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Lymphoma & related disorders

Hodgkin lymphoma

Mixed cellularity

Authors: Carmen Bárcena, M.D., Laurence de Leval, M.D., Ph.D.

Editorial Board Member: Mario L. Marques-Piubelli, M.D.

Last staff update: 8 December 2022 (update in progress)

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PubMed Search: Mixed cellularity classic Hodgkin lymphoma

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Table of Contents

Cite this page: Bárcena C, de Leval L. Mixed cellularity. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomanonBmixed.html. Accessed December 9th, 2022.

Definition / general

Subtype of classic Hodgkin lymphoma (CHL) with Hodgkin / Reed-Sternberg (HRS) cells in a nonneoplastic mixed inflammatory background (Blood 2022;140:1229, Leukemia 2022;36:1720)

Essential features

B cell lymphoma derived from germinal center B cells
HRS cells in a reactive mixed inflammatory microenvironment consisting of small lymphocytes, eosinophils, plasma cells, neutrophils and histiocytes
Immunophenotype of HRS cells: PAX5+ (dim), CD30+, CD15 variable, CD20 variable
EBER+ in 75% of cases

ICD coding

ICD-O: 9652/3 - Hodgkin lymphoma, mixed cellularity, NOS
ICD-10: C81.2 - mixed cellularity (classical) Hodgkin lymphoma
ICD-11: 2B30.12 - mixed cellularity classical Hodgkin lymphoma

Epidemiology

Second most common subtype of classic Hodgkin lymphoma
Accounts for 20 - 25% of classic Hodgkin lymphoma
Bimodal incidence: pediatric population and elderly patients
M > F
More common in patients with immunodeficiency and in developing countries (Expert Rev Hematol 2021;14:547)
EBV infection in 75% of cases; virus is located within the HRS cells and usually shows a type II latency pattern of infection (N Engl J Med 1989;320:502)

Sites

Lymph nodes (70%) > spleen (30%) > bone marrow (10%) > liver (3%) > other organs (1 - 3%) (Leuk Lymphoma 2019;60:3426)
Rarely limited to a single region and is more likely to involve extralymphatic tissues compared to other classic Hodgkin lymphoma subtypes
Mediastinal involvement is rare

Pathophysiology

Pathophysiology incompletely understood
Hodgkin / Reed-Sternberg cells derived from preapoptotic germinal center B cells with a disrupted B cell program (Leukemia 2021;35:968)
HRS harbor monoclonal IgH rearrangements with somatic mutations of their immunoglobulin (Ig) variable region genes, losing the capacity of Ig expression (Leukemia 2021;35:968)
Genetic lesions that promote HRS cell proliferation, survival, immune evasion and interaction with their microenvironment, including alterations in NFκB and JAK-STAT signaling pathways (Leukemia 2021;35:968)
EBV could play a crucial role by infecting and rescuing Hodgkin / Reed-Sternberg cells with a crippled B cell receptor in the germinal centers from apoptosis and thus inducing lymphomagenesis (Blood 2005;106:4339)
EBV infection activates the NFκB pathway, promoting survival and growth (Histopathology 2021;79:451)

Clinical features

B symptoms are common
May be diagnosed in all clinical stages (more commonly with stage II and III disease)

Diagnosis

Excisional lymph node biopsy or tissue biopsy with ancillary techniques (immunohistochemistry)

Laboratory

Nonspecific findings: anemia, leukocytosis, lymphocytopenia, elevated C reactive protein (N Engl J Med 1998;339:1506)

Prognostic factors

About 90 - 95% of patients with early stage CHL and 80 - 85% with advanced stage CHL are cured (Am J Hematol 2020;95:978)
Treatment is individualized according to defined risk groups, based on the following prognostic factors:
- Ann Arbor stage (most important predictor of outcome) (J Clin Oncol 2014;32:3059)
- Bulky (mediastinal) disease
- Extranodal involvement
- B symptoms
- International Prognostic Score (N Engl J Med 1998;339:1506)

Treatment

Intensive polychemotherapy (ABVD or BEACOPP), with or without radiotherapy (Am J Hematol 2020;95:978)
For refractory cases: stem cell transplant, brentuximab vedotin, checkpoint inhibitors (N Engl J Med 2018;378:331)

