Linfoma de Hodgkin

3/29/23, 8:08 PM 4688
Official reprint from UpToDate®

www.uptodate.com © 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved.
Clinical presentation and diagnosis of classic Hodgkin

lymphoma in adults
Authors: Ann S LaCasce, MD, Andrea K Ng, MD, MPH, Jon C Aster, MD, PhD
Section Editor: Arnold S Freedman, MD
Deputy Editor: Alan G Rosmarin, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2023. | This topic last updated: May 19, 2022.
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.
https://www.uptodate.com/contents/4688/print 1/56
3/29/23, 8:08 PM 4688
● (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
3/29/23, 8:08 PM 4688
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'.)
3/29/23, 8:08 PM 4688
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
3/29/23, 8:08 PM 4688
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".)
3/29/23, 8:08 PM 4688
• 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')
3/29/23, 8:08 PM 4688
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
3/29/23, 8:08 PM 4688
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
3/29/23, 8:08 PM 4688
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
3/29/23, 8:08 PM 4688
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:
3/29/23, 8:08 PM 4688
● 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].
3/29/23, 8:08 PM 4688
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
3/29/23, 8:08 PM 4688
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
3/29/23, 8:08 PM 4688
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
3/29/23, 8:08 PM 4688
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.)
3/29/23, 8:08 PM 4688
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-
3/29/23, 8:08 PM 4688
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'.)
3/29/23, 8:08 PM 4688
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 5th 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 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.)
3/29/23, 8:08 PM 4688
● 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,
3/29/23, 8:08 PM 4688
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.
Use of UpToDate is subject to the Terms of Use.
REFERENCES
1. Shimabukuro-Vornhagen A, Haverkamp H, Engert A, et al. Lymphocyte-rich classical

Hodgkin's lymphoma: clinical presentation and treatment outcome in 100 patients treated
within German Hodgkin's Study Group trials. J Clin Oncol 2005; 23:5739.
2. Mauch PM, Kalish LA, Kadin M, et al. Patterns of presentation of Hodgkin disease.
Implications for etiology and pathogenesis. Cancer 1993; 71:2062.
3. Kaplan HS. Hodgkin's Disease, 2nd ed, Harvard University Press, Cambridge, MA 1980.
4. Peters MV, Alison RE, Bush RS. Natural history of Hodgkin's disease as related to staging.
Cancer 1966; 19:308.
5. KAPLAN HS. The radical radiotherapy of regionally localized Hodgkin's disease. Radiology
1962; 78:553.
6. Rosenberg SA, Kaplan HS. Evidence for an orderly progression in the spread of Hodgkin's
disease. Cancer Res 1966; 26:1225.
7. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging,
and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano
classification. J Clin Oncol 2014; 32:3059.
8. Good GR, DiNubile MJ. Images in clinical medicine. Cyclic fever in Hodgkin's disease (Pel-
Ebstein fever). N Engl J Med 1995; 332:436.
