In an adult patient, what is the differential diagnosis and recommended workup for diffuse increased FDG uptake in the appendicular skeleton on PET‑CT?

Diffuse Metabolic Activity in Appendicular Skeleton on PET-CT

Direct Answer

Diffuse increased FDG uptake extending into the appendicular skeleton (limbs and ribs) on PET-CT most commonly indicates either plasma cell disorders (particularly multiple myeloma with diffuse bone marrow infiltration), myeloproliferative neoplasms, recent hematopoietic growth factor administration, or less commonly lymphoma with extensive marrow involvement. 1

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Differential Diagnosis

Malignant Hematologic Disorders

Multiple Myeloma (Most Important)

• Diffuse bone marrow involvement is defined as diffuse glucose uptake in the axial skeleton that is visually greater than liver uptake (either heterogeneous or homogeneous), with disease extending to the periphery (appendicular skeleton). 1
• When diffuse uptake extends to limbs and ribs, this is specifically designated as pattern "A" in the IMPeTUs criteria and indicates more extensive disease burden. 1
• Approximately 48-49% of newly diagnosed multiple myeloma patients demonstrate diffuse bone marrow infiltration on FDG PET-CT. 1
• Diffuse uptake reflects actual bone marrow infiltration by plasma cells and correlates with disease activity. 2

Lymphoma

• Diffuse bone marrow involvement by Hodgkin or non-Hodgkin lymphoma can produce indistinguishable patterns from other causes of diffuse marrow uptake. 3
• Focal bone marrow FDG uptake with or without increased diffuse uptake is more sensitive than bone marrow biopsy for detecting lymphoma infiltration in DLBCL. 1

Myeloproliferative Neoplasms

• Polycythemia vera causes diffuse elevated FDG uptake throughout axial and appendicular skeleton due to hypermetabolic red bone marrow expansion. 4
• Myelodysplastic syndromes can produce diffuse bone marrow FDG uptake suggesting neoplastic disease of hematopoietic tissues. 5

Benign/Reactive Causes

Hematopoietic Growth Factor Administration (Critical Pitfall)

• G-CSF or GM-CSF therapy causes diffuse bone marrow FDG uptake that is often indistinguishable from disseminated metastatic disease. 6
• The bone marrow response to G-CSF decreases rapidly after cessation—imaging should be delayed at least 5 days after the last G-CSF dose. 6
• Recent chemotherapy (within 10 days) and growth factor use (within 2 weeks) cause false-positive bone marrow activation. 7

Other Inflammatory/Infectious Conditions

• Sarcoidosis can demonstrate extensive bone and bone marrow involvement with increased FDG uptake throughout the appendicular skeleton. 1
• Erdheim-Chester disease characteristically shows hypermetabolic lesions throughout the appendicular skeleton with greatest activity in the legs. 1

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Recommended Diagnostic Workup

Immediate Clinical Assessment

History and Laboratory Evaluation

• Document any G-CSF/GM-CSF use within the past 2 weeks—if present, repeat PET-CT after 5-7 days off therapy. 6
• Obtain complete blood count with differential to assess for cytopenias or elevated cell lines. 1
• Measure serum protein electrophoresis, immunofixation, and free light chains to screen for monoclonal gammopathy. 1
• Check lactate dehydrogenase (LDH) as elevated levels suggest high tumor burden in lymphoma or myeloma. 1
• Assess calcium, creatinine, and hemoglobin to evaluate for CRAB criteria in suspected myeloma. 1

PET-CT Interpretation Protocol

Pattern Recognition (IMPeTUs Criteria)

• Grade diffuse uptake using the Deauville 5-point scale comparing bone marrow to liver uptake. 1
• Document extension to appendicular skeleton—specifically note involvement of limbs and ribs (pattern "A"). 1
• Count and characterize focal lesions if present: skull, spine, extra-spine locations using standardized reporting. 1
• Assess for paramedullary disease (soft tissue contiguous with bone) and extramedullary disease (soft tissue without bone contact). 1
• Evaluate CT component for lytic lesions, fractures, or soft tissue masses. 1

