Lymphoma

Quick Answer

Most Hodgkin and aggressive non-Hodgkin lymphomas are FDG-avid, making FDG-PET/CT the standard for staging (Lugano classification) and for interim and end-of-treatment response using the Deauville 5-point score, which compares lesion uptake to mediastinal blood pool and liver. Low-grade lymphomas show variable or low FDG avidity, so PET negativity does not exclude indolent disease. Interim PET is prognostic and underpins response-adapted therapy.

Definition

Lymphomas are clonal malignancies of lymphocytes (B, T, or NK lineage), broadly divided into Hodgkin lymphoma (HL) — defined by Reed–Sternberg cells in a reactive background — and the large, heterogeneous group of non-Hodgkin lymphomas (NHL), which range from indolent to highly aggressive.

Synonyms

Hodgkin disease / Hodgkin lymphoma (HL); non-Hodgkin lymphoma (NHL). Common subtypes: DLBCL (diffuse large B-cell), FL (follicular), MCL (mantle cell), MZL/MALT (marginal zone), SLL/CLL, Burkitt, and the peripheral T-cell lymphomas.

Epidemiology

NHL is far more common than HL. HL has a characteristically bimodal age distribution (young adults and older adults). Among NHL, DLBCL is the most common aggressive subtype and follicular lymphoma the most common indolent subtype. Risk rises with immunosuppression (post-transplant, HIV), certain infections, and some autoimmune diseases.

Etiology & Risk Factors

• Infections: EBV (classical HL, some aggressive NHL, post-transplant lymphoproliferative disease), HTLV-1 (adult T-cell leukemia/lymphoma), H. pylori (gastric MALT — may regress with eradication), HCV, and HHV-8 (primary effusion lymphoma).
• Immunodeficiency: congenital, HIV/AIDS, iatrogenic immunosuppression.
• Autoimmune disease (e.g. Sjögren → MALT; Hashimoto → primary thyroid lymphoma).

Pathophysiology

Lymphomas arise from clonal expansion of lymphocytes arrested or transformed at defined stages of differentiation — many from the germinal center. Characteristic chromosomal translocations juxtapose oncogenes with immunoglobulin (or other active) loci, deregulating growth and survival. Aggressive lymphomas are highly proliferative and glucose-avid (strongly FDG-positive); indolent lymphomas proliferate slowly and are variably avid. Histologic transformation of an indolent lymphoma to an aggressive one is marked by rising metabolic activity.

Genetics & Molecular Biology

• t(14;18) / BCL2 — follicular lymphoma (anti-apoptotic).
• t(8;14) / MYC — Burkitt lymphoma (extremely proliferative, very FDG-avid).
• t(11;14) / cyclin D1 (CCND1) — mantle cell lymphoma.
• BCL6 rearrangements — DLBCL.
• "Double-/triple-hit" lymphomas (MYC with BCL2 and/or BCL6) — high-grade B-cell lymphoma with aggressive behavior.
• DLBCL cell-of-origin (germinal-center vs activated B-cell) carries prognostic and therapeutic weight.

Histopathology

• Classical Hodgkin lymphoma: Reed–Sternberg cells (CD15+, CD30+) in a mixed inflammatory background; nodular-sclerosis is the commonest type. Nodular-lymphocyte-predominant HL is a distinct CD20+ entity.
• DLBCL: sheets of large transformed B cells.
• Follicular lymphoma: nodular growth, graded 1–3 (grade 3B behaves aggressively).
• Mantle cell, Burkitt (starry-sky), MALT, peripheral T-cell each have characteristic morphology and immunophenotype. Flow cytometry and IHC establish lineage and subtype.

Clinical Presentation

Classically painless lymphadenopathy. B symptoms — fever, drenching night sweats, and unexplained weight loss — carry staging weight. Hodgkin lymphoma tends to spread contiguously between adjacent nodal regions; aggressive NHL can be widely disseminated and extranodal (GI tract, CNS, bone, testis, Waldeyer ring). Mediastinal disease may cause cough or SVC symptoms; marrow involvement causes cytopenias.

Laboratory Findings

• LDH — elevated with high tumor burden/proliferation; a component of prognostic indices (IPI).
• CBC (cytopenias from marrow involvement), ESR (HL prognosis), β2-microglobulin.
• Viral serologies (HIV, hepatitis, EBV) and, where relevant, bone-marrow biopsy (often obviated by PET in FDG-avid disease).

Imaging Findings by Modality

• FDG-PET/CT: the metabolic reference for staging and response in avid histologies; detects nodal, extranodal, splenic, and marrow disease.
• CT (contrast): anatomic burden, bulky disease measurement, and sites where PET is limited; still used for follow-up in low-avidity disease.
• MRI: CNS lymphoma, and problem-solving in marrow/soft-tissue.
• Ultrasound: superficial nodal assessment and biopsy guidance.

FDG Avidity by Histology

A rising or focally intense uptake within known indolent disease should raise concern for histologic transformation and guides biopsy site.

Radiopharmaceutical Uptake Mechanisms

FDG enters cells via GLUT transporters and is trapped after hexokinase phosphorylation, reflecting the elevated glucose metabolism of proliferating lymphoma. Avidity broadly tracks with grade. Because inflammatory and physiologic tissues also take up FDG, timing, patient preparation, and reference-region discipline are essential to interpretation.

Typical PET Tracers

Typical SPECT Tracers

• (Historical) Ga-67 citrate — the pre-PET lymphoma agent, now replaced by FDG-PET.
• Bone-marrow / labeled-WBC studies have no routine staging role.