9. Gobbi PG, Cavalli C, Gendarini A, et al. Reevaluation of prognostic significance of symptoms
in Hodgkin's disease. Cancer 1985; 56:2874.
10. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised 4th editio
n, Swerdlow SH, Campo E, Harris NL, et al. (Eds), International Agency for Research on Canc
er (IARC), Lyon 2017.
11. Bobrove AM. Alcohol-related pain and Hodgkin's disease. West J Med 1983; 138:874.
3/29/23, 8:08 PM 4688
12. Kaplan HS, Dorfman RF, Nelsen TS, Rosenberg SA. Staging laparotomy and splenectomy in
Hodgkin's disease: analysis of indications and patterns of involvement in 285 consecutive,
unselected patients. Natl Cancer Inst Monogr 1973; 36:291.
13. Cervantes F, Briones J, Bruguera M, et al. Hodgkin's disease presenting as a cholestatic
febrile illness: incidence and main characteristics in a series of 421 patients. Ann Hematol
1996; 72:357.
14. Dourakis SP, Tzemanakis E, Deutsch M, et al. Fulminant hepatic failure as a presenting
paraneoplastic manifestation of Hodgkin's disease. Eur J Gastroenterol Hepatol 1999;
11:1055.
15. Lucker GP, Steijlen PM. Acrokeratosis paraneoplastica (Bazex syndrome) occurring with
acquired ichthyosis in Hodgkin's disease. Br J Dermatol 1995; 133:322.
16. Perifanis V, Sfikas G, Tziomalos K, et al. Skin involvement in Hodgkin's disease. Cancer
Invest 2006; 24:401.
17. Macintyre EA, Vaughan Hudson B, Linch DC, et al. The value of staging bone marrow
trephine biopsy in Hodgkin's disease. Eur J Haematol 1987; 39:66.
18. Howell SJ, Grey M, Chang J, et al. The value of bone marrow examination in the staging of
Hodgkin's lymphoma: a review of 955 cases seen in a regional cancer centre. Br J Haematol
2002; 119:408.
19. Vassilakopoulos TP, Angelopoulou MK, Constantinou N, et al. Development and validation
of a clinical prediction rule for bone marrow involvement in patients with Hodgkin
lymphoma. Blood 2005; 105:1875.
20. El-Galaly TC, d'Amore F, Mylam KJ, et al. Routine bone marrow biopsy has little or no
therapeutic consequence for positron emission tomography/computed tomography-
staged treatment-naive patients with Hodgkin lymphoma. J Clin Oncol 2012; 30:4508.
21. Adams HJ, Kwee TC, de Keizer B, et al. Systematic review and meta-analysis on the
diagnostic performance of FDG-PET/CT in detecting bone marrow involvement in newly
diagnosed Hodgkin lymphoma: is bone marrow biopsy still necessary? Ann Oncol 2014;
25:921.
22. Re D, Fuchs M, Schober T, et al. CNS involvement in Hodgkin's lymphoma. J Clin Oncol 2007;
25:3182.
23. Morawa E, Ragam A, Sirota R, Nabhan C. Hodgkin's lymphoma involving the CNS. J Clin
Oncol 2007; 25:1437.
24. de Castro AF, Júnior AS, de Lins e Horta H, et al. Primary intracerebral Hodgkin lymphoma.
Br J Haematol 2007; 138:562.
3/29/23, 8:08 PM 4688
25. Gerstner ER, Abrey LE, Schiff D, et al. CNS Hodgkin lymphoma. Blood 2008; 112:1658.
26. Graus F, Dalmau J, Valldeoriola F, et al. Immunological characterization of a neuronal
antibody (anti-Tr) associated with paraneoplastic cerebellar degeneration and Hodgkin's
disease. J Neuroimmunol 1997; 74:55.
27. Graus F, Gultekin SH, Ferrer I, et al. Localization of the neuronal antigen recognized by anti-
Tr antibodies from patients with paraneoplastic cerebellar degeneration and Hodgkin's
disease in the rat nervous system. Acta Neuropathol 1998; 96:1.
28. Hammack J, Kotanides H, Rosenblum MK, Posner JB. Paraneoplastic cerebellar

