Lymphoma & related disorders

Hodgkin lymphoma

Classic Hodgkin lymphoma

Authors: Martha Frances Wright, M.D., Emily Mason, M.D., Ph.D.

Editorial Board Member: Julie Feldstein, M.D.

Deputy Editor-in-Chief: Genevieve M. Crane, M.D., Ph.D.

Topic Completed: 1 December 2021

Minor changes: 1 December 2021

Copyright: 2002-2021, PathologyOutlines.com, Inc.

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Table of Contents

Cite this page: Wright MF, Mason E. Classic Hodgkin lymphoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomanonBclassic.html. Accessed December 3rd, 2021.

Definition / general

Classic Hodgkin lymphoma (CHL): B cell derived lymphoma characterized by distinctive immunophenotype and relatively few malignant cells in a nonneoplastic inflammatory background
4 subgroups (nodular sclerosis, mixed cellularity, lymphocyte rich, lymphocyte depleted) with distinct clinical, morphologic and epidemiologic characteristics

Essential features

B cell derived lymphoma characterized by distinctive immunophenotype and relatively few malignant cells in a nonneoplastic inflammatory background
4 subgroups (nodular sclerosis, mixed cellularity, lymphocyte rich, lymphocyte depleted) with distinct clinical, morphologic and epidemiologic characteristics
Involves lymph nodes (cervical > axillary, mediastinal, paraaortic)
Bimodal age distribution: peaks at 15 - 35 years and 50 - 70 years
Multiple mechanisms to evade immunosurveillance, including upregulation of programmed death ligand 1 / programmed death ligand 2 (PDL1 / PDL2)

Terminology

Classical Hodgkin lymphoma
Hodgkin disease

ICD coding

ICD-10: C.81* - classic Hodgkin lymphoma
ICD-10: C.81.90 - classic Hodgkin lymphoma, unspecified, unspecified site
ICD-11: 2B30.1Z - classical Hodgkin lymphoma, unspecified

Epidemiology

CHL: ~90 - 95% of Hodgkin lymphomas
Bimodal age distribution: peaks at 15 - 35 years and 50 - 70 years
Epidemiology varies by subgroup (Br J Haematol 2019;184:45):
- Nodular sclerosis (~70% of CHL in Western countries): F > M, age 15 - 35 years, most common in urban areas, wealthier nations and individuals with high socioeconomic status, minority (10 - 25%) EBV+
- Mixed cellularity (~20% of CHL): children and adults > 60 years, M > F, more common in developing countries and rural areas, majority (70 - 80%) EBV+
- Lymphocyte rich (~5% of CHL): M > F, age 30 - 50 years
- Lymphocyte depleted (<1% of CHL in Western countries): M > F, age 30 - 70 years

Sites

Lymph nodes (cervical > axillary, mediastinal, paraaortic)
Mediastinal involvement in 80% of nodular sclerosis CHL
Extranodal sites: spleen (20%), liver, lungs, bone marrow (5%)
Typical anatomic distribution varies by subgroup (Br J Haematol 2019;184:45):
- Nodular sclerosis: mediastinal, cervical, supraclavicular lymph nodes
- Mixed cellularity: peripheral lymph nodes, spleen, bone marrow
- Lymphocyte rich: peripheral lymph nodes
- Lymphocyte depleted: retroperitoneal lymph nodes, abdomen, bone marrow

Pathophysiology

Pathophysiology incompletely understood
Malignant Reed-Sternberg cells derived from preapoptotic germinal center B cells with a disrupted B cell program (Blood 2000;95:1443)
In a subset of cases, IgVH mutations lead to dysfunctional / absent B cell receptor, prohibiting antigenic selection; incompatible with survival of normal B cells (J Exp Med 1996;184:1495)
Postulated to circumvent apoptosis by differentiating toward distinct subset of CD30+ post germinal center memory B cells (J Clin Invest 2018;128:2996)
Cell proliferation and survival promoted by alterations in signaling pathways, including JAK / STAT, NFkB, PI3K / AKT and MAPK / ERK (Leukemia 2021;35:968, Cancers (Basel) 2021;13:682)
EBV infection thought to drive aberrant signaling in EBV+ cases (Histopathology 2021;79:451)
Reed-Sternberg cell cytokine secretion recruits nonneoplastic inflammatory infiltrate; reciprocal cytokine / chemokine secretion by immune cells supports Reed-Sternberg cell survival and proliferation
Reed-Sternberg cell evasion of immunosurveillance:
- Increased programmed death ligand 1 / programmed death ligand 2 (PDL1 / PDL2) expression (J Clin Oncol 2016;34:2690, Blood 2017;130:2420)
- Downregulation of MHC I / MHC II expression (Cancer Immunol Res 2016;4:910)
- Secretion of immunosuppressive cytokines
- Infection (EBV, HIV) thought to facilitate in subset of cases

