ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Pathogenesis of Hodgkin lymphoma

Pathogenesis of Hodgkin lymphoma
Literature review current through: Jan 2024.
This topic last updated: Mar 21, 2023.

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 mutationsBCL6 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.)

  1. Campo E, Jaffe ES, Cook JR, et al. The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee. Blood 2022; 140:1229.
  2. Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia 2022; 36:1720.
  3. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised 4th edition, Swerdlow SH, Campo E, Harris NL, et al. (Eds), International Agency for Research on Cancer (IARC), Lyon 2017.
  4. Rengstl B, Newrzela S, Heinrich T, et al. Incomplete cytokinesis and re-fusion of small mononucleated Hodgkin cells lead to giant multinucleated Reed-Sternberg cells. Proc Natl Acad Sci U S A 2013; 110:20729.
  5. Xavier de Carvalho A, Maiato H, Maia AF, et al. Reed-Sternberg cells form by abscission failure in the presence of functional Aurora B kinase. PLoS One 2015; 10:e0124629.
  6. Tzankov A, Zimpfer A, Pehrs AC, et al. Expression of B-cell markers in classical hodgkin lymphoma: a tissue microarray analysis of 330 cases. Mod Pathol 2003; 16:1141.
  7. Falini B, Bigerna B, Pasqualucci L, et al. Distinctive expression pattern of the BCL-6 protein in nodular lymphocyte predominance Hodgkin's disease. Blood 1996; 87:465.
  8. Schwering I, Bräuninger A, Klein U, et al. Loss of the B-lineage-specific gene expression program in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma. Blood 2003; 101:1505.
  9. Marafioti T, Hummel M, Foss HD, et al. Hodgkin and reed-sternberg cells represent an expansion of a single clone originating from a germinal center B-cell with functional immunoglobulin gene rearrangements but defective immunoglobulin transcription. Blood 2000; 95:1443.
  10. Reichel J, Chadburn A, Rubinstein PG, et al. Flow sorting and exome sequencing reveal the oncogenome of primary Hodgkin and Reed-Sternberg cells. Blood 2015; 125:1061.
  11. Kanzler H, Küppers R, Hansmann ML, Rajewsky K. Hodgkin and Reed-Sternberg cells in Hodgkin's disease represent the outgrowth of a dominant tumor clone derived from (crippled) germinal center B cells. J Exp Med 1996; 184:1495.
  12. Bräuninger A, Schmitz R, Bechtel D, et al. Molecular biology of Hodgkin's and Reed/Sternberg cells in Hodgkin's lymphoma. Int J Cancer 2006; 118:1853.
  13. Ushmorov A, Leithäuser F, Sakk O, et al. Epigenetic processes play a major role in B-cell-specific gene silencing in classical Hodgkin lymphoma. Blood 2006; 107:2493.
  14. Ushmorov A, Ritz O, Hummel M, et al. Epigenetic silencing of the immunoglobulin heavy-chain gene in classical Hodgkin lymphoma-derived cell lines contributes to the loss of immunoglobulin expression. Blood 2004; 104:3326.
  15. Doerr JR, Malone CS, Fike FM, et al. Patterned CpG methylation of silenced B cell gene promoters in classical Hodgkin lymphoma-derived and primary effusion lymphoma cell lines. J Mol Biol 2005; 350:631.
  16. Rui L, Emre NC, Kruhlak MJ, et al. Cooperative epigenetic modulation by cancer amplicon genes. Cancer Cell 2010; 18:590.
  17. Mathas S, Hinz M, Anagnostopoulos I, et al. Aberrantly expressed c-Jun and JunB are a hallmark of Hodgkin lymphoma cells, stimulate proliferation and synergize with NF-kappa B. EMBO J 2002; 21:4104.
