Fever is a common physiological response, typically signaling the body’s defense against an infection. A fever that persists without a clear cause can signal a more complex underlying condition. When a fever is deemed “unexplained,” it often falls under the medical classification of Fever of Unknown Origin (FUO). This designation means that despite thorough initial testing, an infection, inflammatory disorder, or malignancy remains a possibility.
The Biological Mechanism of Fever in Cancer
A fever caused directly by cancer, known as neoplastic fever, occurs through a non-infectious inflammatory process. This involves the release of pyrogens, which are chemicals that elevate the body’s temperature setpoint. These substances are produced either directly by the tumor cells or by immune cells, such as macrophages, responding to the presence of the tumor mass.
The most significant pyrogens are signaling proteins known as cytokines, including Interleukin-1 (IL-1), Interleukin-6 (IL-6), and Tumor Necrosis Factor-alpha (TNF-alpha). Once released into the bloodstream, these cytokines travel to the hypothalamus, the brain’s temperature regulation center. There, they stimulate the production of Prostaglandin E2 (PGE2), which resets the body’s thermostat to a higher temperature. This elevated setpoint triggers the body to generate and conserve heat, resulting in a fever.
Primary Cancers Linked to Unexplained Fever
The ability to produce fever-inducing pyrogens is most strongly associated with specific types of cancer. Hematological malignancies, or cancers of the blood and lymph system, are among the most frequent causes of unexplained fever. Lymphomas, including both Hodgkin’s and non-Hodgkin’s lymphoma, are particularly well-known for presenting with fever as a primary symptom.
In lymphoma cases, tumor cells release high levels of cytokines like IL-6 and IL-10, driving the systemic inflammatory response. Hodgkin’s lymphoma, in particular, is highly associated with presenting as FUO.
Several solid tumors also frequently cause neoplastic fever. Renal Cell Carcinoma (RCC), a cancer of the kidney, is a prominent solid tumor associated with unexplained fever. RCC tumor cells produce high amounts of IL-6, and larger tumor sizes often correlate with a higher likelihood of systemic symptoms. Hepatocellular Carcinoma (HCC), the most common type of liver cancer, is also frequently linked to fever. Other recognized causes include Acute Myeloid Leukemia, certain ovarian cancers, and tumors that metastasize to the liver.
Clinical Characteristics of Cancer-Related Fever
The fever caused by malignancy often exhibits distinct characteristics that help differentiate it from a typical infectious fever. Neoplastic fever is generally intermittent, meaning the temperature rises and falls rather than remaining continuously elevated. The fever often lacks the dramatic chills and rigors typically associated with bacterial infections, though a classic cyclical pattern known as Pel-Ebstein fever is rare and debated.
Cancer-related fevers are part of a broader set of systemic indications known as “B symptoms,” which are important in the staging of lymphomas. These symptoms include drenching night sweats and unexplained weight loss (defined as a loss of more than ten percent of body weight over six months). The fever may be only partially responsive to common medications like acetaminophen, but often shows a better response to non-steroidal anti-inflammatory drugs (NSAIDs).
When to Seek Medical Evaluation for Fever
A persistent, unexplained elevation in temperature warrants a medical evaluation. The formal definition of Fever of Unknown Origin (FUO) involves a temperature of 101°F (38.3°C) or higher on several occasions, lasting longer than three weeks, with no determined cause after an initial workup. If a fever meets these criteria or is accompanied by B symptoms like night sweats and unexplained weight loss, seeking professional guidance is important.
The initial diagnostic process begins with a comprehensive review of the patient’s history and a thorough physical examination. Laboratory tests include a complete blood count, inflammatory markers like Erythrocyte Sedimentation Rate (ESR) and C-Reactive Protein (CRP), and multiple sets of blood cultures to rule out common infectious agents.
If initial non-invasive tests are unrevealing, a physician may proceed to advanced imaging. This frequently includes Computed Tomography (CT) scans of the abdomen and chest, and increasingly, Fluorodeoxyglucose Positron Emission Tomography (FDG-PET/CT) scanning. FDG-PET/CT is sensitive because it locates areas of increased metabolic activity, which can correspond to an infection, an inflammatory site, or a malignant tumor. The most definitive step for diagnosing a malignancy is often a targeted biopsy of any suspicious tissue found during imaging.