Non-Hodgkin Lymphoma

Non-Hodgkin Lymphoma
Todd M. Blodgett, MD
Alex Ryan, MD
Omar Almusa, MD
Key Facts
Terminology
  • Non-Hodgkin lymphoma (NHL)
  • NHL: Malignancy of B or T lymphocytes
Imaging Findings
  • Spleen involved in 20% of patients with NHL
  • Other extranodal lymphoma may arise in CNS, peripheral nervous system, lung and pleura, bone, skin, breast, testis, and GU tract
  • PET/CT: Use with contrast-enhanced CT for staging
  • Enlarged LN, extranodal mass with low to moderate FDG uptake
  • Enlarged/normal-sized FDG-avid nodes in liver or spleen; “misty mesentery”
  • PET excellent for predicting prognosis in aggressive NHL after therapy
  • 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)
Top Differential Diagnoses
  • Normal Structures
  • Reactive Lymph Node Hyperplasia
  • Sarcoid
  • Histoplasmosis
  • Other Malignancy
Diagnostic Checklist
  • Perform a baseline PET/CT in all patients with newly diagnosed NHL
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.
TERMINOLOGY
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)
Definitions
  • 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
IMAGING FINDINGS
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
DIFFERENTIAL DIAGNOSIS
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
Sarcoid
  • 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
Histoplasmosis
  • 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
HIV, AIDS
  • 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
PATHOLOGY
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
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Sep 22, 2016 | Posted by in MAGNETIC RESONANCE IMAGING | Comments Off on Non-Hodgkin Lymphoma

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