Pathology (- xxxx) xxx(xxx), xxx

LY M P H O M A 2 0 2 0 : A N U P D AT E

Hodgkin lymphoma: a review of pathological features and

recent advances in pathogenesis
MIGUEL A. PIRIS1, L. JEFFREY MEDEIROS2, KUNG-CHAO CHANG3
1
Pathology Service, Fundación Jiménez Díaz, CIBERONC, Madrid, Spain; 2Department of
Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;
3
Department of Pathology, National Cheng Kung University Hospital, College of Medicine,
National Cheng Kung University, Tainan, Taiwan

Summary Abbreviations: DLBCL, diffuse large B-cell lymphoma; EBV, Epstein–Barr

Hodgkin lymphoma (HL) is composed of two distinct virus; ER, endoplasmic reticulum; HL, Hodgkin lymphoma; IM, infectious
mononucleosis; LD, lymphocyte depleted; LRC, lymphocyte-rich classic;
pathological entities, nodular lymphocyte predominant HL MC, mixed cellularity; NLPHL, nodular lymphocyte predominant Hodgkin
and classic HL, the latter with four subtypes. In contrast lymphoma; NS, nodular sclerosis; RS, Reed–Sternberg.
with most other human lymphomas, in which the
neoplastic cells are a major population of the tumour
constituents, the neoplastic ‘Hodgkin (H) and INTRODUCTION
Reed–Sternberg (RS)’ cells usually account for less than Hodgkin lymphoma
10% of tumour bulk against an inflammatory background.
The designation lymphoma represents a large group of ma-
The neoplastic cells of HL are of B-cell lineage (PAX5+) in
lignant neoplasms arising from components of the immune
virtually all cases. HL usually affects young patients with a
system, namely T and B cells. The first lymphoma type
localised nodal disease and its clinical behaviour is typi-
recognised was by Dr Thomas Hodgkin in 1832. In 1865 Dr
cally indolent. Patients respond well to chemotherapy with
Samuel Wilks recognised additional cases, rediscovered the
cure rates of 80–90% and the recent finding of PD-L1
report by Hodgkin, and designated this neoplasm as ‘Hodg-
expression, an immune checkpoint, warrants the use of
kin disease’, a name used for over 100 years. This disease is
immunotherapy for some patients with recurrent and/or
now known as Hodgkin lymphoma (HL) and represents
refractory HL.
about 10% of all lymphomas. HL is distinct from other non-
The enigmatic RS cells of HL are unique in their abundant
Hodgkin lymphomas, clinically by the contiguous spread of
cytoplasm and characteristic bilobed nuclei with eosino-
tumour along the lymphoid system, and morphologically by
philic prominent nucleoli, imparting an ‘owl-eye’ appear-
the presence of a spectrum of neoplastic cells, including
ance. H cells are mononuclear variants. The viral
mononuclear Hodgkin (H) cells, classic multinucleated
inclusion-like morphology was a clue on the way to
Reed–Sternberg (RS) cells, and mummified (degenerating)
discovering an association between classic HL and
cells against an inflammatory background.1,2 The back-
Epstein–Barr virus (EBV). However, this association is
ground inflammatory cells actively attracted by HL tumour
variable in different geographic regions and in pathological
cells may include T cells, B cells, histiocytes, plasma cells,
subtypes, and correlates with older age (>60 years) and
neutrophils, eosinophils and mast cells.3 Based on the
socioeconomic status, indicating that environmental fac-
morphology and immunophenotype of the neoplastic cells
tors are likely involved in HL pathogenesis. Virus-
and the background cellular infiltrate, HL is subdivided into
associated endoplasmic reticulum (ER) stress also may
nodular lymphocyte predominant (NLPHL) type and classic
contribute to mechanisms underlying the characteristic
type. These diseases should be clearly distinguished because,
morphological features of HRS cells. ER stress has been
in spite of some common morphological features, they differ
found to induce aberrant, cytoplasmic cyclin A expression,
in their molecular pathogenesis, immunophenotype, prog-
leading to nuclear hyperdiploidy. Aberrant expression of
nosis and therapy. Classic HL is further subdivided into
cyclin A is commonly associated with HRS cell
nodular sclerosis (NS), mixed cellularity (MC), lymphocyte-
morphology in HL, probably through EBV-latent membrane
rich classic (LRC), and lymphocyte depleted (LD).4
protein-1 (LMP1) signalling. Shelterin also may play a role
Although RS-like cells may occur in diseases other than
in the morphogenesis of multinucleated RS cells. In addi-
HL, such as peripheral B-cell and T-cell lymphomas and
tion, EBV-positive and -negative HL cases express sur-
infectious mononucleosis (IM),2 the presence of unequivocal
vival, but not death signals of ER stress at similar levels
RS cells is characteristic of HL and required for the diagnosis
and EBV-LMP1 transfection increases expression of sur-
of some types of classic HL. HRS cells and mummified cells
vival signals in HL cell lines. These data suggest that
are thought to be proliferative and apoptotic in nature,
surviving ER stress may be involved in HL pathogenesis.
respectively.2,5,6 However, the inter-relationship among these
Key words: Hodgkin lymphoma; Epstein–Barr virus; epidemiology; variant HL cells, including H cells, RS cells, and apoptotic
morphology; differential diagnosis; pathogenesis. mummified cells, remains mysterious. It was initially thought

