessee Health Science Center
- Section Editors
- Reed E Drews, MD
Reed E Drews, MD
- Section Editor — Complications of Cancer
- Associate Professor of Medicine
- Harvard Medical School
- Arnold S Freedman, MD
Arnold S Freedman, MD
- Section Editor — Lymphoproliferative Disorders
- Professor of Medicine
- Harvard Medical School
- David G Poplack, MD
David G Poplack, MD
- Section Editor — Pediatric Oncology
- Professor of Pediatrics
- Baylor College of Medicine
Tumor lysis syndrome (TLS) is an oncologic emergency that is caused by massive tumor cell lysis with the release of large amounts of potassium, phosphate, and nucleic acids into the systemic circulation. Catabolism of the nucleic acids to uric acid leads to hyperuricemia, and the marked increase in uric acid excretion can result in the precipitation of uric acid in the renal tubules and can also induce renal vasoconstriction, impaired autoregulation, decreased renal blood flow, and inflammation, resulting in acute kidney injury. Hyperphosphatemia with calcium phosphate deposition in the renal tubules can also cause acute kidney injury.
TLS most often occurs after the initiation of cytotoxic therapy in patients with high-grade lymphomas (particularly the Burkitt subtype) and acute lymphoblastic leukemia. However, TLS can occur spontaneously and with other tumor types that have a high proliferative rate, large tumor burden, or high sensitivity to cytotoxic therapy.
The pathogenesis, definition, classification, risk factors, etiology, and clinical presentation of TLS will be reviewed here. Prevention and treatment of TLS are discussed elsewhere, as are issues related to treatment of the particular malignancies that are associated with TLS. (See "Tumor lysis syndrome: Prevention and treatment" and "Treatment of Burkitt leukemia/lymphoma in adults" and "Treatment and prognosis of adult T cell leukemia-lymphoma" and "Overview of the treatment of acute lymphoblastic leukemia in children and adolescents", section on 'Tumor lysis syndrome' and "Overview of the complications of acute myeloid leukemia", section on 'Tumor lysis syndrome'.)
In the setting of a malignancy with a high proliferative rate, large tumor burden, and/or a high sensitivity to treatment, initiation of cytotoxic chemotherapy, cytolytic antibody therapy, radiation therapy, or sometimes glucocorticoid therapy alone can result in the rapid lysis of tumor cells. With the emergence of new effective and targeted anticancer drugs or new combinations of drugs, tumor lysis syndrome (TLS) has also been observed in patients with cancers that were previously rarely associated with this complication. (See 'Etiology and risk factors' below.)
This releases massive quantities of intracellular contents (potassium, phosphate, and nucleic acids that can be metabolized to uric acid) into the systemic circulation. The metabolic consequences include hyperkalemia, hyperphosphatemia, secondary hypocalcemia, hyperuricemia, and acute kidney injury. High levels of both uric acid and phosphate increase the severity of acute kidney injury because uric acid precipitates readily in the presence of calcium phosphate crystals, and calcium phosphate precipitates readily in the presence of uric acid crystals.
- Hande KR, Garrow GC. Acute tumor lysis syndrome in patients with high-grade non-Hodgkin's lymphoma. Am J Med 1993; 94:133.
- van den Berg H, Reintsema AM. Renal tubular damage in rasburicase: risks of alkalinisation. Ann Oncol 2004; 15:175.
- Coiffier B, Mounier N, Bologna S, et al. Efficacy and safety of rasburicase (recombinant urate oxidase) for the prevention and treatment of hyperuricemia during induction chemotherapy of aggressive non-Hodgkin's lymphoma: results of the GRAAL1 (Groupe d'Etude des Lymphomes de l'Adulte Trial on Rasburicase Activity in Adult Lymphoma) study. J Clin Oncol 2003; 21:4402.
- Boles JM, Dutel JL, Briere J, et al. Acute renal failure caused by extreme hyperphosphatemia after chemotherapy of an acute lymphoblastic leukemia. Cancer 1984; 53:2425.
- Kanfer A, Richet G, Roland J, Chatelet F. Extreme hyperphosphataemia causing acute anuric nephrocalcinosis in lymphosarcoma. Br Med J 1979; 1:1320.
- Seegmiller JE. Xanthine stone formation. Am J Med 1968; 45:780.
- Band PR, Silverberg DS, Henderson JF, et al. Xanthine nephropathy in a patient with lymphosarcoma treated with allopurinol. N Engl J Med 1970; 283:354.
- DeConti RC, Calabresi P. Use of allopurinol for prevention and control of hyperuricemia in patients with neoplastic disease. N Engl J Med 1966; 274:481.
- Hande KR, Hixson CV, Chabner BA. Postchemotherapy purine excretion in lymphoma patients receiving allopurinol. Cancer Res 1981; 41:2273.
