INTRODUCTION — Hodgkin lymphoma (HL) refers to lymphoid neoplasms in which distinctive malignant lymphoid cells are admixed with a much larger population of non-neoplastic inflammatory cells and/or fibrosis. There are two broad categories of HL that differ in important ways, including the morphology and immunophenotype of the malignant cells, clinical presentation, prognosis, and management:
●Classic HL (cHL)
●Nodular lymphocyte-predominant HL (NLPHL)
Notably, in one of the two current classifications of hematologic malignancies, the International Consensus Classification (ICC) [1], NLPHL has been renamed nodular lymphocyte predominant B cell lymphoma, while the name NLPHL is retained in the 5th edition of the World Health Organization Classification of Hematologic Malignancies [2].
This topic discusses the pathogenesis of cHL.
The pathogenesis of NLPHL is discussed separately. (See "Nodular lymphocyte-predominant Hodgkin lymphoma: Clinical manifestations, diagnosis, and staging", section on 'Pathogenesis'.)
Clinical presentation and diagnosis of cHL and NLPHL are discussed separately. (See "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults" and "Nodular lymphocyte-predominant Hodgkin lymphoma: Clinical manifestations, diagnosis, and staging".)
OVERVIEW OF HODGKIN LYMPHOMA — HL, formerly called Hodgkin's disease, is a hematologic malignancy in which characteristic, large, dysplastic mononuclear and multinucleated cells are surrounded by variable mixtures of mature, non-neoplastic, inflammatory cells and fibrosis [2,3].
There are two major categories of HL according to current classification systems, the International Consensus Classification (ICC) [1] and the 5th edition of the World Health Organization Classification of Hematologic Malignancies (WHO5) [2]:
●Classic HL (cHL) accounts for approximately 90 to 95 percent of cases of HL
●Nodular lymphocyte-predominant HL (NLPHL; called nodular lymphocyte predominant B cell lymphoma in the ICC) accounts for the remainder
These two broad categories of cHL and NLPHL differ in clinical presentation, demographic features, and pathology and are discussed separately. (See "Hodgkin lymphoma: Epidemiology and risk factors" and "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults" and "Nodular lymphocyte-predominant Hodgkin lymphoma: Clinical manifestations, diagnosis, and staging".)
CLASSIC HODGKIN LYMPHOMA — Classic HL (cHL) typically presents with painless peripheral adenopathy in one or two lymph node-bearing areas and may be associated with mediastinal adenopathy, splenic or other abdominal involvement, and/or constitutional symptoms of fever, drenching sweats, or weight loss. There are four categories of cHL:
●Nodular sclerosis (NS cHL)
●Lymphocyte-rich (LR cHL)
●Mixed cellularity (MC cHL)
●Lymphocyte-depleted (LD cHL)
Demographic features, clinical presentation, and prognosis of these categories are discussed separately. (See "Hodgkin lymphoma: Epidemiology and risk factors" and "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults".)
Histology of cHL — In cHL, the lymph node architecture is effaced by an infiltrate of malignant cells admixed with a large and heterogeneous population of nonmalignant inflammatory cells and a variable degree of fibrosis (picture 1). (See "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults", section on 'Pathology'.)
Cellular components of cHL
Hodgkin/Reed-Sternberg cells — The malignant cells of cHL are called Hodgkin/Reed-Sternberg (HRS) cells and they account for only a small fraction of the cellular infiltrate (estimated to be 0.1 to 10 percent) [3].
Microscopy of cHL — The characteristic microscopic appearance of HRS cells is a distinctive binucleate morphology with large inclusion-like nucleoli (picture 2) that resembles owl's eyes; variants of HRS cells in cHL may be mononuclear or multi-nuclear. The bi- or multi-nucleate morphology of HRS cells results from incomplete cytokinesis of mononuclear Hodgkin cells [4,5].
Immunophenotype — Their characteristic immunophenotype (expression of CD30 and CD15, but not CD20) distinguishes HRS cells from normal B lymphocytes and from other types of lymphoma.
HRS cells typically express CD30 and CD15, and lack CD45 [3]. This immunophenotype is distinctive because CD45 (also known as leukocyte common antigen) is expressed by almost all other types of lymphoid cells; CD15 is usually expressed on granulocytes and monocytes, but not on resting B cells; and expression of CD30 is commonly seen only on HRS cells, anaplastic large cell lymphoma, and embryonal carcinoma [6]. Expression of CD30 enables CD30-directed immunotherapy in cHL. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma".)
HRS cells usually express low levels of PAX5 (also known as BSAP), a transcription factor restricted to B cells, whereas expression of CD20 (a marker on most B cells) and BCL6 (a characteristic marker of germinal center [GC] B cells) is seen on HRS cells in only a minority of cases [7]. Immunohistochemical stains for most other B cell markers and T cell antigens are usually negative.