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DOI: https://doi.org/10.1016/j.pathol.2019.09.005

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2 PIRIS et al.
that H cells fused into terminally differentiated RS cells in a
process likened to monocytic giant cell formation, while the
results of later studies suggested the formation of RS cells
from H cells through centrosome overduplication and
disturbance of cytokinesis.7–9 Immunophenotypically,
classic HL cells express CD30 in all cases, CD15 in about
75% cases and PAX5 in virtually all cases.4 However, little is
known about the cell biology and gene expression underlying
the morphogenesis of RS cells.10,11 Recent studies have
shown that the neoplastic cells in virtually all cases of classic
HL are derived from germinal centre B cells with defective
surface B-cell receptors, crippled immunoglobulin tran-
scripts, and lost B-cell programs due to epigenetic
silencing.4,11–14 The molecular pathogenesis of HL has been
considered to result from a balance of proliferative and
apoptotic effects, involving tumour necrosis factor receptor-
associated factors (TRAFs), nuclear factor-kB (NF-kB),
signal transducer and activator of transcription (STAT) and
cytokine pathways, and expression of cellular FLICE-
inhibitory protein (cFLIP) with inhibition of caspases activ-
ities.4,15 The molecular events associated with HL described
above represent largely secondary or downstream signals in
the pathogenesis of HL. The primary event of HL, however,
remains to be clarified and will be discussed in the patho-
genesis section.
Epstein–Barr virus and Hodgkin lymphoma
Epstein–Barr virus (EBV), also called human herpes virus 4
(HHV-4), is a member of the herpes family and is one of the
most common viruses in humans. Mature virions are
approximately 120–180 nm in diameter, have a double-
stranded, linear DNA genome surrounded by a protein
capsid, and contain approximately 100 genes.16 A protein
tegument lies between the capsid and the envelope, which is
embedded with glycoproteins that are important for cell
tropism, receptor recognition, and infection of host cells.17
More than 90% of adults worldwide have evidence of EBV
infection.18 EBV preferentially infects B cells through the
expression of CD21 and human leukocyte antigen (HLA) on
the cell surface.19 In immunocompetent hosts, EBV-infected
B cells are in a resting state under host T-cell immune sur-
veillance.20 In hosts with immune dysfunction, EBV-infected
cells in the reservoir may be reactivated and proliferate.21
EBV causes IM and is associated with nasopharyngeal car-
cinoma, lymphoepithelioma-like carcinoma, and several
types of lymphoma including a significant proportion of HL
cases and other large B-cell lymphomas.4 In EBV-infected
cells, based on the viral proteins expressed, three latency
transcription programs of EBV are designated: growth pro-
gram (latency III) with expression of EBV nuclear antigens
1–6 (EBNA1-6), latent membrane proteins (LMP1, 2A and
2B); default program (latency II) expressing EBNA1, LMP1
and LMP2A; and latency program (latency I), with none or
only expression of LMP2A.20 EBV-encoded RNA is
expressed in all three phases.
The genomes of EBV were first localised specifically in RS
cells by in situ hybridisation with a DNA probe in 1989.22
Early acquisition of EBV infection is prevalent in devel-
oping countries.23 It has been found that acute EBV infection
or IM is a risk factor for HL,24,25 and it has been proposed
