Residency · Residency · Nuclear Medicine

FDG PET/CT in Lymphoma

Role in Lymphoma Management

FDG-Avid Lymphomas

Not all lymphomas are equally FDG-avid, and understanding which subtypes reliably accumulate FDG is essential for appropriate use of PET/CT. Hodgkin lymphoma is virtually always FDG-avid, making PET the standard for both staging and response assessment. Diffuse large B-cell lymphoma (DLBCL) is highly FDG-avid, and PET is similarly standard. Follicular lymphoma is FDG-avid in most cases, and PET is recommended for staging. Mantle cell lymphoma is usually FDG-avid, and Burkitt lymphoma is intensely FDG-avid.

Variably or Non-FDG-Avid Lymphomas

Marginal zone lymphoma has variable FDG uptake and may show limited activity in its low-grade form. Small lymphocytic lymphoma/CLL often demonstrates low FDG uptake, and PET is not routinely recommended for staging. Cutaneous T-cell lymphoma (mycosis fungoides) has variable avidity. PET is not routinely recommended for non-FDG-avid subtypes unless histologic transformation is suspected.

Staging: Lugano Classification

Modification of Ann Arbor Staging

The Lugano classification, introduced in 2014, replaced the Ann Arbor staging system for lymphoma. FDG PET/CT is the standard imaging modality for staging FDG-avid lymphomas, while CT alone is acceptable for non-FDG-avid histologies.

Stage Definitions

Stage I involves a single lymph node region or single extranodal site. Stage II involves two or more lymph node regions on the same side of the diaphragm. Stage III involves lymph node regions on both sides of the diaphragm. Stage IV involves diffuse or disseminated extranodal disease, including bone marrow, liver, or lung parenchyma. The suffixes A (no B symptoms) and B (fever above 38 degrees Celsius, night sweats, or greater than 10% weight loss) further classify the patient's systemic status.

PET Changes to Staging

PET upstages 15 to 30% of lymphoma patients compared with CT alone. A particularly important application is the detection of bone marrow involvement. Focal bone marrow FDG uptake indicates involvement, while diffuse uptake may be reactive (from G-CSF or infection) or may represent involvement. In Hodgkin lymphoma, FDG PET has greater than 90% sensitivity for marrow involvement, and bone marrow biopsy is no longer routinely required when PET is performed. In DLBCL, PET can detect marrow involvement but may miss a discordant low-grade component, so biopsy is still recommended by some guidelines. PET also detects extranodal disease in the spleen, liver, lungs, and skeleton, and identifies unsuspected supra- or infradiaphragmatic disease.

Interim Response Assessment

Deauville Five-Point Scale (D5PS)

The Deauville five-point scale is the international standard for visual assessment of FDG uptake in lymphoma, using reference organs for comparison. Score 1 indicates no uptake above background. Score 2 indicates uptake at or below the mediastinal blood pool. Score 3 indicates uptake above the mediastinal blood pool but at or below the liver. Score 4 indicates uptake moderately greater than the liver. Score 5 indicates uptake markedly greater than the liver or new lesions. Score X indicates new areas of uptake unlikely to be related to lymphoma.

Interpretation for Interim PET (iPET)

Interim PET is typically performed after 2 to 3 cycles of chemotherapy. Scores 1 through 3 are generally considered negative, indicating complete metabolic response or adequate response. In Hodgkin lymphoma, a score of 1 to 3 after 2 cycles indicates a favorable prognosis and may allow de-escalation of therapy. In DLBCL, a score of 1 to 3 at interim assessment is favorable, and planned therapy is continued. Scores 4 and 5 are positive and suggest residual active disease. In Hodgkin lymphoma, a positive interim PET may trigger treatment escalation. In DLBCL, prognostic value is established, but changing therapy based on interim PET is less established outside clinical trials.

Response-Adapted Therapy

In Hodgkin lymphoma, interim PET directly guides treatment decisions. The RATHL trial demonstrated that patients with a negative interim PET after 2 cycles of ABVD can omit bleomycin (switching to AVD), reducing pulmonary toxicity without compromising outcomes. The GHSG HD18 trial showed that a negative interim PET allows a reduced number of eBEACOPP cycles. In DLBCL, interim PET has prognostic value, but routine treatment modification based on interim PET results is not standard practice outside clinical trials.

End-of-Treatment Response Assessment

Lugano Response Criteria

Complete metabolic response (CMR) is defined as a Deauville score of 1 to 3 with no evidence of disease on CT. A residual mass may be present on CT but is metabolically inactive, representing fibrosis or necrosis rather than active disease. Importantly, a Deauville score of 3 is considered CMR because uptake at or below the liver is acceptable. Partial metabolic response (PMR) is a Deauville score of 4 or 5 with reduced uptake from baseline or residual CT masses with reduced FDG activity. No metabolic response shows a Deauville score of 4 or 5 without significant change. Progressive metabolic disease (PMD) is a Deauville score of 4 or 5 with increased uptake from baseline, new FDG-avid lesions, or new or increased extranodal disease.

Residual Mass Evaluation

Residual mediastinal masses are common after treatment, especially in Hodgkin lymphoma. CT alone cannot distinguish fibrosis or necrosis from residual viable tumor. FDG PET resolves this dilemma: a metabolically inactive residual mass indicates CMR and no further treatment is needed. This is one of the most impactful applications of FDG PET in lymphoma, as it prevents unnecessary additional therapy or biopsy.

