Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults

INTRODUCTION — Hodgkin lymphomas (HL; formerly called Hodgkin's disease) are lymphoid neoplasms in which malignant Hodgkin/Reed-Sternberg (HRS) cells are admixed with a heterogeneous population of non-neoplastic inflammatory cells.

HL is divided into two major categories, based on morphology and immunophenotype (table 1):

●Classic HL (cHL) comprises 90 percent of HL and is further subtyped according to pathologic features:

•Nodular sclerosis cHL (NSCHL)

•Mixed cellularity cHL (MCCHL)

•Lymphocyte rich cHL (LRCHL)

•Lymphocyte depleted cHL (LDCHL)

●Nodular lymphocyte predominant HL (NLPHL)

Evaluation, diagnosis, and pretreatment evaluation of cHL is presented here.

Epidemiology and risk factors; pathogenesis; pretreatment evaluation, staging, and prognosis; and an overview of treatment of cHL are presented separately.

●(See "Hodgkin lymphoma: Epidemiology and risk factors".)

●(See "Pathogenesis of Hodgkin lymphoma".)

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

Clinical manifestations, diagnosis, and treatment of nodular lymphocyte-predominant HL are presented separately. (See "Nodular lymphocyte-predominant Hodgkin lymphoma: Clinical manifestations, diagnosis, and staging" and "Treatment of nodular lymphocyte-predominant Hodgkin lymphoma".)

CLINICAL PRESENTATION

Disease tempo — cHL generally progresses slowly, but the tempo of disease 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 radiograph [1]. Constitutional symptoms ("B" symptoms; ie, fever, night sweats, 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 detectable in more than two-thirds of patients with cHL at presentation (figure 1), and the 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 2) [2,3]. Enlarged axillary nodes are found in approximately 30 percent and inguinal nodes in 10 percent of patients. Although they are not detectable on physical examination, mediastinal nodes are involved in 50 to 60 percent and retroperitoneal nodes in 30 percent of patients. 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 1) [4-6]. 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 hematologic dissemination are uncommon, but are more often encountered in immunosuppressed patients (eg, HIV/AIDS), as discussed below. (See 'Less common presentations' below.)

Mediastinal mass — Discovery of a mediastinal mass on routine chest radiograph is another common presentation of cHL; the 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 specifically refers to fever, night sweats, or weight loss in association with lymphoma. 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 half of patients with advanced disease.

B symptoms are formally defined as follows [7]:

●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.

Fever that accompanies cHL is often more noticeable in the evening and becomes more severe and continuous with time. Pel-Ebstein fever refers to an uncommon but characteristic presentation in which fever cyclically increases and then decreases over a period of one to two weeks [8].

The presence of B symptoms is 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 even a year or longer [9]. Pruritus is typically generalized and occasionally is severe enough to cause intense scratching and excoriations. Pruritus is not considered a B symptom.

Less common presentations — Less common or atypical presentations of cHL include extranodal disease, noncontiguous spread to multiple nodal groups, bone marrow or liver involvement, and isolated laboratory abnormalities. Atypical presentations can be seen in any patient, but are more common in individuals with human immunodeficiency virus (HIV) infection or other immunosuppressed patients [10]. (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 a small amount of alcohol [11]. Alcohol-associated pain 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 a diagnosis of cHL. The mechanism of alcohol-associated pain is unknown.

●Liver disease – Liver involvement may be manifest as abnormal liver function tests or as abdominal pain, nausea, anorexia, other nonspecific findings. However, liver involvement as the sole presenting manifestation of cHL is uncommon. In one study, liver involvement was found in approximately 5 percent of 285 patients who later underwent staging laparotomy [12]. In another study, only 6 of 421 consecutive patients who were diagnosed with HL presented with liver abnormalities that led to a liver biopsy and subsequent diagnosis [13]. Rarely, fulminant liver failure can also occur as a paraneoplastic manifestation without hepatic infiltration [14].

●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 swelling 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 lesions that have been described in association with cHL include ichthyosis, acrokeratosis (Bazex syndrome), urticaria, erythema multiforme, erythema nodosum, necrotizing lesions, hyperpigmentation, and skin infiltration [15,16]. (See "Cutaneous manifestations of internal malignancy".)

●Bone/bone marrow involvement – Bony involvement at presentation is uncommon, but it is suggested by a history of bone pain or elevation of serum alkaline phosphatase or calcium. Bone marrow infiltration may be 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 all patients with newly diagnosed cHL, but in virtually none with early stage disease [17-21].

