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Abstract
Spontaneous tumour lysis syndrome (STLS) is a rare oncological emergency characterised by the spontaneous destruction of tumour cells in the absence of chemotherapy, with the release of large amounts of intracellular ions and metabolic products leading to organ damage and at times death. In chronic lymphocytic leukaemia (CLL), historically, tumour lysis syndrome has been rarely observed owing to low rate of proliferation and slow response to chemotherapy. We report a rare case of STLS in underlying undiagnosed CLL. A man in his 60s presented with vomiting, diarrhoea, breathlessness on exertion and oliguria. Laboratory evaluation revealed a typical constellation of metabolic abnormalities; hyperuricaemia, hyperkalaemia, hyperphosphataemia and hypocalcaemia with acute kidney injury. Peripheral blood examination showed lymphocytosis with smudge cells. Flow cytometry revealed atypical B lymphoid cells positive for CD5, CD19, CD23, CD45 and CD200. Bone marrow studies and lymph node biopsy supported the diagnosis of underlying CLL which was further confirmed by fluorescent in situ hybridisation. With prompt diagnosis, intervention and intensive monitoring, the end-organ damage was successfully prevented. This case report highlights the importance of keeping high index of suspicion for STLS even without a background history of malignancy as this life-threatening condition is potentially salvageable.
- Oncology
- Medical management
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Background
Tumour lysis syndrome is a metabolic and oncological emergency characterised by the destruction of tumour cells with the subsequent release of large number of products of cellular destruction like uric acid, potassium and phosphorus into the systemic circulation. Characteristic metabolic disturbances include hyperphosphataemia, hyperkalaemia, hyperuricaemia and hypocalcaemia with corresponding symptoms and signs.1 These metabolic disturbances can lead to serious sequelae such as acute renal failure, fatal cardiac arrhythmias, seizures and even death.2 3
Although it commonly accompanies the initiation of cytotoxic therapy in high-grade haematological malignancies and lymphomas, cases of spontaneous tumour lysis syndrome (STLS) in the absence of cytotoxic therapy have also been reported. STLS is often seen in acute lymphocytic leukaemia, diffuse large B cell lymphomas (DLBCL), Burkitt’s lymphoma and sometimes in solid tumours but is rarely reported in low-grade malignancies such as chronic lymphocytic leukaemia (CLL).2 3
The inherent risk factors which predispose to tumour lysis syndrome include high tumour burden, high rate of proliferation, high sensitivity to chemotherapy and pre-existing renal impairment.2 According to the risk stratification described by Cairo et al, CLL is a low-risk condition for tumour lysis syndrome.4 A literature search on Medline, PubMed and Embase revealed only four case reports of STLS in CLL. We are reporting a rare case of a man in his 60s, who developed STLS, even prior to detection of underlying CLL and initiation of chemotherapy.
Case presentation
A man in his 60s presented to tertiary care institution with symptoms of vomiting and diarrhoea (an average of three loose stools per day) for 5 days. He developed weakness, dyspnoea on exertion, uneasiness and oliguria in last 24 hours which made him seek medical treatment. He experienced weakness and easy fatigability for past 6–8 weeks but he overlooked it. There was no history of any significant medical illness or intake of any medications. He had not received any medication or vaccination in the recent past nor had any of his family members been suffering from any infectious illness in previous days. He used to run a grocery store with his sons in a small town and was not habituated to tobacco, alcohol or any other substance. Family history was negative for hypertension, diabetes and hyperuricaemia.
His body mass index was 23.5 kg/m2. Clinical examination revealed tachycardia, thready pulse, tachypnoea, pallor and firm non-tender lymphadenopathy in cervical and axillary regions. He reported painful muscle cramps; Trousseau’s sign was positive. He was drowsy but oriented to person, place and time and was responding coherently.
