Ewing Sarcoma Presenting as Fever of Unknown Origin (FUO) in Children: A Case Report and Brief Review of the Literature

Abstract

Introduction:

Fever of unknown origin is one of the challenging medical conditions with a wide differential diagnosis.

Case presentation:

We present a case of 16-year-old patient with Ewing sarcoma diagnosed with neoplastic fever.

Discussion:

Neoplastic fever, which is caused by the tumor itself, is diagnosed when all other causes of fever have been ruled out. It occurs more frequently in hepatic, renal, and hematological cancers. After history and physical examination, a thorough individualized diagnostic approach is required. Removing the underlying cause of fever when feasible and symptomatic relief with NSAIDS are the primary therapeutic approaches.

Conclusion:

Fever is common in patients with cancer and it can be due to infectious and non-infectious causes. After excluding all potential causes, neoplastic fever is diagnosed.

Introduction

Management of cancer-related symptoms is an integral part of cancer treatment. Pain, anorexia, weight loss, depression and other specific symptoms pose an important challenge for cancer care workers, who seek to improve the quality of life of their patients. ¹ Fever is a common symptom in the clinical course of cancer. Its management significantly depends on its origin. Neutropenic fever is considered the most common type, followed by fever secondary to surgical site infection in those who undergo surgery. Fever might also be secondary to diagnostic and/or therapeutic interventions, including drugs, transfusion of blood products, surgical procedures, hematoma and thrombosis. ² Neoplastic fever is a diagnosis of exclusion. Although more common with hematologic malignancies, solid tumors can also be the culprit. ³

Herein we present a case of a 16-year-old male patient with neoplastic fever secondary to Ewing sarcoma, highlighting the challenges of diagnosis and our approach.

Case Presentation

We report the case of a 16-year-old male patient, Palestinian in origin, who is a known case of asthma with a free past surgical history and no previous drugs or allergies. The patient started to complain of right lower limb pain, limiting his movement in November 2021. He was initially treated with simple over-the-counter analgesics without improvement, so his family sought medical advice at an orthopedic clinic where a pelvic magnetic resonance imaging (MRI) was requested. The image (Figure 1) showed a heterogenous large bony mass lesion involving the right iliac bone, measuring 10 × 9 × 9 cm associated with an extraosseous soft tissue component. The right sacral ala showed an abnormal post-contrast enhancement, denoting bone marrow involvement. Multiple scattered foci of abnormal enhancement were seen in the left iliac bone representing metastasis to bone.

Figure 1.

Right iliac bone expansion is seen, associated with marrow infiltration, surrounding cortical disruption and large soft tissue mass showing intra and extra-pelvic components. The extra-pelvic soft tissue component is more sizable posteriorly and laterally infiltrating the right gluteus medius and maximus muscles. In addition, the intra-pelvic soft tissue component is seen infiltrating the iliacus muscles. The mass is eliciting homogenous intermediate signal on T1 WIs and low to intermediate signal on T2WIs (panels [a], [c] and [d]) and low to intermediate signal on T2WIs (panel [b]) with heterogeneous vivid post contrast enhancement. In addition, multiple metastatic lesions are noted at pelvis bones and both femurs in the following cuts.

The patient was referred to oncology clinic. On presentation, he was conscious, oriented, alert. His blood pressure was 114/60 mmHg, heart rate was 86 beats per minute (bpm), afebrile. His cardiopulmonary exam was normal, his abdomen was soft and lax with no palpable organomegaly. He was noted to have an antalgic gait, with limping to the right side. The point of maximal tenderness was at the right hip. There was no swelling, had restricted internal and external rotation of the right hip with no difference in the length compared to the contralateral limb. Baseline labs showed anemia (hemoglobin (Hgb): 8.53 g/dl), normal white blood cell count (6220/µl), normal platelet count (403 × 10³), and normal urine analysis. Full tumor marker profile, shown in Table 1, were all negative.