  18. Stein H, Marafioti T, Foss HD, et al. Down-regulation of BOB.1/OBF.1 and Oct2 in classical Hodgkin disease but not in lymphocyte predominant Hodgkin disease correlates with immunoglobulin transcription. Blood 2001; 97:496.
  19. Theil J, Laumen H, Marafioti T, et al. Defective octamer-dependent transcription is responsible for silenced immunoglobulin transcription in Reed-Sternberg cells. Blood 2001; 97:3191.
  20. Jundt F, Kley K, Anagnostopoulos I, et al. Loss of PU.1 expression is associated with defective immunoglobulin transcription in Hodgkin and Reed-Sternberg cells of classical Hodgkin disease. Blood 2002; 99:3060.
  21. Schmitz R, Stanelle J, Hansmann ML, Küppers R. Pathogenesis of classical and lymphocyte-predominant Hodgkin lymphoma. Annu Rev Pathol 2009; 4:151.
  22. Mathas S, Janz M, Hummel F, et al. Intrinsic inhibition of transcription factor E2A by HLH proteins ABF-1 and Id2 mediates reprogramming of neoplastic B cells in Hodgkin lymphoma. Nat Immunol 2006; 7:207.
  23. Renné C, Martin-Subero JI, Eickernjäger M, et al. Aberrant expression of ID2, a suppressor of B-cell-specific gene expression, in Hodgkin's lymphoma. Am J Pathol 2006; 169:655.
  24. Scheeren FA, Diehl SA, Smit LA, et al. IL-21 is expressed in Hodgkin lymphoma and activates STAT5: evidence that activated STAT5 is required for Hodgkin lymphomagenesis. Blood 2008; 111:4706.
  25. Wein F, Otto T, Lambertz P, et al. Potential role of hypoxia in early stages of Hodgkin lymphoma pathogenesis. Haematologica 2015; 100:1320.
  26. Bohle V, Döring C, Hansmann ML, Küppers R. Role of early B-cell factor 1 (EBF1) in Hodgkin lymphoma. Leukemia 2013; 27:671.
  27. Tiacci E, Döring C, Brune V, et al. Analyzing primary Hodgkin and Reed-Sternberg cells to capture the molecular and cellular pathogenesis of classical Hodgkin lymphoma. Blood 2012; 120:4609.
  28. Weber-Matthiesen K, Deerberg J, Poetsch M, et al. Numerical chromosome aberrations are present within the CD30+ Hodgkin and Reed-Sternberg cells in 100% of analyzed cases of Hodgkin's disease. Blood 1995; 86:1464.
  29. Deerberg-Wittram J, Weber-Matthiesen K, Schlegelberger B. Cytogenetics and molecular cytogenetics in Hodgkin's disease. Ann Oncol 1996; 7 Suppl 4:49.
  30. Steidl C, Telenius A, Shah SP, et al. Genome-wide copy number analysis of Hodgkin Reed-Sternberg cells identifies recurrent imbalances with correlations to treatment outcome. Blood 2010; 116:418.
  31. Küppers R, Schwering I, Bräuninger A, et al. Biology of Hodgkin's lymphoma. Ann Oncol 2002; 13 Suppl 1:11.
  32. Jacob J, Kelsoe G, Rajewsky K, Weiss U. Intraclonal generation of antibody mutants in germinal centres. Nature 1991; 354:389.
  33. Marafioti T, Hummel M, Anagnostopoulos I, et al. Origin of nodular lymphocyte-predominant Hodgkin's disease from a clonal expansion of highly mutated germinal-center B cells. N Engl J Med 1997; 337:453.
  34. Bräuninger A, Wacker HH, Rajewsky K, et al. Typing the histogenetic origin of the tumor cells of lymphocyte-rich classical Hodgkin's lymphoma in relation to tumor cells of classical and lymphocyte-predominance Hodgkin's lymphoma. Cancer Res 2003; 63:1644.
