Classic Hodgkin lymphoma: Presentation, evaluation, and diagnosis in adults

INTRODUCTION — 

Classic Hodgkin lymphoma (cHL; formerly called Hodgkin's disease) refers to a category of lymphoid neoplasms in which malignant Hodgkin/Reed-Sternberg (HRS) cells are admixed with an infiltrate composed of variable proportions of reactive (ie, nonmalignant) lymphocytes, histiocytes, eosinophils, and plasma cells. HRS cells are of B cell origin, but they do not correspond to a normal cellular counterpart.

cHL primarily involves lymph nodes and generally manifests as painless, enlarged lymph nodes. cHL can also present with systemic symptoms (eg, fever, sweats, unexplained weight loss, pruritus), involvement of the liver or spleen, and other findings. There are four histologic subtypes of cHL that have distinct epidemiology and natural history: nodular sclerosis (NS), mixed cellularity (MC), lymphocyte-rich (LR), and lymphocyte-depleted (LD) cHL.

The epidemiology, pathogenesis, evaluation, and diagnosis of cHL are discussed in this topic.

Related topics include:

●(See "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma".)

●(See "Overview of Hodgkin lymphoma in children and adolescents".)

●(See "Treatment of favorable prognosis early (stage I-II) classic Hodgkin lymphoma".)

●(See "Classic Hodgkin lymphoma (cHL): Treatment of unfavorable prognosis early (stage I-II) cHL in adults".)

●(See "Initial treatment of advanced (stage III-IV) classic Hodgkin lymphoma".)

●(See "Treatment of nodular lymphocyte-predominant Hodgkin lymphoma".)

cHL shares some clinical and pathologic features with another type of Hodgkin lymphoma called nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) or nodular lymphocyte-predominant B cell lymphoma (NLPBL). The epidemiology, natural history, and management of NLPBL/NLPHL are discussed separately. (See "Nodular lymphocyte-predominant Hodgkin lymphoma: Clinical manifestations, diagnosis, and staging".)

EPIDEMIOLOGY — 

cHL has a bimodal age distribution; it most often presents in younger adults, but there is also a second peak of incidence in older adults. The age, sex, and geographic distribution differ among the four histologic subtypes of cHL.

●Incidence – In the United States, Europe, and other resource-abundant countries, cHL accounts for approximately 10 percent of all lymphomas (others being non-Hodgkin lymphomas), 0.5 percent of all cancers, and 0.2 percent of all cancer deaths [1-3]. The incidence of cHL in such settings is 2 to 3 cases per 100,000 persons; in the United States, this corresponds to approximately 8500 new cases of cHL and approximately 1000 deaths annually.

●cHL Subtypes – The incidence and distribution of cHL subtypes vary with age, sex, geography, and socioeconomic factors.

The distribution of cHL subtypes in economically developed settings is [4]:

•Nodular sclerosis (NS) cHL: 70 percent

•Mixed cellularity (MC) cHL: 20 to 25 percent

•Lymphocyte-rich (LR) cHL: 5 percent

•Lymphocyte-depleted (LD) cHL: <1 percent

There are higher rates of MC and LD cHL in economically disadvantaged regions; these subtypes are more commonly associated with Epstein-Barr virus (EBV)-positive cHL and higher rates of human immunodeficiency virus (HIV) infection [5-10].

●Age and sex – Most cases of cHL present in patients between 15 and 35 years of age, but there is a bimodal age distribution for some subtypes, with a second peak of incidence in adults in their seventh and eighth decades (figure 1).

In economically advantaged countries, the highest incidence of cHL is in older adolescents/young adults, with a smaller peak in older adults (approximately age 65 years) (figure 1) [11]. Lymphomas are the most common cancer in adolescents (21 percent of new cancer diagnoses in 15- to 19-year-old individuals), and cHL accounts for two-thirds of those cases [1]. By contrast, in economically disadvantaged areas, there is an initial childhood peak for males, relatively low rates in young adults, and a prominent peak in older adults [9,10,12]. In early industrialized or transitional economies, there is an intermediate pattern (peaks of incidence in childhood and the second decade of life) [12-14].

The age and sex distribution of cHL varies with the subtype. NS cHL has a peak incidence between the ages of 15 and 35 years, whereas MC cHL has a bimodal distribution with a peak in young adults and a second peak in older adults [4]. For NS cHL, the incidence is comparable between males and females, but there is a male predominance for other subtypes of cHL [15,16].

●Race/ethnicity – The incidence of cHL varies by race and ethnicity, but it is unclear whether genetic and/or environmental factors account for these differences.

The incidence of cHL was equal in White and Black Americans in the United States (3.1 cases per 100,000 males), but it was lower in Hispanic Americans (2.6 cases/100,000), the Asian population/Pacific Islanders, Native Americans, and Alaska natives according to SEER (Surveillance, Epidemiology, and End Results) data [17]. In another SEER study, the age of peak incidence was older in Hispanic Americans than in other racial/ethnic groups [18]. Compared with non-Hispanic White children, Hispanic children had an increased risk of cHL (odds ratio 2.43; 95% CI 1.14-5.17) and, in particular, were more often diagnosed with MC cHL [19].

●Socioeconomic factors – Socioeconomic factors have been associated with various cHL subtypes, but no environmental or infectious agent has been clearly identified [20,21].

MC and LD cHL are relatively common in economically resource-limited settings, whereas NS predominates and LD is rare in advantaged settings [22,23]. The risk for MC is inversely associated with a higher standard of living (eg, single-family housing, small family size) [24-26]. Among lower socioeconomic groups in economically advantaged settings, the predominant subtypes are MC and LD [27]. In Brazil, MC is more common in rural regions, whereas NS is more common in urban areas [28]. A population-based study in Israel reported a higher risk for NS in Israeli-born individuals compared with immigrants (hazard ratio 1.59 [95% CI 1.32-1.92]), which may reflect socioeconomic factors [29].

RISK FACTORS — 

Epstein-Barr virus (EBV) has been linked to the pathogenesis of cHL, but the absolute risk for developing cHL after EBV infection is very small. Detection of EBV in Hodgkin/Reed-Sternberg (HRS) cells varies with the histologic subtype, geography, and immunocompetence.

Some cases of cHL are associated with immunosuppression, but there is little evidence that other infections or heritable factors play a causal role.

●EBV – Only a very small minority of patients infected with EBV subsequently develop cHL. Detection of EBV in HRS cells varies with the histologic subtype, geography, and immunocompetence of the patient.

Approximately 90 to 95 percent of adults worldwide are seropositive for EBV, but the age of infection varies with socioeconomic conditions [30]. EBV causes infectious mononucleosis (IM), and one study estimated that the absolute risk of developing cHL after IM was approximately 1 in 1000; in this case-control study, there was an increased risk for developing EBV-positive cHL after IM (relative risk 4.0 [95% CI 3.4-4.5]), but no increased risk for EBV-negative cHL [31]. Mechanisms by which EBV may contribute to the pathogenesis of cHL are discussed below. (See 'Pathogenesis' below.)