- LaRosa C, McMullen L, Bakdash S, et al. Acute renal failure from xanthine nephropathy during management of acute leukemia. Pediatr Nephrol 2007; 22:132.
- Pais VM Jr, Lowe G, Lallas CD, et al. Xanthine urolithiasis. Urology 2006; 67:1084.e9.
- Coiffier B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol 2008; 26:2767.
- Common Terminology Criteria for Adverse Events, version 4.0, June 2010, National Institutes of Health, National Cancer Institute http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf (Accessed on May 03, 2011).
- Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 2004; 127:3.
- National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) available online at http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf (Accessed on April 27, 2011).
- Cairo MS, Coiffier B, Reiter A, et al. Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus. Br J Haematol 2010; 149:578.
- Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med 2011; 364:1844.
- Wössmann W, Schrappe M, Meyer U, et al. Incidence of tumor lysis syndrome in children with advanced stage Burkitt's lymphoma/leukemia before and after introduction of prophylactic use of urate oxidase. Ann Hematol 2003; 82:160.
- Montesinos P, Lorenzo I, Martín G, et al. Tumor lysis syndrome in patients with acute myeloid leukemia: identification of risk factors and development of a predictive model. Haematologica 2008; 93:67.
- Baeksgaard L, Sørensen JB. Acute tumor lysis syndrome in solid tumors--a case report and review of the literature. Cancer Chemother Pharmacol 2003; 51:187.
- Howard SC, Trifilio S, Gregory TK, et al. Tumor lysis syndrome in the era of novel and targeted agents in patients with hematologic malignancies: a systematic review. Ann Hematol 2016; 95:563.
- Tsokos GC, Balow JE, Spiegel RJ, Magrath IT. Renal and metabolic complications of undifferentiated and lymphoblastic lymphomas. Medicine (Baltimore) 1981; 60:218.
- Yang H, Rosove MH, Figlin RA. Tumor lysis syndrome occurring after the administration of rituximab in lymphoproliferative disorders: high-grade non-Hodgkin's lymphoma and chronic lymphocytic leukemia. Am J Hematol 1999; 62:247.
- Jensen M, Winkler U, Manzke O, et al. Rapid tumor lysis in a patient with B-cell chronic lymphocytic leukemia and lymphocytosis treated with an anti-CD20 monoclonal antibody (IDEC-C2B8, rituximab). Ann Hematol 1998; 77:89.
- Jabr FI. Acute tumor lysis syndrome induced by rituximab in diffuse large B-cell lymphoma. Int J Hematol 2005; 82:312.
- Linck D, Basara N, Tran V, et al. Peracute onset of severe tumor lysis syndrome immediately after 4 Gy fractionated TBI as part of reduced intensity preparative regimen in a patient with T-ALL with high tumor burden. Bone Marrow Transplant 2003; 31:935.
- Kjellstrand CM, Cambell DC 2nd, von Hartitzsch B, Buselmeier TJ. Hyperuricemic acute renal failure. Arch Intern Med 1974; 133:349.
- Hussain K, Mazza JJ, Clouse LH. Tumor lysis syndrome (TLS) following fludarabine therapy for chronic lymphocytic leukemia (CLL): case report and review of the literature. Am J Hematol 2003; 72:212.
- Fassas AB, Desikan KR, Siegel D, et al. Tumour lysis syndrome complicating high-dose treatment in patients with multiple myeloma. Br J Haematol 1999; 105:938.
- Berenson JR, Yang HH, Vescio RA, et al. Safety and efficacy of bortezomib and melphalan combination in patients with relapsed or refractory multiple myeloma: updated results of a phase 1/2 study after longer follow-up. Ann Hematol 2008; 87:623.
- Sezer O, Vesole DH, Singhal S, et al. Bortezomib-induced tumor lysis syndrome in multiple myeloma. Clin Lymphoma Myeloma 2006; 7:233.
- Malik IA, Abubakar S, Alam F, Khan A. Dexamethasone-induced tumor lysis syndrome in high-grade non-Hodgkin's lymphoma. South Med J 1994; 87:409.
- Tiley C, Grimwade D, Findlay M, et al. Tumour lysis following hydrocortisone prior to a blood product transfusion in T-cell acute lymphoblastic leukaemia. Leuk Lymphoma 1992; 8:143.
- Al-Kali A, Farooq S, Tfayli A. Tumor lysis syndrome after starting treatment with Gleevec in a patient with chronic myelogenous leukemia. J Clin Pharm Ther 2009; 34:607.
- Yamazaki H, Hanada M, Horiki M, et al. Acute tumor lysis syndrome caused by palliative radiotherapy in patients with diffuse large B-cell lymphoma. Radiat Med 2004; 22:52.
- Gemici C. Tumour lysis syndrome in solid tumours. Clin Oncol (R Coll Radiol) 2006; 18:773.