  35. Liso A, Capello D, Marafioti T, et al. Aberrant somatic hypermutation in tumor cells of nodular-lymphocyte-predominant and classic Hodgkin lymphoma. Blood 2006; 108:1013.
  36. Thomas RK, Re D, Wolf J, Diehl V. Part I: Hodgkin's lymphoma--molecular biology of Hodgkin and Reed-Sternberg cells. Lancet Oncol 2004; 5:11.
  37. Marafioti T, Hummel M, Anagnostopoulos I, et al. Classical Hodgkin's disease and follicular lymphoma originating from the same germinal center B cell. J Clin Oncol 1999; 17:3804.
  38. Bräuninger A, Hansmann ML, Strickler JG, et al. Identification of common germinal-center B-cell precursors in two patients with both Hodgkin's disease and non-Hodgkin's lymphoma. N Engl J Med 1999; 340:1239.
  39. Ohno T, Smir BN, Weisenburger DD, et al. Origin of the Hodgkin/Reed-Sternberg cells in chronic lymphocytic leukemia with "Hodgkin's transformation". Blood 1998; 91:1757.
  40. Seitz V, Hummel M, Marafioti T, et al. Detection of clonal T-cell receptor gamma-chain gene rearrangements in Reed-Sternberg cells of classic Hodgkin disease. Blood 2000; 95:3020.
  41. Ghosh S, May MJ, Kopp EB. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 1998; 16:225.
  42. Liou HC, Sha WC, Scott ML, Baltimore D. Sequential induction of NF-kappa B/Rel family proteins during B-cell terminal differentiation. Mol Cell Biol 1994; 14:5349.
  43. Miyamoto S, Schmitt MJ, Verma IM. Qualitative changes in the subunit composition of kappa B-binding complexes during murine B-cell differentiation. Proc Natl Acad Sci U S A 1994; 91:5056.
  44. Joos S, Menz CK, Wrobel G, et al. Classical Hodgkin lymphoma is characterized by recurrent copy number gains of the short arm of chromosome 2. Blood 2002; 99:1381.
  45. Emmerich F, Meiser M, Hummel M, et al. Overexpression of I kappa B alpha without inhibition of NF-kappaB activity and mutations in the I kappa B alpha gene in Reed-Sternberg cells. Blood 1999; 94:3129.
  46. Cabannes E, Khan G, Aillet F, et al. Mutations in the IkBa gene in Hodgkin's disease suggest a tumour suppressor role for IkappaBalpha. Oncogene 1999; 18:3063.
  47. Jungnickel B, Staratschek-Jox A, Bräuninger A, et al. Clonal deleterious mutations in the IkappaBalpha gene in the malignant cells in Hodgkin's lymphoma. J Exp Med 2000; 191:395.
  48. Martín-Subero JI, Gesk S, Harder L, et al. Recurrent involvement of the REL and BCL11A loci in classical Hodgkin lymphoma. Blood 2002; 99:1474.
  49. Mathas S, Hartmann S, Küppers R. Hodgkin lymphoma: Pathology and biology. Semin Hematol 2016; 53:139.
  50. Emmerich F, Theurich S, Hummel M, et al. Inactivating I kappa B epsilon mutations in Hodgkin/Reed-Sternberg cells. J Pathol 2003; 201:413.
  51. Schmitz R, Hansmann ML, Bohle V, et al. TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma. J Exp Med 2009; 206:981.
  52. Kato M, Sanada M, Kato I, et al. Frequent inactivation of A20 in B-cell lymphomas. Nature 2009; 459:712.
  53. Weniger MA, Küppers R. NF-κB deregulation in Hodgkin lymphoma. Semin Cancer Biol 2016; 39:32.
  54. Sun SC, Ganchi PA, Ballard DW, Greene WC. NF-kappa B controls expression of inhibitor I kappa B alpha: evidence for an inducible autoregulatory pathway. Science 1993; 259:1912.