degeneration. II. Clinical and immunologic findings in 21 patients with Hodgkin's disease.
Neurology 1992; 42:1938.
29. Batchelor TT, Platten M, Palmer-Toy DE, et al. Chorea as a paraneoplastic complication of
Hodgkin's disease. J Neurooncol 1998; 36:185.
30. Caress JB, Abend WK, Preston DC, Logigian EL. A case of Hodgkin's lymphoma producing
neuromyotonia. Neurology 1997; 49:258.
31. Deodhare S, O'Connor P, Ghazarian D, Bilbao JM. Paraneoplastic limbic encephalitis in
Hodgkin's disease. Can J Neurol Sci 1996; 23:138.
32. Hughes RA, Britton T, Richards M. Effects of lymphoma on the peripheral nervous system. J
R Soc Med 1994; 87:526.
33. Plante-Bordeneuve V, Baudrimont M, Gorin NC, Gherardi RK. Subacute sensory neuropathy
associated with Hodgkin's disease. J Neurol Sci 1994; 121:155.
34. Ferrari P, Federico M, Grimaldi LM, Silingardi V. Stiff-man syndrome in a patient with
Hodgkin's disease. An unusual paraneoplastic syndrome. Haematologica 1990; 75:570.
35. Briani C, Vitaliani R, Grisold W, et al. Spectrum of paraneoplastic disease associated with
lymphoma. Neurology 2011; 76:705.
36. Graus F, Ariño H, Dalmau J. Paraneoplastic neurological syndromes in Hodgkin and non-
Hodgkin lymphomas. Blood 2014; 123:3230.
37. Dabbs DJ, Striker LM, Mignon F, Striker G. Glomerular lesions in lymphomas and leukemias.
Am J Med 1986; 80:63.
38. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises.
Case 15-1983. A 24-year-old man with cervical lymphadenopathy and the nephrotic
syndrome. N Engl J Med 1983; 308:888.
39. Seymour JF, Gagel RF. Calcitriol: the major humoral mediator of hypercalcemia in Hodgkin's
disease and non-Hodgkin's lymphomas. Blood 1993; 82:1383.
3/29/23, 8:08 PM 4688
40. Rieke JW, Donaldson SS, Horning SJ. Hypercalcemia and vitamin D metabolism in Hodgkin's
disease. Is there an underlying immunoregulatory relationship? Cancer 1989; 63:1700.
41. Shah SJ, Warrier RP, Ode DL, et al. Immune thrombocytopenia and hemolytic anemia
associated with Hodgkin disease. J Pediatr Hematol Oncol 1996; 18:227.
42. Sierra RD. Coombs-positive hemolytic anemia in Hodgkin's disease: case presentation and
review of the literature. Mil Med 1991; 156:691.
43. Di Biagio E, Sánchez-Borges M, Desenne JJ, et al. Eosinophilia in Hodgkin's disease: a role
for interleukin 5. Int Arch Allergy Immunol 1996; 110:244.
44. Teruya-Feldstein J, Jaffe ES, Burd PR, et al. Differential chemokine expression in tissues
involved by Hodgkin's disease: direct correlation of eotaxin expression and tissue
eosinophilia. Blood 1999; 93:2463.
45. Barrington SF, Mikhaeel NG, Kostakoglu L, et al. Role of imaging in the staging and
response assessment of lymphoma: consensus of the International Conference on
Malignant Lymphomas Imaging Working Group. J Clin Oncol 2014; 32:3048.
46. Zukerberg LR, Collins AB, Ferry JA, Harris NL. Coexpression of CD15 and CD20 by Reed-
Sternberg cells in Hodgkin's disease. Am J Pathol 1991; 139:475.
47. Schmid C, Pan L, Diss T, Isaacson PG. Expression of B-cell antigens by Hodgkin's and Reed-
Sternberg cells. Am J Pathol 1991; 139:701.
48. Schmitz R, Stanelle J, Hansmann ML, Küppers R. Pathogenesis of classical and lymphocyte-
predominant Hodgkin lymphoma. Annu Rev Pathol 2009; 4:151.
49. Venkataraman G, Song JY, Tzankov A, et al. Aberrant T-cell antigen expression in classical
Hodgkin lymphoma is associated with decreased event-free survival and overall survival.
Blood 2013; 121:1795.
50. Li Z, Ju X, Lee K, et al. CD83 is a new potential biomarker and therapeutic target for
Hodgkin lymphoma. Haematologica 2018; 103:655.
51. Carbone A, Gloghini A, Gattei V, et al. Expression of functional CD40 antigen on Reed-
Sternberg cells and Hodgkin's disease cell lines. Blood 1995; 85:780.
52. Munro JM, Freedman AS, Aster JC, et al. In vivo expression of the B7 costimulatory molecule
by subsets of antigen-presenting cells and the malignant cells of Hodgkin's disease. Blood
1994; 83:793.
53. Diepstra A, van Imhoff GW, Karim-Kos HE, et al. HLA class II expression by Hodgkin Reed-
Sternberg cells is an independent prognostic factor in classical Hodgkin's lymphoma. J Clin
Oncol 2007; 25:3101.
3/29/23, 8:08 PM 4688
54. Kanzler H, Küppers R, Hansmann ML, Rajewsky K. Hodgkin and Reed-Sternberg cells in
Hodgkin's disease represent the outgrowth of a dominant tumor clone derived from