EBV positivity varies among the histologic subtypes of cHL, is more common in resource-limited settings, and is nearly always detected in cHL in HIV-infected patients.

•Histologic subtype – EBV is most often associated with mixed cellularity (MC) and lymphocyte-depleted (LD) cHL subtypes.

EBV is detected in nearly 100 percent of LD cHL cases, 70 percent of MC cHL, 40 percent of lymphocyte-rich (LR) cHL, and 10 to 25 percent of nodular sclerosis (NS) cHL [32,33]. Most cases of cHL that carry inactivating mutations of immunoglobulin genes are EBV-positive [34].

•Geography – EBV is detected in HRS cells in 20 to 50 percent of cHL cases in North America and Europe, but nearly all cases of cHL are EBV-positive in tropical and economically disadvantaged regions [5-10].

•HIV and other immunosuppressive conditions – Almost all cases of cHL in patients with HIV infection or other immunosuppressive conditions are EBV-positive.

●Other infections – There is no persuasive evidence that other infectious agents play a causal role in cHL.

There is controversy about whether human herpesvirus-6 (HHV6; the cause of roseola or sixth disease) plays a role in cHL, but there is no evidence that cytomegalovirus (CMV), HHV7, HHV8, polyoma JC virus, adenovirus types 5 and 12, human T cell lymphotropic virus 1 and 2, or human retrovirus 5 are present in HRS cells [35-39].

●Immune status – The incidence and nature of cHL are associated with immune status.

•Immunosuppression – The incidence of cHL is increased in people living with HIV (PLWH) and other immunodeficient conditions, and cHL in these populations is almost universally positive for EBV. Although the incidence of cHL is increased in PLWH, cHL is not considered an acquired immunodeficiency syndrome (AIDS)-defining malignancy. (See "HIV infection and malignancy: Epidemiology and pathogenesis", section on 'Non-AIDS-defining cancers'.)

The relative risk of cHL is increased 5- to 25-fold among PLWH [40-44]. In the United States, HIV infection is present in a substantial proportion of non-Hispanic Black, Hispanic, and middle-aged males with LD and MC cHL [45]. The risk for cHL is also increased in patients after solid organ transplantation, hematopoietic cell transplantation, and treatment with immunosuppressive drugs for autoimmune diseases [46-50]. Rarely, cHL can arise as a Richter transformation of chronic lymphocytic leukemia, and this occurrence may be related to immunosuppressive therapy (eg, fludarabine) or EBV infection [51].

Almost all cases of cHL in the setting of HIV infection are EBV-positive, including cases of LD cHL [52].

The risk for cHL in immunosuppressed individuals is less striking than the risk for non-Hodgkin lymphomas (NHLs) [47,49]. The peak incidence of cHL is ≥4 years after transplantation, in contrast to NHL, which most commonly occurs in the first year after transplantation. The CD4 T cell count associated with HIV-associated cHL is typically higher than in other EBV-associated lymphomas. Further discussion of the association of immunosuppression and lymphomas is presented separately. (See "HIV-related lymphomas: Epidemiology, risk factors, and pathobiology" and "Malignancy after solid organ transplantation" and "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders".)

•Autoimmune conditions – Patients with a history of autoimmune disorders are at an increased risk for cHL development, but it is unclear if this is directly related to these conditions or to the immunosuppressive agents used to treat them.

A population-based study reported an increased standardized incidence ratio (SIR) for all subtypes of cHL (SIR 2.0 [95% CI 1.8-2.0]) among patients with autoimmune illnesses, including polyarteritis nodosa, polymyositis/dermatomyositis, Behçet's disease, Sjögren's disease, polymyalgia rheumatica, and psoriasis [53]. A registry data study reported an association of cHL with a personal or family history of autoimmune conditions [54]. Another population-based study reported an increased risk for cHL in Danish patients with rheumatoid arthritis but not with atopic diseases [55].

●Other environmental factors – Other environmental factors have been associated with the incidence of cHL, but no causal relationship has been proven.

Diet, body weight, physical activity, aspirin use, and cigarette smoking have been associated with differing rates of cHL, but many of these relationships may be indirect because of their association with socioeconomic status [56-69].

●Familial/heritable factors – Both familial and genetic factors have been associated with the risk for cHL.

•Familial factors – There is a familial predisposition to cHL, but it is unclear how much of this effect is genetic versus environmental.

The risk for close relatives of probands with cHL is threefold to fivefold greater than the expected rate, but the risk varies with the subtype [70-73]. In a registry-based study, the SIR for cHL was 5.3 in first-degree relatives of patients with cHL [74]. In other registry-based studies, the risk of cHL in first-degree relatives of cHL probands ranged from 1.2- to 5.8-fold [70,71,75-77]. The risk is stronger for affected siblings than for parents [70,75,76,78].

A cohort study of 3.5 million people reported that a family history of cHL was associated with a 7.2- and 8.5-fold increased risk of cHL in children and young adults, respectively [78]. Another cohort study reported a sixfold increase in risk for siblings [79]. A large Scandinavian case-control study reported a 3.3 odds ratio (OR) for cHL in individuals with a family history of cHL [80], while some smaller studies reported larger ORs [81,82].

The SIR for cHL in monozygotic twins was 99 compared with background rates in one study [83], while another study reported a 57-fold increased risk in same-sex twins [73].

•Heritable features – Major histocompatibility complex (MHC)/human leukocyte antigen (HLA) loci have been associated with variations in cHL incidence. Other gene loci have not been consistently identified as risk factors for cHL.

Variations at specific MHC/HLA loci are associated with an increased risk of developing cHL, but this may reflect the coinheritance of multiple risk alleles, rather than a single genetic determinant [84]. There has been consistent association with HLA-A1, and to a lesser extent, HLA-B5, HLA-B8, and HLA-B18 [85-91]. Genome-wide association studies identified specific MHC variants that were independently associated with both EBV-negative and EBV-positive cHL; certain MHC variants were independently associated with only EBV-positive cHL, while other variants were only associated with EBV-negative cHL [91,92].

A systematic review and meta-analysis of 21 studies identified an association with various HLA loci, but no other candidate genes (eg, immune function/response, carcinogen metabolism enzymes, folate metabolism enzymes, deoxyribonucleic acid [DNA] repair proteins) were consistently found [84]. Polymorphisms in REL, EOMES, ERAP1, IL13, PVT1, GATA3, and TCF3 have been proposed as risk factors in some studies [92-98].

PATHOGENESIS — 

Hodgkin/Reed-Sternberg (HRS) cells are the malignant cellular component of cHL.

HRS cells, which account for only a small percentage of cHL masses, are embedded in a microenvironment of diverse immune cells. The pathogenesis of cHL involves acquired mutations and aberrant cellular signaling that enable the HRS cells to escape from immune destruction.

Cytogenetic/molecular abnormalities contribute importantly to the pathophysiology of cHL. Cytogenetic and molecular abnormalities associated with cHL are discussed below. (See 'Cytogenetics' below and 'Molecular features' below.)