Table 1.

Tumor markers with their reference range.

Tumor marker	Value	Reference range
CA 15.3	26	0-25 µ/ml
CA 19.9	7.5	0-27 µ/ml
CEA	1.12	<5.9 ng/ml, heavy smokers < 10.0 ng/ml
PSA	0.1	0-4 ng/ml
AFP	4.5	0-15 ng/ml

Abbreviations: CA, cancer antigen; CEA, carcinoembryonic antigen; PSA, prostate-specific antigen; AFP, alpha-fetoprotein.

Positron emission tomography (PET) showed a large, destructive, right iliac bone lesion with a large soft tissue component, mostly representing a primary osseous malignancy. Taking into account the site and appearance of the mass as well as the age of the patient, the mass mostly represented Ewing sarcoma. Multiple, bilateral, metastatic lung nodules with more predominant involvement of the right lung were also noted, with diffuse axial and appendicular skeletal metastatic deposits mainly corresponding to the lytic changes seen on CT with intense hypermetabolic activity, indicating a stage IV metastatic disease (Figure 2).

Figure 2.

Positron-emission tomography (baseline). Section A shows the primary hypermetabolic iliac tumor. Section B shows bilateral lung nodules. Section C and D show axial bone metastatic hypermetabolic lesions.

The patient underwent core biopsy of the lesion, histopathology and immunohistochemistry, as shown in Figures 3 and 4, showed Ewing sarcoma. The patient was started on IE protocol (ifosfamide 1800 mg/m² intravenously (IV) and etoposide 100 mg/m² IV once daily, in addition to mesna 600 mg/m² IV 3 times daily for 5 days).

Figure 3.

Selected axial cuts of a PET CT scans at the level of the pelvic bones with a 4-months interval between the above (A) and the below (B) scans while the patient was maintained on chemotherapy. They demonstrate the difference in the size and the metabolic activity of the right iliac bone Ewing sarcoma. The below image (B) shows complete metabolic resolution with reduction in the size of the previous hyper-metabolic malignant right iliac bone mass lesion.

Figure 4.

MIP PET CT comparison with a 4-months interval while the patient was maintained on chemotherapy showing complete metabolic response in the known primary right iliac bone Ewing sarcoma. Panel (a) represents an anterior view, panel (b) represents a posterior view. However, more extensive metastatic hyper-metabolic deposits are noted indicated disease progression.

One week following the conclusion of the cycle, the patient presented to treatment room due to fever, his temperature was 38.4, he appeared non-toxic, his cardiopulmonary exam was unremarkable, there was no stigmata of infective endocarditis, and his abdominal exam disclosed no abnormalities. Complete blood count (CBC) was noted for neutropenia (absolute count: 370/µl). C-reactive protein (CRP) was 338 mg/l. There were no complaints of dysuria or burning sensation, his urinalysis was bland. Blood and urine cultures were obtained, and the patient was admitted to hospital as a case of neutropenic fever. Empiric ceftazidime and amikacin were started on admission as acute bacterial infection could not be ruled out. Filgrastim, 300 mcg subcutaneously (SQ) OD was administered as a means of increasing the patient absolute neutrophil count (ANC). Daily serial CBC showed an increase in ANC up to 9000, CRP decreased to 110. Blood and urine cultures returned sterile. The patient was discharged home and his chemotherapy regimen dose was reduced by 20%. When presenting for his third cycle, he was found to have low-grade fever, 37.6°. CBC parameters were within normal, while CRP was elevated (70.5). Urinalysis was unremarkable. As the patient had no focus, looked well, had no active complaints except for his hip pain, blood, and urine cultures were obtained and he was kept off antibiotics for observation. His chemotherapy protocol was held until the culture results were ready. Cultures returned sterile after 48 hours, so the third cycle was commenced. The same scenario recurred twice, the patient would be admitted as a case of fever of unknown origin, investigated extensively, but no focus could be determined.