- Kalemkerian GP, Darwish B, Varterasian ML. Tumor lysis syndrome in small cell carcinoma and other solid tumors. Am J Med 1997; 103:363.
- Drakos P, Bar-Ziv J, Catane R. Tumor lysis syndrome in nonhematologic malignancies. Report of a case and review of the literature. Am J Clin Oncol 1994; 17:502.
- Rostom AY, El-Hussainy G, Kandil A, Allam A. Tumor lysis syndrome following hemi-body irradiation for metastatic breast cancer. Ann Oncol 2000; 11:1349.
- Pentheroudakis G, O'Neill VJ, Vasey P, Kaye SB. Spontaneous acute tumour lysis syndrome in patients with metastatic germ cell tumours. Report of two cases. Support Care Cancer 2001; 9:554.
- Gold JE, Malamud SC, LaRosa F, Osband ME. Adoptive chemoimmunotherapy using ex vivo activated memory T-cells and cyclophosphamide: tumor lysis syndrome of a metastatic soft tissue sarcoma. Am J Hematol 1993; 44:42.
- Bilgrami SF, Fallon BG. Tumor lysis syndrome after combination chemotherapy for ovarian cancer. Med Pediatr Oncol 1993; 21:521.
- Chan JK, Lin SS, McMeekin DS, Berman ML. Patients with malignancy requiring urgent therapy: CASE 3. Tumor lysis syndrome associated with chemotherapy in ovarian cancer. J Clin Oncol 2005; 23:6794.
- Shamseddine AI, Khalil AM, Wehbeh MH. Acute tumor lysis syndrome with squamous cell carcinoma of the vulva. Gynecol Oncol 1993; 51:258.
- Oztop I, Demirkan B, Yaren A, et al. Rapid tumor lysis syndrome in a patient with metastatic colon cancer as a complication of treatment with 5-fluorouracil/leucoverin and irinotecan. Tumori 2004; 90:514.
- Lin CJ, Lim KH, Cheng YC, et al. Tumor lysis syndrome after treatment with gemcitabine for metastatic transitional cell carcinoma. Med Oncol 2007; 24:455.
- Pinder EM, Atwal GS, Ayantunde AA, et al. Tumour Lysis Syndrome Occurring in a Patient with Metastatic Gastrointestinal Stromal Tumour Treated with Glivec (Imatinib Mesylate, Gleevec, STI571). Sarcoma 2007; 2007:82012.
- Jiang RD, Jian WC, Jin N, et al. Tumor Lysis Syndrome: A Serious Complication of Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma. Am J Med 2016; 129:e173.
- Jasek AM, Day HJ. Acute spontaneous tumor lysis syndrome. Am J Hematol 1994; 47:129.
- Hsu HH, Huang CC. Acute spontaneous tumor lysis in anaplastic large T-cell lymphoma presenting with hyperuricemic acute renal failure. Int J Hematol 2004; 79:48.
- Sklarin NT, Markham M. Spontaneous recurrent tumor lysis syndrome in breast cancer. Am J Clin Oncol 1995; 18:71.
- Bertrand Y, Mechinaud F, Brethon B, et al. SFCE (Société Française de Lutte contre les Cancers et Leucémies de l'Enfant et de l'Adolescent) recommendations for the management of tumor lysis syndrome (TLS) with rasburicase: an observational survey. J Pediatr Hematol Oncol 2008; 30:267.
- Andritsos LA, Johnson AJ, Lozanski G, et al. Higher doses of lenalidomide are associated with unacceptable toxicity including life-threatening tumor flare in patients with chronic lymphocytic leukemia. J Clin Oncol 2008; 26:2519.
- Byrd JC, Lin TS, Dalton JT, et al. Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia. Blood 2007; 109:399.
- Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med 2016; 374:311.
- Feng X, Dong K, Pham D, et al. Efficacy and cost of single-dose rasburicase in prevention and treatment of adult tumour lysis syndrome: a meta-analysis. J Clin Pharm Ther 2013; 38:301.
- McBride A, Lathon SC, Boehmer L, et al. Comparative evaluation of single fixed dosing and weight-based dosing of rasburicase for tumor lysis syndrome. Pharmacotherapy 2013; 33:295.
- Mato AR, Riccio BE, Qin L, et al. A predictive model for the detection of tumor lysis syndrome during AML induction therapy. Leuk Lymphoma 2006; 47:877.
- Truong TH, Beyene J, Hitzler J, et al. Features at presentation predict children with acute lymphoblastic leukemia at low risk for tumor lysis syndrome. Cancer 2007; 110:1832.
- CLINICAL MANIFESTATIONS
- DEFINITION AND CLASSIFICATION
- Cairo-Bishop definition
- ETIOLOGY AND RISK FACTORS
- Hematologic malignancies
- Solid tumors
- Spontaneous TLS
- RISK STRATIFICATION
- Risk stratification in acute leukemia