  55. Scott ML, Fujita T, Liou HC, et al. The p65 subunit of NF-kappa B regulates I kappa B by two distinct mechanisms. Genes Dev 1993; 7:1266.
  56. Buri C, Körner M, Schärli P, et al. CC chemokines and the receptors CCR3 and CCR5 are differentially expressed in the nonneoplastic leukocytic infiltrates of Hodgkin disease. Blood 2001; 97:1543.
  57. Küppers R, Engert A, Hansmann ML. Hodgkin lymphoma. J Clin Invest 2012; 122:3439.
  58. Zahn M, Marienfeld R, Melzner I, et al. A novel PTPN1 splice variant upregulates JAK/STAT activity in classical Hodgkin lymphoma cells. Blood 2017; 129:1480.
  59. Skinnider BF, Elia AJ, Gascoyne RD, et al. Signal transducer and activator of transcription 6 is frequently activated in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma. Blood 2002; 99:618.
  60. Hinz M, Lemke P, Anagnostopoulos I, et al. Nuclear factor kappaB-dependent gene expression profiling of Hodgkin's disease tumor cells, pathogenetic significance, and link to constitutive signal transducer and activator of transcription 5a activity. J Exp Med 2002; 196:605.
  61. Joos S, Küpper M, Ohl S, et al. Genomic imbalances including amplification of the tyrosine kinase gene JAK2 in CD30+ Hodgkin cells. Cancer Res 2000; 60:549.
  62. Weniger MA, Melzner I, Menz CK, et al. Mutations of the tumor suppressor gene SOCS-1 in classical Hodgkin lymphoma are frequent and associated with nuclear phospho-STAT5 accumulation. Oncogene 2006; 25:2679.
  63. Gunawardana J, Chan FC, Telenius A, et al. Recurrent somatic mutations of PTPN1 in primary mediastinal B cell lymphoma and Hodgkin lymphoma. Nat Genet 2014; 46:329.
  64. Jundt F, Anagnostopoulos I, Förster R, et al. Activated Notch1 signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma. Blood 2002; 99:3398.
  65. Schwarzer R, Dörken B, Jundt F. Notch is an essential upstream regulator of NF-κB and is relevant for survival of Hodgkin and Reed-Sternberg cells. Leukemia 2012; 26:806.
  66. Pui JC, Allman D, Xu L, et al. Notch1 expression in early lymphopoiesis influences B versus T lineage determination. Immunity 1999; 11:299.
  67. Kapp U, Yeh WC, Patterson B, et al. Interleukin 13 is secreted by and stimulates the growth of Hodgkin and Reed-Sternberg cells. J Exp Med 1999; 189:1939.
  68. Skinnider BF, Elia AJ, Gascoyne RD, et al. Interleukin 13 and interleukin 13 receptor are frequently expressed by Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma. Blood 2001; 97:250.
  69. Skinnider BF, Mak TW. The role of cytokines in classical Hodgkin lymphoma. Blood 2002; 99:4283.
  70. Chomarat P, Banchereau J. Interleukin-4 and interleukin-13: their similarities and discrepancies. Int Rev Immunol 1998; 17:1.
  71. Manna SK, Aggarwal BB. IL-13 suppresses TNF-induced activation of nuclear factor-kappa B, activation protein-1, and apoptosis. J Immunol 1998; 161:2863.
  72. Lentsch AB, Shanley TP, Sarma V, Ward PA. In vivo suppression of NF-kappa B and preservation of I kappa B alpha by interleukin-10 and interleukin-13. J Clin Invest 1997; 100:2443.
  73. Krappmann D, Emmerich F, Kordes U, et al. Molecular mechanisms of constitutive NF-kappaB/Rel activation in Hodgkin/Reed-Sternberg cells. Oncogene 1999; 18:943.
  74. Takeda K, Kamanaka M, Tanaka T, et al. Impaired IL-13-mediated functions of macrophages in STAT6-deficient mice. J Immunol 1996; 157:3220.