●Cellular origin of HRS cells – HRS cells are germinal center (GC) B lymphocytes that underwent transformation during maturation, losing the capacity to express immunoglobulins and other factors that define normal B cells. HRS cells do not correspond to any identified stage of normal B cell development.

The recognition that HRS cells are derived from GC B cells is based on molecular findings. Normal development of B lymphocytes includes rearrangement of immunoglobulin genes in lymph node GCs and subsequent somatic hypermutation in follicles of secondary lymphoid organs. The origin of HRS cells from GC/post-GC B lymphocytes was confirmed by the detection of clonal immunoglobulin heavy chain (IGH) rearrangements and a high load of somatic mutations in microdissected single HRS cells [99-104]. Despite their derivation from GC B lymphocytes, HRS cells have lost or down-regulated expression of characteristic B cell-specific genes [99,105,106].

Clonal Ig rearrangements are detected in >98 percent of cHL cases by polymerase chain reaction (PCR) on microdissected single HRS cells [4]. Even in the rare cases of cHL with T cell antigen expression, most have clonal Ig gene rearrangements [107]. Current classification systems do not recognize cHL of T cell origin [108,109], and rare reported cases of cHL with clonal T cell receptor rearrangements may represent unusual T cell non-Hodgkin lymphomas with cHL-like morphologic features.

Normal B cell development is discussed separately. (See "Normal B and T lymphocyte development", section on 'B cell development'.)

●Aberrant signaling – HRS cells exhibit aberrant autocrine and paracrine signaling that contribute to the abnormal immune microenvironment.

Acquired mutations and/or disordered expression of NF-kB, JAK/STAT, AP-1, and NOTCH pathway genes contribute to altered expression of cytokines, chemokines, and other factors that act via autocrine and paracrine mechanisms [110].

HRS cells produce chemokines, including CCL5, CCL17, CCL22, and interleukin (IL) 8, that recruit various immune cells [111-113]. CD4-positive T cell subsets are attracted through their expression of receptors for these factors; CCL5 attracts macrophages and mast cells; IL-8 attracts neutrophils; CCL17 and CCL22 attract immunosuppressive CCR4-positive T regulatory (Treg) cells; and expression of IL-10 by HRS cells and Treg cells inhibits the function of infiltrating cytotoxic T cells and natural killer (NK) cells.

●Immune evasion – Despite the abundance of immune cells in the cHL microenvironment, HRS cells have developed mechanisms to survive by escaping immune surveillance.

The cellular milieu includes various immune effector cells (eg, cytotoxic T cells, macrophages, mast cells, neutrophils, eosinophils, plasma cells) and regulatory cells (eg, T helper cells, Treg cells). Fibroblasts contribute variable degrees of fibrosis.

Cellular immune responses are regulated by stimulatory and inhibitory receptor ligands on T lymphocytes and antigen-presenting cells (APCs), which are arranged spatially on the surface of these cells to create the immune synapse. This synapse is disordered in HRS cells, leading to suppression of T cell responses. Common alterations include reduced cell surface expression of major histocompatibility complex (MHC) class I or class II expression, which impairs antigen presentation by HRS cells, and frequent overexpression of programmed death receptors PDL1 and PDL2 (because of increased gene copy number on chromosome 9p24.1), leading to T cell exhaustion.

Mechanisms by which HRS cells escape immunosurveillance include:

•Reduced or lost antigen presentation through inactivating mutations/deletion of B2M (beta2 microglobulin; thereby perturbing MHC class I assembly) and/or CIITA-inactivating alterations (perturbing MHC class II) [106,114].

•Secretion of IL-10, TGF beta1, prostaglandin, and galectin-1 to inhibit activation of cytotoxic T lymphocytes and/or APCs [111,115-118].

•Recruitment of immunosuppressive Treg cells and myeloid-derived suppressor cells into the cHL microenvironment [119].

•Enhanced PD-1 signaling via interaction of HRS cells that express PD-1 ligands (PDL1, PDL2) with effector T cells that express PD-1 receptor [120,121].

Further discussion of the immune synapse is presented separately. (See "Principles of cancer immunotherapy", section on 'The "immune synapse"'.)

●Impaired apoptosis – HRS cells avoid cell death that ordinarily results from aberrant B cell maturation.

Normal B cells that lose expression of the B cell receptor die via apoptosis, but HRS cells use deregulated signaling pathways to escape this fate [105]. The activation of NF-kB, JAK-STAT, and MAPK/ERK signaling pathways contributes to the evasion of apoptosis [122].

●Molecular subtypes – Categorization by the types/burden of mutations, association with viral infections, and/or the tumor microenvironment (TME) may have utility for distinguishing subtypes of cHL, but we await clinical validation of these subtypes.

Analysis of circulating tumor DNA identified three biologic subtypes of cHL with different genetic features, clinical characteristics, TMEs, and clinical outcomes [123]. The proposed cHL categories are Inflammatory-immune escape (characterized by frequent gene copy-number variations, including high-level amplifications of the PD-L1 locus, and an inflammatory TME), Virally-driven (associated with Epstein-Barr virus and/or human herpesvirus 6, an inflammatory TME with neutrophils and macrophages, and a low tumor mutational burden), and Oncogene-driven (defined by a high tumor mutational burden; recurrent mutations in oncogenic drivers such as TNFAIP3, ITPKB, and SOCS1; and a "cold" TME).

Another analysis of circulating tumor DNA also identified distinct molecular subtypes with potential diagnostic, prognostic, and/or therapeutic implications [124].

CLINICAL PRESENTATION — 

cHL generally progresses slowly, but the tempo of disease progression is variable.

Lymphadenopathy, constitutional symptoms, fatigue, and/or pruritus are often recognized to have begun weeks to months before the patient is evaluated for cHL. Mediastinal masses can be quite large before causing chest discomfort or respiratory symptoms, which is consistent with a slow rate of growth.

Typical presentations — Most patients with cHL present with asymptomatic lymphadenopathy or a mass on chest imaging [125]. Constitutional "B" symptoms (ie, fever, night sweats, and/or unintended weight loss) are present in approximately 40 percent of cases.

In a minority of cases, the clinical presentation of cHL is relatively nonspecific or atypical. (See 'Less common presentations' below.)

Lymphadenopathy — Lymphadenopathy is found at presentation in more than two-thirds of patients with cHL (figure 2). Involved lymph nodes are usually nontender and have a firm, rubbery consistency.

The neck is the most common site of involvement, as 60 to 80 percent of patients have enlarged cervical and/or supraclavicular nodes (table 1) [126,127]. Enlarged axillary nodes are found in approximately 30 percent of patients and inguinal nodes in 10 percent. Although they are not detectable on physical examination, mediastinal nodes are involved in 50 to 60 percent of patients and retroperitoneal nodes in 30 percent. Infradiaphragmatic lymphadenopathy alone is uncommon, occurring in <10 percent of patients.