Please cite this article as: Piris MA et al., Hodgkin lymphoma: a review of pathological features and recent advances in pathogenesis, Pathology, https://
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Pathology (xxxx), xxx(xxx), -
that EBV rescues crippled germinal centre B cells from
apoptosis,26 but the full contribution of EBV to HL molecular
pathogenesis remains to be fully established. Among the five
subtypes of HL, i.e., NLPHL, NS, MC, LRC, and LD, MC
subtype is most frequently associated with EBV worldwide,
ranging from 72% to 86%, whereas NLPHL type is almost
always EBV-negative in Western countries, with rare
exceptions.27–30
EPIDEMIOLOGY
Hodgkin lymphoma accounts for up to 15–20% of all lym-
phomas in some Western countries, but accounts for less than
10% of all lymphomas in Asia, such as Taiwan, Japan and
China.31–33 Worldwide, about 90% of HLs are one of the
classic types and 10% or less are NLPHL.4,31,32,34 Table 1
summarises the frequency of HL types in Taiwan and
other, mostly Western countries.
The association between EBV infection and HL varies in
different geographic regions worldwide and with different
HL types (Table 2). The overall EBV positivity rate is
30–50% in the USA and Europe, but nearly 100% in Viet-
nam, Kenya and Honduras.27,35 Various explanations have
been proposed for these findings. Perhaps the most compel-
ling potential explanation is the relationship between the age
at which EBV infection occurs and the onset of HL. Previous
studies have shown that acute EBV infection or IM is a risk
factor for HL,24,25 and the infectious manifestations, espe-
cially the age at time of infection, are affected by the socio-
economic status.36,37 In Western industrialised countries, the
peak rate of IM occurs between the ages of 15 and 19 years.25
In Vietnam, the mean age for biopsy-based population was
only 5.3 years.35 Earlier exposure to EBV in the face of a
relatively underdeveloped immune response might thus be a
predisposing factor for EBV-positive HL. In this regard,
Hjalgrim et al. have found a positive association between IM
and EBV-positive HL, and the median incubation time from
IM to the onset of EBV-positive HL was 4.1 years in
developed countries.25 In Vietnam, an early mean age of IM
presentation and high EBV positivity in HL supports the
hypothesis that increased risk of EBV-positive HL may occur
in patients who acquire fulminant IM at an early age. An
alternative explanation, more difficult to study, is that envi-
ronmental and ethnic/genetic factors explain the differing
frequency of EBV positivity in HL.
Epidemiological studies have shown three incidence pat-
terns of HL. In pattern 1, seen in developing nations and in
patients of low socioeconomic status, there is an early
childhood peak in incidence with tumours that are predomi-
nantly MC subtype and EBV-positive. Pattern 3, seen in
developed countries and in patients of high socioeconomic
status, shows a peak incidence in the third decade with tu-
mours that are mainly NS subtype and EBV-negative. Pattern
2, seen in countries with transitional economies, has peaks of
incidence in childhood and a second decade peak and shows a
relatively more equal frequency of the MC and NS
subtypes.34,38–40
The comparison of HL cases from the same geographic
areas during different time periods provides an opportu-
nity to observe the influence of global environmental
factors, such as EBV infection and socioeconomic shifts,
 HODGKIN LYMPHOMA: PATHOLOGICAL FEATURES AND PATHOGENESIS 3

Table 1 Comparison of HL subtypes and EBV association over time in Taiwan and in Western countries

