Neoplastic fever (aka tumor fever) is a challenging yet essential clinical diagnosis. In fevers of unknown origin, studies estimate that the incidence of neoplastic fever is anywhere from 7 to 31% [1, 2, 3]. In the febrile patient with malignancy, tumor fever is the most common cause of non-infectious pyrexia (41%) . While leukemia, lymphoma, sarcoma, atrial myxoma, renal cell carcinoma, and liver metastases are the most common culprits, neoplastic fever has been reported in several other cancer types [5, 6, 7]. The process of making this diagnosis can cause a patient significant morbidity, anxiety, and frustration. This review will focus on the pathophysiology, clinical features, and diagnostic assessments we have to pinpoint this cancer related disorder.
The pathophysiology of neoplastic fever is not completely understood, however, cytokines are known to be the key players. These endogenous pyrogens induce prostaglandin E2, which in turn causes hypothalamic set point surge, and fever. IL-1, TNF, IL-2, IL-6, IL-12, or interferon may be elevated with neoplasm or infection . While the cause of elevated cytokines during infection is precipitated by pathogens, the trigger in cancer is unclear. One study found that activation of Il-1? was induced by mutated RAS . Another possibility includes inflammation secondary to ulceration or necrosis caused by the tumor itself. A key player in this cytokine jumble is IL-6. High levels of IL-6 are seen in Hodgkin’s Lymphoma, Diffuse Large Cell Lymphoma, and CLL. IL-6 is associated with B-symptoms and has prognostic value in these three cancer types, as well as renal cell carcinoma [10, 11, 12, 13, 14]. Notably, in Diffuse-Large Cell Lymphoma, the independent factor that most correlates with complete remission and disease free survival is IL-6 serum level .
The clinical features of fever caused by malignancy are different than those caused by infection. While the temperatures are usually high (above 40 degrees Celsius), the signs and symptoms are muted when compared to infectious pyrexia. The fevers are generally not associated with rigors, chills, tachycardia, or hypotension. Notably, the fever is not relieved by acetaminophen .
Usually chemotherapy, blood transfusion, drug reaction, and radiation induced pyrexia can been ruled out based on signs and symptoms, time course, and duration; however, ruling out occult infection is not as straight forward. All patients with known malignany and fever require a full infectious work up. After 1-2 weeks of continuous fever without positive culture data or response to antibiotics, alternative infectious etiologies should be considered including less common fungal, viral, and parasitic organisms. Neoplastic fever is only considered when other diagnoses have been thoroughly excluded.
Diagnostic Assessment: Does Naproxen Lyse Neoplastic Fever?
In an attempt to successfully diagnose this disorder and provide patients with relief from regular fevers, several studies have examined naproxen and its role in tumor fever lysis. Clinical studies completed in the 1980s by Chang and Gross had affirmative results. The first study examined 22 cancer patients with fever. The patients had a variety of malignancies, including leukemia, lymphoma, primary lung, melanoma, and colon. All patients received naproxen 250 mg twice daily. Of the 22 patients, 15 were clinically diagnosed with neoplastic fever, 5 had infection, and 2 had connective tissue disorders (in addition to cancer). Of the 15 with neoplastic fever, 14/15 had lysis of fever within 24 hours of naproxen treatment; none of the patients with infection or rheumatologic disease responded to naproxen. The striking elements of this study are that naproxen was: successful in lysis in 93% of neoplastic fever patients, effective within 24 hours, and specific to neoplastic fever (no response in patients with infection) . Similar results were seen in the 1985 study – 20/21 patients with neoplastic fever had lysis within 24 hours after starting naproxen . A presentation by Chang, published in 1987, showed that in 68 cancer patients with pyrexia, 50 had neoplastic fever with 46/50 responders (it is unclear if the patients included in this presentation were also part of his previous two studies). Of the infectious patients, only 1/13 had a partial response to naproxen . Of note, these three studies included patients with neutropenic fever and naproxen was just as successful (although there was higher incidence of infection in these patients). In 1995, another clinical study was performed in patients with advanced gynecologic malignancy and suspected neoplastic fever. This investigation had 10/12 naproxen responders (1 of the non-responders was found to have culture negative bacteremia) [xx]. Other NSAIDs, such has rofecoxib, indomethicin, ibuprofen, and diclofenac have been as effective as naproxen in fever lysis [21, 22, 23].
Of the papers written by Chang and Gross, it is unclear if they were using new patients for all of their trials or if they used repetitive data. These studies are limited by their small sample sizes, narrow geographic range, and higher prevalence of neoplastic fever than reported in other literature.  The validity of these trials is also limited by the fact that an exceptional amount has changed in cancer treatment since the 1980’s.
Furthermore, not all studies of naproxen have been positive. A retrospective study of one hospital looked at 290 patients over a 10-year period with prolonged unexplained fever. Of these patients, 72 received naproxen, 11 of whom had neoplastic fevers, 66 with nonneoplastic fever. On review, there was no statistically significant difference in Naproxen response between neoplastic and nonneoplastic fever groups (6/11 for neoplastic fever patients and 25/66 in non-neoplastic disease; 55% vs. 38%, p=0.5)24though this study was not designed with the power to detect a difference between neoplastic and non-neoplastic fever groups.
Despite the limitations of the literature, naproxen may aid in the diagnostic workup of neoplastic fever and provide symptomatic relief from pyrexia in patients with malignancy. 25Other diagnostic and treatment methods, such as ESR/CRP trending and corticosteroids have been investigated, but have not demonstrated a role in the management of neoplastic fever [24, 25].
Neoplastic fever is an important consideration in patients with fever of unknown origin or with known malignancy. Other causes, including infection, must be thoroughly excluded before making the diagnosis. Although these patients have intractable fevers, their signs and symptoms are generally milder than those patients with pyrexia secondary to a pathogen. Some studies have shown Naproxen and NSAIDs to cause defervescence in neoplastic fever and not infectious fever, although these studies were small, geographically limited, and poorly powered. In a patient with fever suspected to be secondary to malignancy without a contraindication to NSAIDs, administering several doses of naproxen to attempt lysis of fever, even while on antibiotics, may have clinical and diagnostic utility.
Dr. David Kudlowitz is an Internal Medicine Resident at NYU Langone Medical Center
Peer reviewed by Theresa Ryan, MD, Oncology Medicine, NYU Langone Medical Center
Image courtesy of Wikimedia Commons
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