Dissemination generally proceeds from a single lymph node region to adjacent lymph nodes via lymphatic channels before involving more distant or nonadjacent sites and organs (figure 2) [128-130]. It is likely that cHL can spread via the thoracic duct, possibly in either direction, without clinical enlargement of mediastinal nodes. Noncontiguous spread and/or hematogenous dissemination are uncommon but are more often encountered in immunosuppressed patients (eg, HIV-associated), as discussed below. (See 'Less common presentations' below.)

Mediastinal mass — Discovery of a mediastinal mass on routine chest imaging is another common presentation of cHL.

A mediastinal mass may be asymptomatic or associated with cough, shortness of breath, or retrosternal chest pain. Pericardial or pleural effusions are uncommon, except in patients with bulky mediastinal disease, and presentation with superior vena cava syndrome is rare. (See "Malignancy-related superior vena cava syndrome".)

Among patients with early-stage cHL, large mediastinal adenopathy is an adverse prognostic factor that influences treatment decisions, as described separately. (See "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma", section on 'Favorable early stage'.)

B symptoms — B symptoms are lymphoma-associated constitutional symptoms.

B symptoms are formally defined as [131]:

●Fever – Persistent temperature >38°C (>100.4°F)

●Sweats – The presence of drenching night sweats

●Weight loss – Unexplained loss of >10 percent of body weight over the past six months

Other symptoms (eg, fatigue, pruritus, alcohol-associated pain) are not considered B symptoms.

The fever that accompanies cHL is often more noticeable in the evening and becomes more severe and continuous with time. Pel-Ebstein fever describes a characteristic but uncommon presentation in which fever cyclically increases and then decreases over a period of one to two weeks [132].

B symptoms generally accompany lymphadenopathy, but patients occasionally present with B symptoms alone. The presence of B symptoms varies with disease stage; B symptoms are present in <20 percent of patients with stage I/II cHL and up to one-half of patients with advanced disease. B symptoms are an adverse prognostic feature that influences treatment decisions, as discussed separately. (See "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma", section on 'Favorable early stage'.)

Pruritus — Pruritus occurs in approximately 10 to 15 percent of patients at presentation and can precede the diagnosis of cHL by months or longer [133]. Pruritus is not considered a B symptom. Pruritus is typically generalized and occasionally is severe enough to cause intense scratching and excoriations.

Less common presentations — Less common or atypical presentations of cHL include extranodal disease, noncontiguous spread to multiple nodal groups, involvement of bone marrow or liver, and isolated laboratory abnormalities. Atypical presentations can be seen in any patient but are more common in immunosuppressed individuals [4]. (See "HIV-related lymphomas: Clinical manifestations and diagnosis", section on 'Clinical manifestations'.)

Examples of less common clinical presentations of cHL include:

●Alcohol-associated pain – Rarely, patients with cHL complain of severe pain following alcohol ingestion.

The pain typically begins within minutes of ingestion of even small amounts of alcohol [134]. It usually occurs at sites of bony involvement, but it may also occur at sites of lymphadenopathy. While alcohol-associated pain is uncommon (<10 percent) and has no prognostic significance, it is highly specific for cHL. The mechanism of alcohol-associated pain is unknown.

●Liver disease – Liver involvement may manifest as abnormal liver function tests or as abdominal pain, nausea, anorexia, or other nonspecific findings. However, liver involvement as the sole presenting manifestation of cHL is uncommon.

Rarely, fulminant liver failure can occur as a paraneoplastic manifestation without hepatic infiltration [135]. Progressive destruction and disappearance of the intrahepatic bile ducts is sometimes labeled vanishing bile duct syndrome.

●Other intra-abdominal disease – Retroperitoneal lymphadenopathy may cause flank discomfort or pain, but isolated infradiaphragmatic lymphadenopathy (ie, without other involved nodal regions) is uncommon. Some patients experience abdominal distention due to splenomegaly, hepatomegaly, or rarely ascites, but involvement of the gastrointestinal tract by cHL is rare. Extensive intra-abdominal disease can cause ureteral obstruction or compression of renal veins.

●Skin lesions – Skin abnormalities described in association with cHL include ichthyosis, acrokeratosis (Bazex syndrome), urticaria, erythema multiforme, erythema nodosum, necrotizing lesions, hyperpigmentation, and skin infiltration [136,137]. (See "Cutaneous manifestations of internal malignancy".)

●Bone/bone marrow involvement – Bony involvement at presentation is uncommon, but it may be suspected in a patient with bone pain or elevation of serum alkaline phosphatase or calcium. Bone marrow infiltration may manifest as unexplained cytopenias or bone pain.

Bone marrow involvement by cHL at presentation is associated with advanced clinical stage; it has been reported in up to 6.5 percent of patients with newly diagnosed cHL [138-142].

●Neurologic findings – Direct involvement of the central nervous system by cHL is rare (eg, ≤0.5 percent at presentation) [143-146]. Several paraneoplastic syndromes, including cerebellar degeneration, chorea, neuromyotonia, limbic encephalitis, subacute sensory neuropathy, subacute lower motor neuropathy, and the stiff person syndrome have been described in association with cHL [147-157]. (See "Overview of paraneoplastic syndromes of the nervous system" and "Paraneoplastic cerebellar degeneration" and "Stiff-person syndrome".)

●Nephrotic syndrome – Nephrotic syndrome can occur as a paraneoplastic syndrome in patients with cHL. The usual pathologic pattern is minimal change disease, but focal segmental glomerulosclerosis can also occur [158,159]. (See "Minimal change disease: Etiology, clinical features, and diagnosis in adults", section on 'Malignancies'.)

●Laboratory abnormalities – A variety of laboratory abnormalities can occur in patients with cHL. Some of these abnormalities (eg, anemia, lymphopenia, leukocytosis, hypoalbuminemia) are associated with adverse outcomes, as discussed separately. (See "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma", section on 'International Prognostic Score (IPS)'.)

Examples of laboratory findings at presentation include:

•Hypercalcemia – Hypercalcemia is usually due to increased production of calcitriol (1,25-dihydroxyvitamin D3) and less commonly is caused by direct bony involvement [160,161]. (See "Hypercalcemia in granulomatous diseases".)

•Anemia – Anemia can be due to diverse causes, including bone marrow replacement by cHL, hypersplenism, anemia of chronic inflammation, and (rarely) Coombs-positive hemolytic anemia, with or without immune thrombocytopenia [162,163]. (See "Causes of anemia in patients with cancer".)

Microcytic anemia that can mimic iron deficiency is common with cHL, even in patients with early-stage disease; this is likely a cytokine-mediated phenomenon.

•Eosinophilia – Eosinophilia is common in cHL and is caused by the production of chemokines (eg, interleukin-5, eotaxin) that recruit eosinophils and/or stimulate eosinophil production [164,165].

•Other – Other laboratory abnormalities may include leukocytosis, thrombocytosis, lymphopenia, and hypoalbuminemia. Some of these findings are associated with an inferior prognosis, as discussed separately. (See "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma".)

