What is the likely cause of death in a patient with newly diagnosed non-Hodgkin lymphoma (NHL), uncontrolled diabetes mellitus type 2 (DM2) for 20 years, and hypertension (HTN), who presented with hyperuricemia and hyperkalemia before starting chemotherapy?

Spontaneous Tumor Lysis Syndrome (TLS)

The most likely cause of death is spontaneous tumor lysis syndrome (TLS) occurring before chemotherapy initiation, making the answer B - Tumor lysis syndrome. 1

Clinical Reasoning

This patient presents with the classic laboratory hallmarks of TLS—hyperuricemia and hyperkalemia—in the setting of newly diagnosed non-Hodgkin lymphoma, before receiving any chemotherapy. 1 While TLS typically occurs 12-72 hours after initiating cytotoxic therapy, spontaneous TLS can occur in patients with high tumor burden, rapid proliferation rates, or highly chemosensitive malignancies such as NHL, even without treatment. 1, 2

Why TLS is the Most Likely Diagnosis

• The Cairo-Bishop classification system explicitly accounts for TLS occurring "3 days before or 7 days after the initiation of treatment," recognizing that TLS can develop before therapy begins. 1

• Laboratory TLS is defined by two or more abnormal serum values (uric acid, potassium, phosphate, or calcium) at presentation, which this patient clearly demonstrates. 1

• NHL is one of the highest-risk malignancies for TLS development, with incidence rates of 19.6% for hyperuricemia and 6.1% for TLS in NHL patients. 1

• The combination of hyperuricemia and hyperkalemia indicates massive tumor cell lysis with release of intracellular contents into the bloodstream, overwhelming normal homeostatic mechanisms. 1, 3, 2

Why Other Options Are Less Likely

Drug-induced (Option A) is incorrect because the patient died one week before starting chemotherapy—no cytotoxic drugs were administered. 1

Undiscovered renal failure (Option C) is a consequence of TLS, not the primary cause. The patient's 20-year history of uncontrolled diabetes and hypertension certainly predisposes to chronic kidney disease, but the acute presentation with hyperuricemia and hyperkalemia points to acute uric acid nephropathy from TLS. 1, 3 Uric acid precipitation in renal tubules leads to acute kidney injury, which then exacerbates hyperkalemia—this is the pathophysiologic cascade of TLS, not pre-existing renal failure. 1, 2

Renal tubular acidosis (Option D) does not explain the hyperuricemia or the acute clinical deterioration in a patient with newly diagnosed NHL. 1

Mechanism of Death in Spontaneous TLS

The most likely immediate cause of death was cardiac arrhythmia or sudden cardiac death from severe hyperkalemia. 1 The guidelines explicitly state that elevated potassium levels produce "cardiac irregularities such as arrhythmias, ventricular tachycardia, fibrillation, or cardiac arrest." 1

Pathophysiologic Cascade

• Massive spontaneous tumor cell lysis releases intracellular potassium and nucleic acids into the bloodstream. 1, 3, 2

• Nucleic acids are metabolized to uric acid, causing hyperuricemia, which precipitates in renal tubules causing acute uric acid nephropathy. 1, 2

• Acute kidney injury impairs potassium excretion, further exacerbating hyperkalemia. 1, 3

• Severe hyperkalemia causes fatal cardiac arrhythmias. 1

Risk Factors Present in This Patient

This patient had multiple risk factors that increased TLS risk and mortality: 1, 4

• Newly diagnosed NHL with presumably high tumor burden (given the rapid clinical deterioration) 1
• Uncontrolled diabetes for 20 years, likely causing baseline renal impairment that reduced capacity to clear uric acid 4
• Hypertension, further compromising renal function 4
• No prophylactic measures were initiated (no hydration, allopurinol, or rasburicase) 1

Critical Clinical Lesson

The mortality rate from TLS can be as high as one in three patients, but it is preventable in practically 100% of cases with appropriate prophylaxis. 4 This case underscores the importance of:

• Immediate risk stratification upon NHL diagnosis, before any treatment 1, 5
• Initiating aggressive hydration (≥2 L/m²/day) and prophylactic rasburicase or allopurinol in high-risk patients, ideally 48 hours before chemotherapy 1, 5
• Recognizing that spontaneous TLS can occur without any treatment in patients with high tumor burden 1, 2, 6
• Monitoring electrolytes, uric acid, and renal function at least daily in newly diagnosed NHL patients, even before treatment begins 5