Mixed Cellularity Hodgkin Lymphoma

C. Cameron Yin, MD, PhD

Key Facts

Terminology

Subtype of classical Hodgkin lymphoma (CHL) with diffuse or interfollicular pattern, without nodular fibrosis

Etiology/Pathogenesis

Epstein-Barr virus (EBV) appears to play pathogenic role in EBV(+) cases
HIV infection predisposes to development of EBV-associated CHL, mainly mixed cellularity CHL
Considered preapoptotic germinal center B cell

Clinical Issues

Accounts for 20-25% of CHL
Most patients present with stages II or III disease
Clinical and laboratory parameters are more relevant to prognosis and to determine mode of therapy

Microscopic Pathology

Complete or partial effacement of nodal architecture
Diagnostic Hodgkin and Reed-Sternberg (HRS) cells are readily identifiable

Ancillary Tests

CD30(+) in 100%; CD15(+) in ˜ 80% of cases
Epstein-Barr virus (EBV) latency type II infection
Monoclonal Ig gene rearrangements in HRS cells using single-cell analysis

Top Differential Diagnoses

Peripheral T-cell lymphoma
T-cell/histiocyte-rich large B-cell lymphoma
Lymphocyte-depleted Hodgkin lymphoma

Mixed cellularity Hodgkin lymphoma (MCHL) involving lymph node. A low-power view shows diffuse effacement of the lymph node architecture.

MCHL shows lymph node architecture completely effaced by abundant inflammatory cells

and scattered HRS cells

TERMINOLOGY

Abbreviations

Mixed cellularity Hodgkin lymphoma (MCHL)

Synonyms

Mixed cellularity classical Hodgkin lymphoma
Mixed cellularity Hodgkin disease

Definitions

Classical Hodgkin lymphoma (CHL) is a lymphoid neoplasm composed of Hodgkin and Reed-Sternberg (HRS) cells in a variable inflammatory background
Mixed cellularity is a type of CHL composed of classic HRS cells in a heterogeneous inflammatory cell background
- MCHL has a diffuse or interfollicular pattern without nodules or fibrosis

ETIOLOGY/PATHOGENESIS

Infectious Agents

Epstein-Barr virus (EBV) is present in HRS cells in ˜ 75% of cases and has pathogenic role
HIV infection predisposes to development of EBV-associated CHL and often MCHL

Pathogenesis

HRS cells arise from late germinal center or early post-germinal center B cells that
- Have undergone immunoglobulin gene (Ig) rearrangements with somatic mutations
- Have undergone crippling Ig mutations in a subset of cases
- Lack B-cell antigen receptors
HRS cells lose much of the normal B-cell immunophenotype due to
- Severe impairment of transcription factor network that regulates B-cell gene expression
- Low or undetectable levels of transcription factors: OCT2, BOB1, PU.1, and early B-cell factor (EBF)
  - Leads to low level of Ig transcripts in HRS cells
  - Made worse by epigenetic silencing (promoter hypermethylation) of Ig transcription
- Impaired function of early B-cell development transcription factors: pax-5, E2A, and EBF
Overall, these abnormalities physiologically should lead to apoptosis
Development of antiapoptotic mechanisms to achieve survival
- Dysregulation of many signaling pathways
- Expression of EBNA1 and latent membrane proteins LMP1 and LMP2a
Role of microenvironment
- Reactive cellular infiltrate is induced, in part, by HRS cells
  - Protects HRS cells from apoptosis
- HRS cells produce a variety of cytokines, chemokines, and growth factors

CLINICAL ISSUES

Epidemiology

Incidence
- Accounts for 20-25% of CHL cases in developed countries
- Most common type of CHL in underdeveloped countries
Age
- Median: 38 years
Gender
- Male to female ratio is 2:1

Site

Cervical and supraclavicular lymph nodes
Mediastinal involvement is uncommon
Spleen (˜ 30%), bone marrow (˜ 10%), and liver (˜ 3%)

Presentation

B symptoms are common
Patients usually present with peripheral lymphadenopathy
- Abdominal lymph nodes common; often with splenic involvement
Most patients present with stage II or III disease

Treatment

Current chemotherapy &/or radiation can cure disease in many patients
Chemotherapy with or without radiation
- ABVD: Adriamycin (doxorubicin), bleomycin, vinblastine, and dacarbazine

Prognosis

Clinical and laboratory parameters are relevant to predicting prognosis and determining mode of therapy
Recent study suggests that number of histiocytes in background predicts prognosis

IMAGE FINDINGS

General Features

Lymphadenopathy

MICROSCOPIC PATHOLOGY

Histologic Features

Complete or partial effacement of lymph node architecture
- Interfollicular pattern can occur
HRS cells
- Readily identifiable with classic features
  - Reed-Sternberg cells are bilobed with large eosinophilic nucleoli and perinuclear halo
  - Hodgkin cells are mononuclear cells with large eosinophilic nucleolus and perinuclear halo
Background infiltrate
- Variable mixture of small lymphocytes, plasma cells, histiocytes, eosinophils, &/or neutrophils
- Histiocytes can be singly scattered or present as illdefined or epithelioid granulomas
Occasional foci of necrosis
Mild to moderate interstitial fibrosis may be present
- No nodular collagen bands; no thickening of lymph node capsule

Cytologic Features

HRS cells in inflammatory background can be appreciated in fine needle aspiration smears
- Immunophenotype can be assessed in cell block
- Difficult to determine type as MCHL versus other types of CHL

ANCILLARY TESTS

Immunohistochemistry

CD30(+) > 95%; CD15(+) in ˜ 70-80% of cases
- Characteristic membranous pattern with accentuation in Golgi area
pax-5(dim +) ˜ 90%, CD20 (variable +) ˜ 20%, CD79a(+) ˜ 10-20%
Ki-67(+), p53(+), MUM1(+)
CCL17(TARC)(+), fascin(+/-), Bcl-2(+/-)
OCT2(-/+), BOB1(-/+), PU.1(-)
CD45/LCA(-), EMA(-), Ig(-), clusterin(-)
EBV(+) latency type II pattern in ˜ 75% of cases
T-cell antigens can be aberrantly expressed by HRS cells in small subset of cases

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