Additional details of the immunophenotype of HRS cells in cHL are provided separately. (See "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults", section on 'Immunophenotype' and "Nodular lymphocyte-predominant Hodgkin lymphoma: Clinical manifestations, diagnosis, and staging", section on 'Immunophenotype'.)
Protein and gene expression — Characteristic patterns of protein and gene expression distinguish HRS cells from normal B lymphocytes and other malignancies.
Despite their derivation from GC B lymphocytes, HRS cells have lost or down-regulated expression of characteristic B cell-specific genes [8-10]. As an example, decreased levels of immunoglobulin (Ig) mRNA and/or frameshift mutations in IGH prevent expression of Ig proteins in many cases of HL [11,12]. Epigenetic silencing of gene promoters also contributes to dysregulated gene expression [13-16].
Transcription factors are implicated in aberrant gene expression by the HRS cells:
●AP1 (Activator protein 1) – The dimeric transcription factor, AP-1, is composed of proteins from the Jun (eg, c-Jun, JunB, JunD) and Fos (eg, c-Fos, FosB, Fra1, Fra2) families. HRS cells typically express high levels of c-Jun and JunB, and AP-1 is constitutively activated [17].
●Regulators of Ig expression – Transcription factors that are required for expression of Ig, including PU.1, Oct-2, and BOB1, are usually decreased or undetectable in HRS cells [18-21]. Although PAX5 is usually present, its low level of expression and/or codependence on transcription factors that are lost in HRS cells impair target gene expression.
●BCL6 – In most cases, the HRS cells of cHL fail to express BCL6, a transcriptional repressor that is characteristic of normal GC B lymphocytes [7].
●Others:
•High levels of activated B cell factor 1 antagonize the function of E2A and PAX5 and may contribute to loss of expression of B cell-specific genes [22,23]. Excessive activation of STAT5A and STAT5B have also been implicated in the downregulation of B cell-specific genes [24].
•Hypoxia-induced upregulation of Id2 and NOTCH1 leads to increased JUN expression and enhanced nuclear factor kappa B (NF-kB) activity, both of which are characteristic of HRS cells [25]. Transient hypoxic conditions in the GC may thereby initiate an epigenetic switch towards an HRS cell-like phenotype and promote survival.
•Downregulation of EBF1 may contribute to the loss of B cell phenotype, based on a report that enforced expression of EBF1 in cHL cell lines can upregulate several B cell markers (eg, CD19, CD79A, CD79B) [26].
Gene expression profiling has identified two major subgroups of HL that differentially express MYC, IRF4, and NOTCH1, but these patterns are not associated with particular histologic subtypes of cHL or Epstein-Barr virus (EBV) status [27].
Cytogenetics and mutations — HRS cells are frequently aneuploid and chromosomal abnormalities and gene mutations contribute to the development of HL [10,28,29]. Gain or loss of specific chromosomal regions and mutations of important regulatory genes promote altered growth and differentiation, enhanced survival, and may be responsible for the atypical nuclear morphology of HRS cells. The basis for genomic instability in HRS cells is uncertain.
●Common cytogenetic abnormalities: The most common cytogenetic findings in cHL are:
•Gain of chromosomes 2p, 9p, 16p, and 17q
•Loss of 13q, 6q, and 11q
●Common gene mutations:
•Genomic gains of REL, JAK2, STAT6, NOTCH1, and JUNB
•Inactivating mutations in NFKB1A, NFKB1E, TNFAIP3, PIM1, Rho/TTF, SOCS1, IKBKB, CD40, BTK, CARD11, BCL10, MAP3K14, MYC, and PAX5
•Mutations in the tumor suppressor genes, CD95 and TP53
•Mutations of major histocompatibility complex (MHC)-associated genes, such as CIITA and beta-2 microglobulin (B2M) (see 'Loss of MHC molecule expression' below)
Gene amplification of chromosome 9p24.1 is one of the most common abnormalities in cHL [30]. Chromosomal gains in this region deregulate at least four genes (JAK2, JMJD2C, PDL1, and PDL2) that contribute to the pathogenesis of HL. JMJD2C encodes a histone demethylase whose downregulation in HL cell lines induces cell death [16].
Contributions of cytogenetic and molecular abnormalities to the pathogenesis of cHL are described below. (See 'Aberrant signaling' below and 'Immune evasion' below.)
Cellular origin of HRS cells — HRS cells are derived from germinal center (GC) B lymphocytes that have transformed during maturation, losing the capacity to express immunoglobulins and transcription factors that define normal B cells. HRS do not correspond to any identified stage of normal B cell development. (See "Normal B and T lymphocyte development", section on 'B cell development'.)
The recognition that HRS cells are derived from GC or post-GC B cells is based on their molecular features. Rearrangement of Ig genes in lymph node GCs and subsequent somatic hypermutation of Ig genes in follicles of secondary lymphoid organs are the most distinctive molecular events in mature B lymphoid cells [31,32]. Detection in microdissected single HRS cells of clonal rearrangements of the Ig heavy chain (IGH) and the high load of somatic mutations demonstrates they originate from GC/post-GC B lymphocytes [9,11,31,33-36].