Etiology

Cause incompletely understood
Factors associated with increased risk of developing CHL:
- EBV positive CHL: prior infectious mononucleosis, HLA-A*01 allele (Blood 2019;134:591)
- HIV infection (Blood 2006;108:3786)
- Family history of CHL, particularly siblings

Diagrams / tables

Images hosted on other servers:

Reed-Sternberg cell and microenvironment

Clinical features

Peripheral lymphadenopathy
30 - 40% of patients present with B symptoms (fever, night sweats, weight loss), pruritis
Stage at presentation (Blood Rev 2002;16:111):
- Nodular sclerosis, lymphocyte rich usually present with early stage disease
- Mixed cellularity and lymphocyte depleted associated with HIV infection and EBV often present with advanced stage disease
- Immunosuppression (including HIV infection) associated with advanced stage disease

Diagnosis

Excisional lymph node biopsy or tissue biopsy
FNA and core needle biopsy may be insufficient given importance of tissue architecture for diagnosis and potential rarity of Reed-Sternberg cells

Laboratory

Nonspecific
Elevated C reactive protein
Eosinophilia (20%)

Radiology description

Lower cervical, supraclavicular and mediastinal lymphadenopathy
Bulky mediastinal disease in 50% of nodular sclerosis subtype
PET / CT recommended for staging (J Clin Oncol 2014;32:3059)
PET / CT has high sensitivity for detecting bone marrow involvement

Radiology images

Images hosted on other servers:

PET scan before and after therapy

Prognostic factors

Differences in prognosis between different subgroups largely gone with modern therapy
Immunosuppression, HIV infection associated with worse prognosis
Staging critical for accurate prognostication and treatment
- Early stage disease includes favorable and unfavorable groups
  - Unfavorable prognosis associated with B symptoms, bulky mediastinal disease, elevated erythrocyte sedimentation rate (ESR), involvement of multiple lymph node groups, extranodal disease, older age (> 40 - 50 years)
- Advanced stage disease: prognosis associated with International Prognostic Score, based on 7 variables that independently predict outcome (N Engl J Med 1998;339:1506)
80 - 90% cure rates with stage adapted therapy
10 - 25% of patients have primary refractory disease or relapse
Increased percentage of CD68 positive macrophages in a diagnostic lymph node biopsy associated with shorter progression free and disease specific survival and increased failure rate after secondary treatment, including autologous stem cell transplant (N Engl J Med 2010;362:875)

Case reports

11 year old boy with initial extranodal osseous presentation of CHL (AME Case Rep 2019;3:22)
52 year old man with bilateral cervical lymphadenopathy (Clin Case Rep 2020;8:466)
53 year old man with CHL associated superior vena cava syndrome (Am J Case Rep 2021;22:e929437)
56 year old man with cutaneous involvement by CHL (World J Clin Cases 2019;7:2513)
85 year old woman with a 10 year history of chronic lymphocytic leukemia (Case Rep Oncol 2020;13:120)

Treatment

ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) with or without IFRT (involved field radiation therapy)
BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) or AVD with brentuximab vedotin (anti-CD30 antibody drug conjugate) sometimes used in advanced disease
Options for relapsed / refractory disease include brentuximab vedotin, chemotherapy, checkpoint inhibitors, high dose therapy and autologous stem cell transplant, allogeneic stem cell transplant
Risks of treatment related morbidity, including therapy related malignancy (> 4x risk of cancer compared with general population), cardiovascular complications from mediastinal IFRT (Br J Haematol 2019;184:9)
Interim PET scan after 2 cycles of chemotherapy may be used to guide treatment (PET adapted therapy) (Br J Haematol 2019;184:9)

Gross description

Nodular sclerosis subtype: enlarged lymph node, thickened capsule, fibrotic bands with prominent nodularity
Nodular involvement of spleen

Gross images

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Fleshy lymph node

Liver with multifocal involvement

Frozen section description

Effacement of nodal architecture
Nodularity
Mixed inflammatory background (small lymphocytes, neutrophils, eosinophils, histiocytes)
May see scattered large Reed-Sternberg cells with multilobated nuclei and prominent nucleoli

Frozen section images

Contributed by Emily Mason, M.D., Ph.D.