Microscopic (histologic) description

Diffuse or interfollicular proliferation of HRS cells (< 10% of the cellularity) in a reactive microenvironment composed of lymphocytes, eosinophils, neutrophils, plasma cells, histiocytes, fibroblasts (Leukemia 2022;36:1720)
CD4+ T cells are the most abundant immune cells in the CHL microenvironment (Cytometry B Clin Cytom 2008;74:1, Blood 2004;103:1755, Lab Invest 2008;88:482)
In EBV+ cases, there may be numerous epithelioid histiocytes and even granulomas
Fine interstitial fibrosis may be seen but without collagen broad bands and with no capsular thickening
Bone marrow is involved in 10% of cases and shows scattered HRS cells in a background that is rich in histiocytes with ill defined granulomas merging with inflammatory cells and normal hematopoiesis

Microscopic (histologic) images

Contributed by Laurence de Leval, M.D., Ph.D. and Carmen Bárcena, M.D.

Interfollicular zones

Interfollicular expansion

Reed-Sternberg / Hodgkin cells

Reed-Sternberg / Hodgkin cells and microgranulomas

Polymorphous microenvironment

Focal necrosis

CD45

PAX5

MUM1

CD30

CD15

EBER in situ hybridization

EBV LMP1

PDL1 SP263

Positive stains

PAX5 (dim), CD30 (strong and uniform), CD15 variable (75% of cases), MUM1 (Ann Diagn Pathol 2019;39:105)
STAT6^YE361, PDL1, PDL2 (Histopathology 2018;72:1156, Mod Pathol 2020;33:834, Blood 2018;131:68)
EBV positive cases: EBV LMP1 variable, EBER

Negative stains

Variable: CD20 (weak), CD79a, OCT2, BOB1 (Leukemia 2022;36:1720, J Pathol 2004;202:60)
BCL2, BCL6 (Leukemia 2022;36:1720)
CD45, ALK, EMA, CD23, EBNA2 (Int J Surg Pathol 2010;18:121, Ann Diagn Pathol 2019;40:72, Proc Natl Acad Sci U S A 1991;88:4766)
Immunoglobulins, light and heavy chains, are negative (Leukemia 2022;36:1720)

Molecular / cytogenetics description

Aneuploidy is seen in nearly all cases (Blood 1995;86:1464, Cancer Res 2006;66:10332, Cancers (Basel) 2018;10:91)
High constitutive activity of the NFκB pathway is the hallmark of HRS cells, which is essential for HRS survival (Semin Cancer Biol 2016;39:32)
Mutations in members of the JAK-STAT signaling pathway, main mediator of cytokine signaling (Nat Genet 2014;46:329)
Mutations in ITPKB, PI3K-AKT and MAP-ERK pathways (Leukemia 2020;34:151)
Lesions in genes involved in immune evasion of HRS: PDL1, PDL2, B2M, CIITA, CD58 (Blood 2010;116:3268, J Clin Oncol 2016;34:2690)
Mutations in additional genes: ARID1A, TNFRS14, XPO1 (Leukemia 2021;35:968)

Sample pathology report

Lymph node, right neck, excision:
- Mixed cellularity classic Hodgkin lymphoma (see comment)
- Comment: H&E stained sections show a lymph node with architectural effacement by an interfollicular mixed inflammatory infiltrate comprising small lymphocytes, eosinophils, neutrophils, plasma cells, with scattered admixed large atypical lymphoid cells. The neoplastic cells have monolobated / bilobated / multilobated nuclei, vesicular chromatin, prominent nucleoli and amphophilic cytoplasm, consistent with Hodgkin and Reed-Sternberg cells.
- Immunophenotypically, the large atypical cells are positive for PAX5 (weak), CD30 (strong), CD15 and MUM1. These cells are negative for CD20 and CD45.
- T cell markers reveal a rich background composed of small lymphocytes.
- In situ hybridization for EBV encoded RNA (EBER) is positive on the large atypical cells.