Rare patients have coexistent cHL and a non-Hodgkin lymphoma (NHL) in whom the HRS and NHL cells share identical IGH VDJ rearrangements and somatic mutations [37-39]. Thus, the initial transforming event occurred in a GC B lymphocyte that was the precursor of both the NHL and HRS cells, followed by acquisition of distinct secondary molecular lesions that accounted for the divergent phenotypes of the two diseases. Rarely, HRS cells have clonal rearrangements of T cell receptor genes, however, even in such cases the tumor cells generally also have clonal Ig rearrangements, indicating that such cases are also derived from GC B lymphocytes [40].
Nonmalignant infiltrate — The cellular infiltrate in cHL consists of a heterogeneous mixture of nonmalignant inflammatory cells, which includes lymphocytes, macrophages, eosinophils, neutrophils, plasma cells, and mast cells. The inflammatory cells are attracted by signals from the malignant HRS cells. In turn, the inflammatory cells support the growth of the malignant cells and induce variable stromal reactions (eg, activation of fibroblasts and collagen deposition). The host immune cells fail to eliminate the malignant cells due to immunosuppressive factors expressed by HRS cells and the presence of immunosuppressive host cells, particularly infiltrating macrophages. (See 'Immune evasion' below.)
PATHOGENESIS OF cHL — The pathogenesis of classic HL (cHL) involves acquired mutations in oncogenes and tumor suppressor genes, aberrant autocrine and paracrine signaling, and escape from immune destruction:
●Mutations - Acquired mutations in oncogenes and tumor suppressor genes lead to enhanced signaling and aberrant activation of the transcription factor NF-kB. (See 'Cytogenetics and mutations' above and 'Cellular origin of HRS cells' above.)
●Autocrine/paracrine signaling – Aberrant autocrine and paracrine signaling by Hodgkin/Reed-Sternberg (HRS) cells that attracts inflammatory cells, which in turn support the proliferation and survival of HRS cells. (See 'Aberrant signaling' below and 'Apoptosis' below.)
●Amplification of genes on chromosome 9 – Gene amplifications associated with chromosome 9p24.1 led to deregulation of at least four genes (JAK2, JMJD2C, PDL1, and PDL2) that are important in the pathogenesis of HL. (See 'Cytogenetics and mutations' above.)
●Protection from immune destruction – Protection of the malignant cells from immune destruction. (See 'Immune evasion' below.)
●Epstein-Barr virus (EBV) – EBV present in a subset of cHL cells and may contribute to HL pathogenesis by augmenting growth and/or inhibiting apoptosis. (See 'Epstein-Barr virus' below.)
Aberrant signaling — Mutations and disordered expression affect key signaling pathways in HRS cells, including nuclear factor kappa B (NF-kB), JAK/STAT, activator protein 1 (AP-1), tumor necrosis factor (TNF), and NOTCH1. These abnormalities, together with the robust inflammatory lymph node milieu and expression of cytokines and chemokines by HRS cells, contribute to the pathophysiology of cHL.
NF-kB — NF-kB refers to a family of multimeric transcription factors that play important roles in normal B cell function and neoplasia. NF-kB is constitutively activated in cHL, which promotes proliferation, reduces apoptosis, and induces expression of cytokines that recruit the immune cells that surround HRS cells.
●NF-kB function in normal lymphoid cells – NF-kB is a key regulator of the immune response to infections, stress, and cytokines. NF-kB is composed of homodimers and heterodimers that translocate from the cytoplasm to the nucleus in response to signals [41]. Most resting B cells do not have NF-kB in the nucleus because I-kappa-B (IkB) or other inhibitory proteins sequester NF-kB in the cytoplasm.
Cellular stimuli lead to phosphorylation, ubiquitination, and degradation of IkB, which permits NF-kB factors to translocate to the nucleus and activate transcription of target genes. Normal mature B cells and HRS cells have two major types of NF-kB heterodimers: NF-kB1/c-REL and NF-kB1/REL-A [42,43].
●NF-kB activation in HRS cells – Activation of NF-kB in HRS cells is mediated by [30,44-53]:
•Inactivating point mutations or deletions of negative regulators (eg, IKB, TNFAIP3, NFKBIA, NFKBIE, TRAF3, CYLD).
•Amplification by copy number gains of positive regulators or various components of the NF-kB pathway (eg, NIK, REL, MAP3K14).
●Expression of NF-kB target genes – Many NF-kB target genes are highly expressed in HRS cells. As an example, NF-kB activates expression of IKBA, which sequesters NF-kB and reduces signaling in normal B cells. However, mutations of IKBA in cHL may interrupt this negative feedback loop [45,54,55]. Other NF-kB target genes expressed in HRS cells include intercellular adhesion molecule (ICAM-1), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-6, and TNF, which contribute to recruitment and/or activation of non-neoplastic leukocytes that form the characteristic background of cHL [56]. (See "Hodgkin lymphoma: Epidemiology and risk factors".)