  75. Iciek LA, Delphin SA, Stavnezer J. CD40 cross-linking induces Ig epsilon germline transcripts in B cells via activation of NF-kappaB: synergy with IL-4 induction. J Immunol 1997; 158:4769.
  76. Shen CH, Stavnezer J. Interaction of stat6 and NF-kappaB: direct association and synergistic activation of interleukin-4-induced transcription. Mol Cell Biol 1998; 18:3395.
  77. Messner B, Stütz AM, Albrecht B, et al. Cooperation of binding sites for STAT6 and NF kappa B/rel in the IL-4-induced up-regulation of the human IgE germline promoter. J Immunol 1997; 159:3330.
  78. Ikushima S, Inukai T, Inaba T, et al. Pivotal role for the NFIL3/E4BP4 transcription factor in interleukin 3-mediated survival of pro-B lymphocytes. Proc Natl Acad Sci U S A 1997; 94:2609.
  79. Alizadeh A, Eisen M, Botstein D, et al. Probing lymphocyte biology by genomic-scale gene expression analysis. J Clin Immunol 1998; 18:373.
  80. Chu CC, Paul WE. Expressed genes in interleukin-4 treated B cells identified by cDNA representational difference analysis. Mol Immunol 1998; 35:487.
  81. Liu WR, Shipp MA. Signaling pathways and immune evasion mechanisms in classical Hodgkin lymphoma. Blood 2017; 130:2265.
  82. Tamura T, Yanai H, Savitsky D, Taniguchi T. The IRF family transcription factors in immunity and oncogenesis. Annu Rev Immunol 2008; 26:535.
  83. Kreher S, Bouhlel MA, Cauchy P, et al. Mapping of transcription factor motifs in active chromatin identifies IRF5 as key regulator in classical Hodgkin lymphoma. Proc Natl Acad Sci U S A 2014; 111:E4513.
  84. Janz M, Hummel M, Truss M, et al. Classical Hodgkin lymphoma is characterized by high constitutive expression of activating transcription factor 3 (ATF3), which promotes viability of Hodgkin/Reed-Sternberg cells. Blood 2006; 107:2536.
  85. Watanabe M, Ogawa Y, Itoh K, et al. Hypomethylation of CD30 CpG islands with aberrant JunB expression drives CD30 induction in Hodgkin lymphoma and anaplastic large cell lymphoma. Lab Invest 2008; 88:48.
  86. Gause A, Keymis S, Scholz R, et al. Increased levels of circulating cytokines in patients with untreated Hodgkin's disease. Lymphokine Cytokine Res 1992; 11:109.
  87. Küpper M, Joos S, von Bonin F, et al. MDM2 gene amplification and lack of p53 point mutations in Hodgkin and Reed-Sternberg cells: results from single-cell polymerase chain reaction and molecular cytogenetic studies. Br J Haematol 2001; 112:768.
  88. Aldinucci D, Lorenzon D, Cattaruzza L, et al. Expression of CCR5 receptors on Reed-Sternberg cells and Hodgkin lymphoma cell lines: involvement of CCL5/Rantes in tumor cell growth and microenvironmental interactions. Int J Cancer 2008; 122:769.
  89. Fhu CW, Graham AM, Yap CT, et al. Reed-Sternberg cell-derived lymphotoxin-α activates endothelial cells to enhance T-cell recruitment in classical Hodgkin lymphoma. Blood 2014; 124:2973.
  90. Weniger MA, Küppers R. Molecular biology of Hodgkin lymphoma. Leukemia 2021; 35:968.
  91. Samoszuk M, Nansen L. Detection of interleukin-5 messenger RNA in Reed-Sternberg cells of Hodgkin's disease with eosinophilia. Blood 1990; 75:13.
  92. Hanamoto H, Nakayama T, Miyazato H, et al. Expression of CCL28 by Reed-Sternberg cells defines a major subtype of classical Hodgkin's disease with frequent infiltration of eosinophils and/or plasma cells. Am J Pathol 2004; 164:997.
