Mixed Cellularity Hodgkin Lymphoma
C. Cameron Yin, MD, PhD
Key Facts
Terminology
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Subtype of classical Hodgkin lymphoma (CHL) with diffuse or interfollicular pattern, without nodular fibrosis
Etiology/Pathogenesis
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Epstein-Barr virus (EBV) appears to play pathogenic role in EBV(+) cases
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HIV infection predisposes to development of EBV-associated CHL, mainly mixed cellularity CHL
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Considered preapoptotic germinal center B cell
Clinical Issues
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Accounts for 20-25% of CHL
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Most patients present with stages II or III disease
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Clinical and laboratory parameters are more relevant to prognosis and to determine mode of therapy
Microscopic Pathology
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Complete or partial effacement of nodal architecture
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Diagnostic Hodgkin and Reed-Sternberg (HRS) cells are readily identifiable
Ancillary Tests
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CD30(+) in 100%; CD15(+) in ˜ 80% of cases
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Epstein-Barr virus (EBV) latency type II infection
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Monoclonal Ig gene rearrangements in HRS cells using single-cell analysis
Top Differential Diagnoses
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Peripheral T-cell lymphoma
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T-cell/histiocyte-rich large B-cell lymphoma
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Lymphocyte-depleted Hodgkin lymphoma
TERMINOLOGY
Abbreviations
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Mixed cellularity Hodgkin lymphoma (MCHL)
Synonyms
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Mixed cellularity classical Hodgkin lymphoma
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Mixed cellularity Hodgkin disease
Definitions
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Classical Hodgkin lymphoma (CHL) is a lymphoid neoplasm composed of Hodgkin and Reed-Sternberg (HRS) cells in a variable inflammatory background
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Mixed cellularity is a type of CHL composed of classic HRS cells in a heterogeneous inflammatory cell background
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MCHL has a diffuse or interfollicular pattern without nodules or fibrosis
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ETIOLOGY/PATHOGENESIS
Infectious Agents
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Epstein-Barr virus (EBV) is present in HRS cells in ˜ 75% of cases and has pathogenic role
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HIV infection predisposes to development of EBV-associated CHL and often MCHL
Pathogenesis
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HRS cells arise from late germinal center or early post-germinal center B cells that
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Have undergone immunoglobulin gene (Ig) rearrangements with somatic mutations
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Have undergone crippling Ig mutations in a subset of cases
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Lack B-cell antigen receptors
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HRS cells lose much of the normal B-cell immunophenotype due to
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Severe impairment of transcription factor network that regulates B-cell gene expression
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Low or undetectable levels of transcription factors: OCT2, BOB1, PU.1, and early B-cell factor (EBF)
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Leads to low level of Ig transcripts in HRS cells
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Made worse by epigenetic silencing (promoter hypermethylation) of Ig transcription
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Impaired function of early B-cell development transcription factors: pax-5, E2A, and EBF
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Overall, these abnormalities physiologically should lead to apoptosis
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Development of antiapoptotic mechanisms to achieve survival
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Dysregulation of many signaling pathways
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Expression of EBNA1 and latent membrane proteins LMP1 and LMP2a
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Role of microenvironment
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Reactive cellular infiltrate is induced, in part, by HRS cells
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Protects HRS cells from apoptosis
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HRS cells produce a variety of cytokines, chemokines, and growth factors
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CLINICAL ISSUES
Epidemiology
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Incidence
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Accounts for 20-25% of CHL cases in developed countries
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Most common type of CHL in underdeveloped countries
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Age
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Median: 38 years
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Gender
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Male to female ratio is 2:1
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Site
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Cervical and supraclavicular lymph nodes
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Mediastinal involvement is uncommon
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Spleen (˜ 30%), bone marrow (˜ 10%), and liver (˜ 3%)
Presentation
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B symptoms are common
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Patients usually present with peripheral lymphadenopathy
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Abdominal lymph nodes common; often with splenic involvement
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Most patients present with stage II or III disease
Treatment
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Current chemotherapy &/or radiation can cure disease in many patients
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Chemotherapy with or without radiation
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ABVD: Adriamycin (doxorubicin), bleomycin, vinblastine, and dacarbazine
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Prognosis
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Clinical and laboratory parameters are relevant to predicting prognosis and determining mode of therapy
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Recent study suggests that number of histiocytes in background predicts prognosis
IMAGE FINDINGS
General Features
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Lymphadenopathy
MICROSCOPIC PATHOLOGY
Histologic Features
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Complete or partial effacement of lymph node architecture
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Interfollicular pattern can occur
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HRS cells
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Readily identifiable with classic features
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Reed-Sternberg cells are bilobed with large eosinophilic nucleoli and perinuclear halo
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Hodgkin cells are mononuclear cells with large eosinophilic nucleolus and perinuclear halo
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Background infiltrate
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Variable mixture of small lymphocytes, plasma cells, histiocytes, eosinophils, &/or neutrophils
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Histiocytes can be singly scattered or present as illdefined or epithelioid granulomas
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Occasional foci of necrosis
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Mild to moderate interstitial fibrosis may be present
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No nodular collagen bands; no thickening of lymph node capsule
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Cytologic Features
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HRS cells in inflammatory background can be appreciated in fine needle aspiration smears
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Immunophenotype can be assessed in cell block
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Difficult to determine type as MCHL versus other types of CHL
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ANCILLARY TESTS
Immunohistochemistry
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CD30(+) > 95%; CD15(+) in ˜ 70-80% of cases
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Characteristic membranous pattern with accentuation in Golgi area
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pax-5(dim +) ˜ 90%, CD20 (variable +) ˜ 20%, CD79a(+) ˜ 10-20%
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Ki-67(+), p53(+), MUM1(+)
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CCL17(TARC)(+), fascin(+/-), Bcl-2(+/-)
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OCT2(-/+), BOB1(-/+), PU.1(-)
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CD45/LCA(-), EMA(-), Ig(-), clusterin(-)
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EBV(+) latency type II pattern in ˜ 75% of cases
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T-cell antigens can be aberrantly expressed by HRS cells in small subset of cases
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