JAK-STAT — Altered JAK-STAT signaling affects differentiation, proliferation, and survival of B lymphocytes and contributes to the development of cHL.
Janus kinase (JAK) proteins are tyrosine kinases that activate the signal transducer and activator of transcription (STAT) pathway. Most cases of cHL have mutations that are predicted to increase JAK-STAT signaling. Copy number gains of JAK2 are seen in 20 percent of HL, inactivating mutations of the main negative regulators of the STAT pathway (ie, suppressor of cytokine signaling 1 [SOCS1] and protein tyrosine phosphatase N1 [PTPN1]) are common, and a variety of other aberrations involving JAK-STAT signaling pathway components have been described [30,57-63].
NOTCH — The NOTCH signaling pathway regulates normal T cell development and has been implicated in controlling some aspects of B cell maturation. The HRS cells of cHL express NOTCH1, they are surrounded by lymphocytes that express the NOTCH ligand JAGGED1, and HRS cell lines derived from cHL grow at an increased rate when exposed to NOTCH ligands [64,65]. NOTCH1 signals may contribute to aberrant differentiation of HRS cells because NOTCH1 activates T cell programs of gene expression at the expense of B cell programs [66].
Cytokines/chemokines — HRS cells express cytokines, chemokines, and other factors that act via autocrine and paracrine mechanisms. Together with mutations in signaling pathways, these factors contribute to HRS cell growth and survival.
●IL-13 – HRS cells frequently express both IL-13 and its receptor and establish an autocrine signaling loop may contribute to HL tumorigenesis [67-69]. The receptors for both IL-13 and IL-4 have two signaling chains in common and may activate overlapping downstream targets [70]. In normal B cells, IL-13 inhibits NF-kB activity by activating IKBA transcription, but IKBA mutations and/or constitutive degradation of IkB in HRS cells may interrupt this negative regulatory pathway and contribute to unbridled NF-kB activation [45-47,71-73]. IL-13 and IL-4 also activate JAK kinases and stimulate STAT6, a transcription factor that can interact with NF-kB to synergistically activate some target genes [59,74-77]. Expression of E4BP4/NF-IL3, which encodes a transcription factor that prevents apoptosis, may be due to autocrine signaling by IL-13 and IL-4 [67,78-80]. (See 'Aberrant signaling' above.)
●TNF (Tumor necrosis factor) – HRS cells express TNF receptor proteins, including CD30, CD40, CD95, transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), B cell maturation antigen (BCMA), and receptor activator of NF-kB (RANK) [81]. Engagement of these receptors by their ligands activates signaling pathways that augment NF-kB activity [62]. In addition, as described below, EBV expresses latent membrane protein (LMP1), which is a constitutively active member of the TNF receptor (TNFR) superfamily. (See 'Epstein-Barr virus' below.)
●Interferon regulatory factors – HRS cells express abundant interferon regulatory factor 5 (IRF5), which plays a central role in Toll-like receptor (TLR)-mediated immune responses [82]. Constitutive activity of IRF5 may protect HRS cells from cell death and, in combination with NF-kB, IRF5 may contribute to expression of proinflammatory genes, downregulation of genes required for B cell differentiation, and upregulation of their transcriptional antagonists [83]. IRF5 mediates transcriptional activation of AP-1 (which increases CD30 expression) and upregulation of JUN, JUNB, and ATF3 (which may modify NF-kB activity in HRS cells) [17,84,85].
Inflammatory cytokines released from the HRS cells of cHL may also contribute to fever, leukocytosis, anemia of chronic inflammation, elevation of the erythrocyte sedimentation rate, and immune abnormalities (eg, hypergammaglobulinemia, anergy) of HL [86]. (See "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults", section on 'Clinical presentation'.)
Apoptosis — Abnormal regulation of apoptosis enhances survival of HRS cells.
In normal B lymphocytes, the presence of nonfunctional immunoglobulin (Ig) genes leads to loss of anti-apoptosis signals. In cHL, HRS cells survive despite the presence of nonfunctional Ig genes, in part due to excessive NF-kB activation. Nonfunctional Ig genes occur most often in EBV-positive cHL, and EBV-associated activation of NF-kB may rescue HRS cells from apoptosis, as described below. (See 'Epstein-Barr virus' below.)
HRS cells of cHL often demonstrate abnormalities of p53, but they only rarely have mutations in TP53, which encodes p53. Amplification of MDM2, which encodes a protein that promotes p53 degradation, may cause p53 loss-of-function in some cases [87].
Immune evasion
Immune milieu — Despite the abundance of immune cells in the cHL microenvironment that are attracted by signals from HRS cells, the malignant cells have developed mechanisms to survive by escaping immune surveillance.