Subtype Total
NLP NS MC LRC LD Unclassified

Taiwan, 1982–1995
% 8% 53% 35% 1% 3% 0%
EBER+ 17% 59% 62% 0% 100% – 57%
M/F 4/2 29/10 20/6 0/1 2/0 – 55/19
Mean age 55.0 42.4 36.8 32.0 64.0 – 41.9
Taiwan, 1996–2007
% 6% 68% 13% 6% 2% 5%
EBER+ 0% 40% 85% 33% 0% 80% 44%
M/F 5/1 39/28 12/1 3/3 2/0 5/0 66/33
Mean age 50.8 36.6 48.2 56.7 25.0 62.6 41.3
p valuea 0.60 0.045 <0.001 0.12 0.77 – 0.004
Studies from Western countries
% 10% 70% 20–25% 5% <2% 4%
EBER+ 3–5% 10–25% 75% (72–85%) 57% 75% 33–100% 30–50%
M/F Maleb 1/1 7/3 2/1 2–3/1 NA
Peak age 30–50 15–34 38 30–50 30–71 NA
Reference 4 4,27,30 4,27,30 4,96 4,30,131 27,30 44

LD, lymphocyte depleted; LRC, lymphocyte-rich classic; MC, mixed cellularity; M/F, male/female; NA, not available; NLP, nodular lymphocyte predominant; NS,
nodular sclerosis.
a
p value for difference in each subtype frequency in Taiwan.
b
Male: male predominance.

Table 2 Detection rate of EBV in HL in different series

Country Method NLP NS MC LD LRC Unclassified Cases Reference

Vietnam EBER 3/3 (100%) 23/24 (96%) 11/11 (100%) 2/2 (100%) 2/4 (50%) – Children 35
Hong Kong EBER 0/1 (0%) 9/16 (56%) 5/5 (100%) 1/1 (100%) – – All ages 132
Philippines EBER/LMP 0/2 (0%) 3/10 (30%) 6/9 (67%) – – – All ages 133
Costa Rica LMP1 0/5 (0%) 3/20 (15%) 12/14 (86%) 1/1 (100%) – – All ages 134
Mexico EBER 0/1 (0%) 6/13 (46%) 7/7 (100%) 5/6 (83%) – – All ages 135
Mexico LMP1 1/1 (100%) 10/20 (50%) 18/22 (81%) 6/7 (86%) – – Adult 136
Kenya LMP1 2/2 (100%) 25/25 (100%) 16/16 (100%) 5/5 (100%) – 5/5 (100%) Children 137
Kenya LMP1 2/3 (67%) 26/39 (67%) 2/2 (100%) 2/4 (50%) – – Adult 137
Greece EBER/LMP 0/1 (0%) 4/10 (40%) 8/11 (72%) – – – Children 29
Honduras EBER 1/1 (100%) 3/3 (100%) 6/6 (100%) – – 1/1 (100%) Children 27
US EBER 0/2 (0%) 2/15 (13%) 6/7 (86%) – – 1/1 (100%) Children 27
UK LMP1 4/13 (31%) 14/36 (39%) 17/20 (85%) 1/2 (50%) – 1/3 (33%) Children 30
Germany PCR 4/13 (31%) 27/98 (27%) 34/68 (50%) 1/8 (12%) – – All ages 131
Germany PCR 29/71 (40%) – – – – – All ages 138

LD, lymphocyte depleted; LRC, lymphocyte-rich classic; MC, mixed cellularity; NLP, nodular lymphocyte predominant; NS, nodular sclerosis.

on disease patterns in HL. In a previous study in which we
compared the distribution of HL subtypes and EBV as-
sociation in 1996–2007 versus 1982–1995 in Taiwan
(Table 1), we found an increased frequency of NS subtype
and a decreased frequency of MC subtype, a reduced
mean age and M/F ratio in the NS subtype, and a
decreased overall rate of EBV positivity particularly in the
NS and LD subtypes.41 These data indicate a shift in
Taiwan from pattern 2 towards pattern 3 of HL, as pre-
viously reported in Western countries.42
EBV-positive HL is observed more frequently in
childhood (<10 years) and in older adults (>60 years), and
is highest in MC type and lowest in NLPHL type.43 – 45
Physiological immunosenescence and an imbalanced
Th1/Th2 cytokine profile may account for the higher fre-
quency of EBV infection in older patients.46 This biphasic
pattern possibly represents two distinct phenomena, one
related to age of EBV acquisition and the other to the
decline in immune function, each of which would likely
predominate in different populations. With improvements
in public health status, it appears that EBV positivity in
HL is becoming associated with older age. These findings
support the hypothesis that HL may have different aeti-
ologies in different age groups and indicate that the as-
sociation of EBV with HL likely becomes more common
in older patients as age of primary EBV infection rises in
any given country.45 Interestingly, this trend of decreased
EBV positivity rate in HL over time has been similarly
observed in Japanese patients and was thought to reflect
an increase in the incidence of EBV-negative NS subtype,
along with the progress in improvement of living stan-
dards.47 These findings suggest that environmental factors
can have profound effects on the role of pathogens in
tumour development and provide insights into how stra-
tegies for improvement of public health can influence the
incidence and biological features of cancers.

