Non-Hodgkin Lymphoma

Non-Hodgkin Lymphoma

Todd M. Blodgett, MD

Alex Ryan, MD

Omar Almusa, MD

Although axial CT (top) shows no abnormalities, fused PET/CT (bottom) demonstrates multiple areas of osseous involvement image.

Graphic shows the infiltrative nature of lymphoma within the right iliac bone image.


Abbreviations and Synonyms

  • Non-Hodgkin lymphoma (NHL)

  • Large B-cell lymphoma

  • Low grade follicular B-cell lymphoma (FL)

  • Small lymphocytic lymphoma (SLL)

  • Chronic lymphocytic leukemia (CLL)

  • Marginal zone lymphoma (MZL)

  • Mucosa-associated lymphoid tissue (MALT)

  • Cutaneous T-cell lymphoma (CTCL)

  • Post-transplant lymphoproliferative disease (PTLD)

  • Hodgkin disease (HD)


  • NHL: Malignancy of B or T lymphocytes

  • Low grade lymphoma

    • Slow growing, indolent non-Hodgkin lymphoma

    • Low grade diffuse B-cell lymphoma

      • SLL: Termed CLL when 1° in blood or marrow

      • Lymphoplasmacytic lymphoma (immunocytoma)

      • MZL: MALT; nodal marginal zone; splenic marginal zone

    • FL

      • Small-cleaved cell type: < 20-25% large cells

      • Mixed small-cleaved and large cell type: Survival inversely proportional to large cell percentage

      • Large cell type: Intermediate grade but more aggressive in nature

    • CTCL: Mycosis fungoides (MF), Sézary syndrome (leukemic variant)

      • CTCL: Rarely transforms into more aggressive large cell lymphoma

    • Separate entity from aggressive peripheral T-cell lymphoma (PTL)

    • Also separate from adult T-cell lymphoma/leukemia (ATLL)

  • Extranodal lymphomas

    • Refer to lymphomas located in Waldeyer throat ring, thymus, and spleen


General Features

  • Best diagnostic clue

    • Pre-therapy evaluation

      • High grade NHL: Multiple enlarged lymph nodes or nodal groups with intense FDG activity ± splenic/other organ involvement

      • Low grade NHL: Enlarged LN, extranodal mass with low to intense FDG uptake

      • Marked FDG uptake may represent high grade transformation

      • “Misty mesentery” also a common finding in NHL

      • Occasionally normal-sized FDG-avid nodes

    • PET/CT Post-therapy evaluation

      • Absence of metabolic activity on FDG PET following treatment (high predictive value for disease free survival)

      • Persistent metabolic activity on FDG PET following treatment (moderate predictive value for recurrence)

  • Location

    • Superior mediastinal and paraaortic nodes common

    • NHL known for less predictable spread than HD

    • Head and neck region

      • Second most common site of NHL

      • Primary head and neck lymphoma accounts for 10-20% of all cases of NHL

      • Prone to be asymptomatic and unsuspected clinically

      • Usually presents on PET/CT as asymmetrical intense FDG activity in a lymphoid structure

      • Common locations: Palatine, lingual, sublingual tonsils, and adenoids

    • Pulmonary

      • Pulmonary involvement uncommon

      • Involvement without nodal disease seen more commonly in recurrent disease than at presentation

      • Also seen more commonly in PTLD

    • Bone marrow

      • PET/CT can help direct bone marrow biopsy to most metabolically active areas

      • Frequently have abnormal focal FDG activity without a correlative CT abnormality

      • Involvement found in 50-80% of low grade NHL and 25-40% of high grade NHL

      • Tends to signify advanced stage disease

    • Spleen

      • Involved in 20% of patients with NHL

      • Defined as nodal in HD, extranodal in NHL

      • Organ size is poor predictor; spleen can be large but not involved or normal with infiltration

      • PET/CT significantly more accurate than CT alone for detecting splenic involvement

