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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