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4 PIRIS et al.
CLINICAL PRESENTATION
Classic HL
All classic HL subtypes share some common findings.
Classic HL is a nodal disease with virtually all cases arising in
peripheral lymph nodes, and commonly in the mediastinum.
When the disease advances, it may infiltrate spleen, liver and
other extranodal locations, but always associated with nodal
disease. Thus, cases of classic HL arising in extranodal lo-
cations must be carefully reviewed to exclude B-cell or T-cell
non-Hodgkin lymphoma. Inguinal lymph nodes may be
involved in the course of disease progression, but very rarely
classic HL may originate in this location.
Each classic HL subtype has some specific clinical and
histological features. NS HL is typically a disease arising in
the mediastinum of patients in the second and third decades.
MC HL, in contrast, is more commonly diagnosed in pe-
ripheral lymph nodes or spleen and found to be associated
with EBV and more common in immunodeficient patients.
LRCHL cases show overlapping clinical features with
NLPHL, with most of the cases diagnosed in early stages. LD
classic HL, a very uncommon (<2%) form of classic HL, is
frequently diagnosed in the context of HIV infection and
associated with EBV infection. Clinical stage remains the
most important prognostic factor in HL. Patients with LD HL
are usually diagnosed in more advanced clinical stages and
have a shorter survival probability.
Nodular lymphocyte predominant HL (NLPHL)
Patients with NLPHL are typically young males (2nd to 4th
decade) with disease diagnosed in early stages and involving
lymph nodes in cervical, axillary, inguinal or mesenteric
location. Most patients experience slow growth of the
lymphadenopathies, sometimes for several years. No extra-
nodal location for NLPHL has been described. A small
Fig. 1 Nodular sclerosis Hodgkin lymphoma (NS HL) cases exhibit characteristic morphological features including (A) sclerosis surrounding neoplastic nodules, (B)
presence of HRS and lacunar cells, (C) strong expression of CD30, and (D) frequent expression of CD15.
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Pathology (xxxx), xxx(xxx), -
subgroup of patients are diagnosed with advanced clinical
stage disease, frequently with bone marrow infiltration; his-
tological study in these cases may show findings mimicking
T-cell histiocyte-rich large B-cell lymphoma.48,49
PATHOLOGY
Classic HL
Diagnosis is based on the presence of HRS cells in the
context of a polymorphic infiltrate comprising small lym-
phocytes, histiocytes, plasma cells and eosinophils. In any
case, the diagnosis requires a combination of these histo-
logical features. Additionally, the presence of RS-like cells
can be seen in different disorders including IM, peripheral T-
cell lymphoma and large B-cell lymphoma, something that
should be taken into account before making a diagnosis of
classic HL. CD30 is a universal marker for classic HL cases;
all cases are positive without exception. Additionally, almost
all HL cases exhibit weak PAX5 staining of HRS cells, thus
reflecting the B-cell origin of the neoplastic cells. CD15 is
present in about 75% classic HL cases, but again this is not an
entirely specific marker, since CD15 expression can be found
in other B- and T-cell lymphomas.50 Expression of EBV
markers (both EBER and EBV-LMP) is a useful finding in
classic HL cases, where EBV-LMP expression is character-
istically seen in the HRS cells. Cytotoxic markers and other
T-cell (CD2, CD4) or B-cell (CD23) markers can be observed
uncommonly in the neoplastic cells of classic HL cases.51,52
Nodular sclerosis (NS) HL
Diagnosis is based on the presence of nodules surrounded by
collagen bands (nodular sclerosis) and HRS cells, together
with the polymorphic inflammatory infiltrate characteristic
for HL cases (Fig. 1). Most cases also show fibrosis,
geographic necrosis and lacunar cells (large pleomorphic