      • May appear as multiple lesions or diffuse involvement on FDG PET

    • Other extranodal lymphoma

      • CNS, peripheral nervous system, lung and pleura, bone, skin, breast, testis, and GU tract

      • GI lymphoma represents approximately 10-15% of all NHL

  • Size

    • Most patients being evaluated for new onset lymphoma will have enlarged nodes

    • PET/CT will often detect additional normal-sized but malignant nodes

    • Lymph node size is a poor predictor of tumor involvement

Imaging Recommendations

  • Best imaging tool

    • PET/CT

      • Preferred modality for staging NHL

      • Sensitivity/specificity for evaluating malignant nodes: PET/CT 91%, 90% vs. CT 88%, 86%

      • Sensitivity/specificity for extranodal involvement: PET/CT 88%, 100% vs. CT 50%, 90%

    • Current and potential clinical applications of FDG PET/CT

      • Initial diagnosis: Evaluate adenopathy ± systemic symptoms without current pathologic diagnosis of NHL

      • Determine staging

      • Guide biopsy

      • Assess conversion to higher grade

      • Evaluate early response to chemotherapy

      • Determine restaging

      • Monitor post-treatment progress

    • Conventional imaging staging technique

      • CECT of neck, chest, abdomen, pelvis; occasionally MR

      • Uni- or bilateral bone marrow biopsy

  • Protocol advice

    • Consider PET/CT with contrast-enhanced CT for staging

    • Stage with PET/CT before any therapy is administered

      • One dose of chemotherapy may ↓ FDG uptake

    • Consider low dose CT for restaging/surveillance after a negative PET/CT following therapy

CT Findings

  • NECT

    • Enlarged lymph nodes

    • Can be large conglomerate masses with lobulated margins

    • Calcification rarely seen prior to treatment; frequently seen after therapy in larger confluent nodal masses

    • Size is not an independent predictive factor

  • CECT

    • Slight to moderate uniform enhancement following IV contrast

    • Marked enhancement unusual (low attenuation in 20% of cases)

    • Masses from lymphoma more likely to encase and displace the mediastinal structures

      • Unusual to constrict or invade them

    • Lung/Mediastinum

      • Intrathoracic involvement in 50% of newly diagnosed cases (vs. 85% in HD)

      • 20% present with mediastinal adenopathy

      • Single or multiple discrete pulmonary nodules less well-defined and less dense than carcinoma

    • May cavitate (10-20%)

      • Consolidation with air bronchograms (solitary or multiple, includes pseudolymphoma)

      • Diffuse reticulonodular opacities (lymphocytic interstitial pneumonia)

      • Post-obstructive atelectasis due to nodal compression

    • Pleura

      • Pleural effusions seen in 10% of patients at presentation, due to lymphatic or venous obstruction

      • Effusion, may resolve with irradiation of mediastinal lymph nodes

      • Pleural masses rare

    • Pericardial

      • Pericardial effusion mostly coexists with adenopathy adjacent to pericardial margins

      • Associated with high grade peripheral T lymphoma, large B-cell lymphoma, and PTLD

    • Chest wall

      • Invasion with rib destruction uncommon

Nuclear Medicine Findings

  • Initial diagnosis

    • PET/CT used to evaluate enlarged nodes in patients without a history of lymphoma

      • Covered indication by CMS, but rarely used for initial diagnosis

    • Some NHL may not be FDG avid

      • MALT generally less FDG avid, but as a group MALTs have complex histology and may demonstrate uptake

    • PET for differentiation of indolent vs. aggressive lymphoma

      • Controversial topic

      • SUV ≥ 10 confers higher likelihood for aggressive disease (considerable overlap exists)

  • Staging

    • PET/CT more sensitive than CT for staging NHL

      • Consider baseline PET/CT for all patients with newly diagnosed NHL

      • Consider directed bone marrow biopsy to most metabolically active osseous structures detected on PET

    • Splenic involvement much more accurately assessed with PET/CT than with CT alone