EVALUATION

Clinical and laboratory evaluation

●History – The history should evaluate the presence, duration, and extent of lymphadenopathy; cough or other respiratory symptoms; and unexplained fever, sweating, weight loss, pruritus, and alcohol-induced pain in bone or other sites.

It is important to document a personal history of previous malignancy (including other lymphomas); prior treatment with chemotherapy or radiotherapy; HIV infection or other immunosuppressive condition; and a family history of lymphoproliferative, myeloproliferative, or other malignancies.

●Examination – Physical examination must evaluate all accessible lymphoid tissues, including the size, number, and regions of lymph node enlargement and the presence of splenomegaly or hepatomegaly (figure 2).

●Laboratory

•Complete blood count (CBC) with differential count and erythrocyte sedimentation rate (ESR)

•Serum chemistries, including electrolytes, liver function tests, kidney function, and albumin

•HIV testing (see "Screening and diagnostic testing for HIV infection in adults", section on 'Preferred approach')

●Imaging – Imaging is performed to identify potential sites for biopsy and assess organ involvement, as clinically needed.

Pretreatment evaluation and staging of cHL are discussed separately. (See "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma", section on 'History and physical examination'.)

Tissue biopsy — A tissue biopsy is required to diagnose cHL and determine the histologic subtype. The site and type of biopsy are informed by the clinical presentation.

Excisional or incisional biopsy of a peripheral lymph node is generally preferred because of ease of access, safety, and high yield of material for microscopy, specialized testing, and histologic subtyping. Multiple core needle biopsies of a peripheral lymph node or via image-guided biopsy may be adequate in many cases. However, fine needle aspiration generally does not provide sufficient tissue for all required analyses and does not permit definitive histologic classification.

●Lymph node – The selection of a lymph node for biopsy is guided by the clinical presentation.

Biopsy of suspicious cervical, supraclavicular, or axillary lymph nodes is generally favored. By contrast, inguinal lymph nodes are frequently distorted by prior inflammatory/immune reactions, and these changes may make the diagnosis of cHL more difficult.

Ultrasonography, computed tomography (CT), or positron emission tomography (PET) can be used to identify a suspicious site and/or guide a tissue biopsy if there is no accessible peripheral lymphadenopathy. (See "Evaluation of peripheral lymphadenopathy in adults".)

●Mediastinum – For patients with a mediastinal mass, chest CT and/or PET may identify a site for biopsy.

Tissue can be obtained by anterior mediastinotomy (Chamberlain procedure), cervical mediastinoscopy, or video-assisted thoracoscopy/biopsy (VATS). (See "Approach to the adult patient with a mediastinal mass", section on 'Tissue diagnosis'.)

An adequate specimen is needed to distinguish cHL from other conditions in the differential diagnosis of an anterior mediastinal mass. We generally avoid CT-guided percutaneous biopsy or endobronchial biopsy because they may provide insufficient tissue and/or be subject to crush artifact that makes it difficult to distinguish cHL from lymphomas.

●Extranodal sites – For patients without identifiable adenopathy who are suspected of organ involvement, imaging may be useful for guiding a tissue biopsy. (See 'Less common presentations' above.)

A confirmatory lymph node biopsy is desirable when cHL is identified with a biopsy of an extranodal site unless the diagnosis is considered unequivocal. (See 'Diagnosis' below.)

Pathologic evaluation of biopsy material is described below. (See 'Pathology' below.)

Evaluation of extranodal sites — PET is a routine component of staging for cHL, and it is generally effective for detecting the involvement of bone marrow and extranodal sites. However, ambiguous PET results in patients who are suspected of organ involvement by clinical evaluation or laboratory studies may require additional studies.

Bone marrow examination is not routinely used for staging cHL, but it may be performed if there are unexplained cytopenias. (See "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma", section on 'Other procedures'.)

Following are examples of extranodal disease/organ involvement and methods for evaluation:

●Liver – Additional imaging may be needed if there is unexplained abdominal fullness/pain, nausea, jaundice, weight loss, or abnormal liver function tests (LFTs). LFTs can be abnormal even in the absence of histologic involvement.

Radiologic diagnosis of liver involvement by cHL is challenging because it usually consists of microscopic or small macroscopic foci. Some experts suggest that liver involvement should be documented with two different imaging techniques (eg, ultrasound, CT, magnetic resonance imaging [MRI], PET) [131,166].

Ultrasound, CT, PET, and/or MRI can guide a liver biopsy if no suspicious lymph node sites are identified. (See 'Tissue biopsy' above.)

●Spleen – PET/CT or MRI are the most reliable imaging approaches for evaluating suspected splenic involvement in patients with early satiety, weight loss, abdominal fullness, splenomegaly, or related findings. Spleen involvement generally manifests as diffuse infiltration with miliary lesions, focal nodular lesions, and/or a large solitary mass; some patients with early-stage disease have low-level splenic uptake due to inflammation [131,166].

For patients with no other apparent sites for tissue biopsy, the evaluation of isolated splenomegaly is described separately. (See "Splenomegaly and other splenic disorders in adults", section on 'Evaluation (splenomegaly)'.)

●Central nervous system (CNS) – For patients with unexplained neurologic abnormalities, the CNS should be evaluated by lumbar puncture and MRI, with and without gadolinium. CNS involvement can be due to parenchymal and/or leptomeningeal involvement. Neurologic abnormalities may also be caused by a paraneoplastic neurologic syndrome. (See 'Less common presentations' above and "Overview of paraneoplastic syndromes of the nervous system".)

●Gastrointestinal (GI) tract – The GI tract is rarely involved by cHL. CT with intravenous contrast may be required to distinguish GI tract involvement from that of adjacent abdominal lymphadenopathy. Endoscopic biopsy can confirm suspected involvement.

●Bone – For patients with focal bony pain, plain radiographs may reveal predominantly osteoblastic/sclerotic lesions. PET is highly sensitive for the identification of bony involvement. The approach to bone biopsy, if needed, is described separately. (See "Bone tumors: Diagnosis and biopsy techniques".)

Documentation of disease stage and extranodal involvement is an important component of cHL staging, as discussed separately. (See "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma", section on 'Extranodal involvement'.)

PATHOLOGY

Microscopy — In cHL, the lymph node is effaced by variable numbers of Hodgkin/Reed-Sternberg (HRS) cells admixed with a polymorphous inflammatory infiltrate. In general, HRS cells constitute only a small component of the involved tissue (eg, 0.1 to 10 percent) [4]. Characteristics of HRS cells are described below. (See 'Hodgkin/Reed-Sternberg cells' below.)

The composition of the inflammatory infiltrate varies with the histologic subtype. The infiltrate generally includes variable percentages of small lymphocytes, eosinophils, neutrophils, macrophages (histiocytes), plasma cells, and fibroblasts and may be associated with collagen deposition and fibrosis (picture 1). Granuloma formation is found in lymph nodes, spleen, or liver in approximately 15 percent of cHL cases, and they may or may not be associated with direct involvement by cHL. (See 'Histologic subtypes' below.)

