Recurrent Spontaneous Tumor Lysis Syndrome in Undiagnosed Follicular T-Cell Lymphoma

Abstract

Introduction

Spontaneous tumor lysis syndrome (TLS) is a rare, life-threatening metabolic complication that typically occurs in malignancies with high tumor burden. Early recognition is critical, even in the absence of a known malignancy, to prevent severe outcomes.

Case Presentation

We report the case of an 89-year-old male with a history of chronic kidney disease, hyperparathyroidism, and myasthenia gravis, who experienced three episodes of TLS within 1 month. Initially, his metabolic disturbances were misattributed to dehydration. During his second admission, imaging revealed extensive lymphadenopathy, and a lymph node biopsy confirmed follicular helper T-cell lymphoma before his third hospitalization. Despite aggressive treatment, he developed metabolic encephalopathy and lost his decision-making capacity, while his family declined palliative care discussions.

Conclusion

This case highlights the importance of considering TLS in patients with unexplained hyperkalemia, hyperuricemia, and hyperphosphatemia, even in the absence of a malignancy diagnosis. Early diagnosis and multidisciplinary care are essential to improve outcomes.

Introduction

Tumor lysis syndrome (TLS) is an uncommon but potentially life-threatening metabolic complication that typically occurs with chemotherapy when neoplastic cells undergo rapid rupture and disintegration, leading to the release of intracellular contents into the bloodstream. This phenomenon varies depending on, but not limited to, the type of cancer, tumor burden, tumor sensitivity to chemotherapy, preexisting renal disease, or patient’s age. It is most commonly associated with hematologic malignancies, particularly acute leukemias and aggressive lymphomas. High-risk tumors, such as acute lymphocytic leukemia or Burkitt lymphoma, have reported incidences of TLS up to 23%. Intermediate-risk tumors, such as diffuse large B-cell lymphoma and acute myeloid leukemia with WBC counts between 25,000 and 50,000, have reported incidences of TLS at 6%. Reported incidences of TLS are less than 1% in low-risk tumors such as chronic lymphocytic leukemia, chronic myelogenous leukemia, and solid tumors. Indolent lymphomas such as follicular lymphoma are also considered low-risk tumors regarding TLS [1].

While TLS is generally associated with chemotherapy, spontaneous cases are far rarer but still possible. Chemotherapy-related TLS has an incidence rate of 4–42%, depending on the type of cancer and chemotherapy the patient received while the incidence of spontaneous TLS in patients with diagnosed hematological malignancy is 1.08% [2]. Here, we report a rare case where a patient experienced spontaneous TLS three times within a month. When clinicians are presented with abnormal electrolyte results that might be consistent with TLS along with ambiguous symptoms, TLS should be considered as a potential diagnosis, even if the malignancy has not been diagnosed yet. While the diagnosis of TLS was appropriately made during the patient’s second admission, this case highlights the challenges in identifying rare conditions like spontaneous TLS during an initial presentation. Early imaging or additional investigations may not always be justifiable, particularly in patients without a known history of malignancy, but maintaining a high index of suspicion is critical for timely management [3]. This case also presents the exceptional occurrence of multiple episodes of spontaneous TLS in an indolent lymphoma, which contradicts the typically low-risk profile associated with such malignancies.

Case Presentation

We present a case report where a patient who was recently diagnosed with T-cell lymphoma had three episodes of spontaneous TLS. This was an 89-year-old male with a past medical history of hypertension, chronic kidney disease stage 4, primary hyperparathyroidism, myasthenia gravis, and recently diagnosed T-cell lymphoma who was transferred from an outside facility for labs that were consistent with spontaneous TLS.

The first time the patient presented for concerns of spontaneous TLS, he had not been diagnosed with T-cell lymphoma yet. The patient’s initial symptoms were tiredness and fatigue. The patient decided to get blood work done, and when his primary care physician received the lab results, he informed the patient to go into the emergency department. The patient presented with hyperkalemia of 7.0 mEq/L, hyperuricemia of 8.6 mg/dL, hypercalcemia of 13.2 mg/dL, hyperphosphatemia of 5.3 mg/dL, and creatine elevation to 3.17 mg/dL when his baseline was at 1.8 mg/dL. An EKG was completed which did not show any changes. During this initial hospitalization, the patient’s labs were attributed to dehydration from suspected gastritis. He was treated aggressively with intravenous fluids and Lokelma to bring his potassium within normal limits. The patient was deemed stable for discharge and sent back to his skilled nursing facility without further workup. This was his first occurrence of TLS.