●Immune effector and regulator cells – HRS cells recruit CD4-positive T cells, macrophages, mast cells, and neutrophils by expression of CCL5, CCL17, CCL22, IL-8, lymphotoxin-alpha, and other cytokines and chemokines [69,88-90]. CCL17 and CCL22 also attract immunosuppressive T regulatory cells, while production of the immunosuppressive cytokine, IL-10, inhibits the function of infiltrating natural killer cells and cytotoxic T cells.
●Eosinophils – The HRS cells recruit eosinophils by expressing IL-5, CCL28, and TNF (which induces tissue fibroblasts to make eotaxin [CCL11]), and other chemoattractants [91-93]. IL-5 also increases marrow production of eosinophils through growth and survival effects on eosinophilic precursors.
●Fibrosis – Tissue fibrosis, which is most characteristic of nodular sclerosis cHL, has been linked to HRS production of transforming growth factor (TGF) beta and basic fibroblast growth factor [94,95].
●Plasma cells – HRS cells elaborate CCL28, which together with galectin-1, IL-13, MDC, and TARC, promote accumulation and growth of T helper type 2 (TH2) cells. TH2 cells, in turn, augment plasma cell development.
●Granuloma formation – Granuloma formation can be seen in tissues involved by cHL and occasionally at distant sites (eg, spleen and liver), even in the absence of direct cHL involvement. Distant granulomata were reported in approximately 15 percent of cHL cases, based on pathologic evaluation of staging splenectomies, liver biopsies, and autopsy studies [96-99]. Granulomata may persist following treatment in the absence of residual disease and are not thought to be clinically significant.
Normal T cell activation — Despite abundant T cells in the cHL tumor milieu, HRS cells are not eliminated because they exist in an immunoprotected niche that prevents T cell activation.
Activation of T cells requires two signals:
●Interaction of the T cell receptor (TCR) with a major histocompatibility complex (MHC)-bound antigen presented on the surface of an antigen presenting cell (APC).
●A costimulatory signal from binding of B7-1 (CD80) or B7-2 (CD86) on the APC to CD28 on the surface of the T cell.
The strength and duration of T cell activation is modulated by co-inhibitory receptors, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). Further details of T cell activation are presented separately. (See "The adaptive cellular immune response: T cells and cytokines", section on 'T cell activation and functions'.)
Mechanisms by which T cells fail to eliminate HRS cells in HL are described below.
Abnormal immune checkpoint activation in cHL — Abnormal activation of the PD-1 immune checkpoint by multiple mechanisms is critical for T cell immunosuppression and immune evasion by HRS cells.
●Immune checkpoint – In the normal immune response, PD-1 signaling helps prevent excessive activation of T cells, thereby limiting tissue damage, maintaining immune tolerance, and suppressing the development of autoimmune diseases and allergic reactions [100-102]. PD-1 regulates signaling from the TCR and costimulatory receptors by down-regulating the immune response after disease elimination. Further details of the immune checkpoint and tumor immunology are presented separately. (See "Principles of cancer immunotherapy", section on 'Tumor immunology'.)
PD-1 is expressed on activated T cells (but not by resting T cells), T regulatory cells (Tregs), T follicular helper cells, natural killer cells, B cells, and macrophages [100,103]. PD-1 has two ligands: PD-L1 and PD-L2. PD-L1 is highly expressed on HRS cells, tumor-infiltrating macrophages, dendritic cells, and certain other malignant cells [100,104]. Binding of ligands to PD-1 cross-links it to the antigen-TCR complex. This leads to recruitment of SHP-2, which dephosphorylates ZAP-70 in T cells and, in turn, attenuates downstream signaling through the phosphatidylinositol 3-kinase (PI3K)/AKT and RAS-MEK-extracellular signal regulated kinase pathways, downregulates TNF alpha and IL-2, and inhibits T cell proliferation [100-102,105,106].
●Abnormal immune checkpoint activation in cHL – Overexpression of PD-L1 and PD-L2 contributes to the creation of an immunoprotected niche that is implicated in the "exhaustion" of PD1+ cytotoxic T cells in cHL and enhanced HRS cell survival.
Nearly all cases of cHL have alterations of the PD-L1 and/or PD-L2 genetic loci [104,107]. Gene amplification or polysomy of chromosome 9p24.1 (the chromosomal locus of PD-L1 and PD-L2) causes a copy number-dependent increase of protein expression [107]. In addition, the chromosome 9p amplicon almost always includes JAK2, which further increases PD-1 ligand expression by HRS cells of cHL via the JAK/STAT signaling pathway [104]. HRS cells also transmit local signals that drive expression of PD-L1 on macrophages, and PD-L1+ macrophages co-localize with PD-L1+ HRS to enhance the immunoprotected niche [108]. The microenvironment of cHL also contains an expanded population of T cells that express lymphocyte-activation gene 3 (LAG3), which binds MHC class II proteins and inhibits T cell activation [109]. Expression of certain proteins in EBV-positive HL may also contribute to increased PD-1 ligand expression. (See 'Epstein-Barr virus' below.)