(crippled) germinal center B cells. J Exp Med 1996; 184:1495.
55. Pinkus GS, Pinkus JL, Langhoff E, et al. Fascin, a sensitive new marker for Reed-Sternberg
cells of hodgkin's disease. Evidence for a dendritic or B cell derivation? Am J Pathol 1997;
150:543.
56. Poppema S, Kaleta J, Hepperle B. Chromosomal abnormalities in patients with Hodgkin's
disease: evidence for frequent involvement of the 14q chromosomal region but infrequent
bcl-2 gene rearrangement in Reed-Sternberg cells. J Natl Cancer Inst 1992; 84:1789.
57. M'kacher R, Bennaceur-Griscelli A, Girinsky T, et al. Telomere shortening and associated
chromosomal instability in peripheral blood lymphocytes of patients with Hodgkin's
lymphoma prior to any treatment are predictive of second cancers. Int J Radiat Oncol Biol
Phys 2007; 68:465.
58. Schlegelberger B, Weber-Matthiesen K, Himmler A, et al. Cytogenetic findings and results
of combined immunophenotyping and karyotyping in Hodgkin's disease. Leukemia 1994;
8:72.
59. Weber-Matthiesen K, Deerberg J, Poetsch M, et al. Numerical chromosome aberrations are
present within the CD30+ Hodgkin and Reed-Sternberg cells in 100% of analyzed cases of
Hodgkin's disease. Blood 1995; 86:1464.
60. Inghirami G, Macri L, Rosati S, et al. The Reed-Sternberg cells of Hodgkin disease are clonal.
Proc Natl Acad Sci U S A 1994; 91:9842.
61. Green MR, Monti S, Rodig SJ, et al. Integrative analysis reveals selective 9p24.1
amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular
sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood
2010; 116:3268.
62. Roemer MG, Advani RH, Ligon AH, et al. PD-L1 and PD-L2 Genetic Alterations Define
Classical Hodgkin Lymphoma and Predict Outcome. J Clin Oncol 2016; 34:2690.
63. Müschen M, Rajewsky K, Bräuninger A, et al. Rare occurrence of classical Hodgkin's disease
as a T cell lymphoma. J Exp Med 2000; 191:387.
64. Reichel J, Chadburn A, Rubinstein PG, et al. Flow sorting and exome sequencing reveal the
oncogenome of primary Hodgkin and Reed-Sternberg cells. Blood 2015; 125:1061.
65. Tiacci E, Ladewig E, Schiavoni G, et al. Pervasive mutations of JAK-STAT pathway genes in
classical Hodgkin lymphoma. Blood 2018; 131:2454.
3/29/23, 8:08 PM 4688
66. Spina V, Bruscaggin A, Cuccaro A, et al. Circulating tumor DNA reveals genetics, clonal
evolution, and residual disease in classical Hodgkin lymphoma. Blood 2018; 131:2413.
67. Schmitz R, Hansmann ML, Bohle V, et al. TNFAIP3 (A20) is a tumor suppressor gene in
Hodgkin lymphoma and primary mediastinal B cell lymphoma. J Exp Med 2009; 206:981.
68. Otto C, Giefing M, Massow A, et al. Genetic lesions of the TRAF3 and MAP3K14 genes in
classical Hodgkin lymphoma. Br J Haematol 2012; 157:702.
69. Mata E, Díaz-López A, Martín-Moreno AM, et al. Analysis of the mutational landscape of
classic Hodgkin lymphoma identifies disease heterogeneity and potential therapeutic
targets. Oncotarget 2017; 8:111386.
70. Tiacci E, Döring C, Brune V, et al. Analyzing primary Hodgkin and Reed-Sternberg cells to
capture the molecular and cellular pathogenesis of classical Hodgkin lymphoma. Blood
2012; 120:4609.
71. Mathas S, Janz M, Hummel F, et al. Intrinsic inhibition of transcription factor E2A by HLH
proteins ABF-1 and Id2 mediates reprogramming of neoplastic B cells in Hodgkin
lymphoma. Nat Immunol 2006; 7:207.
72. Stein H, Marafioti T, Foss HD, et al. Down-regulation of BOB.1/OBF.1 and Oct2 in classical
Hodgkin disease but not in lymphocyte predominant Hodgkin disease correlates with
immunoglobulin transcription. Blood 2001; 97:496.
73. Ehlers A, Oker E, Bentink S, et al. Histone acetylation and DNA demethylation of B cells
result in a Hodgkin-like phenotype. Leukemia 2008; 22:835.
74. Janz M, Hummel M, Truss M, et al. Classical Hodgkin lymphoma is characterized by high
constitutive expression of activating transcription factor 3 (ATF3), which promotes viability
of Hodgkin/Reed-Sternberg cells. Blood 2006; 107:2536.
75. Küppers R, Klein U, Schwering I, et al. Identification of Hodgkin and Reed-Sternberg cell-
specific genes by gene expression profiling. J Clin Invest 2003; 111:529.
76. Marafioti T, Pozzobon M, Hansmann ML, et al. Expression of intracellular signaling
molecules in classical and lymphocyte predominance Hodgkin disease. Blood 2004;