Investigations
Initial laboratory evaluation revealed anaemia (haemoglobin—10 g/L), leucocytosis (22.5×109/L), lymphocytosis (16×109/L), thrombocytopaenia (96×109/L), raised creatinine level, hyperuricaemia, hyperkalaemia, hyperphosphataemia, hypocalcaemia, normal serum transaminases and raised lactate dehydrogenase levels (table 1). Peripheral blood smear examination showed atypical lymphocytosis with smudge cells, thrombocytopaenia but the absence of schistocytes (figure 1). Urate crystals and red cells were observed on urine examination. Serum creatine phosphokinase, ACE, fasting insulin, parathormone (PTH), vitamin A and D levels were normal. Antigen panel and serological tests for infectious diseases including malaria, dengue, scrub typhus, Epstein-Barr virus, HIV, hepatitis B and C virus were negative. There were peaked T waves in ECG.
Time trend of laboratory parameters
Peripheral blood smear shows lymphocytosis – small mature lymphocytes with darkly stained nucleus, condensed chromatin and indistinguishable nucleoli with a narrow rim of basophilic cytoplasm. Pathognomonic smudge cells (arrow) are more fragile and get disrupted while preparing smear. Thrombocytopenia is also present.
The patient was subjected to radiological investigations and oncology consultation. Ultrasonography, CT and positron emission tomography (PET) revealed the presence of cervical, axillary and bulky multifocal intra-abdominal lymphadenopathy indicating the presence of lymphoma/leukaemia (figure 2A,B).
(A) Coronal plane, (B) transaxial plane of positron emission tomography CT scan
Immunophenotyping by flow cytometry revealed atypical B cell hyperproliferation which was positive for markers CD5, CD 19, CD20, CD 23, CD 45 and CD200 (figure 3). Bone marrow aspirate displayed infiltration of mature lymphoid cells constituting more than 30% of the nucleated cells. Bone marrow biopsy revealed non-diffuse type of infiltrative pattern of malignant lymphocytes (figure 4). Excisional biopsy of PET avid cervical lymph node demonstrated diffuse effacement of architecture, the presence of small mature lymphocytes (having a round nucleus, clumped chromatin, inconspicuous nucleoli and scanty cytoplasm) and occasional pseudo follicles, confirming CLL. Immunohistochemistry of lymph node biopsy specimen was positive for PAX5, CD5, CD20, CD23, showed increased mitotic activity with Ki 67 of 15%–20% and absence of cyclin D (figure 5). Fluorescent in situ hybridisation reported heterozygous deletion of 13q (del 13q14.3 positive using probe 13q14.3/13q34/12p11.1-q11: SPEC 13q14.3 Spectrum Orange/LSI 13q34 Spectrum Aqua/CEP 1 Spectrum Green Probe) in 166/200 interphase nuclei (83%) (figure 6).
Flowcytometric analysis.
Histopathology of bone marrow biopsy specimen.
Immunohistochemistry of lymph node biopsy.
Fluorescent in situ hybridisation of peripheral blood.
Differential diagnosis
The combination of hyperuricaemia, hyperphosphataemia, hyperkalaemia and hypocalcaemia in conjunction with lymphocytosis made tumour lysis syndrome related to an underlying malignancy a possible diagnosis, yet we preferred to maintain a broad differential diagnosis base. Low blood urea nitrogen/serum creatinine ratio (<20), low urinary osmolality, high urinary sodium concentration and high fractional excretion of sodium ruled out the exclusive prerenal mechanism of acute kidney injury. There was no evidence of post renal obstruction or parenchymal disorder on imaging. He did not have any pre-existing conditions contributing to hyperuricaemia like obesity, hypertension, insulin resistance, gout or alcoholism. The absence of hyponatraemia and normal serum cortisol levels eliminated the possibility of Addison’s disease. Other potential causes of hyperphosphataemia such as hypoparathyroidism, hypervitaminosis D, vitamin A intoxication, sarcoidosis, hypermagnesaemia or hypomagnesaemia and rhabdomyolysis were ruled out by normal serum PTH, vitamin D, vitamin A, ACE, serum magnesium and creatine kinase levels, respectively. He had no history of intake of any drug known to cause similar electrolyte disturbances. Negative serology for infections eliminated precipitating infectious causes of TLS.