Hodgkin/Reed-Sternberg cells

Morphology — HRS cell is a collective term for classic Reed-Sternberg (RS) cells and characteristic variant cells (Hodgkin cells).

Prototypical RS cells have at least two nucleoli in separate nuclear lobes and present a characteristic "owl's eyes" appearance (picture 1 and picture 2). HRS cells have rounded bilobed, double, or multiple nuclei; pale chromatin; a prominent eosinophilic nucleolus with perinucleolar clearing (halo); and abundant, slightly basophilic cytoplasm [4].

RS variant cells include:

●Hodgkin cell – Mononuclear variants of RS cells (picture 3).

●Lacunar cells – Lacunar cells have multilobated nuclei, small nucleoli, and abundant, pale cytoplasm and lie in what appears to be an empty space (a lacune) (picture 4). The lacune results from shredding or partial loss of cellular content upon sectioning when tissue fixation is incomplete. Lacunar cells are characteristically seen only in tissues fixed with formalin, which is not as effective at penetrating and fixing tissues as other fixatives.

●Mummified cells – Mummified cells are neoplastic cells that contain condensed cytoplasm and pyknotic reddish nuclei with smudged chromatin (picture 4).

Lymphocytic and histiocytic (L&H) cells refer to the malignant cells in nodular lymphocyte-predominant Hodgkin lymphoma (also called nodular lymphocyte predominant B cell lymphoma), as discussed separately. (See "Nodular lymphocyte-predominant Hodgkin lymphoma: Clinical manifestations, diagnosis, and staging", section on 'LP cells'.)

Immunophenotype — The immunophenotype of HRS cells is typically characterized by the following pattern of antigen expression:

●CD30 and CD15 – CD30 is expressed in virtually 100 percent of cHL cases, while CD15 is expressed in 75 to 85 percent (picture 5A-B) [4].

●CD45 – HRS cells do not express CD45 (leukocyte common antigen), which distinguishes them from normal leukocytes and most other malignant lymphoid cells.

●B cell antigens – B cell-specific surface antigens, such as CD20, CD79a, and/or CD19, are characteristically absent or seen on only a subset of HRS cells [167,168]. PAX5 is weakly expressed in approximately 95 percent of cases, whereas expression of other B cell-specific transcription factors (BOB1, OCT2) is typically diminished or absent in HRS cells [169].

●T cell antigens – Pan-T cell antigens (eg, CD3, CD7) are usually not expressed by HRS cells, but expression of a single T cell antigen (eg, CD4) may occasionally be seen; expression of multiple T cell antigens by HRS cells is rare [170].

●PD-1 and PD-1 ligands – HRS cells express PD-L1 and PD-L2, which are ligands for the PD-1 immune checkpoint receptor. Other antigens expressed by HRS cells that are involved with immune cell interactions include CD83, CD40, and CD86 [100,167,168,171-175].

The role of the PD-1 immune checkpoint in immune evasion by HRS cells is discussed above. (See 'Pathogenesis' above.)

●Epstein-Barr virus (EBV) antigens – In EBV-positive cases of cHL, the tumor cells express EBV latent membrane protein (LMP)-1 and LMP-2, but not Epstein-Barr nuclear antigen (EBNA)-2. Most EBV-positive cases are identified by chromogenic in situ hybridization for EBV-encoded small nuclear ribonucleic acids. The presence of EBV in various histologic subtypes and the roles of EBV gene products in cHL pathogenesis are discussed above. (See 'Pathogenesis' above.)

●Other antigens – HRS cells may also express CD25, HLA-DR, ICAM-1, Fascin, CD95, and TRAF1.

Multiparameter flow cytometry utilizing ≥6 colors can identify rare RS cells in suspensions prepared from tissue specimens, but it is not sufficient to establish the diagnosis or characterize the histologic subtype of cHL. (See 'Diagnosis' below.)

Cytogenetics — Cytogenetic abnormalities are found in most cases of cHL.

Diverse cytogenetic abnormalities and intraclonal variability are seen, but no consistent or specific karyotypic finding has been associated with cHL [176-178]. Aneuploidy and hypertetraploidy are consistent with the multinucleation of RS cells. The cause of chromosomal instability in HRS cells is not known.

The most common karyotypic abnormalities in cHL are:

•Gain of chromosomes 2p, 9p, 16p, and 17q

•Loss of chromosomes 13q, 6q, and 11q

Clonal chromosomal abnormalities were reported in all cases of cHL that were tested by fluorescence in situ hybridization (FISH) [179,180].

Chromosome 9p24.1 is frequently amplified and this is associated with copy number gains of PDL1, PDL2, and JAK2, all of which contribute to the pathogenesis of cHL [120,121]. (See 'Pathogenesis' above.)

Many cases of cHL have abnormalities of chromosome 14q, but it is rare to identify the t(14;18)/IGH::BCL2 rearrangement that is typical of certain B cell non-Hodgkin lymphomas.

Molecular features — Mutations, gene rearrangements, and other molecular abnormalities are common and contribute to the pathophysiology of cHL.

●Mutations – The mutational landscape of cHL is heterogeneous, but most cases have abnormalities related to intracellular signaling (eg, NFkB or JAK-STAT pathways) and/or immune evasion (eg, PD-1-related genes).

Mutations that have been implicated in the pathogenesis of cHL include [106,122,181]:

•Mutations of major histocompatibility complex (MHC)-associated genes, CIITA and B2M (beta-2 microglobulin)

•Mutations in NFKB1A, NFKB1E, TNFAIP3, PIM1, Rho/TTF, SOCS1, IKBKB, CD40, BTK, CARD11, BCL10, MAP3K14, MYC, and PAX5

•Mutations in CD95 and TP53 tumor suppressor genes

B2M is involved by loss-of-function mutations in approximately 70 percent of cases of cHL, leading to loss of expression of MHC class I antigens and contributing to immune evasion by HRS cells [106].

Abnormalities of the JAK-STAT pathway were reported in nearly 90 percent of cases. Mutations of STAT6 and SOCS1 were found in 32 and 59 percent of 34 cases of cHL, respectively, by whole-exome sequencing [182]. Other abnormalities include gain-of-function mutations of signal transducers (eg, JAK1, JAK2, STAT3, STAT5B) and loss-of-function mutations in inhibitors (eg, PTPN1).

Other mutations are found in genes that encode components of the NFkB, PI3K/AKT, Notch, and immune checkpoint pathways [183]. As an example, inactivating mutations in TNFAIP3, which encodes a negative regulator of NFkB signaling and is predicted to upregulate NFkB signaling, were reported in 44 percent of cHL [184]. Mutations of other components of the NFkB signaling pathway (eg, TRAF3 and MAP3K14) have also been reported [185].

Mutations of GMCSF/IL3 and CBP/EP300 and variants of BTK, CARD11, and BCL10 may affect HRS cell viability [186].

●Gene amplification – Amplification of genes on chromosome 9p24.1 is one of the most common abnormalities in cHL [187]. Chromosomal gains in this region deregulate at least four genes (JAK2, JMJD2C, PDL1, and PDL2) that contribute to the pathogenesis of cHL. JMJD2C encodes a histone demethylase whose downregulation in cHL cell lines induces cell death [188].