103:188.
77. Schwering I, Bräuninger A, Klein U, et al. Loss of the B-lineage-specific gene expression
program in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma. Blood 2003;
101:1505.
78. Hinz M, Lemke P, Anagnostopoulos I, et al. Nuclear factor kappaB-dependent gene
expression profiling of Hodgkin's disease tumor cells, pathogenetic significance, and link to
3/29/23, 8:08 PM 4688
constitutive signal transducer and activator of transcription 5a activity. J Exp Med 2002;
196:605.
79. Hinz M, Löser P, Mathas S, et al. Constitutive NF-kappaB maintains high expression of a
characteristic gene network, including CD40, CD86, and a set of antiapoptotic genes in
Hodgkin/Reed-Sternberg cells. Blood 2001; 97:2798.
80. Höpken UE, Foss HD, Meyer D, et al. Up-regulation of the chemokine receptor CCR7 in
classical but not in lymphocyte-predominant Hodgkin disease correlates with distinct
dissemination of neoplastic cells in lymphoid organs. Blood 2002; 99:1109.
81. Skinnider BF, Elia AJ, Gascoyne RD, et al. Signal transducer and activator of transcription 6
is frequently activated in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma. Blood
2002; 99:618.
82. Mathas S, Hinz M, Anagnostopoulos I, et al. Aberrantly expressed c-Jun and JunB are a
hallmark of Hodgkin lymphoma cells, stimulate proliferation and synergize with NF-kappa
B. EMBO J 2002; 21:4104.
83. Lukes R, Butler J, Hicks E. Natural history of Hodgkin's disease as related to its pathological
picture. Cancer 1966; 19:317.
84. Lukes RJ, Butler JJ. The pathology and nomenclature of Hodgkin's disease. Cancer Res 1966;
26:1063.
85. Strickler JG, Michie SA, Warnke RA, Dorfman RF. The "syncytial variant" of nodular
sclerosing Hodgkin's disease. Am J Surg Pathol 1986; 10:470.
86. Ashton-Key M, Thorpe PA, Allen JP, Isaacson PG. Follicular Hodgkin's disease. Am J Surg
Pathol 1995; 19:1294.
87. Sextro M, Diehl V, Franklin J, et al. Lymphocyte predominant Hodgkin's disease--a workshop
report. European Task Force on Lymphoma. Ann Oncol 1996; 7 Suppl 4:61.
88. Klimm B, Franklin J, Stein H, et al. Lymphocyte-depleted classical Hodgkin's lymphoma: a
comprehensive analysis from the German Hodgkin study group. J Clin Oncol 2011; 29:3914.
89. Neiman RS, Rosen PJ, Lukes RJ. Lymphocyte-depletion Hodgkin's disease. A
clinicopathological entity. N Engl J Med 1973; 288:751.
90. Leoncini L, Del Vecchio MT, Kraft R, et al. Hodgkin's disease and CD30-positive anaplastic
large cell lymphomas--a continuous spectrum of malignant disorders. A quantitative
morphometric and immunohistologic study. Am J Pathol 1990; 137:1047.
91. Stein H, Herbst H, Anagnostopoulos I, et al. The nature of Hodgkin and Reed-Sternberg
cells, their association with EBV, and their relationship to anaplastic large-cell lymphoma.
Ann Oncol 1991; 2 Suppl 2:33.
3/29/23, 8:08 PM 4688
92. Dojcinov SD, Venkataraman G, Raffeld M, et al. EBV positive mucocutaneous ulcer--a study
of 26 cases associated with various sources of immunosuppression. Am J Surg Pathol 2010;
34:405.
93. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization
classification of lymphoid neoplasms. Blood 2016; 127:2375.
94. Vassallo J, Lamant L, Brugieres L, et al. ALK-positive anaplastic large cell lymphoma
mimicking nodular sclerosis Hodgkin's lymphoma: report of 10 cases. Am J Surg Pathol
2006; 30:223.
95. Bakshi NA, Finn WG, Schnitzer B, et al. Fascin expression in diffuse large B-cell lymphoma,
anaplastic large cell lymphoma, and classical Hodgkin lymphoma. Arch Pathol Lab Med
2007; 131:742.
96. Traverse-Glehen A, Pittaluga S, Gaulard P, et al. Mediastinal gray zone lymphoma: the
missing link between classic Hodgkin's lymphoma and mediastinal large B-cell lymphoma.
Am J Surg Pathol 2005; 29:1411.
97. García JF, Mollejo M, Fraga M, et al. Large B-cell lymphoma with Hodgkin's features.
Histopathology 2005; 47:101.
98. Dunleavy K, Wilson WH. Primary mediastinal B-cell lymphoma and mediastinal gray zone
lymphoma: do they require a unique therapeutic approach? Blood 2015; 125:33.
Topic 4688 Version 24.0
3/29/23, 8:08 PM 4688
GRAPHICS
Classification of Hodgkin lymphomas
World Health
Jackson and Lukes and Rye R.E.A.L. Organization
Parker Butler Conference Classification (WHO)
Classification
Paragranuloma Lymphocytic Lymphocyte Nodular Nodular lymphocyte

