Advertisement

Tumor Fever Due to Metastatic Esophageal Squamous Cell Carcinoma

      To the Editor:
      Fever is common in patients with cancer. Up to one-quarter of non-infectious fevers may be caused by the tumor itself (tumor fever), a diagnosis of exclusion.
      • Toussaint E
      • Bahel-Ball E
      • Vekemans M
      • et al.
      Causes of fever in cancer patients (prospective study over 477 episodes).
      Tumor fever occurs most commonly in hematologic malignancies, although solid tumors can also be culprits.
      • Foggo V
      • Cavenagh J
      Malignant causes of fever of unknown origin.
      To our knowledge, metastatic esophageal squamous cell carcinoma causing tumor fever has not been reported.

      Case Presentation

      A 58-year-old woman with esophageal squamous cell carcinoma with spinal metastases presented with bilateral lower extremity weakness and was found to have L4 vertebral collapse and cauda equina syndrome. On admission, temperature was 39°C and white blood cell count was 21.2 × 109 with neutrophilic predominance. She reported no subjective fevers or infectious symptoms prior to presentation. She underwent decompressive laminectomy with tumor debulking and received cefazolin and dexamethasone postoperatively, with reduction in temperature and white blood cell count.
      On postoperative day 11, her temperature increased to 39.1°C. Assessment revealed no new localizing findings. Urine, blood, and surgical site cultures were sterile. Vancomycin and piperacillin/tazobactam were initiated. She had recurrent febrile episodes associated with chills, encephalopathy, and tachycardia over the next 2 weeks despite antibiotics and acetaminophen (Figure, A).
      Figure
      Figure(A) Temperature over the initial 2-week period. Each vertical line represents one 24-hour period. (B) Temperature over the subsequent 2-week period. Naproxen challenge was administered at the first black line, and the patient was switched to prednisone at the second black line.
      A broad infectious and allergic workup remained negative. Antibiotics were discontinued after 5 days, but fevers persisted. Tumor fever was suspected, so 2 doses of naproxen 250 mg were administered 12 hours apart, with subsequent decrease in temperature (Figure, B). The response to naproxen, along with persistent fevers despite antibiotics, supported the diagnosis of tumor fever. Naproxen was continued, and she remained largely afebrile (Figure, B). However, 5 days later the fevers recurred despite naproxen. Prednisone 30 mg twice daily was started as second-line therapy for tumor fever. She remained afebrile for more than 48 hours and was discharged on prednisone 10 mg daily.
      Two weeks later she was readmitted with a pathologic hip fracture. Prednisone was held, but recurrent fevers prompted re-initiation, after which her temperature stabilized. The febrile episodes gradually resolved as she received chemotherapy. She was tapered off of prednisone as an outpatient 5 months later with no recurrence of fever.

      Discussion

      In patients with cancer, tumor fever is defined as a temperature >37.8°C occurring at least daily for more than 2 weeks without evidence of infection or allergy, without response to antibiotic therapy, and with resolution with naproxen.
      • Foggo V
      • Cavenagh J
      Malignant causes of fever of unknown origin.
      Tumor fever is most commonly associated with hematologic malignancies, renal cell carcinoma, hepatocellular carcinoma, and solid tumors metastatic to the liver.
      • Foggo V
      • Cavenagh J
      Malignant causes of fever of unknown origin.
      An association with metastatic esophageal squamous cell carcinoma has not been previously reported to our knowledge. Importantly, liver metastases were radiologically absent in this case.
      The use of naproxen to diagnose and treat tumor fever was first reported in 1984—tumor fever abated within 24 hours of naproxen use and patients remained afebrile as long as naproxen therapy was continued.
      • Chang JC
      • Gross HM
      Utility of naproxen in the differential diagnosis of fever of undetermined origin in patients with cancer.
      Subsequent studies verified the impact of naproxen on tumor fever.
      • Tsavaris N
      • Zinelis A
      • Tsoutsos H
      • Kosmidis P
      The response of paraneoplastic fever of lymphomas and solid tumors to the administration of naproxen.
      Corticosteroids have some impact on tumor fever, although to a lesser extent than naproxen.
      • Chang JC
      Antipyretic effect of naproxen and corticosteroids on neoplastic fever.
      This case provides an important diagnostic lesson in the workup of fever in the setting of malignancy—metastatic solid tumors not typically associated with fevers may cause tumor fever even in the absence of liver involvement. After ruling out other causes, a challenge of naproxen may be diagnostically and therapeutically useful. This can be followed by sustained treatment with naproxen or corticosteroids if a response is observed, along with treatment of the underlying malignancy.

      References

        • Toussaint E
        • Bahel-Ball E
        • Vekemans M
        • et al.
        Causes of fever in cancer patients (prospective study over 477 episodes).
        Support Care Cancer. 2006; 14: 763-769
        • Foggo V
        • Cavenagh J
        Malignant causes of fever of unknown origin.
        Clin Med (Lond). 2015; 15: 292-294
        • Chang JC
        • Gross HM
        Utility of naproxen in the differential diagnosis of fever of undetermined origin in patients with cancer.
        Am J Med. 1984; 76: 597-603
        • Tsavaris N
        • Zinelis A
        • Tsoutsos H
        • Kosmidis P
        The response of paraneoplastic fever of lymphomas and solid tumors to the administration of naproxen.
        J Intern Med. 1991; 230: 549-550
        • Chang JC
        Antipyretic effect of naproxen and corticosteroids on neoplastic fever.
        J Pain Symptom Manage. 1988; 3: 141-144