    • Liver involvement may present as diffuse disease with patchy infiltrates originating in portal areas

      • Other patterns include miliary with multiple small lesions or, rarely, large focal lesions

    • False negative bone marrow biopsy may result due to patchy nondisseminated marrow involvement

      • Bone marrow biopsy (BMB) alone can detect minimal bone marrow disease, which may escape detection by PET

    • PET/CT shown to modify radiotherapy planning in 44% of patents with head/neck lymphoma

    • CLL/SLL: PET of limited use in staging 2° ↓ FDG uptake (sensitivity 58%)

      • SUV > 3.5 suggests Richter transformation of CLL/SLL → diffuse large B-cell lymphoma (sensitivity 91%, specificity 80%, PPV 53%, NPV 97%)

    • MZL: FDG PET staging sensitivity 71% (lower for extranodal)

      • MALT lymphoma: Typically no or low FDG uptake; SUV > 3.5 suggests plasmacytic differentiation

    • CTCL: FDG PET useful in staging, especially in suspected single cutaneous site

      • CTCL: Intense nodal sites suspicious for large cell transformation

    • FL: FDG PET useful in staging all grades (sensitivity 94%, specificity 100%)

      • Wide overlap between FDG uptake by lower (SUV 2.3-13) and higher grade (SUV 3.2-43) FL

      • Emergence of sites of ↑ FDG uptake (SUV > 10): Transformation to higher grade (specificity 81%)

    • Upstaging of extranodal disease observed mostly in stage I and II disease

  • Response to therapy

    • FDG PET demonstrates poor sensitivity for predicting likelihood of response/progression in patients with indolent lymphoma

    • PET excellent for predicting prognosis in aggressive NHL after therapy

      • Usefulness of follow-up scan hinges on existence of pre-therapy scan indicating FDG-avid disease

      • Early identification of therapy response allows modification of ineffective treatment

      • Nonresponders may avoid unnecessary side effects

      • Tumor FDG uptake decreases dramatically as early as first week post-treatment in aggressive NHL

      • Strong predictive value for 18 month outcome when imaged early in chemotherapy cycle, after only one cycle

      • FDG PET in early response assessment (after 1-4 cycles): Sensitivity 79%, specificity 92%, PPV 90%, NPV 81%, accuracy 85%

      • FDG PET in post-Rx assessment (mixed population HD, NHL): Sensitivity 79%, specificity 94%, PPV 82%, NPV 93%, accuracy 91%

      • FDG PET in post-Rx assessment NHL: Sensitivity 67%, specificity 100%, PPV 100%, NPV 83%, accuracy 88%

      • FDG PET in post reinduction chemo (before stem cell transplant): Sensitivity 84%, specificity 83%, PPV 84%, NPV 83%, accuracy 84%

    • 1999 European Organization for Research

      • Post-therapy SUV that increases 25% over baseline indicates progressive disease

      • SUV decrease of 15-25% after cycle 1 of chemotherapy and 25% after more than 1 cycle indicates partial metabolic response

    • Ga-67-citrate less sensitive and specific than FDG PET for aggressive lymphomas

    • Chemotherapy can cause marrow hyperplasia and also generalized FDG uptake

    • G-CSF and recombinant erythropoietin can result in diffusely increased FDG uptake bone marrow and spleen, limiting sensitivity

      • Uptake due to growth factors usually returns to baseline by one month post-therapy

  • Restaging

    • Rationale for FDG PET imaging post-therapy

      • Allow for treatment of residual/progressive disease before it spreads further

    • PET can be positive months before histological confirmation of an asymptomatic relapse

      • Especially for diffuse large B-cell lymphoma patients

  • Benign FDG uptake patterns directly/indirectly associated with chemotherapy

    • Low level, patchy uptake in residual fibrotic mass and scars

      • Decreases over months but may persist

      • Diffuse FDG uptake in all adipose tissue (brown + yellow fat), adrenal/periadrenal regions