The patient fulfilled all four laboratory and two clinical criteria of tumour lysis syndrome according to the modified Cairo and Bishop classification system5 (table 2). Although the case also fulfils criterion proposed exclusively for STLS by Weeks and Kimple, lack of international recognition of the same necessitates authors to follow Cairo-Bishop classification instead.6 The typical constellation of metabolic abnormalities in the absence of primary renal pathology with the presence of bulky CLL makes STLS the most probable diagnosis.
Modified Cairo-Bishop classification of tumour lysis syndrome in adults
Although lymphocytosis, smudge cells, flowcytometry and cytogenetics established the diagnosis; considering the rare occurrence of STLS in a low-grade malignancy like CLL, bone marrow aspiration/biopsy and lymph node biopsy was performed in second week after patient’s condition was stabilised. The absence of immunoblast or centroblast-like large B cell morphology, Reid-Sternberg cell morphology and negative MUM1/IRF4 immunohistochemistry, along with a relatively low Ki67 index, the absence of classical B symptoms and extranodal features, the presence of symptomatic hypocalcaemia, and the lack of TP53, NOTCH1, MYC and CDKN2A mutations, ruled out Richter transformation.7 8 Lack of t(11;14) and cyclin D1 expression excluded possibility mantle cell lymphoma.9 10
Malignant lymphocyte infiltration with suppression of erythrocytic and megakaryocytic series in bone marrow biopsy suggested CLL as a cause of anaemia and thrombocytopaenia (iWCLL guidelines).11 Lymphocytosis in peripheral blood and marrow, anaemia, thrombocytopaenia and lymphadenopathy considered together places the patient I Rai stage 4 and Binet stage C.12
Treatment
He was admitted to the intensive care unit and aggressive treatment for tumour lysis syndrome as per guidelines was initiated,9 including intravenous fluids (normal saline 200 mL per hour), followed by furosemide and allopurinol (100 mg/m2 every 8 hourly). Insufficient control of hyperuricaemia and worsening renal failure led to switch over to rasburicase (0.2 mg per kg intravenously once a day for 5 days).13 Oral potassium binding resin (patiromer 16.8 g daily for a week), oral phosphate binder aluminium hydroxide, intravenous calcium gluconate and dextrose insulin infusion were also started. Intensive monitoring of vital parameters along with periodic measurements of laboratory and biochemical parameters (figure 7) including estimation of electrolytes, renal function test, uric acid and arterial blood gas analysis were performed. For worsening AKI, volume overload and electrolyte abnormalities, intermittent haemodialysis was started due to insufficient improvement with medications.14
Graph of laboratory profile during hospitalisation (illustrated by KVS).
Outcome and follow-up
With continuous monitoring and aggressive management, the patient’s condition improved over a period of 5 days with a return of appetite, improved sense of well-being, improved urine output and recovery of laboratory and biochemical parameters. He was discharged with advice of follow-up consultation in oncology division. On the basis of anaemia, thrombocytopaenia, bulky lymphadenopathy11 and spontaneous tumour lysis leading to organ failure considered together with absent immunoflobulin heavy chain variable region gene (IGHV) status treatment for CLL was initiated. He was given acalabrutinib (Bruton tyrosine kinase inhibitor) considering its better targeting, potency, additional ability to address tumour microenvironment, good efficacy, safety profile and the patient’s age, functional status, absent IGHV mutation and drug preference.10 The patient was back to his routine by the sixth week. Follow-up PET CT after 3 months displayed regression of disease.
Discussion
TLS is a common adverse consequence of chemotherapy in high-grade haematological malignancies and solid tumours. STLS constitutes only 15% of all TLS cases. STLS has been reported in aggressive haematological malignancies like Burkitt’s lymphoma and acute lymphoblastic leukaemia and some solid tumours. STLS is an exceedingly rare phenomenon in CLL, with only four case reports to date.
