Tumor lysis syndrome (TLS) is a life-threatening oncological condition that is typically characterized by metabolic derangements that are often labeled as an acute kidney injury. The recent advancement in cancer treatment has led to the mounting rate of TLS in solid tumors that were previously rarely linked to this complication. Given that its prognosis is dismal, it is essential to increase recognition of this condition by describing more sensitive markers. Currently, the management of TLS is mainly supportive due to the lack of specific therapy targeting its specific pathology. This review aims to summarize the most recent literature on the underlying mechanism of TLS and the potential implications for novel TLS therapy.
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Tumor lysis syndrome (TLS) is a life-threatening medical condition that can occur spontaneously or as a complication of cancer therapy for rapidly proliferating and chemo-sensitive malignancies such as acute lymphoblastic leukemia or high-grade lymphoma [
A definitive TLS diagnosis requires one clinical and two laboratory criteria. Laboratory TLS is characterized by one of three scenarios. The first two are in the setting of a normal uric acid where a deranged phosphate and potassium levels, either exceed the upper limit of normal (ULN) or exhibit at least a 25% increase from normal levels. The third scenario is where uric acid exceeds the ULN or shows a 25% increase from baseline, including either elevated potassium or phosphate levels simultaneously. Coupled with these laboratory findings are many clinical criteria that often present as results of the underlying electrolyte abnormalities and accumulation of toxic metabolites within the blood. One key finding is creatinine elevation greater than or equal to 1.5 times the ULN, which may manifest as oliguria or anuria. Other common findings include cardiac arrhythmias and/or sudden death because of hyperkalemia [
Interestingly, acute kidney injury (AKI) may result from the deposition of uric acid or calcium phosphate crystals within renal tubules. AKI, besides hyperphosphatemia-driven hypocalcemia, can cause tetany and seizures [
Incidence of TLS in solid tumors
TLS typically occurs in patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). The incidence of TLS comprises about 10% among patients undergoing remission-induction chemotherapy [
Current understanding of TLS
An expanding body of research centered on the pathophysiology of TLS is utilized in order to understand its relation to clinical outcomes. Traditionally, AKI has been cited as the most common cause of death in patients with TLS due to solid tumors [
New insight of TLS
Animal Models: Understanding the Pathophysiology of TLS
Despite the aforementioned predisposing factors, animal models of TLS have shown resilience in some mice with heavy tumor burdens, suggesting that heavy tumor burden itself is necessary but not sufficient to cause TLS. This has notably prompted efforts to investigate further pathophysiologic mechanisms of tissue damage that may explain the high mortality of TLS [
RCT: Randomized controlled trial; TLS: Tumor lysis syndrome; STLS: Spontaneous TLS; LN: Lymph nodes; NNC: Necrotic neoplastic cells; NM: Not mentioned; N/A: Not applicable; MOF: Multi-organ failure; RF: Renal failure; DIC: Disseminated intravascular coagulation; Ref: Reference.
Author | Experimental Model | Treatment Type vs. Spontaneous | Cancer Pathology | Metastases | Microemboli Composition | Post-Mortem Pathology | Clinical Presentation | Ref |
Lovelace et al. | Case Report: 10-month-old female sentinel mouse | STLS | Leukemic lymphoma | Cranial, liver, spleen, and mediastinal, submandibular, and mesenteric LN | Mixed eosinophilic and basophilic (aggregated chromatin) NNC | Embolic vascular occlusions within the lungs, kidneys, brain, liver | Seizure | [ |
Vogel et al. | RCT: p53+/- mice (50% female, 50% male) | STLS | Disseminated lymphoblastic lymphoma and leukemia, bladder neoplasia | Spleen, liver, multiple LN chains | Mixed basophilic (aggregated chromatin) and eosinophilic NNC | Microembolic occlusions within liver, lung, brain | NM | [ |
Calia et al. | Case Report: 2-year-old female domestic short hair cat, feline leukemia virus-positive | Chemotherapy: IP injection L-asparaginase (400 mg/kg), prednisone (5 mg PO bid) Radiation: Cobalt 60 teletherapy, 800 cGy | Lymphoma | Brain, and mediastinal mass | N/A | N/A | Respiratory failure, arrhythmia | [ |
LaCarrubba et al. | Case Report: 11-year-old mare (female horse) | STLS | Peritoneal mesothelioma | Direct extension into thoracic cavity | High-grade neoplastic cells staining positive for cytokeratin and vimentin | Myxomatous degeneration of ascending aorta, main pulmonary artery | SIRS, MOF, arrhythmia, RF | [ |
Mylonakis et al. | Case Report: 5-year-old female German Shepherd dog | Chemotherapy 1st protocol: Cyclophosphamide, vincristine, cytosine, arabinoside, prednisolone. Chemotherapy 2nd protocol: Vincristine, L-asparaginase, prednisolone, cyclophosphamide, doxorubicin. | B-cell multicentric lymphoma | N/A | N/A | N/A | MOF, DIC, RF | [ |
Human Autopsy Studies
Several documented case reports of TLS in humans appear to echo animal model findings, as microemboli appear to play a direct role in widespread tissue damage [
M: Male; F: Female; TLS: Tumor lysis syndrome; STLS: Spontaneous TLS; MOF: Multi-organ failure; SIRS: Systemic inflammatory response syndrome; RF: Renal failure; BM: Bone marrow; LN: Lymph nodes; DIC: Disseminated intravascular coagulation; PE: Pulmonary embolism; ICH: Intracranial hemorrhage; VAC: Vincristine, actinomycin D, cyclophosphamide; RCC: Renal cell carcinoma; cGY: Centigray.