●Neurologic findings – Direct involvement of the central nervous system (CNS) by cHL is rare (eg, ≤0.5 percent at presentation) [22-25]. 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 [26-36]. (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 early stage cHL. The usual pathologic pattern is minimal change disease, but focal segmental glomerulosclerosis, can also occur [37,38]. (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 [39,40]. (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 may be due to a Coombs-positive hemolytic anemia, with or without immune thrombocytopenia [41,42]. (See "Causes of anemia in patients with cancer".)

•Eosinophilia – Eosinophilia is relatively common in HL and is caused by production of chemokines (eg, interleukin-5, eotaxin) that recruit eosinophils and/or stimulate eosinophil production [43,44]. (See "Pathogenesis of Hodgkin lymphoma".)

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

EVALUATION

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

Physical examination must evaluate all accessible lymphoid regions, including the size, number, and regions of lymph node enlargement, and the presence of splenomegaly or hepatomegaly (figure 1). Waldeyer's ring (tonsils, base of the tongue, nasopharynx) should be examined, especially in patients with adenopathy in the neck.

Aspects of the history and physical examination that are required for 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'.)

Laboratory studies — Laboratory studies for all patients should include:

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

●Serum chemistries, including electrolytes, liver and renal function tests, and albumin

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

Imaging — Imaging may be used to identify potential sites for biopsy and to evaluate organ involvement. The nature of the clinical presentation determines the need for imaging (see 'Clinical presentation' above):

●Biopsy

•Lymphadenopathy – For the patient who does not have accessible peripheral lymphadenopathy, ultrasonography, computed tomography (CT), or positron emission tomography (PET) may identify a suspicious site and/or guide a tissue biopsy. (See "Evaluation of peripheral lymphadenopathy in adults".)

•Mediastinal mass – For patients with a mediastinal mass, but without other accessible lymphadenopathy, chest CT and/or PET may identify a site for biopsy. Tissue biopsy may be obtained by CT-guided percutaneous approach, endobronchial biopsy, or a surgical procedure, such as anterior mediastinotomy (Chamberlain procedure), cervical mediastinoscopy, or video-assisted thoracoscopy/biopsy (VATS), as discussed separately. (See "Approach to the adult patient with a mediastinal mass", section on 'Tissue diagnosis'.)

•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.)

●Organ involvement – Imaging for evaluation of organ involvement is described below. (See 'Evaluation of extranodal sites' below.)

PET/CT is used for staging cHL, as described separately. (See "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma", section on 'PET/CT'.)

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

Excisional or incisional biopsy of a peripheral lymph node is generally preferred as the source of tissue because of ease of access, safety, and high yield and because it provides abundant material for microscopic evaluation, 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, but fine needle aspiration (FNA) generally does not provide sufficient tissue for all required analyses and does not permit definitive histologic classification.

Selection of a lymph node for biopsy depends on the patient's clinical presentation. If multiple lymph node groups are enlarged, biopsy of suspicious cervical, supraclavicular, or axillary lymph nodes is generally favored; in contrast, inguinal lymph nodes are frequently distorted by prior inflammatory/immune reactions, and these changes may make the diagnosis of cHL more difficult. When the diagnosis of cHL is made from biopsy of an extranodal site, confirmation with a lymph node biopsy is desirable unless the diagnosis is considered unequivocal. (See 'Diagnosis' below.)

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

Evaluation of extranodal sites — Additional studies may be required for evaluation of patients who are suspected of having organ involvement based on history, physical examination, or laboratory studies. Following are examples of extranodal disease/organ involvement and methods for evaluation:

●Liver – Suspected liver involvement (eg, due to abdominal fullness/pain, nausea, jaundice, weight loss, abnormal liver function tests [LFTs]) should be evaluated with imaging. LFTs are not reliable in this setting, since they may 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, MRI, PET) [7,45].

Ultrasound, CT, PET, and/or MRI may be used to guide a liver biopsy if no suspicious lymph node sites are identified. (See 'Imaging' above.)

●Spleen – PET/CT or MRI are the most reliable imaging approaches for evaluating suspected splenic involvement (eg, in patients with early satiety, weight loss, abdominal fullness, splenomegaly, or related findings). Spleen involvement is generally manifest 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 [7,45].

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 neurologic symptoms or signs, the CNS should be evaluated by lumbar puncture and MRI, with and without gadolinium. Although CNS involvement by cHL is extremely rare, it may be missed on PET/CT due to the increased physiologic FDG uptake in the normal brain. 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 gastrointestinal (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. If indicated, endoscopy and biopsy are the preferred method to 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 extranodal involvement by cHL is an important component of disease staging, as discussed separately. (See "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma", section on 'Extranodal involvement'.)