and/or predominance lymphocyte predominant HL
histiocytic, predominance
nodular
Lymphocytic Classical Lymphocyte-rich

and/or Lymphocyte-rich classical HL
histiocytic, HL*
diffuse
Granuloma Nodular Nodular Classical Nodular Nodular sclerosis

sclerosis sclerosis sclerosis HL classical HL
Mixed cellularity Mixed cellularity Classical Mixed Mixed cellularity

cellularity HL classical HL
Sarcoma Diffuse fibrosis Lymphocyte Classical Lymphocyte depleted

depletion Lymphocyte classical HL
depletion HL
Reticular
HL: Hodgkin lymphoma.
* Includes some L&H nodular cases.
Graphic 76591 Version 1.0
3/29/23, 8:08 PM 4688
Lymph node regions in lymphoma
Lymph node regions used to determine stage in lymphoma.
3/29/23, 8:08 PM 4688
Frequency of involved sites in pathologically staged untreated patients with

Hodgkin lymphoma
Site Percent involved
Nodal sites, spleen, and liver
Cervical nodes
Left side 60 to 70
Right side 50 to 60
Mediastinal nodes 50 to 60
Paraaortic nodes 30 to 40
Axillary nodes
Left side 30 to 35
Right side 25 to 35
Spleen 30 to 35
Hilar nodes 15 to 35
Iliac nodes 15 to 20
Inguinal nodes 8 to 15
Liver 2 to 6
Mesenteric nodes 1 to 4
Waldeyer's ring 1 to 2
Extranodal sites
Total extranodal 10 to 15
Bone marrow 1 to 4
Other (eg, lungs, bone) 10 to 12
Data from: Gupta RK, Gospodarowicz MK, Lister TA. Clinical evaluation and staging of Hodgkin's disease. In: Hodgkin's
disease, Mauch PM, Armitage JO, Diehl V, et al. (Eds), Lippincott Williams & Wilkins, Philadelphia 1999.
3/29/23, 8:08 PM 4688
Diagnostic Reed-Sternberg cell in Hodgkin lymphoma
A diagnostic Reed-Sternberg cell is seen in the center, and many

mononucleated and multinucleated Reed-Sternberg variants are seen
throughout the field.
Reproduced with permission from: Weiss LM, Warnke RA, Hansmann ML, et al. Pathology of
Hodgkin Lymphoma. In: Hodgkin Lymphoma, 2nd ed, Hoppe RT, Mauch PT, Armitage JO, et al
3/29/23, 8:08 PM 4688
(Eds), Lippincott Williams & Wilkins, Philadelphia 2007. Copyright © 2007 Lippincott Williams
& Wilkins. www.lww.com.
3/29/23, 8:08 PM 4688
Diagnostic Reed-Sternberg cell with two nuclei
A diagnostic Reed-Sternberg cell with two nuclei is seen in the center (arrow)
with a prominent eosinophilic nucleolus present in each nucleus. There is
some chromatin clearing around each nucleolus. Several mononuclear Reed-
Sternberg variants are also present in the upper half of the field (dashed
arrow).
3/29/23, 8:08 PM 4688
(Eds), Lippincott Williams & Wilkins, Philadelphia 2007. Copyright © 2007 Lippincott Williams &
Wilkins. www.lww.com.
3/29/23, 8:08 PM 4688
Mononuclear Hodgkin cells
Bone marrow biopsy with mononuclear Hodgkin cells. Mononuclear Hodgkin cells are indicated with
arrows.
Courtesy of Olga Pozdnyakova, MD, PhD, Department of Pathology, Brigham and Women's Hospital.
3/29/23, 8:08 PM 4688
Lacunar cells and mummified Reed-Sternberg cell
Several "lacunar cells" are present. They are characterized by multilobated

nuclei, small nucleoli, and abundant, pale cytoplasm that often "retracts"
during tissue fixation and sectioning, leaving the nucleus in what appears to
be an empty space (lacune). "Mummified cells" are neoplastic cells that
contain condensed cytoplasm and pyknotic reddish nuclei. A "mummified"
Reed-Sternberg cell is in the upper left corner.
3/29/23, 8:08 PM 4688
(Eds), Lippincott Williams & Wilkins, Philadelphia 2007. Copyright © 2007 Lippincott Williams &
Wilkins. www.lww.com.
3/29/23, 8:08 PM 4688
Immunostaining for CD30 in Hodgkin lymphoma
Immunostaining for CD30 demonstrates strong membrane and paranuclear

staining, and weaker cytoplasmic staining, of the Hodgkin cells.
3/29/23, 8:08 PM 4688
3/29/23, 8:08 PM 4688
Immunostaining for CD15 in Hodgkin lymphoma
Immunostaining for CD15 demonstrates strong membrane and paranuclear

staining of the Hodgkin cells.
3/29/23, 8:08 PM 4688
3/29/23, 8:08 PM 4688
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and classic