Author | Age/Gender | Treatment-Driven vs. Spontaneous | Primary Tumor Histology | Metastatic Site(s) | Clinical Features | Outcomes | Pathologic Findings | Ref |
Allen et al. | 55/M | STLS | RCC, rhabdoid features | Liver | SIRS, RF, MOF | Death | MOF | [ |
Takeuchi et al. | 62/M | STLS | Stage IV Melanoma | Liver, lungs, vertebrae | MOF, arrhythmia | Death | Massive hepatocyte necrosis and pulmonary tumor cells, disseminated tumor thrombi in the portal system. | [ |
Kearney et al. | 47/F | STLS | Stage IV sigmoid adenocarcinoma | Liver | SIRS, RF, MOF | Death | Extensive necrosis and widespread tumor thrombi in portal venous system, tumor deposits in lungs, near total replacement of LN with tumor and necrosis | [ |
Ito et al. | 63/F | Tri-weekly docetaxel, carboplatin | Recurrent stage IV uterine serous carcinoma | Lung, kidney, spine, pelvis, aorta | SIRS, MOF, arrhythmia, respiratory failure, RF | Death | Pulmonary tumor embolus | [ |
Bien | 14/M | STLS | Embryonal rhabdomyosarcoma, not detected | BM, pleura, peritoneum, LN | DIC | Survived | DIC, pulmonary hemorrhage | [ |
Bien | 14/F | STLS | Parietal rhabdomyosarcoma | BM | DIC, PE | Survived | DIC, PE, ICH | [ |
Watanabe and Tanaka | 16/M | STLS and treatment-driven (VAC) | Alveolar rhabdomyosarcoma, Prostate | BM, LN, bladder wall | DIC, RF | Survived | DIC, bladder hemorrhage | [ |
Nguyen and Ticona | 72/M | STLS | Stage IV prostate carcinoma | Bone | SIRS, arrhythmia, DIC, RF | Survived | DIC, retro-peritoneal hemorrhage | [ |
Teh and Tsoi | 54/M | Carboplatin, etoposide, direct trauma (biopsy) | Neuroendocrine carcinoma, pancreatic primary | Liver | DIC, RF, MOF | Death | RF, Liver failure, DIC | [ |
Liu and Monaco | 43/M | Radiation therapy (2,000 cGy) to the stomach | Stage IV gastric adenocarcinoma | Liver, liver, stomach, LN, gall bladder | SIRS, RF, MOF | Death | Extensive necrosis in the metastatic sites | [ |
Barton | 57/F | Cyclophosphamide, methotrexate, 5-fluorouracil | Metastatic infiltrating ductal breast carcinoma | Liver, pleurae, lungs, chest wall | SIRS, RF | Death | Extensive lymphangitic carcinoma of the lungs, tumor infiltrating the pleurae, acute necrosis of hepatic metastasis | [ |
Understanding Disseminated Intravascular Coagulation (DIC) and TLS
The association between DIC and neoplasms is well-known and is not uncommon. DIC is estimated to present in 15-20% of patients with acute leukemia, specifically the acute promyelocytic leukemia (APL) variant, and 7-15% of patients with solid metastatic tumors [
The Role of Hypercytokinemia in TLS
Further complicating the management of TLS, clinicians must be aware of the potential of hypercytokinemia, or cytokine storm as a consequence of cancer treatment and how this may necessitate alternate therapy modalities to address systemic inflammatory response syndrome (SIRS) and multi-organ failure (MOF). Hypercytokinemia involves the release of intracellular cytokines (e.g., TNF-alpha, IL-6, IL-10), which induces SIRS leading to MOF and hemodynamic instability marked by hypotension and tachycardia [
The question remains as to the temporal relationship between TLS and cytokine storm, but the comorbidity and interplay of processes cannot be ignored. Hyperuricemia itself, a key marker for TLS, may act as a free-radical scavenger and increase in response to oxidative stress. Additionally, urate crystals are known to activate inflammatory pathways and induce a systemic inflammatory response [
TLS is an oncological emergency that challenges providers to imply hypervigilance in monitoring fluid status, hemodynamics, clotting factors, electrolytes, and cytokines in order to expeditiously identify, respond, and, ultimately, prevent many devastating downstream consequences. Based on the latest studies, TLS-associated DIC as well as hypercytokinemia are novel therapeutic targets in treating this potentially fatal condition. We are in the process of developing a clinical study evaluating this novel strategy.
The authors have declared that no competing interests exist.