Abnormal findings from FNA — Some patients have already undergone fine needle aspiration (FNA) at the time of evaluation for cHL.

For the patient with FNA findings that are suspicious for cHL (eg, presence of Hodgkin/Reed-Sternberg cells and/or an unexplained polymorphous inflammatory cell infiltrate), we suggest a tissue biopsy to confirm the diagnosis and to determine the histologic subtype. Our reasons for suggesting a tissue biopsy rather than an FNA alone are described above. (See 'Tissue biopsy' above.)

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) [10]. Characteristics of HRS cells are described below. (See 'Hodgkin/Reed-Sternberg cells' below.)

The composition of the inflammatory infiltrate varies according to the histologic subtype. The infiltrate generally includes variable percentages of small lymphocytes, eosinophils, neutrophils, macrophages (also referred to as 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.)

Grading schemes have been developed within specific subtypes of cHL (eg, nodular sclerosis cHL), but they have not been proven to be useful in determining prognosis and are not used for selecting treatment. Grading schemes and other features of the cellular infiltrate that may have prognostic significance for cHL are described separately. (See "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma", section on 'Other prognostic factors'.)

Hodgkin/Reed-Sternberg cells

Morphology — Hodgkin/Reed-Sternberg (HRS) cell is a collective term for classic Reed-Sternberg (RS) cells and characteristic variant cells that are referred to as 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). RS cells of cHL have rounded bilobed, double, or multiple nuclei; pale chromatin; a prominent eosinophilic nucleolus with perinucleolar clearing (halo); and abundant, slightly basophilic cytoplasm [10].

Characteristic RS variant cells include:

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

●Lacunar cells – Lacunar cells have multilobated nuclei, small nucleoli, and abundant, and pale cytoplasm 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 used by hematopathologists (eg, B+ fixative).

●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 are a variant of RS cells that are seen in nodular lymphocyte predominant HL, 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:

●CD30 and CD15 – CD30 is expressed by virtually 100 percent of HL cases, while CD15 is expressed in 75 to 85 percent (picture 5A-B) [10].  

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

●B cell antigens – Expression of the B cell-specific surface antigens, CD20, CD79a, and/or CD19, is characteristically either absent or is seen on only a subset of HRS cells [46,47]. PAX5/BSAP (a key B cell transcription factor) is weakly expressed in approximately 95 percent of cases, whereas expression of other B cell-specific transcription factors (BOB1, OCT2) is typically diminished or lost altogether in HRS cells [48].

●T cell antigens – Pan-T cell antigens (eg, CD3, CD7) are 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 [49].

●PD-1 and its 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 [46,47,50-55].

The role of the PD-1 checkpoint in immune evasion by HRS cells is discussed separately. (See "Pathogenesis of Hodgkin lymphoma", section on 'Immune evasion'.)

●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. The presence of EBV in various histologic subtypes and roles of EBV gene products in HL pathogenesis are discussed separately. (See "Hodgkin lymphoma: Epidemiology and risk factors", section on 'Epstein-Barr virus' and "Pathogenesis of Hodgkin lymphoma".)

●Other antigens that may be expressed by HRS cell include CD25, HLA-DR, ICAM-1, Fascin, CD95 (apo-1/fas), and TRAF1.

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

Cytogenetics — Clonal cytogenetic abnormalities are found in most cases, but no consistent or specific karyotypic finding has been associated with cHL [56-58].

Chromosomal instability is manifest by diverse cytogenetic abnormalities and intraclonal variability of HRS cells. Clonal chromosomal abnormalities were reported in all cases of cHL that were tested by fluorescence in situ hybridization (FISH) [59,60]. Aneuploidy and hypertetraploidy are consistent with the multi-nucleation of RS cells. (See 'Morphology' above.)

There is frequent amplification of chromosome 9p24.1, which is associated with copy number gains of PDL1 (also known as CD274 or B7 homolog 1), PDL2, and JAK2, all of which contribute to the pathogenesis of HL [61,62]. Although many cases of cHL show abnormalities of chromosome 14q, it is rare to identify the t(14;18)/BCL2 rearrangement that is typical for B cell non-Hodgkin lymphomas. (See "Pathogenesis of Hodgkin lymphoma", section on 'Cytogenetics and mutations'.)

