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" and "Pathogenesis of
Hodgkin lymphoma" and "Pretreatment evaluation, staging, and treatment
stratification of classic Hodgkin lymphoma" and "Overview of the treatment of
classic Hodgkin lymphoma in adults".)
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 "Etiology, clinical features, and diagnosis of minimal
change disease in adults", section on 'Neoplasms'.)
●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", 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 "Evaluation of
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".)
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 6th 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 10th to 12th 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 lymphomas (cHL; 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. Following are histologic subtypes of cHL:
•Nodular sclerosis cHL (NSCHL)
•Mixed cellularity cHL (MCCHL)
•Lymphocyte rich cHL (LRCHL)
•Lymphocyte depleted cHL (LDCHL)
●Most patients with cHL present with asymptomatic lymphadenopathy or a
mass on chest radiograph. These presentations may be accompanied by B
symptoms (fever, night sweats, unintended weight loss) or other symptoms.
Dissemination of cHL generally proceeds from a single lymph node region to
adjacent lymph nodes before disseminating to nonadjacent sites and organs.
However, in some cases the clinical presentation is nonspecific or atypical, as
described above. (See 'Clinical presentation' above.)
●Evaluation includes (see 'Evaluation' above):
•History of lymphadenopathy, B symptoms, pruritus, alcohol-induced pain,
and family history of lymphoma or the cancer.
•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.
•Laboratory studies should include:
-Complete blood count (CBC) with differential count and erythrocyte
sedimentation rate (ESR)
-Serum chemistries, including electrolytes, liver and renal function
tests, albumin, and lactate dehydrogenase
•Imaging may be used to guide a biopsy and to evaluate possible organ
involvement.
●A tissue biopsy is required to diagnose cHL and to determine the histologic
subtype. In general, excisional biopsy of a peripheral lymph node is preferred,
but multiple core needle biopsies may be adequate. However, fine needle
aspiration (FNA) generally does not provide sufficient tissue for all required
analyses and does not permit definitive histologic classification. (See 'Tissue
biopsy' above.)
●Characterization of the biopsy specimen by microscopy, immunophenotype,
and other studies is described above. (See 'Pathology' above.)
●The diagnosis of cHL should be suspected in a patient with lymphadenopathy
or a mass on a chest radiograph, with or without B symptoms (ie, fever,
sweats, weight loss) or other symptoms. However, the clinical presentation of
cHL is variable and may present with nonspecific symptoms, such as fatigue,
pruritus, or other clinical findings, as described above.
(See 'Diagnosis' above.)
The diagnosis of cHL in a lymph node requires characteristic microscopic
findings of Hodgkin/Reed-Sternberg (HRS) cells admixed with a pleomorphic
inflammatory cell infiltrate plus HRS cells that express CD30, but do not
express CD45 or CD3.
●The differential diagnosis of cHL includes other causes of lymphadenopathy,
including infectious, autoimmune, benign, and other malignant disorders.
Other lymphomas that must be distinguished from cHL include lymphocyte-
predominant HL and various non-Hodgkin lymphomas. (See 'Differential
diagnosis' above.)