Pitfalls in Lymphoma PET

False Positives

Thymic rebound, the re-expansion of the thymus after chemotherapy, is the most common pitfall in young lymphoma patients. It produces triangular or sail-shaped anterior mediastinal uptake and is more common in patients under 30 years. Post-treatment infections (pneumonia, fungal disease) and reactive lymph nodes cause inflammatory uptake. Sarcoid-like reactions with granulomatous inflammation can occur after chemotherapy and mimic disease. Brown fat produces bilateral symmetric cervical and supraclavicular uptake. G-CSF causes diffuse bone marrow and splenic uptake from growth factor stimulation; PET should be deferred at least 2 weeks after the last G-CSF dose. A flare phenomenon with transiently increased uptake may occur early after therapy initiation. Post-radiation changes cause inflammatory uptake within the radiation field.

False Negatives

Imaging performed too early after therapy may not yet show residual activity. Small-volume residual disease may fall below PET resolution. Non-FDG-avid histologies can result in missed low-grade transformation.

Timing Recommendations

Interim PET should be performed after 2 cycles in Hodgkin lymphoma and after 2 to 4 cycles in DLBCL. End-of-treatment PET should be obtained 6 to 8 weeks after the last cycle of chemotherapy and 8 to 12 weeks after radiation therapy. After G-CSF administration, a minimum 2-week wait is required. After stem cell transplant, at least 6 to 8 weeks should elapse before imaging.

Transformation Detection

Richter Transformation

Richter transformation refers to CLL/SLL transforming to DLBCL (or rarely Hodgkin lymphoma). It is clinically suspected when there is rapid nodal enlargement, new B symptoms, or rising LDH. FDG PET identifies areas of high uptake suspicious for transformation, with an SUVmax above 5 to 10 suggesting transformation. PET guides biopsy to the most FDG-avid site.

Follicular Lymphoma Transformation

Low-grade follicular lymphoma can transform to high-grade disease, usually DLBCL, at a rate of approximately 3% per year. This is suggested by discordant FDG uptake, where most nodes show moderate avidity but one or more are intensely avid. PET identifies the most suspicious site for biopsy to confirm transformation.

Surveillance After Treatment

Routine surveillance PET is not recommended for lymphoma patients in remission. Most relapses are detected clinically through symptoms, physical examination, and laboratory studies before PET would identify them. Routine surveillance PET has a high false-positive rate, leading to unnecessary biopsies and patient anxiety. An exception may be made for high-risk patients in the first 1 to 2 years after treatment. Current NCCN guidelines recommend against routine surveillance PET for most lymphomas.

<image>A series of FDG PET/CT maximum intensity projection (MIP) images demonstrating the Deauville five-point scale. Score 1: no residual uptake. Score 2: uptake less than or equal to mediastinal blood pool. Score 3: uptake greater than blood pool but less than or equal to liver. Score 4: uptake moderately above liver. Score 5: markedly increased uptake above liver with new lesions. Include reference regions (mediastinal blood pool and liver) annotated on each image with arrows.</image>

<image>A clinical example of FDG PET/CT in Hodgkin lymphoma showing three time points: baseline staging PET with extensive bilateral cervical, mediastinal, and hilar lymphadenopathy (stage II bulky disease); interim PET after 2 cycles of ABVD showing complete metabolic response (Deauville score 2) with small residual mediastinal mass on CT but no FDG uptake; and an annotated comparison showing the residual mass is fibrosis, not active disease. Demonstrate the clinical decision point where treatment de-escalation can be considered.</image>

<image>A pitfalls panel in lymphoma PET showing: (A) thymic rebound after chemotherapy with triangular anterior mediastinal FDG uptake corresponding to thymic tissue on CT, (B) diffuse bone marrow hypermetabolism from recent G-CSF administration, (C) sarcoid-like reaction with bilateral hilar and mediastinal lymph node uptake mimicking recurrent lymphoma, and (D) brown fat uptake in the cervical and supraclavicular regions mimicking lymphadenopathy. For each, show the PET/CT fused image and explain the distinguishing features from recurrent lymphoma.</image>

Clinical Pearls

The Deauville 5-point scale is the international standard for lymphoma PET response assessment. Scores 1 through 3 are considered negative (CMR) at end of treatment.

A residual mediastinal mass on CT with no FDG uptake (Deauville 1 to 3) represents fibrosis, not active disease. This is one of the most important contributions of PET in lymphoma management.

In Hodgkin lymphoma, a negative interim PET after 2 cycles of ABVD allows treatment de-escalation (omitting bleomycin). PET directly guides therapy modification.

Wait at least 2 weeks after G-CSF and 6 to 8 weeks after chemotherapy before restaging PET. G-CSF causes diffuse marrow and splenic uptake that can be misinterpreted as disease.

Thymic rebound is the most common pitfall in young lymphoma patients. The triangular anterior mediastinal uptake with thymic morphology on CT is characteristic and should not be mistaken for recurrent disease.

FDG PET can replace bone marrow biopsy for detecting marrow involvement in Hodgkin lymphoma. Focal marrow uptake is highly specific for involvement.

Routine surveillance PET after achieving complete remission is not recommended. It has a high false-positive rate, and most relapses are detected clinically.

References

• Cheson BD, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3068.
• Barrington SF, et al. Role of imaging in the staging and response assessment of lymphoma: consensus of the ICML Imaging Working Group. J Clin Oncol. 2014;32(27):3048-3058.
• Johnson P, et al. Adapted treatment guided by interim PET-CT scan in advanced Hodgkin's lymphoma (RATHL). N Engl J Med. 2016;374(25):2419-2429.
• Meignan M, et al. Report on the 4th International Workshop on PET in Lymphoma held in Menton, France. Leuk Lymphoma. 2014;55(1):31-37.

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