Hodgkin lymphoma (HL): Morphologic and immunophenotypic features
Classic HL NLPHL
Pattern Diffuse, interfollicular, nodular Nodular, at least in part
Tumor cells Diagnostic RS cells; mononuclear or "L&H" or "popcorn" cells

lacunar cells
Background Lymphocytes, histiocytes, eosinophils, Lymphocytes, histiocytes

plasma cells
Fibrosis Common Rare
CD15 + -
CD30 + -
CD20 -/+ +
CD45 - +
EMA - +
EBV (in RS cells) + (∼50%) -
Oct2 -/+ +
BOB.1 -/+ +
Background T cells > B cells B cells > T cells

lymphocytes
CD57+ Tcells - +
Ig genes (single- Rearranged, clonal, mutated, Rearranged, clonal, mutated,

cell PCR) "crippled", no ongoing somatic productive, ongoing somatic
hypermutation hypermutation
3/29/23, 8:08 PM 4688
Nodular sclerosis Hodgkin lymphoma
Broad bands of fibrosis separate several nodules in nodular sclerosis

Hodgkin lymphoma.
3/29/23, 8:08 PM 4688
3/29/23, 8:08 PM 4688
Nodular sclerosis Hodgkin lymphoma
Prominent fibrous bands divide this lymph node into nodules.
From Warnke RA, Weiss LM, Chan JK, et al. Tumors of the lymph nodes and spleen.
Atlas of tumor pathology (electronic fascicle), Third series, fascicle 14, 1995,
Washington, DC. Armed Forces Institute of Pathology.
3/29/23, 8:08 PM 4688
Syncytial form of nodular sclerosis Hodgkin lymphoma
Sheets of lacunar cells are clustered around a center area of necrosis in the
syncytial form of nodular sclerosis Hodgkin lymphoma.
3/29/23, 8:08 PM 4688
3/29/23, 8:08 PM 4688
Mixed-cellularity Hodgkin lymphoma
There is an absence of fibrous bands in mixed-cellularity Hodgkin

lymphoma.
3/29/23, 8:08 PM 4688
3/29/23, 8:08 PM 4688
Hodgkin lymphoma variants
Left panel: Mixed cellularity variant. The characteristic background infiltrate

of reactive cells (eosinophils, lymphocytes) and uninucleate Reed-Sternberg
cells is present in this field (red arrow). Right panel: Lymphocyte depletion
variant. Diffuse fibrosis is seen, and a diagnostic binucleate Reed-Sternberg
cell is present (blue arrow).
From: Warnke RA, Weiss LM, Chan JK, et al. Tumors of the lymph nodes and spleen. Atlas of
tumor pathology (electronic fascicle), Third series, fascicle 14, 1995, Washington, DC. Armed
Forces Institute of Pathology.
3/29/23, 8:08 PM 4688
Hodgkin lymphoma, lymphocyte-rich type
Few Reed-Sternberg cells or variants within a mass of lymphocytes. Hematoxylin,

phloxine, and saffron stain.
Reproduced with permission from: Ioachim HL, Medeiros LJ. Hodgkin lymphoma: Classical. In:
Ioachim's Lymph Node Pathology, 4th ed, Lippincott Williams & Wilkins, Philadelphia 2009. Copyright
© 2009 Lippincott Williams & Wilkins. www.lww.com.
3/29/23, 8:08 PM 4688
Lymphocyte depletion Hodgkin lymphoma
Numerous Reed-Sternberg cells are seen in a background of fibrosis.
From: Warnke RA, Weiss LM, Chan JK, et al. Tumors of the lymph nodes and spleen.
Atlas of tumor pathology (electronic fascicle), Third series, fascicle 14, 1995,
Washington, DC. Armed Forces Institute of Pathology.
3/29/23, 8:08 PM 4688
Lymphocyte depleted diffuse fibrous type Hodgkin

lymphoma
There is a reticulin collagen fibrosis around single cells. Although the

Hodgkin cells appear atypical, results of immunophenotyping studies were
characteristic of Hodgkin lymphoma in this case.
3/29/23, 8:08 PM 4688
3/29/23, 8:08 PM 4688
Nodular lymphocyte-predominant Hodgkin lymphoma

(NLPHL)
Large multilobated LP cells can be seen in this field. Most of the LP cells in
this case had distinct or prominent eosinophilic nucleoli, unlike classic
"popcorn" cells. Hematoxylin and eosin stain.
Reproduced with permission from: Ioachim HL, Medeiros LJ. Hodgkin lymphoma: Nodular
lymphocyte predominant. In: Ioachim's Lymph Node Pathology, 4th ed, Lippincott Williams &
Wilkins, Philadelphia 2009. Copyright © 2009 Lippincott Williams & Wilkins. www.lww.com.
3/29/23, 8:08 PM 4688
Contributor Disclosures
Ann S LaCasce, MD Grant/Research/Clinical Trial Support: Forty Seven [Lymphoma]. Consultant/Advisory
Boards: Bristol-Myers Squibb [Hodgkin lymphoma DSMB]. Speaker's Bureau: Research To Practice
[Lymphoma]. All of the relevant financial relationships listed have been mitigated. Andrea K Ng, MD,
MPH No relevant financial relationship(s) with ineligible companies to disclose. Jon C Aster, MD,
PhD Equity Ownership/Stock Options: neuAPC [Immunotherapy]. Consultant/Advisory Boards: Ayala
[Hematologic malignancies];Cellestia [Hematologic malignancies];Remix Therapeutics[Hematologic
malignancies]. All of the relevant financial relationships listed have been mitigated. Arnold S Freedman,
MD Other Financial Interest: Bayer [Lymphoma DSMB]. All of the relevant financial relationships listed
have been mitigated. Alan G Rosmarin, MD No relevant financial relationship(s) with ineligible companies
to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
Conflict of interest policy