The functional importance of PD-1 T cell-dependent immunoevasion by HRS cells of cHL is illustrated by the efficacy of anti-PD-1 monoclonal antibodies in relapsed and refractory cHL, as discussed separately. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma", section on 'PD-1 blockade'.)
Loss of MHC molecule expression — Loss of expression of MHC molecules is a common feature of cHL, especially in EBV-negative cases, and may contribute to immune evasion by the HRS cells of cHL [110].
Mutations that contribute to loss of HLA expression by the HRS cells of cHL involve:
●CIITA – Gene rearrangements involving CIITA, which encodes a transactivator that regulates MHC class II expression, are found in approximately 15 percent of cHL cases [111]. CIITA rearrangements create fusion genes encoding abnormal factors that decrease MHC class II expression, while also increasing PD-L1 and PD-L2 expression.
●Beta-2 microglobulin – Beta-2 microglobulin (B2M) forms a heterodimer with MHC class I proteins and is required for their surface expression. In one study, biallelic inactivating mutations of B2M were found in 7 of 10 cases of cHL and caused loss of MHC class I expression [10]. B2M mutations with concordant HLA class I downregulation were also reported in HL cell lines [112].
Epstein-Barr virus — Detection of EBV varies with histologic subtype of HL and patient characteristics. EBV appears to contribute to the pathogenesis of cHL by replacing one or more of the genetic alterations are required for the development of HL.
The prevalence of EBV ranges from approximately 75 percent in mixed cellularity cHL and lymphocyte-depleted cHL to 10 to 25 percent in nodular sclerosing cHL [3]. By contrast, EBV is detected in only approximately 5 percent in nodular lymphocyte-predominant HL (NLPHL). The prevalence of EBV infection also varies according to age, geography, and immune competence, but is >90 percent in all adult populations worldwide. (See "Hodgkin lymphoma: Epidemiology and risk factors", section on 'Epstein-Barr virus'.)
EBV infection of HRS cells is latent (ie, the virus does not replicate) and the viral genome is carried as an episome (a circular configuration that is physically separate from chromosomal DNA). The clonal nature of EBV in HL indicates that viral infection preceded cellular transformation and clonal expansion. The virology of EBV, including genomic structure, gene products, and the nature of EBV infection and transformation are discussed separately. (See "Virology of Epstein-Barr virus".)
The precise mechanisms by which EBV contributes to cHL pathogenesis are uncertain, but EBV gene products may replace one of the genetic alterations that are required for the development of HL [113]. EBV-infected tumor cells express a subset of EBV genes, some of which contribute to aberrant signaling, suppression of apoptosis, and immune evasion by HRS cells:
●Latent membrane protein 1 (LMP1) – LMP1 encodes a transmembrane protein that is essential for EBV-mediated lymphocyte immortalization, and constitutive expression of LMP1 is sufficient to induce B cell lymphomas in transgenic mice [114-116]. LMP1 may contribute to HL by several possible mechanisms:
•Escape from apoptosis – LMP1 may enable HRS cells to escape apoptotic destruction in germinal centers (GC). LMP1 resembles CD40 (tumor necrosis factor receptor) and may function like a constitutively activated CD40 molecule [117,118]. Signaling through CD40 can delay apoptosis of B cells in GCs. LMP1 also leads to increased expression of discoidin domain receptor 1 (DDR1), which is commonly overexpressed in HRS cells. DDR1 is a receptor tyrosine kinase that, upon binding with collagen, increases lymphoma cell survival in vitro [119]. (See 'Apoptosis' above.)
•Activation of NF-kB – In HL tumor cell lines, LMP1 activates NF-kB by promoting IkB turnover; constitutive activation of NF-kB is linked to the growth and survival of HRS cells [120]. (See 'NF-kB' above.)
•PD-L1 expression – LMP1 increases expression of PD-L1, which is important for immune evasion, via AP-1 and JAK/STAT pathways [121]. LMP1 also induces expression on HRS cells of CD137, a potent costimulatory molecule that is normally expressed on activated T cells. Aberrant expression of CD137 supports growth of HRS cells and, like PD-L1, leads to escape from immune surveillance. In an HL tissue microarray, 96 percent of the CD137-positive HL cases stained positive for LMP1, providing an additional link between EBV and cHL pathogenesis [122]. (See 'Immune evasion' above.)
●Latent membrane protein 2a (LMP2a) – LMP2a is an integral membrane protein that co-localizes with LMP1 in the plasma membrane of EBV-infected lymphocytes [123]. LMP2a contains an activation motif that resembles those of Ig molecules. In developing B lymphocytes, a failure to express Ig ordinarily leads to apoptosis, but expression of LMP2a on the cellular membrane produces a constitutive signal that prevents apoptosis of pre-B cells that do not express Ig [12,123-127]. The large majority of cases of HL that carry inactivating Ig mutations are EBV positive, suggesting that EBV infection in HRS cells in the GC microenvironment may protect these cells from apoptosis [12].