Molecular features

●Immunoglobulin (Ig) and T cell receptor (TCR) gene rearrangements – Clonal immunoglobulin (Ig) gene rearrangements can be detected in >98 percent of cHL by polymerase chain reaction (PCR) on microdissected single HRS cells [10]. The presence of mutated VDJ rearrangements indicates that HRS cells originated from germinal center or post-germinal center B cells. (See "Pathogenesis of Hodgkin lymphoma".)

Even in the rare cases of cHL with T cell antigen expression, most have clonal Ig gene rearrangements; only one-third has TCR gene rearrangements [63]. cHL of T cell origin, if it occurs at all, is extremely rare.

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

The most common mutations in HRS cells involve beta-2 microglobulin (B2M; approximately 70 percent of cases). Inactivating mutations of B2M lead to loss of expression of major histocompatibility complex (MHC) class I and contribute to immune evasion by HRS cells [64]. Whole exome sequencing of HRS cells from 34 patients with cHL detected mutations of STAT6 and SOCS1 in 32 and 59 percent of cases, respectively [65]. Abnormalities of the JAK-STAT pathway were reported in nearly 90 percent of cases, including mutations of transducers (eg, JAK1, JAK2, STAT3, STAT5B) and inhibitors (eg, PTPN1). Other mutations include genes that encode components of the NF-kB, PI3K/AKT, Notch, and immune checkpoint pathways [66]. As an example, inactivating mutations in TNFAIP3, which encodes a negative regulator of NF-kB signaling and is predicted to upregulate NF-kB signaling, were reported in 44 percent of cHL [67]. Mutations of other components of the NF-kB signaling pathway (eg, TRAF3 and MAP3K14) have also been reported [68]. Mutations of GMCSF/IL3 and CBP/EP300 and variants of BTK, CARD11, and BCL10 may affect HRS cell viability [69].

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. In one study, 97 percent of 108 cHL cases had concordant gains of the PDL1 and PDL2 loci (polysomy, 5 percent; copy gain, 56 percent; amplification, 36 percent) [62].

Roles of the various mutated genes and signaling pathways in the pathogenesis of cHL are discussed separately. (See "Pathogenesis of Hodgkin lymphoma".)

●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 [70-77]. HRS cells have a gene expression profile that is distinct from other types of lymphoma. Based on patterns of gene expression, there appears to be at least two classes of cHL; their gene expression signatures resemble those associated with activity of the transcription factors, NOTCH1, MYC, and IRF4.

Altered expression of NF-kB B target genes, components of the JAK/STAT signaling pathway, and/or the AP-1 complex is characteristic of cHL [71,78-82]. Interestingly, EBV+ and EBV- 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-cHL. (See "Pathogenesis of Hodgkin lymphoma", section on 'Epstein-Barr virus'.)

DIAGNOSIS — The diagnosis of cHL should be suspected in a patient with lymphadenopathy or a mediastinal mass on a chest radiograph, 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 CD30+ mononuclear 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 [10].

●Immunophenotype – HRS cells of cHL express CD30, but not CD45 or CD3 (table 3). Most cases of cHL express CD15, but the absence of CD15 does not preclude a diagnosis of HL. However, absence of both CD15 and CD30 strongly points to other diagnoses. (See 'Differential diagnosis' below.)

Determination of the histologic subtype is an essential aspect of the diagnosis of cHL. (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

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

Some histologic variants of NSCHL 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 NSCHL [83,84].

●Syncytial NSCHL 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) [85].

Mixed cellularity — Mixed cellularity cHL (MCCHL) is a heterogeneous subtype of classic HL with a diffuse or vaguely nodular growth pattern without band-forming sclerosis (picture 9). Fine interstitial fibrosis may be present, and classic diagnostic RS cells are readily identified. The background infiltrate is variable, but typically consists of eosinophils, neutrophils, macrophages, and plasma cells (picture 10) [83].

Lymphocyte rich — Lymphocyte-rich cHL (LRCHL) 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 LRCHL 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" HL, or nodular lymphocyte-rich cHL [86,87].

In some cases, HRS cells of LRCHL resemble the lymphocytic and histiocytic (L&H) cells that are characteristic of nodular lymphocyte-rich HL. (See "Nodular lymphocyte-predominant Hodgkin lymphoma: Clinical manifestations, diagnosis, and staging", section on 'Pathology'.)

Lymphocyte depleted — Lymphocyte-depleted cHL (LDCHL) is the least common subtype of cHL, accounting for <1 percent of cases. LDCHL 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 LDCHL are more likely to present with advanced stage disease (74 versus 42 percent) and systemic B symptoms (76 versus 41 percent) [88].