  93. Jundt F, Anagnostopoulos I, Bommert K, et al. Hodgkin/Reed-Sternberg cells induce fibroblasts to secrete eotaxin, a potent chemoattractant for T cells and eosinophils. Blood 1999; 94:2065.
  94. Kadin ME, Agnarsson BA, Ellingsworth LR, Newcom SR. Immunohistochemical evidence of a role for transforming growth factor beta in the pathogenesis of nodular sclerosing Hodgkin's disease. Am J Pathol 1990; 136:1209.
  95. Hsu SM, Lin J, Xie SS, et al. Abundant expression of transforming growth factor-beta 1 and -beta 2 by Hodgkin's Reed-Sternberg cells and by reactive T lymphocytes in Hodgkin's disease. Hum Pathol 1993; 24:249.
  96. Abrams J, Pearl P, Moody M, Schimpff SC. Epithelioid granulomas revisited: long-term follow-up in Hodgkin's disease. Am J Clin Oncol 1988; 11:456.
  97. O'Connell MJ, Schimpff SC, Kirschner RH, et al. Epithelioid granulomas in Hodgkin disease. A favorable prognostic sign? JAMA 1975; 233:886.
  98. Kadin ME, Donaldson SS, Dorfman RF. Isolated granulomas in Hodgkin's disease. N Engl J Med 1970; 283:859.
  99. Al-Maghrabi JA, Sawan AS, Kanaan HD. Hodgkin's lymphoma with exuberant granulomatous reaction. Saudi Med J 2006; 27:1905.
  100. Baumeister SH, Freeman GJ, Dranoff G, Sharpe AH. Coinhibitory Pathways in Immunotherapy for Cancer. Annu Rev Immunol 2016; 34:539.
  101. Boussiotis VA. Molecular and Biochemical Aspects of the PD-1 Checkpoint Pathway. N Engl J Med 2016; 375:1767.
  102. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008; 26:677.
  103. Gordon SR, Maute RL, Dulken BW, et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature 2017; 545:495.
  104. Green MR, Monti S, Rodig SJ, et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood 2010; 116:3268.
  105. Chemnitz JM, Parry RV, Nichols KE, et al. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol 2004; 173:945.
  106. Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, et al. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med 2012; 209:1201.
  107. Roemer MG, Advani RH, Ligon AH, et al. PD-L1 and PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict Outcome. J Clin Oncol 2016; 34:2690.
  108. Carey CD, Gusenleitner D, Lipschitz M, et al. Topological analysis reveals a PD-L1-associated microenvironmental niche for Reed-Sternberg cells in Hodgkin lymphoma. Blood 2017; 130:2420.
  109. Aoki T, Chong LC, Takata K, et al. Single-Cell Transcriptome Analysis Reveals Disease-Defining T-cell Subsets in the Tumor Microenvironment of Classic Hodgkin Lymphoma. Cancer Discov 2020; 10:406.
  110. Diepstra A, Poppema S, Boot M, et al. HLA-G protein expression as a potential immune escape mechanism in classical Hodgkin's lymphoma. Tissue Antigens 2008; 71:219.
  111. Steidl C, Shah SP, Woolcock BW, et al. MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature 2011; 471:377.
  112. Liu Y, Abdul Razak FR, Terpstra M, et al. The mutational landscape of Hodgkin lymphoma cell lines determined by whole-exome sequencing. Leukemia 2014; 28:2248.
  113. Renné C, Hinsch N, Willenbrock K, et al. The aberrant coexpression of several receptor tyrosine kinases is largely restricted to EBV-negative cases of classical Hodgkin's lymphoma. Int J Cancer 2007; 120:2504.