EBV infection is estimated to have occurred in 90 to 95 percent of adults, yet only a small fraction of infected individuals develops EBV-positive HL. The triggers for HL tumorigenesis in B lymphocytes are poorly defined, but certain environmental factors (eg, age at infection) and genetic factors (eg, certain variations of MHC loci) are associated with higher risk of progressing to EBV-positive cHL, as described separately. (See "Hodgkin lymphoma: Epidemiology and risk factors", section on 'Risk factors'.)
NODULAR LYMPHOCYTE-PREDOMINANT HL — Nodular lymphocyte-predominant HL (NLPHL) accounts for <10 percent of HL.
The International Consensus Classification (ICC) refers to NLPHL as nodular lymphocyte predominant B-cell lymphoma [1], based on major biological and clinical differences between NLPHL and cHL (eg, retention of functional B cell program in NLPHL and the close relationship of NLPHL with T-cell/histiocyte-rich large B-cell lymphoma) [128]. The 5th edition of the World Health Organization Classification of Hematologic Malignancies retained the name NLPHL [2]:
NLPHL is characterized by scattered neoplastic cells, known as lymphocyte predominant (LP; formerly called lymphocytic and histiocytic variants [L&H cells]), surrounded by an infiltrate of small lymphocytes and other nonmalignant cells. The clinical presentation, pathology, prognosis, diagnosis, and treatment of NLPHL differ significantly from classic HL (cHL), as discussed separately. (See "Nodular lymphocyte-predominant Hodgkin lymphoma: Clinical manifestations, diagnosis, and staging" and "Treatment of nodular lymphocyte-predominant Hodgkin lymphoma".)
Microscopy — Lymph nodes in NLPHL are partially or totally effaced by an infiltrate of small lymphocytes, histiocytes, epithelioid histiocytes, with intermingled LP cells. NLPHL usually assumes a nodular pattern, but nodular and diffuse or predominantly diffuse patterns are also seen [129]. Unusual cases, which are usually associated with loss of nodularity and increased infiltration by T cells, may have a more aggressive clinical course and can be challenging to distinguish from T-cell/histiocyte rich large B cell lymphoma (THRLBCL).
The nonmalignant infiltrative component of NLPHL comprises small B lymphocytes, follicular dendritic cells, and follicular CD57+/PD-1+ T lymphocytes, which often form rosettes around the LP cells; the cellular background of NLPHL is less heterogeneous than the polymorphous infiltrate in cHL. (See "Nodular lymphocyte-predominant Hodgkin lymphoma: Clinical manifestations, diagnosis, and staging", section on 'Morphology'.)
LP cells — The presence of malignant LP cells is required for the diagnosis of NLPHL. LP cells are also called "popcorn cells" because of their distinctive morphology.
Although both LP cells and Hodgkin/Reed-Sternberg cells (HRS; the malignant counterparts in cHL) are both derived from germinal center (GC) B cells, they differ morphologically, genetically, and phenotypically. (See 'Hodgkin/Reed-Sternberg cells' above.)
●Morphology – LP cells have a characteristic irregular, polypoid nuclear morphology (picture 3) that accounts for the description as popcorn cells. LP cells are readily distinguished from the characteristic binucleate appearance of HRS cells (picture 2).
●Immunophenotype – LP cells consistently express CD20 and CD45 but do not express CD30 or CD15 [130]. By contrast, expression of CD30 is a hallmark of HRS cells, which also express CD15, infrequently express CD20, and do not express CD45.
●Protein and gene expression – LP cells generally express B lineage proteins, including CD20, BCL6, and PAX5, but are usually negative for CD10 (a characteristic marker of normal GC B cells) [131,132]. The presence of functionally rearranged immunoglobulin genes (IGHV) with a high load of somatic mutations is consistent with the GC B cell origin of LP cells [33,131,133-135].
LP cells exhibit activation of nuclear factor kappa B (NF-kB) and increased expression of cytokines, as compared to normal GC B cells [136]. Patterns of gene expression in NLPHL resemble those of cHL and T cell/histiocyte-rich large B cell lymphomas (THRLBCL) (see 'Relationship to THRLBCL' below) [136,137].
●Cytogenetics and mutations – BCL6 rearrangements are found in approximately half of NLPHL cases, which contrasts with the lower prevalence in HRS cells [138,139]. Approximately 80 percent of cases have somatic mutations of PAX5, MYC, and other genes [35]. Genome sequencing identified recurrent mutations in the kinase SGK1, the phosphatase DUSP2, and the transcription factor JUNB [140], which are also frequently mutated in THRLBCL [141].
●Epstein-Barr virus (EBV) – EBV is detected in a small minority of cases of NLPHL (approximately 5 percent) [142].
Pathogenesis of NLPHL — Both NLPHL and cHL share features of aberrant signaling and immune evasion, but the pathogenic mechanisms of NLPHL are less well-defined. LP cells do not express PD-1 ligands, so the mechanism of immune evasion by NLPHL in the face of abundant effector cells is uncertain.