    • Concurrent chemo + protease inhibitors (lymphoma + HIV)

      • Skeletal muscle uptake

      • Pattern similar to carbohydrate-insulin effect

    • Granulocyte colony stimulating factor (G-CSF) or other marrow stimulant drugs

      • Intense red bone marrow + splenic uptake/enlargement

      • May persist 2-3 months

    • Following cessation of chemotherapy

      • Increased thymic uptake (thymic rebound); diffuse FDG activity in thymus usually 4-8 months following chemotherapy


Normal Structures

  • Thymus, salivary glands, muscle, tonsils

  • Look for symmetry

  • Can be asymmetrical if contralateral normal structure paralyzed (vocal cord) or surgically removed (muscle, glands)

  • Correlate with anatomical findings for confirmation of structure

Reactive Lymph Node Hyperplasia

  • Typically ↑ FDG uptake

  • Numerous sites, often symmetrical

  • LN mildly to moderately enlarged

  • May resolve over weeks to months

  • When equivocal, short term follow-up exam is usually helpful

Granulomatous Disease

  • FDG uptake moderate to marked

  • Stable over time

  • Often symmetrical hilar/mediastinal LN


  • Lung nodules: Sarcoid “galaxy” sign; multitude of tiny clustered lung nodules along bronchovascular bundle

  • Garland triad (1-2-3 sign): Symmetrically enlarged bilateral hilar & right paratracheal LN

  • Enlarged anterior mediastinal LN favors lymphoma

Viral Infections; Infectious Mononucleosis

  • Minimally enlarged LN

  • Sub-cm lung nodules that usually resolve completely


  • Sub-cm lung nodules that often calcify (granuloma)

  • Calcified normal-sized mildly FDG-avid mediastinal & hilar LN, calcified splenic & hepatic granulomas

Tuberculosis (TB)

  • Enlarged LN & ipsilateral consolidation in primary TB

  • Lung nodules may calcify, apical scarring, positive PPD

  • Cavitary lung lesion in the posterior segment right upper lobe or superior segment of the lower lobes

Cat-Scratch Fever

  • Enlarged, painful LN

  • Symptoms resolve over weeks

Whipple Disease

  • Enlarged abdominal LN with low attenuation center


  • Enlarged LN in HIV

    • Reactive follicular hyperplasia (50%)

    • AIDS-related lymphoma (20%)

    • Mycobacterial infection (17%)

    • Kaposi sarcoma (10%)

    • Opportunistic infection (multiple pathogens)

    • Metastases

    • Drug reaction

Higher Grade Lymphomas on Therapy

  • May show ↓ FDG uptake, mimicking low grade lymphoma

Other Malignancy

  • FDG PET may identify best candidate site for biopsy

Thoracic, Extrathoracic Malignancy

  • Enlarged FDG-avid LN accompanied by multiple FDG-avid lung nodules that increase in size and number over time

Small Cell Lung Carcinoma

  • Markedly enlarged, prominently FDG-avid hilar and mediastinal LN


General Features

  • General path comments

    • Most common subtype in adults is diffuse large B-cell lymphoma

      • Most aggressive subtype with 60% of patients having disseminated disease at diagnosis

    • More aggressive types

      • Diffuse large B-cell

      • Mantle cell

      • Peripheral T-cell

    • Fast-growing types

      • Burkitt lymphoma

      • Lymphoblastic

    • Slow-growing types

      • Marginal zone

      • Small cell (= CLL when principally in lymph nodes)

      • Lymphoplasmacytic

      • Follicular

    • Extranodal marginal zone lymphomas

      • GI tract, lung, salivary gland, conjunctiva, and thyroid

      • Diagnosed as separate entity termed MALT

  • Etiology

    • Unknown in most patients

    • MALT lymphoma (stomach) associated with H. pylori infection

    • Lymphoplasmacytic lymphoma: 1/3 associated with hepatitis C infection

    • Hashimoto thyroiditis associated with primary thyroid lymphoma

  • Epidemiology

    • NHL incidence ↑ 75% in the past 20 years, with ↑ mortality

    • Primary NHL of thyroid unusual, only 3.4% of primary thyroid malignancies

    • Malignant lymphomas as a group compose 5th most frequently occurring type of cancer in the USA