A week later, the patient presented to the hospital again for confusion and generalized weakness (shown in Fig. 1). Initial lab work showed hyponatremia of 121 mEq/L, hyperkalemia of 5.3 mEq/L, hypercalcemia of 11.7 mg/dL, hyperphosphatemia of 5.9 mg/dL, and hyperuricemia of 9.0 mg/dL, consistent with TLS. During this hospitalization, the patient underwent further evaluation with CT imaging, which revealed numerous enlarged mediastinal, left axillary, upper abdominal lymph nodes, as well as significant enlargement of retroperitoneal and bilateral inguinal lymph nodes. A skeletal survey showed no definitive lytic lesions. Given these findings, the oncologist was consulted, and it was decided to proceed with an excisional biopsy of an axillary lymph node along with a fine-needle aspiration or core biopsy of a retroperitoneal lymph node. Interventional radiology proceeded with an inguinal lymph node biopsy which was successful. The patient was discharged to a skilled nursing facility as he was medically stable, and the biopsy was sent out for analysis.

Fig. 1.

Three episodes of spontaneous TLS within 1 month. Timeline of the patient’s spontaneous TLS episodes within 1 month to display when the patient was admitted to the hospital, discharged, and diagnosed.

After 1 week, the biopsy results were obtained (shown in Fig. 1). The normal lymphoid architecture was completely effaced and replaced by a polymorphous cellular infiltrate composed of small uniform lymphocytes, intermediate-sized lymphocytes, and scattered eosinophils. The lymphoid infiltrate was predominantly composed of CD3-positive/CD5-positive T cells. CD20 highlights small areas of residual B cells. The T cells appear to co-express BCL6 and CD10. The patient was diagnosed with T-cell lymphoma consistent with follicular helper T-cell lymphoma.

The third time the patient presented with TLS was 1 week after the biopsy results came back (shown in Fig. 1). The patient once again presented with abnormal lab work with generalized weakness and confusion. The patient’s presenting labs showed hyperkalemia of 5.7 mEq/L, hyperuricemia of 9.1 mg/dL, hypercalcemia of 10.8 mg/dL, hyperphosphatemia of 6.3 mg/dL, creatinine elevation of 4.08 mg/dL, leukocytosis of 17.9 × 10⁹/L, and mild anemia with hemoglobin of 11.9 g/dL. Urinalysis showed small leukocyte esterase with the presence of calcium oxalate crystals and moderate amount of hemoglobin. Upon presentation, the patient was alert and oriented. The patient was treated for TLS with 1 dose of rasburicase which had successfully lowered his uric acid levels to 1.2 mg/dL. The patient also received extensive fluid resuscitation with lactated ringers running at 100 mL/h. The patient had multiple indications for dialysis, including managing electrolyte abnormalities; however, it was withheld due to his advanced age and comorbidities. The decision also considered the risks and potential complications associated with dialysis in a patient of his frailty. Unfortunately, the patient subsequently lost decision-making capacity due to metabolic encephalopathy from uremia.

The patient’s family was informed by several different specialists of the patient’s guarded prognosis given his age and comorbidities. Palliative care physicians had an in-depth discussion with the patient’s family about the patient’s quality of life, goals of care, and prognosis. It was explained that chemotherapy was not a definitive solution and that the patient was starting to have poor oral intake, so to continue with chemotherapy, a PEG tube or feeding tube would need to be placed. However, the patient’s family stated that they had not made up their minds about a PEG tube or feeding tube, as the patient had never made his wishes clear, but did want to start chemotherapy as soon as possible.

The patient underwent chemo port placement and received mini-CHOP therapy while in the hospital. After the patient’s first chemotherapy session, the patient’s mentation further deteriorated. The patient refused oral intake and the patient’s family did not want to pursue a PEG tube or feeding tube. The patient’s family felt that occasional consumption of apple sauce or milk was sufficient; however, the medical team gently explained that this may not be enough to fully meet his nutritional needs. As the family declined additional interventions beyond continued chemotherapy, the patient was ultimately discharged to a skilled nursing facility. The patient continued to deteriorate due to poor nutritional status and metabolic encephalopathy on an outpatient basis, so the family wanted to pursue PEG tube placement. However, the patient passed away a day before any intervention could take place. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000544865).

Discussion

Spontaneous TLS is a rare and poorly understood phenomenon. The chances of having multiple episodes of spontaneous TLS within a month are even rarer. Follicular T-cell lymphoma is usually considered an indolent lymphoma with a lower tissue burden and lower risk of TLS as compared to more aggressive lymphomas such as high-grade non-Hodgkin lymphoma or acute lymphoblastic leukemia. While specific studies may report varying incidence rates, estimates suggest that TLS occurs in about 1–5% of patients with indolent lymphomas such as the one this patient was diagnosed with [4]. The likelihood of a patient with follicular lymphoma having several episodes prior to starting chemotherapy is much lower.

The suspected mechanism of spontaneous TLS is poorly understood. TLS after chemotherapy is induced due to cellular death, causing the sudden release of intracellular substances like potassium, phosphorus, and nucleic acids, precipitating a cascade of metabolic disturbances such as hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia [1, 5]. It is predicted that spontaneous TLS works in the same manner, but the inciting event that causes cellular death is unclear. It is predicted that cancers with high turnover rates can overwhelm the kidneys, potentially causing TLS, but in our patient’s case, follicular helper T-cell lymphoma is usually considered an indolent lymphoma with a lower tissue burden, so the mechanism is not understood.