The first assessment of disease response took place in November 2022 via PET scan, which showed a good metabolic response despite morphological pseudo-progression at the primary tumor site (Figures 3 and 4).

The patient continued on the same line, receiving the fifth cycle. Due to increasing severity of pain in the right hip (the primary site of tumor), chemotherapy was temporarily held and the patient was scheduled for 15 fractions of palliative radiotherapy. During that period, the patient had another episode of fever, as no focus could be determined, the patient was diagnosed with neoplastic fever, he was discharged on naproxen, 250 mg per os twice daily, which failed to lyse his fever as he had many episodes of fever prior to the third assessment following the ninth cycle.

As the third assessment showed significant disease progression. IE was stopped, and VAC protocol (vincristine, 1.5 mg/m² IV, cyclophosphamide, 1200 mg/m² IV, and doxorubicin 75 mg/m² IV every 21 days, in addition to filgrastim 300 mcg SQ OD for 10 days 24 hours following the conclusion of chemotherapy) was commenced. Zoledronic acid 4 mg IV was added at the fourth cycle due to persistent bony pain mainly in the right flank and right hip. He received 6 cycles of VAC over a period of 6 months, during which he had a single episode of fever. Evaluation via PET scan on August showed a mixed response, so the patient was planned to continue on the same line, but with dactinomycin, 1.25 mg/m² replacing doxorobucin as a means of reducing cardiotoxicity.

The patient received a single cycle, after which he returned to treatment room complaining of high-grade fever (38.9), associated with increasing pain in the left tibia. Similar to all previous scenarios, full investigations failed to disclose a focus. The patient had recurrent febrile episodes with increasing severity of pain, refractory to opioid therapy, so he was planned for palliative radiotherapy to tibia. On CT simulation, he was found to have significant disease progression in the lungs, so he was switched to a third line, consisting of irinotecan, 180 mg/m² IV on day one and temozolomide, 100 mg/m² PO OD on days 1 to 5. The patient received 2 cycles, with no recorded episodes of fever. He is scheduled for evaluation after 4 cycles. A summary of fever episodes over the treatment course is highlighted in Figure 5.

Figure 5.

Episodes of fever over the course of treatment in correspondence with the line used. The patient had the most episodes of fever while on IE, had only 2 episodes of fever while on VAC, on multiple episodes of consecutive fevers on VCD prior to commencing CPT11-TMZ. .

Discussion

Neoplastic fever is defined as fever caused by the cancer itself. It is encountered more in solid tumors and hematological malignancies, including hepatic cancer and renal carcinoma. It is more prevalent in the metastatic setting, particularly with metastasis to the liver.^4,5 Fever in cancer patients is often linked to infection, but in cases like Ewing sarcoma, where no focus of infection is found, neoplastic fever must be considered. Unlike neutropenic fever or fever due to infection, neoplastic fever is a diagnosis of exclusion, and its occurrence in Ewing sarcoma is very rare. However, most types of cancer and even benign tumors such as atrial myoma can cause neoplastic fever. ⁶

While there have been no reports specifically addressing the incidence of neoplastic fever in Ewing sarcoma patients, Nakamura et al ² study demonstrated that in 195 patients with bone and soft tissue sarcomas, the incidence of neoplastic fever has been reported in 11 patients (5.5%). This case adds to the limited evidence on the association between Ewing sarcoma and neoplastic fever, highlighting the challenges in recognizing and managing this complication in solid tumors.