  114. Kilger E, Kieser A, Baumann M, Hammerschmidt W. Epstein-Barr virus-mediated B-cell proliferation is dependent upon latent membrane protein 1, which simulates an activated CD40 receptor. EMBO J 1998; 17:1700.
  115. Yates JL, Warren N, Sugden B. Stable replication of plasmids derived from Epstein-Barr virus in various mammalian cells. Nature 1985; 313:812.
  116. Kulwichit W, Edwards RH, Davenport EM, et al. Expression of the Epstein-Barr virus latent membrane protein 1 induces B cell lymphoma in transgenic mice. Proc Natl Acad Sci U S A 1998; 95:11963.
  117. MacLennan IC. Germinal centers. Annu Rev Immunol 1994; 12:117.
  118. Jarrett RF, MacKenzie J. Epstein-Barr virus and other candidate viruses in the pathogenesis of Hodgkin's disease. Semin Hematol 1999; 36:260.
  119. Cader FZ, Vockerodt M, Bose S, et al. The EBV oncogene LMP1 protects lymphoma cells from cell death through the collagen-mediated activation of DDR1. Blood 2013; 122:4237.
  120. Sylla BS, Hung SC, Davidson DM, et al. Epstein-Barr virus-transforming protein latent infection membrane protein 1 activates transcription factor NF-kappaB through a pathway that includes the NF-kappaB-inducing kinase and the IkappaB kinases IKKalpha and IKKbeta. Proc Natl Acad Sci U S A 1998; 95:10106.
  121. Green MR, Rodig S, Juszczynski P, et al. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clin Cancer Res 2012; 18:1611.
  122. Aravinth SP, Rajendran S, Li Y, et al. Epstein-Barr virus-encoded LMP1 induces ectopic CD137 expression on Hodgkin and Reed-Sternberg cells via the PI3K-AKT-mTOR pathway. Leuk Lymphoma 2019; 60:2697.
  123. Mancao C, Hammerschmidt W. Epstein-Barr virus latent membrane protein 2A is a B-cell receptor mimic and essential for B-cell survival. Blood 2007; 110:3715.
  124. Merchant M, Caldwell RG, Longnecker R. The LMP2A ITAM is essential for providing B cells with development and survival signals in vivo. J Virol 2000; 74:9115.
  125. Murray PG, Constandinou CM, Crocker J, et al. Analysis of major histocompatibility complex class I, TAP expression, and LMP2 epitope sequence in Epstein-Barr virus-positive Hodgkin's disease. Blood 1998; 92:2477.
  126. Bechtel D, Kurth J, Unkel C, Küppers R. Transformation of BCR-deficient germinal-center B cells by EBV supports a major role of the virus in the pathogenesis of Hodgkin and posttransplantation lymphomas. Blood 2005; 106:4345.
  127. Chaganti S, Bell AI, Pastor NB, et al. Epstein-Barr virus infection in vitro can rescue germinal center B cells with inactivated immunoglobulin genes. Blood 2005; 106:4249.
  128. Falini B, Martino G, Lazzi S. A comparison of the International Consensus and 5th World Health Organization classifications of mature B-cell lymphomas. Leukemia 2023; 37:18.
  129. Fan Z, Natkunam Y, Bair E, et al. Characterization of variant patterns of nodular lymphocyte predominant hodgkin lymphoma with immunohistologic and clinical correlation. Am J Surg Pathol 2003; 27:1346.
  130. Nogová L, Reineke T, Brillant C, et al. Lymphocyte-predominant and classical Hodgkin's lymphoma: a comprehensive analysis from the German Hodgkin Study Group. J Clin Oncol 2008; 26:434.
  131. Fromm JR, Thomas A, Wood BL. Characterization and Purification of Neoplastic Cells of Nodular Lymphocyte Predominant Hodgkin Lymphoma from Lymph Nodes by Flow Cytometry and Flow Cytometric Cell Sorting. Am J Pathol 2017; 187:304.