STLS results from spontaneous lysis of tumour cells with release of intracellular contents mainly potassium, phosphorus along with nucleic acids and their metabolic products into bloodstream. Nucleic acid breakdown and purine catabolism result in hyperuricaemia which is hallmark of STLS. When the concentration of ions and metabolites exceeds the handling capacity of kidneys, it results in progressive end-organ damage, especially acute kidney injury. Crystallisation of uric acid in renal tubule leads to obstructive uropathy, increased proximal and distal tubular pressure and decreased glomerular filtration. Accompanying deficiency of nitric oxide leads to vasoconstriction and renal ischaemia. The proinflammatory potential of uric acid also contributes to further renal damage.15 Massive release of intracellular potassium ions and incipient obstructive uropathy results in life-threatening hyperkalaemia16 manifesting as muscle cramps, cardiac arrythmias and cardiac arrest. Similar mechanisms result in hyperphosphataemia with chelation of calcium leading to hypocalcaemia, potentially one of the most fatal components of tumour lysis syndrome as it can cause cardiac arrhythmias, tetany, seizures and death17 (figure 8).
Flow chart demonstrating pathophysiology of tumour lysis syndrome (illustrated by KVS).
Although various mechanisms have been hypothesised for STLS like disproportionate tumour burden resulting in spontaneous lysis, insufficient perfusion and ischaemic necrosis of tumour cells, defective molecular programming and signalling pathways leading to enhanced tumour cell death, and influence of external factors like enhanced systemic inflammatory response to infection, the exact mechanism of STLS is yet to be precisely defined.14
Various tumour-specific attributes and host-related factors have been identified as risk factors in the development of tumour lysis syndrome. Tumour-specific attributes are large tumour bulk, high proliferation rate, certain tumour types, disseminated disease and high sensitivity to chemotherapy and radiation.3 Host-related factors include renal dysfunction, hyperuricaemia and dehydration.18
Extensive literature search including Medline, PubMed and Embase databases revealed only four case reports of STLS in CLL to date,19–22 as summarised in table 3. For more details, refer to online supplemental table.
Supplemental material
Comparative account of reported cases of STLS in CLL
The unique biochemical abnormality, in this case, is hyperphosphataemia, an uncommon feature of STLS, as phosphate released is expected to be reused by rapidly proliferating tumour cells. However, hyperphosphataemia is a common feature in tumour lysis following chemotherapy or targeted therapy as phosphate released due to rapid tumour kill is not reused.23
Another important observation from the comparative analysis of these four reported cases is variation in the laboratory parameters, that is, leucocyte count, serum phosphorus and creatinine levels. The absence of a proportionate relationship among these variables is remarkable. This phenomenon can be explained on the basis of multitude of complex processes involved in STLS. The greater mass of disease in this patient is nodal rather than leukaemic, consequently the overall disease burden is of greater clinical importance.
In the context of tumour lysis in CLL, it is crucial to account for the possibility of Richter’s transformation (RT). RT is conversion of CLL/SLL into more aggressive malignant conditions like DLBCL-RT or Hodgkin’s lymphoma, which has a relatively higher likelihood of developing TLS. RT can be diagnosed on the basis of characteristic histopathology, immunostaining and cytogenetic profile.8
Intravenous crystalloids with the aim of improving renal perfusion, glomerular filtration and urine outflow is the cornerstone of the treatment of tumour lysis syndrome, however, the composition may vary according to metabolic profile of the patient. In the presence of renal compromise, loop diuretics are indicated but only after correction of hypovolaemia and exclusion of obstructive uropathy. Allopurinol—a xanthine oxidase inhibitor and rasburicase—a recombinant urate oxidase are targeted towards different steps of urate metabolism.24 Allopurinol by inhibiting uric acid production and rasburicase by converting uric acid to soluble allantoin, bring about significant reduction in urate burden, thus preventing renal shutdown. Rasburicase, with rapid onset of action, greater efficacy and less chance of crystallisation of xanthine and other purine metabolites, has emerged as treatment of choice in TLS; however, G6PD deficiency must be ruled out.13 25
Management of hyperkalaemia includes potassium lowering agents (patiromer and sodium polystyrene sulfonate), intravenous glucose-insulin infusion, inhaled beta agonist Albuterol and intravenous calcium; however, haemodialysis may be required for dangerous hyperkalaemia unresponsive to conservative measures.9 Hyperphosphataemia and hypocalcaemia of TLS are managed with intravenous hydration, phosphate binders and sometimes renal replacement therapy. Serum phosphate must be lowered prior to intravenous calcium to avoid nephrocalcinosis. Haemodialysis is indicated in the presence of deteriorating renal function, intractable volume overload, life-threatening electrolyte abnormalities and poor response to medications26 27 (table 4).