Critical Distinction

• Bone marrow uptake should be reported as pathological when visually higher than normal liver uptake. 1, 7
• Diffuse homogeneous uptake throughout axial and appendicular skeleton without focal lesions favors reactive marrow (G-CSF effect, polycythemia) over focal malignancy. 6, 4
• Heterogeneous diffuse uptake with focal areas of intense activity favors malignant infiltration (myeloma, lymphoma). 1

Tissue Diagnosis

Bone Marrow Biopsy

• Mandatory when PET-CT shows diffuse uptake without prior hematologic diagnosis. 1
• Biopsy is not required if PET-CT already demonstrates focal bone or marrow involvement indicating advanced-stage disease in known lymphoma. 1
• In multiple myeloma, biopsy confirms plasma cell percentage and allows for cytogenetic/FISH testing for risk stratification. 1

Additional Sampling

• If extramedullary or paramedullary disease is present, image-guided biopsy of accessible lesions provides tissue for histology and molecular studies. 1

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Algorithmic Approach

Step 1: Exclude Iatrogenic Causes

• If G-CSF/GM-CSF within 2 weeks → Delay PET-CT 5-7 days after last dose and repeat. 6
• If recent chemotherapy (within 10 days) → Consider delaying imaging or interpret with extreme caution. 7

Step 2: Characterize the Pattern

• Diffuse uptake > liver + extension to appendicular skeleton + NO focal lesions → Consider polycythemia vera, myelodysplastic syndrome, or residual G-CSF effect. 5, 4
• Diffuse uptake > liver + extension to appendicular skeleton + multiple focal lesions → Multiple myeloma is most likely. 1
• Diffuse uptake + lymphadenopathy or extramedullary masses → Lymphoma with marrow involvement. 1, 3

Step 3: Obtain Definitive Diagnosis

• Order serum protein studies (SPEP, immunofixation, free light chains) immediately. 1
• Perform bone marrow biopsy with aspirate for flow cytometry, cytogenetics, and FISH. 1
• If protein studies and biopsy negative → Consider myeloproliferative workup (JAK2 mutation, erythropoietin level) or repeat imaging after 4-6 weeks. 4

Step 4: Risk Stratification and Staging

• If multiple myeloma confirmed → Complete staging with skeletal survey or whole-body MRI, assess for high-risk cytogenetics (del17p, t(4;14), t(14;16)). 1
• If lymphoma confirmed → Complete Ann Arbor staging, consider CNS prophylaxis if high-risk features present. 1

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Common Pitfalls and How to Avoid Them

Pitfall 1: Attributing All Diffuse Uptake to G-CSF

• While G-CSF is a common cause, do not dismiss diffuse uptake without excluding hematologic malignancy, especially if uptake persists >5 days after G-CSF cessation. 6

Pitfall 2: Missing Myeloma in "PET-Negative" Patients

• Approximately 10-20% of newly diagnosed myeloma patients have false-negative FDG PET-CT due to low hexokinase-2 expression—always correlate with MRI and serum markers. 1

Pitfall 3: Relying on SUV Cutoffs Alone

• Never use SUV thresholds in isolation—visual comparison to liver uptake using Deauville criteria is the validated standard for bone marrow assessment. 1, 7

Pitfall 4: Inadequate Follow-Up After Treatment

• Complete metabolic response in myeloma requires uptake in previous focal lesions and bone marrow to be visually lower than liver—schedule repeat PET-CT at defined intervals per protocol. 1, 8

Pitfall 5: Ignoring Geographic and Clinical Context

• In tuberculosis-endemic regions or patients with known granulomatous disease, specificity of FDG-PET drops dramatically—pursue tissue diagnosis when uncertainty exists. 7