  132. Uherova P, Valdez R, Ross CW, et al. Nodular lymphocyte predominant Hodgkin lymphoma. An immunophenotypic reappraisal based on a single-institution experience. Am J Clin Pathol 2003; 119:192.
  133. Braeuninger A, Küppers R, Strickler JG, et al. Hodgkin and Reed-Sternberg cells in lymphocyte predominant Hodgkin disease represent clonal populations of germinal center-derived tumor B cells. Proc Natl Acad Sci U S A 1997; 94:9337.
  134. Ohno T, Stribley JA, Wu G, et al. Clonality in nodular lymphocyte-predominant Hodgkin's disease. N Engl J Med 1997; 337:459.
  135. Prakash S, Fountaine T, Raffeld M, et al. IgD positive L&H cells identify a unique subset of nodular lymphocyte predominant Hodgkin lymphoma. Am J Surg Pathol 2006; 30:585.
  136. Brune V, Tiacci E, Pfeil I, et al. Origin and pathogenesis of nodular lymphocyte-predominant Hodgkin lymphoma as revealed by global gene expression analysis. J Exp Med 2008; 205:2251.
  137. Hartmann S, Döring C, Jakobus C, et al. Nodular lymphocyte predominant hodgkin lymphoma and T cell/histiocyte rich large B cell lymphoma--endpoints of a spectrum of one disease? PLoS One 2013; 8:e78812.
  138. Wlodarska I, Nooyen P, Maes B, et al. Frequent occurrence of BCL6 rearrangements in nodular lymphocyte predominance Hodgkin lymphoma but not in classical Hodgkin lymphoma. Blood 2003; 101:706.
  139. Renné C, Martín-Subero JI, Hansmann ML, Siebert R. Molecular cytogenetic analyses of immunoglobulin loci in nodular lymphocyte predominant Hodgkin's lymphoma reveal a recurrent IGH-BCL6 juxtaposition. J Mol Diagn 2005; 7:352.
  140. Hartmann S, Schuhmacher B, Rausch T, et al. Highly recurrent mutations of SGK1, DUSP2 and JUNB in nodular lymphocyte predominant Hodgkin lymphoma. Leukemia 2016; 30:844.
  141. Schuhmacher B, Bein J, Rausch T, et al. JUNB, DUSP2, SGK1, SOCS1 and CREBBP are frequently mutated in T-cell/histiocyte-rich large B-cell lymphoma. Haematologica 2019; 104:330.
  142. Huppmann AR, Nicolae A, Slack GW, et al. EBV may be expressed in the LP cells of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) in both children and adults. Am J Surg Pathol 2014; 38:316.
  143. Al-Mansour M, Connors JM, Gascoyne RD, et al. Transformation to aggressive lymphoma in nodular lymphocyte-predominant Hodgkin's lymphoma. J Clin Oncol 2010; 28:793.
  144. Kenderian SS, Habermann TM, Macon WR, et al. Large B-cell transformation in nodular lymphocyte-predominant Hodgkin lymphoma: 40-year experience from a single institution. Blood 2016; 127:1960.
  145. Biasoli I, Stamatoullas A, Meignin V, et al. Nodular, lymphocyte-predominant Hodgkin lymphoma: a long-term study and analysis of transformation to diffuse large B-cell lymphoma in a cohort of 164 patients from the Adult Lymphoma Study Group. Cancer 2010; 116:631.
  146. Hartmann S, Döring C, Vucic E, et al. Array comparative genomic hybridization reveals similarities between nodular lymphocyte predominant Hodgkin lymphoma and T cell/histiocyte rich large B cell lymphoma. Br J Haematol 2015; 169:415.
  147. Van Loo P, Tousseyn T, Vanhentenrijk V, et al. T-cell/histiocyte-rich large B-cell lymphoma shows transcriptional features suggestive of a tolerogenic host immune response. Haematologica 2010; 95:440.
Topic 4698 Version 24.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