Microdissected LP cells of NLPHL exhibit constitutive nuclear factor kappa B (NF-kB) activity, aberrant extracellular signal-regulated kinase (ERK) signaling, an anti-apoptotic phenotype, and partial loss of the B cell phenotype [136]. Gene expression by LP cells resembles that of cHL and THRLBCL and is consistent with the origin of LP cells arising from GC B cells at the transition to memory B cells.
Pathogenic mechanisms that contribute to HL are discussed separately. (See 'Pathogenesis of cHL' above.)
Relationship to THRLBCL — T cell/histiocyte-rich large B cell lymphoma (THRLBCL) is an aggressive B cell lymphoma [3]. NLPHL and THRLBCL share biologic and clinical features, and NLPHL can undergo THRLBCL-like transformation. It has been speculated that THRLBCL may represent a diffuse variant or an extension of NLPHL.
NLPHL (especially cases with a diffuse growth pattern) can resemble the microscopic appearance of THRLBCL, and NLPHL can undergo THRLBCL-like transformation that is indistinguishable from primary THRLBCL [143-145].
NLPHL and THRLBCL also share molecular and immunophenotypic features; they appear to differ primarily in the cellular composition of the tumor microenvironment. Tumor cells of NLPHL and THRLBCL have similar patterns of gene expression, mutation profiles, and deregulation of apoptosis-associated genes and both exhibit partial loss of the B cell phenotype [136,137,146]. In contrast with the B cell-rich nodules associated with follicular dendritic cell meshworks and rosetting T cells of NLPHL, the THRLBCL cellular milieu has a high content of non-rosetting T cells, macrophages, and dendritic cells [147].
SUMMARY
●Description – Hodgkin lymphoma (HL) is characterized by relatively small numbers of malignant cells admixed with an abundant infiltrate of immune effector and inflammatory cells. The broad category of HL includes (see 'Overview of Hodgkin lymphoma' above):
•Classic HL (cHL), which accounts for >90 of HL
•Nodular lymphocyte-predominant HL (NLPHL)
●Classic Hodgkin lymphoma (cHL) – In cHL, the lymph node architecture is effaced by an infiltrate of scarce malignant cells admixed with an abundance of nonmalignant inflammatory and immune effector cells and a variable degree of fibrosis (picture 1).
Hodgkin/Reed-Sternberg (HRS) cells are the malignant cells of cHL and are typically binucleate (picture 2). HRS cells are derived from germinal center (GC) B cells, but they have lost the characteristic immunophenotype and gene expression of normal B cells. HRS cells have constitutively activated nuclear factor kappa B (NF-kB), increased extracellular signal-regulated kinase (ERK) signaling, and immune checkpoint abnormalities.
●Pathogenesis of cHL – Mechanisms that contribute to the pathogenesis of cHL include:
•Mutations - Mutations that transform B lymphocytes as they are undergoing maturation. (See 'Cytogenetics and mutations' above and 'Cellular origin of HRS cells' above.)
•Aberrant signaling - Aberrant autocrine and paracrine signaling by HRS cells (eg, NF-kB, JAK-STAT) that attracts inflammatory cells, which in turn support the proliferation and survival of HRS cells. (See 'Aberrant signaling' above and 'Apoptosis' above.)
•Gene amplification - Amplification of genes associated with chromosome 9p24.1 led to deregulation of at least four genes (JAK2, JMJD2C, PDL1, and PDL2) that are important in the pathogenesis of HL. (See 'Cytogenetics and mutations' above.)
•Immune escape - Protection of the malignant cells from immune destruction. (See 'Immune evasion' above.)
•Epstein-Barr virus (EBV) EBV is detected in a subset of cHL cells and it contributes to pathogenesis by augmenting growth and/or inhibiting apoptosis. (See 'Epstein-Barr virus' above.)
●Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) – NLPHL, which accounts for 5 to 10 percent of HL, differs from cHL by demographics, clinical presentation, immunophenotype, natural history, and management. This subtype is called nodular lymphocyte predominant B-cell lymphoma by the International Consensus Classification (ICC), whereas the term NLPHL is retained in the WHO 5th edition classification. (See 'Nodular lymphocyte-predominant HL' above.)
•Microscopy - NLPHL is characterized by scattered neoplastic cells, known as lymphocyte predominant (LP) cells (also called popcorn cells or L&H cells) that are surrounded by a nodular infiltrate of small lymphocytes and other nonmalignant cells. (See 'Microscopy' above.)
•LP cells - Although both LP cells and HRS cells are derived from GC B cells, they differ morphologically, genetically, and phenotypically. (See 'LP cells' above.)
•Pathogenesis - NLPHL shares with cHL features of aberrant signaling (eg, NF-kB), an antiapoptotic phenotype, and partial loss of the B cell phenotype, but the pathogenesis of NLPHL is less well-defined. (See 'Pathogenesis of NLPHL' above.)
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