    • Most common NHL subtypes

      • Diffuse large B-cell lymphoma, 31%

      • Follicular lymphoma, 22%

      • Small lymphocytic lymphoma, 16%

      • Mantle cell lymphoma, 6%

      • Peripheral T-cell lymphoma, 2%

      • Anaplastic large T-cell/null cell lymphoma, 2%

      • Burkitt-like lymphoma, 2%

      • Marginal zone nodal-type lymphoma, 1%

      • Lymphoplasmacytic lymphoma, 1%

      • Burkitt lymphoma, < 1%

Microscopic Features

  • T- or B-cell clonality: No Reed-Sternberg cells

  • Fine-needle aspiration is diagnostic in NHL

  • FL: Aggressiveness proportionate to percentage of large cells

Staging, Grading, or Classification Criteria

  • Histologic grading more important than staging of anatomic sites in NHL

  • Clinical staging

    • Includes history & physical examination

    • Imaging of the chest, abdomen, & pelvis

    • Blood count, chemistry, and bone marrow biopsy

  • Pathologic staging

    • Staging laparotomy & pathologic staging no longer routinely performed

  • REAL/WHO classification

    • Revised European-American Classification of Lymphoid Neoplasms (REAL), adopted by World Health Organization (WHO)

    • Distinct disease entities defined by combination of morphology, immunophenotype & genetic features, and distinct clinical features

    • Relative importance of features varies by disease; no “gold standard”

    • Includes all lymphoid neoplasms: HD, NHL, lymphoid leukemias, & plasma cell neoplasms

    • Lymphomas & lymphoid leukemias included because solid + circulating phases are present in many lymphoid neoplasms

  • REAL/WHO classification of B-cell neoplasms

    • Precursor B-cell neoplasm: Precursor B-lymphoblastic leukemia/lymphoma (precursor B-cell acute lymphoblastic leukemia)

    • Mature (peripheral) B-cell neoplasms

      • B-cell CLL/SLL; B-cell prolymphocytic leukemia

      • Lymphoplasmacytic lymphoma; splenic marginal zone B-cell lymphoma

      • Hairy cell leukemia; plasma cell myeloma/plasmacytoma

      • Marginal zone B-cell/MALT lymphoma

      • Nodal marginal zone B-cell lymphoma; follicular lymphoma; mantle cell lymphoma

      • Diffuse large B-cell lymphoma; Burkitt lymphoma/Burkitt cell leukemia

  • REAL/WHO classification of T-cell and natural killer (NK)-cell neoplasms

    • Account for 10-15% of NHL

    • Precursor T-cell neoplasm: Precursor T-lymphoblastic lymphoma/leukemia (precursor T-cell ALL)

    • Mature (peripheral) T-/NK-cell neoplasms

      • T-cell prolymphocytic leukemia; T-cell granular lymphocytic leukemia; aggressive NK-cell leukemia

      • Adult T-cell lymphoma/leukemia (HTLV1+); extranodal NK-/T-cell lymphoma, nasal type

      • Enteropathy-type T-cell lymphoma; hepatosplenic T-cell lymphoma; subcutaneous panniculitis-like T-cell lymphoma

      • Mycosis fungoides/Sézary syndrome; anaplastic large cell lymphoma, T/null cell, primary cutaneous type

      • Peripheral T-cell lymphoma, not otherwise characterized; angioimmunoblastic T-cell lymphoma

      • Anaplastic large cell lymphoma, T/null cell, primary systemic type

  • Ann Arbor classification

Sep 22, 2016 | Posted by in MAGNETIC RESONANCE IMAGING | Comments Off on Non-Hodgkin Lymphoma

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