What malignancies, including lymphomas, most commonly present with Fever of Unknown Origin (FUO) and what imaging or lab findings raise suspicion of an occult malignancy?

Malignancies Presenting with Fever of Unknown Origin

Most Common Malignancies in FUO

Lymphomas are the most common malignancy causing FUO, accounting for the majority of malignant FUO cases, with non-Hodgkin lymphoma and Hodgkin lymphoma being the predominant subtypes. 1, 2

• Lymphomas represent the leading malignant cause of FUO, particularly aggressive subtypes, with 94% of lymphoma-associated FUO cases being aggressive lymphomas 1
• Large B-cell lymphoma is a frequent culprit, often presenting with hepatosplenomegaly and highly elevated alkaline phosphatase 3
• Natural killer/T-cell lymphoma can present with atypical symptoms such as prolonged pharyngodynia, making early diagnosis particularly challenging 4
• Cancers of unknown primary site (CUP) account for 3-5% of all malignancies and can present with fever 5
• Renal cell carcinoma (hypernephroma) and hepatoma are solid tumors that occasionally present as FUO with hepatosplenomegaly 3

Why Lymphomas Cause Prolonged Fever

Lymphomas frequently cause prolonged fever because they typically present at advanced stages (96.97% stage III/IV disease) with extensive extranodal involvement and aggressive biological behavior that triggers sustained cytokine release. 1

Pathophysiologic Mechanisms:

• Advanced disease at presentation: 96.97% of lymphoma-FUO patients have stage III/IV disease with more than one extranodal site involved (65.15%) 1
• Aggressive tumor biology: 94% are aggressive lymphomas with rapid progression and high metabolic activity 1
• Systemic inflammatory response: Characterized by highly elevated inflammatory markers including ESR, serum ferritin, and β2-microglobulin (92.45% elevated serum β2-microglobulin, 93.48% elevated urine β2-microglobulin) 1, 6, 3
• Bone marrow involvement: Frequent pancytopenia and hypohepatia suggest extensive marrow infiltration 1
• Constitutional symptoms: 46.97% have unexplained weight loss and 21.21% have night sweats, indicating high tumor burden 1

Clinical Presentation Patterns:

• High-grade fevers: 83.33% of lymphoma-FUO patients have temperatures ≥39°C 1
• Young male predominance: 71.21% are young men 1
• Atypical presentations: Lymphomas can present with isolated pharyngitis or other non-specific symptoms, delaying diagnosis by >3 months 4

Imaging and Laboratory Findings Raising Suspicion for Occult Malignancy

High-Yield Imaging Studies:

FDG-PET/CT is the highest-yield advanced imaging modality with 84-86% sensitivity and 56% diagnostic yield, and should be performed when conventional workup is unrevealing. 7, 5

• FDG-PET/CT whole body has pooled sensitivity of 80-100% and specificity of 66.7-79.2% in pediatric FUO, with 53% of patients having treatment modifications after the scan 8
• Critical timing: FDG-PET/CT should be performed within 3 days of starting oral glucocorticoid therapy if steroids are necessary 7, 5
• Diagnostic contribution: PET/CT identified lesion sites in 15.91% of lymphoma patients that were not detected by conventional scans 1
• Whole body MRI has 71% detection rate for inflammatory foci in adults and is useful to rule out oncologic disease and occult abscesses 8
• Chest radiography is the only first-line imaging study recommended, particularly when there is concern for malignancy 7, 9
• CT chest, abdomen, and pelvis with IV contrast serves as the minimal imaging standard for FUO evaluation 5
• Abdominal ultrasonography has diagnostic contribution in 55% of lymphoma-FUO patients 2

Laboratory Red Flags for Malignancy:

The combination of highly elevated serum ferritin (>1000 ng/mL), elevated alkaline phosphatase, and polyclonal gammopathy strongly suggests lymphoma in FUO patients. 6, 3

Hematologic Abnormalities:

• Pancytopenia with hypohepatia suggests bone marrow involvement by lymphoma 1
• Leukopenia and thrombocytopenia can indicate malignancy but also suggest tickborne diseases, dengue, or typhoid 9
• Lymphopenia is common in both viral infections and lymphomas 9

Biochemical Markers:

• Highly elevated serum ferritin levels (otherwise unexplained) suggest rheumatic/inflammatory disorders or malignancy, particularly lymphoma 6, 3
• Significantly elevated LDH (15.50% of lymphoma-FUO patients) indicates high tumor burden 1
• Elevated serum β2-microglobulin (92.45%) and elevated urine β2-microglobulin (93.48%) are highly prevalent in lymphoma-FUO 1
• Hypoalbuminemia occurs in 61.54% of lymphoma-FUO patients 1
• Elevated alkaline phosphatase (30.77%) is particularly significant when highly elevated 1, 3
• Elevated vitamin B12, ACE, and LDH together point toward lymphoma 3
• Polyclonal gammopathy on SPEP suggests lymphoma (elevated α1/α2 globulins) or atrial myxoma when combined with negative blood cultures and heart murmur 6, 3

Inflammatory Markers:

• Highly elevated ESR is characteristic but nonspecific 6, 3
• Elevated CRP warrants further investigation, though FDG-PET/CT has insufficient evidence for FUO with normal inflammatory markers 5

Critical Diagnostic Procedures:

Tissue diagnosis through lymph node biopsy or bone marrow biopsy is essential, as lymphoma-FUO diagnosis was established by peripheral/deep lymphadenopathy biopsy in 44% and bone marrow biopsy in 33% of cases. 2

• Lymph node biopsy (peripheral or deep) is the gold standard when adenopathy is present 2
• Bone marrow biopsy established diagnosis in 33% of lymphoma-FUO cases 2
• Repeated biopsies may be necessary, as demonstrated by a case requiring a second tongue base biopsy after >3 months 4
• Immunohistochemistry is mandatory to exclude lymphomas in poorly differentiated cases 5
• Thorough physical examination including head/neck, rectal, pelvic, and breast examination is essential 5

Common Diagnostic Pitfalls:

• Delayed diagnosis: Most lymphoma-FUO patients have advanced disease at diagnosis because routine laboratory tests and imaging may fail to provide definitive diagnosis 4, 1
• Atypical presentations: Lymphomas can present with isolated symptoms (pharyngitis, fever alone) without obvious adenopathy 4
• Negative initial biopsies: Multiple biopsies may be required, and 22% of lymphoma-FUO cases were only diagnosed at autopsy 2
• Empiric antibiotics: Avoid starting antibiotics before obtaining at least 3 sets of blood cultures, as this obscures diagnosis 7, 9
• Steroid administration: High-dose steroids should be avoided without specific indication, as they increase complications and may mask lymphoma 7
• Most common presentation: 50% of lymphoma-FUO patients have peripheral lymphadenopathy and 72% have weight loss—actively search for these findings 2

Risk Stratification:

• Poor prognostic indicators: 96.97% of lymphoma-FUO patients have poor performance status, and 96.61% are in high-intermediate or high-risk classification 1
• Lower complete remission rate: Lymphoma-FUO patients have significantly lower CR rates (61.11% vs. 93.75% in non-FUO lymphoma) 1
• Positive Naprosyn test: A positive response to Naprosyn (fever reduction) indicates malignancy rather than infection 3