Tumour lysis syndrome pathophysiology and treatment
STLS has potential implications for patient’s health. First is its potential lethality. Second, residual renal insufficiency and clinical instability influence the therapeutic approach to primary neoplastic condition in terms of compromised dose and avoidance of drugs with renal excretion. However, early identification, intensive monitoring, timely and aggressive intervention and organ support can improve patient outcomes.
We reported a case of STLS being detected in an apparently healthy individual, where the diagnosis of haematological malignancy was made after manifestation of STLS. The patient, unaware of his underlying haematological disease, presented with typical tumour lysis syndrome without any discernible external precipitating factor. This case fulfilled both laboratory and clinical criteria prescribed by Cairo and Bishop, which is the most widely used defining criteria for tumour lysis syndrome.5 He also fulfilled Weeks criterion for STLS which proposed that in the absence of cytotoxic therapy in suspected malignancy, patients with hyperuricaemia (uric acid ≥8.0 mg/dL), elevated lactate dehydrogenase (>2× upper limit of normal), acute non-postobstructive oliguric or anuric renal failure despite adequate volume resuscitation, and urinary uric acid to creatinine ratio greater than 1.0 should be considered having STLS until proven otherwise.6 Besides potentially problematic hyperuricaemia with consequent renal tubular damage, he also suffered from significant hyperkalaemia. Hyperphosphataemia and consumptive hypocalcaemia were also distinctive features in this case of STLS because hyperphosphataemia usually accompanies chemotherapy-induced tumour lysis syndrome and is less often observed in STLS.
Internists must keep in mind the importance of maintaining a broad differential diagnosis and avoiding anchoring bias in patients presenting with a laboratory profile seemingly classic for TLS. This is crucial as many conditions such as infections, inflammation or toxin-mediated insults may simulate metabolic derangements of TLS. This case implores the readership to keep a high index of suspicion for STLS even in the absence of a history of malignancy. Use of rasburicase helped reduce the degree of renal damage and promote recovery of glomerular filtration towards normal. Intermittent haemodialysis helped control dangerous hyperkalaemia, hyperphosphataemia and improved oliguria.
Patient’s perspective
Some time ago I was leading a normal healthy life following my daily pursuits. One day I developed vomiting and diarrhoea which persisted for five days and during this period I started feeling weak and became breathless on walking and I was passing very little urine. I was taken to nearby tertiary care hospital where I was admitted and a battery of investigations were performed. In the intensive care unit, I underwent haemodialysis to purify my blood besides receiving lot of oral and injectable medications. The treating physician told me that I could be suffering from some undiagnosed malignancy for which I was to undergo some specialized investigations. With a week of impatient treatment, I started feeling better, gained my appetite and started passing urine. I was found to be suffering from a disorder of blood cells for which I was referred to the oncologist. I am on treatment for leukaemia and my condition is improving with treatment.
Learning points
Spontaneous tumour lysis syndrome (STLS) is an oncometabolic emergency diagnosed by modified Cairo-bishop criteria. It is commonly observed in aggressive haematological malignancies but may develop in low-grade malignancies.
A very high degree of clinical suspicion is required for early identification and prompt intervention to improve clinical outcome. Even in the absence of history of malignancy, clinician should be vigilant to identify the combination of manifestations which define tumour lysis syndrome.
The absence of history of malignancy necessitates elaborate investigative workup to narrow down the diagnosis of STLS. It is essential to carefully consider the potential for Richter’s transformation when evaluating and treating patients experiencing TLS in chronic lymphocytic leukaemia.
Hydration, rasburicase, patiromer, phosphate binders and calcium gluconate are effective therapeutic modalities.
Although medical management corrects the metabolic disturbance, early intermittent haemodialysis reduces morbidity and improves survival in STLS.
Ethics statements
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Supplementary materials
Supplementary Data
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Footnotes
X @KomalSaluja2403
Contributors The following authors were responsible for drafting of the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms, and critical revision for important intellectual content: KVS and YA. CPS gave final approval of the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.