Patient Education

Introduction

Many people would associate having a fever with infection. This is true most of the time. However, there are many situations where the body temperature is above normal and it is not due to infections. Some of these can be physiological causes (such as hot flashes), automimmune diseases, drugs, vaccinations, thyroid illnesses, blood clots etc.

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A person is often uncomfortable with fever, but may also sometimes not be aware that

their body temperature is high. Other significant symptoms associated with the fever may

make it more obvious that it is something that needs attention. These may include:

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• Shivering and chills

• Aching muscles and joints

• Palpitation or fast heart beat

• Dizziness or lightheadedness

• Headaches

• Eye pain or sore eyes

• Weakness

• Intermittent or excessive perspiration or sweating

• Seizures

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Cancers can sometimes produce fever with relatively obvious causes such:

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• A necrotic tumour with infection eg  in breast cancer, rectal cancer, anal cancer

• Blockage causing obstruction and infection such as lung cancer blocking airways, lymph nodes from lymphoma blocking urinary tract, bile duct, pancreas or gallbladder cancer blocking biliary tract etc

• Low immunity from treatment or from leukemia predisposing to fever from infections

At OncoCare Cancer Centre, Singapore, we also have patients presenting with fever from an unknown source. Some malignancies or cancers are known to present with a fever without a known clear cause after investigations. About 25% of such cases of fever or pyrexia of unknown origin (PUO) is due to malignancy. Such malignant fevers can occur in many types of solid cancers (such as kidney cancer, pancreas cancer, stomach cancer, colon cancer, breast cancer, lung cancer etc ), and in some of these situations, the primary may be occult.

However, malignant fever is still most commonly associated with hematological or blood malignancies such as lymphoma (Table 1).  Before considering the diagnosis of malignant fever, it is necessary to do the appropriate work-up to exclude infections as that is still the main cause of PUO.

Table 1. Neoplasms associated with Malignant Fever

Lymphoma – Hodgkin and Non-Hodgkin Lymphomas

Leukemia – Acute Myeloid Leukemia, Chronic Myeloid Leukemia with Blast Crisis, Hairy Cell Leukemia, Adult T-Cell Leukemia

Solid Cancers – Renal Cell Carcinoma (Kidney Cancer), Hepatocelluar Carcinoma (Liver Cancer), Glioblastoma Multiforme (Brain Cancer), Pancreas Cancer, Stomach Cancer etc

APPROACH TO THE PATIENT WITH FEVER OF UNKNOWN SOURCE

​The initial definition of  fever of unknown origin was first proposed in 1961 by Petersdorf and Beeson, and later revised in 1991, as fever of 38.3C or higher lasting for at least three weeks with no identifiable cause after three days of investigation in hospital or after at least three outpatient visits. This is a fairly technical definition but since there are numerous causes of PUO, they can be broadly categorized into infections, malignancy, inflammatory diseases and miscellaneous causes such as drug-induced fever and thromboembolic disease (Table 2).

​The initial diagnostic approach for PUO would include full blood count, electrolyte panel, liver enzymes, erythrocyte sedimentation rate, C-reactive protein, procalcitonin, lactate dehydrogenase, anti-nuclear antibodies, rheumatoid factor, blood cultures, urine analysis, urine culture, chest radiography, abdominal and pelvic ultrasonography or computer tomography. Sometimes, despite extensive investigations, the underlying etiology may still not be found. This can then become a source of frustration for both patient and doctor. Less common causes of fever will have to be considered.

Table 2. Causes of PUO

Cancers : Lymphoma, Leukemia, Renal Cell Carcinoma, Glioblastoma Multiforme (GBM), Hepatocellular Carcinoma etc

Infections : Intra-Abdominal Abscesses, Endocarditis, Sinusitis, Tuberculosis (TB), Human Immunodeficiency Virus (HIV)

Inflammatory Disease : Systemic Lupus Erythematosus, Rheumatoid Arthritis, Adult Still Disease, Crohn Disease, Sarcoidosis, Giant Cell Arthritis, Temporal Arteritis

Drugs : Anti-Convulsants (Carbamazepine, Phenytoin), Antibiotics (Carbapenems, Cephalosporins, Rifampin, Isoniazid, Sulfonamides), Cardiovascular Drugs (Captopril, Hydralazine, Procainamide, Nifedipine), Anti-Histamines (Cimetidine, Ranitidine)

Others : Thromboembolic Disease,  Thrombotic Thrombocytopenic Purpura

UNDERLYING CAUSE OF MALIGNANT FEVER

The pathophysiology of malignant fever may be due to several mechanisms. Research has shown that the release of cytokines such as tumor necrosis factor, interleukin-2 and interleukin-6 play a vital role in the pathogenesis of malignant fever. These chemicals or cytokines are thought to be triggered by the tumour itself, the surrounding infiltrating mononuclear cells or from inflammation secondary to tumor necrosis. Then there are cancers such as multiple myeloma and chronic lymphoid leukemia, that are associated with hypogammaglobulinemia. Such patients are prone to developing fever from exposure to infectious agents as a result of the immunosuppressed state.

Patients may also develop fever due to obstruction of a viscus by tumor resulting in infection. For example, cholangiocarcinoma (bile duct cancer) can cause biliary obstruction leading to cholangitis or infection in the biliary system. Bulky retroperitoneal tumors or lymph nodes in the abdomen from lymphoma or sarcoma can compress the urinary tracts (ureters) leading to swelling of the kidneys (hydronephrosis) and urinary tract infection.

Cancer is also linked to a hypercoagulable state, whereby blood clots occur easily, due to the ability of tumour cells to activate the coagulation pathways, resulting in an increased risk of thrombosis. Deep vein thrombosis and pulmonary embolism are the two most common thromboembolic complications in cancer and can present as persistent fever in cancer patients. Malignant fever may also arise in patients with tumor involving the hypothalamus in the brain, due to the brain temperature regulating (thermoregulatory) center being affected. This may occur either from brain metastasis or from primary brain cancers such as glioblastoma multiforme (GBM).

“Expert knowledge means better care for cancer”

Malignant Fever - Cancer (Part 2)

Written by:

Dr Kevin Tay
MBBS (Singapore)
ABIM Int. Med (USA)
ABIM Med Onc(USA)
FAMS (Medical Oncology)