Genomic gains of REL, JAK2, STAT6, NOTCH1, and JUNB are frequently seen.

Copy number gains of REL, BCL11A, XPO1, and MYCN (chromosome 2) and loss of TNFAIP3 (chromosome 6), ATM and BIRC3 (chromosome 11), and RB1 and BRCA2 (chromosome 13) are common in cHL.

●Aberrant gene expression – Despite their derivation from germinal center B lymphocytes, HRS cells express genes aberrantly and have lost much of the B cell-specific expression program [105,189-195]. HRS cells have a gene expression profile that is distinct from other lymphomas.

Altered expression of NFkB B target genes, components of the JAK/STAT signaling pathway, and/or the AP-1 complex is characteristic of cHL [190,196-200]. Interestingly, EBV-positive and EBV-negative cases of cHL have similar expression profiles, which is consistent with the idea that EBV components mimic the effects of somatic mutations found in EBV-negative cHL.

DIAGNOSIS — 

The diagnosis of cHL should be suspected in a patient with lymphadenopathy or a mediastinal mass, with or without B symptoms (ie, fever, sweats, weight loss). However, the clinical presentation of cHL is variable, and a patient may present with nonspecific symptoms, such as fatigue, pruritus, or other less common or atypical clinical findings, as described above. (See 'Clinical presentation' above.)

The diagnosis of cHL requires the following microscopic findings plus the defining immunophenotype of Hodgkin/Reed-Sternberg (HRS) cells:

●Lymph node – Diagnostic HRS cells in a polymorphous inflammatory infiltrate of small lymphocytes, eosinophils, neutrophils, histiocytes, plasma cells, and fibroblasts, with or without collagen deposition and fibrosis. The HRS cells may be prototypical Reed-Sternberg (RS) cells or Hodgkin variants, as described above. (See 'Morphology' above.)

Diagnosis of cHL involvement of a secondary site (eg, bone marrow, liver) requires the presence of HRS cells in an appropriate inflammatory background; diagnostic RS cells are not required to make a diagnosis of cHL at an extranodal site in a patient with known disease [4].

●Immunophenotype – HRS cells express CD30 but not CD45 or CD3 (table 2). Most cases of cHL express CD15, but the absence of CD15 does not preclude a diagnosis of cHL. However, the absence of both CD15 and CD30 strongly points to other diagnoses. (See 'Differential diagnosis' below.)

The histologic subtype of cHL should be determined, as discussed below. (See 'Histologic subtypes' below.)

Pretreatment evaluation, staging, and treatment stratification are discussed separately. (See "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma".)

HISTOLOGIC SUBTYPES — 

cHL subtypes have distinct demographics and prognoses.

Nodular sclerosis — Nodular sclerosis (NS) cHL is characterized by a nodular growth pattern in the lymph node, with fibrous bands separating cellular nodules (picture 6 and picture 7). Diagnostic Reed-Sternberg (RS) cells may be rare; typically, the majority of Hodgkin/Reed-Sternberg (HRS) cells in NS cHL are lacunar cells. The inflammatory background usually contains eosinophils, macrophages, and neutrophils and may have areas of necrosis. Only a small minority of cases is associated with EBV.

Some histologic variants of NS have been described:

●In some cases, the fibrous bands may be poorly developed or inconspicuous, making the distinction from other forms of cHL difficult. This appearance has been referred to as the "cellular phase" of NS [201,202].

●Syncytial NS refers to tumors in which lacunar cells are found in large aggregates or sheets, which may lead to a focal loss of the nodular sclerotic pattern (picture 8) [203].

Mixed cellularity — Mixed cellularity (MC) is a heterogeneous subtype of classic cHL with a diffuse or vaguely nodular growth pattern without band-forming sclerosis (picture 9). Fine interstitial fibrosis may be present, and classic diagnostic HRS cells are readily identified. The background infiltrate is variable but typically consists of eosinophils, neutrophils, macrophages, and plasma cells (picture 10) [201]. Approximately two-thirds of cases are EBV-associated.

Lymphocyte-rich — Lymphocyte-rich (LR) cHL most commonly has a nodular growth pattern but may also be diffuse. The background infiltrate consists predominantly of lymphocytes, with few eosinophils or neutrophils (picture 11). Diagnostic RS cells and mononuclear Hodgkin cells are present. Some cases of LR cHL have a nodular pattern, containing remnants of regressed germinal centers, with both classic and variant RS cells in the mantle zones and interfollicular regions; this entity has been termed "follicular" cHL, or nodular LR cHL [204,205]. Approximately 40 percent of cases are EBV-associated.

In some cases, HRS cells of LR cHL resemble the lymphocytic and histiocytic cells that are characteristic of nodular lymphocyte predominant HL and can only be reliably distinguished by immunophenotyping. (See "Nodular lymphocyte-predominant Hodgkin lymphoma: Clinical manifestations, diagnosis, and staging", section on 'Pathology'.)

Lymphocyte-depleted — Lymphocyte-depleted (LD) cHL is the least common subtype of cHL, accounting for <1 percent of cases. LD has a diffuse growth pattern and often appears hypocellular due to fibrosis, necrosis, and a paucity of inflammatory cells (picture 12). Typically, large numbers of diagnostic RS cells and bizarre variant HRS cells are present (picture 10). Compared with other cHL subtypes, patients with LD cHL are more likely to present with advanced-stage disease (74 versus 42 percent) and systemic B symptoms (76 versus 41 percent) [206]. More than 90 percent of cases are EBV-associated.

The terms "reticular" variant or "Hodgkin sarcoma" have been used to describe LD cHL with confluent sheets of HRS cells (picture 13) [201,207]; this variant may be particularly difficult to distinguish from anaplastic large cell lymphoma [208,209]. (See 'Anaplastic large cell lymphoma' below.)

DIFFERENTIAL DIAGNOSIS — 

Numerous conditions cause lymphadenopathy that may be accompanied by fever, sweats, weight loss, or other findings. The differential diagnosis includes infectious, autoimmune, and various malignant disorders.

Reactive processes — Infectious, autoimmune, and other inflammatory processes can cause lymphadenopathy, organomegaly, fever, and other systemic symptoms that can be difficult to distinguish from cHL. Reactive processes have a polymorphous infiltrate that resembles cHL, but they lack diagnostic Hodgkin/Reed-Sternberg (HRS) cells, which are defined by their distinctive morphology and immunophenotype. (See 'Hodgkin/Reed-Sternberg cells' above.)

Differentiating between reactive processes and cHL is especially challenging if a fine needle aspirate is performed because it yields only limited cellular material and does not provide intact nodal architecture. As described above, an excisional biopsy or multiple core biopsies is required to confirm the diagnosis of cHL and distinguish it from reactive causes of lymphadenopathy. (See 'Tissue biopsy' above.)

Evaluation and diagnosis of various conditions that may cause lymphadenopathy are discussed separately. (See "Evaluation of peripheral lymphadenopathy in adults".)