The terms "reticular" variant or "Hodgkin sarcoma" have been used to describe LDCHL with confluent sheets of HRS cells (picture 13) [83,89]; this variant may be particularly difficult to distinguish from anaplastic large cell lymphoma [90,91]. (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 cells (HRS; 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 (FNA) was 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".)

EBV-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 [10,92]. 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 [92,93]. (See "Classification of primary cutaneous lymphomas", section on 'EBV-positive mucocutaneous ulcer'.)

Nodular lymphocyte-predominant HL — Nodular lymphocyte-predominant HL (NLPHL) can resemble cHL with regard to clinical and pathologic presentation, and can be especially challenging to distinguish from lymphocyte-rich cHL (LRCHL). NLPHL can generally be distinguished from cHL by the presence of lymphocytic and histiocytic (L&H) HRS cells embedded within nodules composed mainly reactive B cells (picture 14), and distinctive immunophenotypic and molecular features (table 3), including the uniform expression of B cell antigens (eg, CD20) and the absence of CD30 and CD15. NLPHL is rarely, if ever, 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 cHL (LDCHL) and, in some cases, can produce inflammatory responses and tissue fibrosis that mimic the host response to HRS cells [90,91,94]. However, cases can generally be resolved by a combination of morphologic and immunophenotypic features as either:

●Classic Hodgkin lymphoma: CD15+, CD30+, PAX/BSAP+, T cell antigens-, ALK-

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

Nonetheless, there are occasional cases in which the combination of morphology, immunophenotype, and even genetic studies may not resolve ALCL and HL with certainty. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)".)

Other B cell lymphomas

●Primary mediastinal B cell lymphoma (PMBL) – Primary mediastinal B cell lymphoma (PMBL) and nodular sclerosis cHL (NSCHL) share certain clinical features, including the presence of a mediastinal mass and occurrence predominantly in young women. 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 weak expression of CD30, and only rarely express CD15. In contrast, HRS cells of cHL typically express both CD15 and CD30. Expression of fascin by HRS cells can help to distinguish EBV-negative cHL from PMBL [95]. (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 combine features of PMBL and cHL and thereby fall into a "gray-zone." In the World Health Organization classification, these are formally described as B cell lymphoma, unclassifiable, with features intermediate between DLBCL and classic Hodgkin lymphoma [10]. MGZL is most common in young men who present with a large anterior mediastinal mass [96,97]. Tumors are histologically heterogeneous with strong expression of CD15 and CD30 by the malignant cells [10]. Recognition of MZGL is clinically relevant, because compared with cHL and PMBL, MGZL generally has a more aggressive course and inferior outcomes [98].  

●T cell histiocyte-rich large B cell lymphoma (THRLBCL) – 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 "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'T cell histiocyte-rich large B cell lymphoma'.)

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

●Classic Hodgkin lymphoma (cHL) – 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 proceeds from a lymph node to adjacent lymph nodes before disseminating to nonadjacent sites and organs (figure 1). (See 'Clinical presentation' above.)

●Evaluation – (See 'Evaluation' above.)

•Clinical – History of lymphadenopathy, B symptoms, pruritus, alcohol-induced pain, or other symptoms. Examination should document the size, number, and involved regions of lymph nodes and hepatosplenomegaly. (See 'Typical presentations' above.)

•Laboratory – (See 'Laboratory studies' above.)

-Complete blood count (CBC)

-Erythrocyte sedimentation rate (ESR)

-Serum chemistries: Electrolytes, liver and renal function tests, albumin, and lactate dehydrogenase (LDH)

•Imaging – Positron emission tomography (PET)/computed tomography (CT); other imaging as clinically indicated.

•Biopsy – An excisional biopsy (or multiple core needle biopsies) is required to diagnose cHL and determine the histologic subtype; a fine needle aspiration (FNA) is generally not sufficient for diagnosis and classification of cHL. (See 'Tissue biopsy' above.)

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

The diagnosis requires characteristic microscopic findings of Hodgkin/Reed-Sternberg (HRS) cells (picture 1) (or variant forms) that express CD30, but do not express CD45 or CD3 (table 3), admixed with a pleomorphic inflammatory cell infiltrate. (See 'Pathology' above.)

●Histologic subtypes

•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-Hodgkin lymphomas. (See 'Differential diagnosis' above.)

ACKNOWLEDGMENT — UpToDate acknowledges the late Peter M Mauch, MD, who contributed to earlier versions of this topic.