Linfoma de Hodgkin

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Linfoma de Hodgkin

Uploaded by

Copyright:

Available Formats

3/29/23, 8:08 PM 4688

Official reprint from UpToDate®

Clinical presentation and diagnosis of classic Hodgkin

HL is divided into two major categories, based on morphology and immunophenotype

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

• 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.

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

Clinical manifestations, diagnosis, and treatment of nodular lymphocyte-predominant HL are

Lymphadenopathy — Lymphadenopathy is detectable in more than two-thirds of patients

clinical enlargement of mediastinal nodes. Noncontiguous spread and/or hematologic

Mediastinal mass — Discovery of a mediastinal mass on routine chest radiograph is another

B symptoms — B symptoms specifically refers to fever, night sweats, or weight loss in

B symptoms are formally defined as follows [7]:

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

● Sweats – The presence of drenching night sweats

The presence of B symptoms is an adverse prognostic feature that influences treatment

Pruritus — Pruritus occurs in approximately 10 to 15 percent of patients at presentation and

Less common presentations — Less common or atypical presentations of cHL include

Examples of less common clinical presentations of cHL include:

● Other intra-abdominal disease – Retroperitoneal lymphadenopathy may cause flank

nodosum, necrotizing lesions, hyperpigmentation, and skin infiltration [15,16]. (See

● Bone/bone marrow involvement – Bony involvement at presentation is uncommon, but

● Nephrotic syndrome – Nephrotic syndrome can occur as a paraneoplastic syndrome in

● Laboratory abnormalities – A variety of laboratory abnormalities can occur in patients

Examples of laboratory findings at presentation include:

• Hypercalcemia – Hypercalcemia is usually due to increased production of calcitriol

• Eosinophilia – Eosinophilia is relatively common in HL and is caused by production of

• Other – Other laboratory abnormalities may include leukocytosis, thrombocytosis,

Laboratory studies — Laboratory studies for all patients should include:

● Organ involvement – Imaging for evaluation of organ involvement is described below.

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

Radiologic diagnosis of liver involvement by cHL is challenging because it usually consists

Neurologic abnormalities may also be caused by a paraneoplastic neurologic syndrome.

Documentation of extranodal involvement by cHL is an important component of disease

Microscopy — In cHL, the lymph node is effaced by variable numbers of Hodgkin/Reed-

Morphology — Hodgkin/Reed-Sternberg (HRS) cell is a collective term for classic Reed-

Characteristic RS variant cells include:

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

Immunophenotype — The immunophenotype of HRS cells is typically characterized by:

Chromosomal instability is manifest by diverse cytogenetic abnormalities and intraclonal

● Immunoglobulin (Ig) and T cell receptor (TCR) gene rearrangements – Clonal

Altered expression of NF-kB B target genes, components of the JAK/STAT signaling

The diagnosis of cHL should be suspected in a patient with lymphadenopathy or a mediastinal

● Lymph node – Diagnostic HRS cells in a polymorphous inflammatory infiltrate of small

Nodular sclerosis — Nodular sclerosis cHL (NSCHL) is characterized by a nodular growth

Some histologic variants of NSCHL have been described:

Mixed cellularity — Mixed cellularity cHL (MCCHL) is a heterogeneous subtype of classic HL

background infiltrate is variable, but typically consists of eosinophils, neutrophils,

Lymphocyte depleted — Lymphocyte-depleted cHL (LDCHL) is the least common subtype of

Numerous conditions cause lymphadenopathy that may be accompanied by fever, sweats,

EBV-positive mucocutaneous ulcer — Epstein-Barr virus (EBV)-positive mucocutaneous ulcer

Nodular lymphocyte-predominant HL — Nodular lymphocyte-predominant HL (NLPHL) can

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

Nonetheless, there are occasional cases in which the combination of morphology,

Other B cell lymphomas

● Primary mediastinal B cell lymphoma (PMBL) – Primary mediastinal B cell lymphoma

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

● Classic Hodgkin lymphoma (cHL) – cHL refers to lymphoid neoplasms in which