Differential diagnosis

EBV+ diffuse large B cell lymphoma, NOS:
- Large cells are usually CD45+, CD20+, CD79a+, PAX5+ (strong), CD30+, CD15- and may show monotypic Ig expression
- EBV is located within both large and small lymphoid cells
- Frequently extranodal
- Geographic necrosis is common
- Adults and elderly patients
EBV+ mucocutaneous ulcer:
- Solitary ulcers in mucocutaneous sites with or without locoregional lymph node involvement
- In immunosuppression settings or in the elderly
- HRS-like cells are CD30+, CD15-
Lymphomatoid granulomatosis:
- Angiocentric and angiodestructive lymphoproliferation, composed of EBV positive B cells, may include HRS-like cells (CD20+, CD30+, CD15-)
- Pulmonary involvement is mandatory for the diagnosis (Blood 2020;135:1344)
T cell / histiocytic rich large B cell lymphoma (THRLBCL):
- Composed of a background rich in small lymphocytes and histiocytes with scattered, large neoplastic B cells
- CD20+, BCL6+, CD30-, CD15-, EBER-
- Eosinophils, plasma cells and neutrophils are uncommon
- These characteristics argue against a diagnosis of CHL (Leukemia 2022;36:1720)
Posttransplant lymphoproliferative disorder, polymorphic type:
- A spectrum of maturation of lymphoid cells, including small lymphocytes, lymphoplasmocytoid cells, plasma cells, immunoblasts and large HRS-like cells
- HRS-like cells are usually CD45+, CD20+, PAX5+ (strong), CD30+, CD15-
- Most EBV positive cases reveal a type III EBV latency pattern
- Classic Hodgkin lymphoma is uncommon in the posttransplant setting
Angioimmunoblastic T cell lymphoma (AITL) and other subtypes of follicular helper T cell lymphoma:
- Proliferation of atypical neoplastic T follicular helper (TFH) cells
- Proliferation of high endothelial venules
- Expansion of the follicular dendritic cell meshwork
- HRS-like cells are usually CD20+, CD30+, CD15- (or sometimes CD15+)
- Rosettes of neoplastic TFH cells around HRS-like cells
- Monoclonal T cell receptor gene rearrangement
Reactive conditions:
- Infectious mononucleosis:
  - Lymph node architecture may be partially effaced and may reveal a mottled appearance
  - Hyperplasic follicles with prominent germinal centers
  - Paracortical expansion with polymorphic lymphoid cells, including immunoblasts, polytypic plasma cells and HRS-like cells (CD30+, CD15-), numerous mitoses and a high proliferative index (Ki67)
  - Monocytoid cells and sinus histiocytosis may be present

Board review style question #1

What is the characteristic immunophenotype of the large, atypical cells shown in the image above?

CD2+, CD30+, CD15-, ALK+
CD20+, PAX5+, CD23+, CD30+
CD45+, OCT2+, CD20+, CD30-
CD45-, PAX5+, CD30+, CD15+
PAX5-, CD4+, CD30+, ALK-

Board review style answer #1

D. CD45-, PAX5+, CD30+, CD15+. This is the characteristic immunophenotype of Hodgkin / Reed-Sternberg cells. The immunophenotype in answer A is diagnostic of ALK positive anaplastic large cell lymphoma. The lymphocyte predominant (LP) cells in nodular lymphocyte Hodgkin lymphoma (WHO) / nodular lymphocyte predominant B cell lymphoma (ICC) typically express the immunophenotype in answer C. The immunophenotype in answer E is not specific. T cells could show this immunophenotype.

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Reference: Mixed cellularity classic Hodgkin lymphoma

Board review style question #2

Which subtype of classic Hodgkin lymphoma is most frequently encountered in patients with HIV / AIDS?

Lymphocyte depleted
Lymphocyte rich
Mixed cellularity
Nodular sclerosis

Board review style answer #2

C. Mixed cellularity. Mixed cellularity classic Hodgkin lymphoma is the most common subtype of CHL associated with immunodeficiency states, including HIV infection / AIDS, immunodeficiency secondary to immunosenescence and immunodeficiency secondary to solid organ transplantation.

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Reference: Mixed cellularity classic Hodgkin lymphoma

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