Reed-Sternberg cells

Microscopic (histologic) description

Total or partial effacement of nodal architecture
Nodular sclerosis subtype: nodularity, dense collagen bands, thickened capsule
Diagnostic cell = Reed-Sternberg cell: large size (up to 100 microns), bilobated to multilobated nucleus, prominent eosinophilic nucleolus, ample amphophilic cytoplasm
Mononuclear variants = Hodgkin cells: single round to oval nucleus with prominent eosinophilic nucleolus
Mummified forms: degenerated Hodgkin and Reed-Sternberg cells, condensed hyperchromatic nuclei
Lacunar cells: characteristic of nodular sclerosis subtype, lobulated nuclei, pale retracted cytoplasm (artifact of formalin fixation), creating lacunae-like spaces
Mixed inflammatory background (Br J Haematol 2019;184:45):
- Nodular sclerosis: small lymphocytes, neutrophils, eosinophils, histiocytes, plasma cells, necrosis and microabscesses common, with banding fibrosis
- Mixed cellularity: small lymphocytes, neutrophils, eosinophils, histiocytes, plasma cells, epithelioid granulomas common
- Lymphocyte depleted: reduced background infiltrate
- Lymphocyte rich: nodules of small B cells, epithelioid histiocytes
Diagnostic Hodgkin and Reed-Sternberg cells may be rare to frequent depending on subtype
- Syncytial variant: variant of nodular sclerosis subtype; Hodgkin and Reed-Sternberg cells present in aggregates and sheets, with typical inflammatory background and immunophenotype of nodular sclerosis subtype

Microscopic (histologic) images

Contributed by Emily Mason, M.D., Ph.D.

Hodgkin and Reed-Sternberg cells

Nodular sclerosis CHL

Scattered Reed-Sternberg cells

Lacunar cell

Syncytial variant

Weak PAX5 expression

CD30 expression

Variable CD20 expression

EBV positivity

Syncytial variant, CD30 stain

Virtual slides

Images hosted on other servers:

Nodular sclerosis CHL

Cytology description

Mixed inflammatory background (small lymphocytes, neutrophils, eosinophils, histiocytes)
May see scattered large Reed-Sternberg cells with multilobated nuclei and prominent nucleoli

Cytology images

Contributed by Emily Mason, M.D., Ph.D.

Reed-Sternberg cell

Positive stains

Hodgkin and Reed-Sternberg cells positive for:
- PAX5 (weak)
- CD30
- CD15 (75 - 80% of cases)
- MUM1 / IRF4
- Fascin (EBV positive and negative cases; EBV LMP1 induces fascin expression) (Cell Commun Signal 2014;12:46)
- EBER and EBV LMP1 positive in EBV positive cases (more common in mixed cellularity)
- PDL1 / PDL2

Negative stains

Hodgkin and Reed-Sternberg cells negative for:
- CD20 (may be variably positive in Hodgkin and Reed-Sternberg cells, particularly with improved antigen retrieval) (Br J Haematol 2019;184:45)
- CD45
- CD43
- CD79a (rarely positive)
- OCT2 and BOB1 (typically at least 1 downregulated)
- CD3
- ALK1
- T cell markers (rarely positive)
- Cytokeratins
- EMA

Flow cytometry description

Hodgkin and Reed-Sternberg cells typically not identified by flow cytometry
Flow cytometry shows background infiltrate
Typically, mixed T cells with increased CD4:CD8 ratio

Electron microscopy description

Large rounded or oblong nuclei with folding, indentation and lobulation (Am J Pathol 1976;85:195)
Occasional multinucleation
Very large nucleoli

Electron microscopy images

Images hosted on other servers:

Reed-Sternberg cell nucleus

Molecular / cytogenetics description

Hodgkin and Reed-Sternberg cells = B cells with clonal immunoglobulin heavy chain rearrangements (microdissection of Hodgkin and Reed-Sternberg cells required for detection) (Blood 2000;95:1443)
Immunoglobulin gene expression silenced in Hodgkin and Reed-Sternberg cells (Blood 2000;95:1443)
Hodgkin and Reed-Sternberg cells show numerical chromosome abnormalities in almost all cases (Blood 1995;86:1464)
90% of CHL shows copy number gain or amplification at 9p24.1; causes increased expression of PDL1 and PDL2 (J Clin Oncol 2016;34:2690)
Gene mutations in components of the JAK / STAT and NFkB signaling pathways promote cell proliferation and survival (Leukemia 2021;35:968, Cancers (Basel) 2021;13:682)

Molecular / cytogenetics images

Images hosted on other servers:

PDL1 / PDL2 gain, amplification

Sample pathology report

Lymph node, left neck, excision:
- Classic hodgkin lymphoma, nodular sclerosis subtype (see comment)
- Comment: H&E stained sections show an enlarged lymph node with near total architectural effacement by a nodular mixed inflammatory infiltrate composed of small lymphocytes, plasma cells, neutrophils and numerous eosinophils, with scattered admixed large abnormal cells. The large abnormal cells have oval to occasionally multilobated nuclei, vesicular chromatin, prominent nucleoli and abundant cytoplasm, consistent with Reed-Sternberg cells and mononuclear variants. Lacunar cells are present. The lymph node capsule is thickened and banding fibrosis is present
- Immunostains show that the large abnormal cells are positive for PAX5 (weak), CD30 and CD15 (subset) and are negative for CD20, CD45 and CD3. In situ hybridization for EBV encoded RNA (EBER) is negative. CD3 highlights background small T cells.
- Flow cytometry showed polytypic B cells and mixed T cells subsets.