Symptoms of TLS may include nausea, vomiting, diarrhea, muscle cramping or twitching, weakness, numbness or tingling, or decreased urine output. If left untreated, TLS can lead to acute kidney injury, cardiac arrhythmias, and even death. TLS is considered an oncologic and renal emergency, and requires immediate treatment [6]. One feature typical of TLS is hypocalcemia, which is partially a consequence of hyperphosphatemia. Phosphate acts as a serum calcium binder, decreasing calcium stores. However, in this case, the patient consistently presented with hypercalcemia, which could be the result of hypercalcemia of malignancy. This would point to either high turnover of cells or high metastatic burden driving the hypercalcemia. Hypercalcemia in spontaneous TLS is a rare finding, but when discovered, treatment should be initiated immediately with intravenous fluids and calcitonin at the discretion of your institution’s nephrologist [7].

The typical treatment plan for TLS aims to promote the excretion of metabolic waste products from the blood. Fluids and hydration are used both as prevention and management, enhancing urine and renal blood flow, increasing intravascular volume, and enhancing glomerular filtration. Allopurinol can be used as treatment for hyperuricemia caused by TLS as it blocks the conversion of xanthine and hypoxanthine to uric acid. This decreases uric acid formation and thus reduces the incidence of urinary tract obstruction caused by uric acid precipitation. Rasburicase also decreases uric acid precipitation by metabolizing uric acid to allantoin. In severe cases of metabolic disturbance or acute kidney injury due to TLS, hemodialysis can be considered. Hemodialysis filters blood through a dialysis machine to remove excess electrolytes and metabolic waste products. Indications for hemodialysis include, but are not limited to, severe hyperkalemia (above 6.0 mEq/L) or hyperuricemia (above 10 mg/dL) [8]. In patients undergoing chemotherapy, it is important to note that dialysis can increase the clearance of chemotherapeutic agents and possibly cause under-treatment of malignancy. Once again, TLS is considered a renal and oncological emergency, so immediate treatment is crucial [4].

Goals of care, quality of life, and prognosis are crucial to be discussed with patients and their families so that there is clear direction of medical care. However, in the patient case above, palliative care should have been introduced during the patient’s second hospitalization. It is crucial that palliative care be introduced early in the course of serious illness before any end-of-life decisions must be made [9]. Not only does this give patients more autonomy and time to think but it also improves the quality of life and reduces emotional burden on family members when it comes to treatment and symptom management [10]. In the case presentation above, it was unclear about what the patient wanted due to his altered mental status; therefore, the decisions were left up to the patient’s family. These decisions took an emotional toll on the family and might have caused the patient to unnecessarily undergo treatment. Lastly, the palliative care discussions must be compassionate but also firm to help avoid unwanted treatments. Clear goals of care should be established before any treatment takes place to help physicians and other health professionals make the best treatment decisions [11].

Conclusion

When patients present with abnormal electrolytes such as hyperkalemia (potassium >7.0 mEq/L) and hypercalcemia (calcium >13.0 mg/dL), particularly without a known history of malignancy, clinicians should consider spontaneous TLS as a potential diagnosis. Although there may not be strong evidence of having TLS in your diagnosis, this case report displays the importance of having a broad differential when approaching patients. In our case, the patient’s recurrent episodes of spontaneous TLS, despite being diagnosed with a low-risk malignancy like follicular helper T-cell lymphoma, highlight the importance of early recognition and treatment of TLS. The initial misattribution of initial lab abnormalities to dehydration delayed the diagnosis and likely contributed to the patient’s subsequent complications. This case highlights the need for vigilance when managing patients with unexplained metabolic disturbances and the potential for serious underlying conditions, even when a malignancy has not yet been diagnosed. Early intervention is crucial, as TLS is a renal and oncological emergency that can lead to life-threatening outcomes if not promptly addressed.

Furthermore, palliative discussions must be compassionate and firm to avoid unwanted treatment that may not align with the patient’s or family’s wishes. Palliative discussions should be introduced early in the disease course rather than later. These strategies help improve the quality of life, allow more time for the patient to determine their wishes, and reduce emotional burden on family members.

Statement of Ethics

This case report complies with the ethical guidelines of COPE. This study was performed in accordance with the Declaration of Helsinki. Ethics approval for this human study was waived by ProMedica Toledo Hospital and the University of Toledo Medical Center. The patient provided written informed consent to participate in this study. Written informed consent for publication of this case report was obtained from the patient’s next of kin.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

All authors substantially contributed to the conception or design of the work along with drafting the work and finalizing the version to be published. They agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Funding Statement

This study was not supported by any sponsor or funder.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.