Epstein-Barr virus-positive mucocutaneous ulcer — Epstein-Barr virus (EBV)-positive mucocutaneous ulcer is a disorder characterized by isolated circumscribed ulcerative lesions, typically in older individuals and sometimes in the setting of immunosuppression [4,210]. The lesions are most common in the oropharynx but may also occur in the skin or gastrointestinal tract. The lesions contain a polymorphous inflammatory infiltrate mixed with scattered EBV-infected B cells, which may include cells that morphologically and immunophenotypically resemble HRS cells. This entity is distinguished from cHL by its extranodal presentation, benign course, frequent spontaneous regression, and excellent response to conservative treatment [210,211]. (See "Classification of primary cutaneous lymphomas", section on 'EBV-positive mucocutaneous ulcer'.)

Nodular lymphocyte-predominant HL — The clinical and pathologic presentation of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL; also called nodular lymphocyte-predominant B cell lymphoma) can resemble cHL, and it can be especially challenging to distinguish from lymphocyte-rich (LR) cHL.

NLPHL can generally be distinguished from cHL by the presence of lymphocytic and histiocytic HRS cells embedded within nodules composed mainly of reactive B cells (picture 14), and distinctive immunophenotypic and molecular features (table 2), including the uniform expression of B cell antigens (eg, CD20) and the absence of CD30 and CD15. NLPHL is rarely Epstein-Barr virus (EBV)-positive, which may also help to distinguish it from cHL. (See "Nodular lymphocyte-predominant Hodgkin lymphoma: Clinical manifestations, diagnosis, and staging".)

Anaplastic large cell lymphoma — Anaplastic large cell lymphoma (ALCL) may be difficult to distinguish from certain variants of lymphocyte-depleted (LD) cHL and, in some cases, can produce inflammatory responses and tissue fibrosis that mimic the host response to HRS cells [208,209,212]. However, cases can generally be resolved by a combination of morphologic and immunophenotypic features as either:

●cHL: CD15-positive, CD30-positive, PAX-positive, T cell antigens-negative, ALK-negative

●ALCL: CD15-negative, strongly CD30-positive, PAX5-negative, positive for one or more T cell antigens, ALK-positive/negative, and positive for cytotoxic markers (perforin, granzyme B, TIA-1)

Nonetheless, there are occasional cases in which even with the combination of morphology, immunophenotype, and genetic studies it may be difficult to distinguish ALCL and cHL with certainty. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)".)

Other B cell lymphomas

●Primary mediastinal large B cell lymphoma – Primary mediastinal large B cell lymphoma (PMBL) and nodular sclerosis (NS) cHL share certain clinical features, including the presence of a mediastinal mass and frequent occurrence in young adults. Biopsy of PMBL may reveal cells that resemble HRS cells of cHL, and the entities have similar patterns of gene expression. However, in PMBL, the malignant cells typically express pan-B cell antigens, have a weak expression of CD30, and only rarely express CD15. By contrast, HRS cells of cHL typically express CD15 and are strongly CD30-positive. Expression of fascin by HRS cells can help to distinguish EBV-negative cHL from PMBL [213]. (See "Primary mediastinal large B cell lymphoma".)

●Mediastinal gray zone lymphoma – Mediastinal gray zone lymphoma (MGZL) is a term that is commonly applied to lymphomas that share features that are usually confined to PMBL or cHL.

MGZL is most common in young males who present with a large anterior mediastinal mass [214,215]. Tumors are histologically heterogeneous and are usually identified by immunophenotypic findings that are inconsistent with the diagnosis of either cHL or PMBL, such as expression of CD15 and strong CD30 expression in a tumor that retains expression of multiple B cell markers [4]. Recognition of MGZL is clinically relevant because compared with cHL and PMBL, MGZL generally has a more aggressive course and inferior outcomes [216].

●T cell histiocyte-rich large B cell lymphoma – T cell histiocyte-rich large B cell lymphoma (THRLBCL) can also be difficult to distinguish from cHL. THRLBCL occurs most commonly in middle-aged males and, like cHL, the tumor cells may comprise only a minor fraction of the total cellularity. However, the malignant B cells in THRLBCL usually have an immunophenotype similar to other B cell lymphomas (eg, positive for pan-B cell markers and negative for CD15, CD30, and EBV). (See "Diffuse large B cell lymphoma and other large B cell lymphomas: Presentation, diagnosis, and classification".)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of Hodgkin lymphoma".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Hodgkin lymphoma in adults (The Basics)")

●Beyond the Basics topics (see "Patient education: Hodgkin lymphoma in adults (Beyond the Basics)")

SUMMARY

●Description – Classic Hodgkin lymphoma (cHL) refers to lymphoid neoplasms in which malignant Hodgkin/Reed-Sternberg (HRS) cells are admixed with a heterogeneous population of non-neoplastic inflammatory cells.

●Presentation – Most patients present with asymptomatic lymphadenopathy or a mass on chest radiograph. These findings may be accompanied by B symptoms (fever, night sweats, weight loss), pruritus, or other symptoms. cHL generally spreads from lymph node to adjacent lymph nodes before disseminating to nonadjacent sites and organs (figure 2). (See 'Clinical presentation' above.)

Less common presentations, including alcohol-associated pain, isolated involvement of skin or other organs, and neurologic abnormalities, are discussed above. (See 'Less common presentations' above.)

●Evaluation – (See 'Evaluation' above.)

•Clinical and laboratory – Evaluation of lymphadenopathy, B symptoms, pruritus, alcohol-induced pain, or other symptoms; description of the size, number, and involved regions of lymph nodes and hepatosplenomegaly; routine laboratory studies; and imaging, as needed. (See 'Clinical and laboratory evaluation' above.)

•Biopsy – An excisional biopsy (or multiple core needle biopsies) is required to diagnose cHL and determine the histologic subtype. (See 'Tissue biopsy' above.)

Fine needle aspiration is generally not sufficient for the diagnosis and classification of cHL.

●Diagnosis – cHL should be suspected in a patient with lymphadenopathy, a chest mass, unexplained B symptoms, pruritus, or alcohol-associated pain.

The diagnosis requires characteristic microscopic findings of HRS cells (picture 1) (or variant forms) that express CD30 but do not express CD45 or CD3 (table 2), admixed with a pleomorphic inflammatory cell infiltrate. (See 'Pathology' above.)

●Histologic subtypes – The histologic subtype should be defined as:

•Nodular sclerosis cHL (picture 6)

•Mixed cellularity cHL (picture 9)

•Lymphocyte-rich cHL (picture 11)

•Lymphocyte-depleted cHL (picture 12)

●Differential diagnosis – Other causes of lymphadenopathy, including infectious, autoimmune, benign, and other malignancies, should be excluded by clinical and pathologic evaluation. cHL must also be distinguished from lymphocyte-predominant HL, anaplastic lymphoma, and various other non-HLs. (See 'Differential diagnosis' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Peter M Mauch, MD, who contributed to earlier versions of this topic review.