The pathophysiology of neoplastic fever is not fully understood. It is believed to involve the release of pyrogenic cytokines such as IL-1, IL-6, and tumor necrosis factor (TNF) from tumor cells or macrophages responding to the tumor. They induce the production of prostaglandin E2, which changes the thermostatic set point in the hypothalamus. ⁷ Other mechanisms are related to tumor necrosis which is followed by the release of TNF and other pyrogens from dead tissue. In addition, direct tissue damage and the activation of phospholipase A2 is thought to be the cause of neoplastic fever in patients with brain metastasis. ⁴

Fever in Ewing sarcoma, although rare, presents a unique challenge in terms of management and differentiation from other causes of fever in cancer patients, such as neutropenic fever and infection-related fever. Traditional biomarkers like CRP and ESR are unreliable in distinguishing neoplastic fever from infectious causes, but recent evidence suggests that procalcitonin could be a valuable tool in such scenarios. Procalcitonin levels are typically low in patients with neoplastic fever and high in those with bacterial infections. ⁸ This case underscores the importance of utilizing available diagnostic tools to differentiate between fever types and avoid unnecessary antibiotic use.

In this patient, fever presented after chemotherapy-induced neutropenia, initially suggestive for neutropenic fever. However, subsequent episodes of fever, particularly low-grade fevers, were observed during treatment. It was classified as fever of unknown origin (FUO) after performed of extensive investigations, including serial CBC, CRP, and cultures, which failed to reveal a specific infectious cause. The neutrophil count during the first fever episode was 370/µl, and further investigations, including blood cultures, urine analysis, and imaging, were unremarkable, indicating the diagnosis of neoplastic fever.

Fever of unknown origin should be treated by addressing the underlying cause. This isn’t always possible so non-steroidal anti-inflammatory drugs (NSAIDs), paracetamol and corticosteroids are frequently used. ⁷ The antipyretic effect of naproxen on neoplastic fever was compared to that of corticosteroid. It was noted that naproxen is superior as it results in complete lysis of fever in 90% of febrile patients as compared to 50% of patients treated with corticosteroid. In addition, naproxen had the most rapid effect compared to other NSAIDS like indomethacin and diclofenac sodium as reported in a randomized trial including 48 cases. ² While naproxen is considered highly effective in managing neoplastic fever in general, patient’s responses can vary, particularly in complex cases with advanced metastatic disease, as in this patient. Its failure in this case could be attributed to the aggressive progression of the disease or other undetermined factors that may have influenced the fever’s persistence.

In 1984, Chang and Gross described the diagnostic value of naproxen and other NSAIDS to distinguish between neoplastic and non-neoplastic fever. About 14 of 15 patients with neoplastic fever had complete resolution of fever within 24 hours after the administration of naproxen. In contrast, none of the 5 patients with infectious fever had improvement. ⁶ A meta-analysis by Zhang et al revealed that the success rate of using naproxen for the treatment of neoplastic fever was 94.1%. Success rate in suspected neoplastic fever was 79.8% and for fever of unknown origin it was 67.7%. As a result, after ruling out all other possible differential diagnoses, naproxen should be administered as the first treatment for individuals with neoplastic fever. In addition, the earlier use of naproxen for patients with neoplastic fever and fever of unknown origin is recommended as this reduces patient’s suffering and improve their quality of life. Common adverse effects of NSAIDS such as gastritis and gastrointestinal bleeding should be considered during the use of naproxen. In addition to the additional contraindication like heart, kidney and liver dysfunction. ⁹

In terms of prognosis, neoplastic fever often signals disease progression, particularly in advanced malignancies like Ewing sarcoma. Prognosis in patients with fever of malignancy varies significantly, with a 5-year mortality rate ranging from 52% to 100%, compared to just 3.2% in patients with fever of unknown origin who receive no specific diagnosis. ¹⁰ Early identification and management of neoplastic fever are crucial for improving outcomes in cancer patients.

Conclusion

Fever is common in patients with cancer and it can be due to infectious and non-infectious causes. After excluding all potential causes, neoplastic fever is diagnosed. For complete and continuous fever lysis radical tumor resection when feasible combined with antipyretic are the mainstay of management. This case highlights the extensive workup required. Any findings in history and physical examination should be further investigated. As the diagnosis of such cases is challenging, reporting them will provide clinicians a foundation for similar cases.