Differential diagnosis

Reactive immunoblastic reaction:
- Lymph node architecture is maintained
Infectious mononucleosis:
- Particularly in children and young adults
- Although potentially distorted, lymph node architecture is overall maintained
Anaplastic large cell lymphoma (ALCL):
- T cell lymphoma
- Hallmark cells with bean or horseshoe shaped nuclei
- Involvement of lymph node sinuses
- May show loss of some T cell markers but typically positive for CD43, CD4 and cytotoxic markers (TIA1, granzyme B)
- ALK1 typically positive in children and young adults
Nodular lymphocyte predominant Hodgkin lymphoma:
- Typically low stage at presentation
- Large neoplastic cells are positive for CD20, CD45 and EMA
- Neoplastic cells typically negative for CD15 and CD30, although rare cases may be positive
- Nonneoplastic CD30 positive immunoblasts may be present
Primary mediastinal large B cell lymphoma:
- Bulky mediastinal disease
- Diffuse proliferation of intermediate to large sized B cells
- Fine compartmentalizing fibrosis common
- Neoplastic cells positive for CD20 and CD45
- May show variable / heterogeneous CD30 expression
- Often CD23 positive
B cell lymphoma unclassifiable, with features intermediate between diffuse large B cell lymphoma and CHL (gray zone lymphoma):
- Sparse inflammatory infiltrate with high cell density
- Disconnect between morphology and immunophenotype: Reed-Sternberg cell morphology with strong homogenous expression of multiple B cell markers or diffuse proliferation of large cells with strong, homogenous expression of CD30 and often CD15 and loss of B cell markers (Blood Adv 2017;1:2600)
- Uniform CD20 expression in a tumor that is otherwise typical for nodular sclerosis CHL should not lead to a diagnosis of gray zone lymphoma (Br J Haematol 2019;184:45)
T cell / histiocyte rich large B cell lymphoma:
- Diffuse growth pattern
- Scattered large CD20 positive B cells in a background of small T cells and histiocytes
- Neoplastic cells typically negative for CD15 and CD30
EBV positive diffuse large B cell lymphoma:
- More commonly involves extranodal sites, particularly in elderly patients
- Can show morphologic overlap with EBV positive CHL
- Lesional cells positive for EBV and multiple B cell markers (PAX5, CD20, OCT2, BOB1, CD79a)
- Most cases CD30 positive but typically CD15 negative
EBV positive mucocutaneous ulcer:
- Localized involvement of cutaneous or mucosal sites (Am J Surg Pathol 2010;34:405)
- Occurs in the setting of iatrogenic or age related immunosuppression
- Sharply circumscribed ulcerative lesion
- Most cases CD30 positive but typically CD15 negative
Peripheral T cell lymphoma, not otherwise specified:
- T cell lymphoma with expression of T cell markers
- May show positivity for CD15 or CD30
- T cell clonality studies often positive for T cell clone
Angioimmunoblastic T cell lymphoma:
- T cell lymphoma with expression of T cell markers
- Mixed inflammatory infiltrate
- May show scattered large B cells that are often EBV positive
- T cell clonality studies usually positive for T cell clone

Additional references

Swerdlow: WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues, 4th Edition, 2017, Am J Hematol 2020;95:978, Lancet 2021 Jan 22 [Epub ahead of print], Br J Haematol 2019;184:30

Board review style question #1

Which of the following is most likely to be negative in the large abnormal cells in the image above?

CD15
CD30
CD45
MUM1
PDL1

Board review style answer #1

C. CD45

Comment Here

Reference: Classic Hodgkin lymphoma

Board review style question #2

Which of the following is most consistent with the immunophenotype of Reed-Sternberg cells?

Positive: CD3, CD30, CD45, ALK1; negative: CD15, CD20, EBER, MUM1
Positive: CD15, CD20, MUM1, ALK1; negative: CD3, CD15, CD45, EBER
Positive: CD15, CD30, MUM1; negative: CD3, CD20, CD45
Positive: CD15, CD45, EBER; negative: CD20, CD30, MUM1
Positive: CD20, CD30, CD45, ALK1; negative: CD15, CD3, EBER

Board review style answer #2

C. Positive: CD15, CD30, MUM1; negative: CD3, CD20, CD45

Comment Here

Reference: Classic Hodgkin lymphoma

Board review style question #3

Which of the following subtypes of classic Hodgkin lymphoma is most commonly associated with EBV?

Lymphocyte depleted
Lymphocyte rich
Mixed cellularity
Nodular lymphocyte predominant
Nodular sclerosis

Board review style answer #3

C. Mixed cellularity

Comment Here

Reference: Classic Hodgkin lymphoma