Therapy Indications

• Hodgkin lymphoma: chemotherapy (e.g. ABVD or escalated regimens) ± radiotherapy, increasingly response-adapted by interim PET; brentuximab vedotin and checkpoint inhibitors in relapsed disease.
• DLBCL: R-CHOP-type immunochemotherapy; salvage with CAR-T cells, bispecific antibodies, and autologous transplant.
• Indolent NHL: observation, rituximab-based therapy, or local radiotherapy; H. pylori eradication for gastric MALT.
• Radioimmunotherapy (theranostic): ⁹⁰Y-ibritumomab tiuxetan (Zevalin) — an anti-CD20 antibody delivering β-radiation — for selected relapsed/refractory follicular/CD20+ B-cell NHL (I-131-tositumomab was withdrawn).

Theranostics

Anti-CD20 radioimmunotherapy is the lymphoma theranostic: a monoclonal antibody targets CD20 on B cells and carries a therapeutic radionuclide (⁹⁰Y). It exploits the crossfire effect (β-range irradiates neighboring cells, useful in bulky or antigen-heterogeneous disease). Use has narrowed with the rise of immunochemotherapy and cellular therapy, but it remains a conceptually important image-and-treat approach.

Deauville 5-Point Scale

Scores 1–3 are generally a complete metabolic response in most contexts (interpretation depends on the clinical setting and trial — in some interim de-escalation trials only 1–2 counts as negative), while 4–5 indicate residual metabolic disease.

Staging with Lugano

The Lugano classification uses FDG-PET/CT to define anatomic extent (nodal regions above/below the diaphragm and extranodal sites; stages I–IV) and adds "A/B" for the absence/presence of B symptoms and "E/bulk" descriptors. In FDG-avid lymphoma, PET reliably detects bone-marrow involvement — a diffuse or focal marrow pattern assessed against the liver — often making a staging marrow biopsy unnecessary.

In avid histologies (classical Hodgkin, DLBCL), a baseline and end-of-treatment PET reported with a Deauville score is the backbone of staging and response — 1–3 generally complete metabolic response (context-dependent), 4–5 residual disease. Use the same reference regions (mediastinal blood pool, liver) on every serial scan.

Interim PET & Response-Adapted Therapy

Interim FDG-PET (typically after 2 cycles) is prognostic and drives response-adapted strategies: escalating therapy when interim PET is positive and de-escalating (e.g. omitting bleomycin) when negative — as shown in RATHL for Hodgkin lymphoma and explored in H10 and PETAL for Hodgkin and aggressive NHL. Response-adaptation is protocol-specific: the score guides, it does not dictate.

Differential Diagnosis

• Reactive/infectious lymphadenopathy (viral, tuberculous, other).
• Sarcoidosis (FDG-avid symmetric nodal disease — a classic mimic).
• Metastatic carcinoma to nodes; thymic rebound hyperplasia after therapy.
• Post-G-CSF marrow and inflammatory uptake.

Reporting Checklist

• State PET indication (baseline / interim / end-of-treatment) and the reference regions used.
• Report a Deauville score — not merely "positive/negative."
• Describe nodal regions, extranodal sites, spleen, and marrow pattern.
• Flag focally intense uptake in otherwise indolent disease (possible transformation) and suggest a biopsy target.
• Address benign mimics (thymic rebound, brown fat, G-CSF marrow) explicitly.

Prognosis

Prognosis depends on subtype, stage, and indices such as the IPI (age, stage, LDH, performance status, extranodal sites) for aggressive NHL and disease-specific scores for HL and FL. Interim and end-of-treatment PET response are independently prognostic and increasingly define management. Hodgkin lymphoma and DLBCL are frequently curable; indolent lymphomas are typically chronic-relapsing.

Board Pearls

Report lymphoma response with a Deauville score against mediastinal blood pool and liver, using the same reference regions across serial scans; 1–3 is generally a complete metabolic response (context-dependent), 4–5 residual disease.

Interim PET after ~2 cycles is prognostic and underpins response-adapted therapy (RATHL) — but it guides rather than dictates, and thresholds are protocol-specific.

FDG negativity does not exclude indolent lymphoma (MALT, small lymphocytic, low-grade follicular can be poorly avid). Conversely, a new focally intense focus in known indolent disease suggests histologic transformation — biopsy the most avid site. Watch the classic false positives: thymic rebound, G-CSF-stimulated marrow, brown fat, and inflammatory uptake.

Related Pages

• Tracer: FDG (uptake mechanism, preparation, physiologic distribution).
• Response criteria: Theranostics / oncology response criteria and the Deauville tool.
• Pitfalls: Incidental findings on FDG-PET and Pearls, pitfalls & normal variants.

Figure / Diagram Suggestions

• A Deauville 5-point visual reference plate (uptake vs blood pool vs liver).
• Lugano staging schematic (nodal regions above/below diaphragm, extranodal, spleen).
• An interim-PET response-adapted decision flow (positive → escalate; negative → de-escalate).
• The transformation concept: indolent (low FDG) developing a focally intense aggressive clone.

Common Pitfalls

• Imaging too soon after chemotherapy (within ~2 weeks) or radiotherapy: treatment-related inflammation causes false-positive uptake — allow an adequate interval before response scoring.
• Uncontrolled hyperglycemia or recent insulin degrades tumor FDG uptake and shifts tracer into skeletal muscle, risking false-negative reads and unreliable Deauville comparisons.
• Reading diffusely increased splenic uptake as splenic involvement when it is reactive/cytokine-driven; focal splenic lesions are the more reliable sign of disease.
• Low sensitivity at physiologically avid sites — brain/CNS, gastric wall, and bowel — can mask disease (a reason MALT and CNS lymphoma are underdetected).
• Applying the stricter interim de-escalation cutoff (only Deauville 1–2 negative) at the end of treatment, where 1–3 generally denotes complete metabolic response — mismatched thresholds misclassify response.

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