 HODGKIN LYMPHOMA: PATHOLOGICAL FEATURES AND PATHOGENESIS
CD30+ cells with abundant clear cytoplasm). The inflam-
matory infiltrate may be rich in eosinophils or, more rarely,
neutrophils. Presence of necrotic areas surrounded by his-
tiocytes and scattered pleomorphic large cells should prompt
CD30 staining for recognising these NS HL cases.
Grading for NS has been proposed, based on the relative
proportion of neoplastic cells (BNLI),53 but the widespread
use of core biopsies and the improvement on the therapeutic
protocols render this impractical or unnecessary for routine
clinical diagnosis.54 A syncytial variant of NS HL has been
proposed (Fig. 2),55 associated with a more aggressive
behaviour.56 Further studies are still necessary to confirm the
clinical utility of the recognition of this variant. The latest
World Health Organization (WHO) classification recognises
the entity of B-cell lymphoma, unclassifiable, with features
intermediate between diffuse large B-cell lymphoma
(DLBCL) and classic Hodgkin lymphoma, a provisional
disorder whose diagnostic criteria will likely benefit from a
more precise definition.57 Lymphoma experts in most cases
require these cases to exhibit a combination of intermediate
morphological (sheets of large cells) and immunophenotyp-
ical features (strong expression of CD20 and other B-cell
markers). These cases are frequently recognised as medias-
tinal grey-zone lymphoma (MGZL), since a large majority is
diagnosed in patients with mediastinal masses. Histology for
these MGZL has some overlapping features with NS HL and
some cases may exhibit a combination of areas of NS HL and
with primary mediastinal large B-cell lymphoma features.
Patients with MGZL may benefit from treatments targeting a
combination of CD30 and PD1/PD-L1.58,59
Mixed cellularity (MC) HL
These cases lack nodular sclerosis and lacunar cells, but they
contain classic HRS cells in an inflammatory background
environment. Cases may show a diffuse or interfollicular
Fig. 2 Nodular sclerosis Hodgkin lymphoma (NS HL) tumour-rich. Nodular sclerosis classic HL cases may show increased neoplastic cellularity as shown in (A) H&E,
and (B) CD30 staining. (C) The neoplastic cells also may express PD-L1 strongly, mostly associated with 9p24 amplification and increased sensitivity to PD-L1 in-
hibitors; (D) p53 expression can be observed in HRS cells with or without TP53 mutation. In this case strong p53 expression was associated with TP53 mutation.
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5
pattern, occasionally associated with hyperplastic reactive
lymphoid follicles. Epithelioid granulomas can be observed
in MC classic HL cases.
Lymphocyte-rich classic (LRC) HL
These cases show typical CD30-positive HRS cells
surrounded by small lymphocytes in a microenvironment
lacking the polymorphic cell composition and rich in small
cells (Fig. 3). Neoplastic HRS cells can be seen around
reactive lymphoid follicles, sometimes closely surrounded by
follicular dendritic cell networks. Immunostaining helps to
recognise PD1-positive TFH cells rosetting around the
neoplastic cells.60 Neoplastic HRS cells in this HL variant
show some overlapping features with NLPHL cases, with
more frequent expression of B-cell markers.60
Lymphocyte depleted (LD) classic HL
By definition, these are rich in neoplastic cells and show a
diminished representation of the other cell populations that
can be seen in classic HL. Two different patterns have been
described, one pattern with diffuse fibrosis and the other rich
in pleomorphic neoplastic cells. EBV-LMP is relatively
frequent in LD HL cases. Immunostaining is particularly
useful in the recognition of this variant, because the differ-
ential diagnosis includes other B- and T-cell lymphomas that
may show overlapping morphological features, such as EBV-
positive large B-cell lymphoma or anaplastic large T-cell
lymphoma.
Nodular lymphocyte predominant HL (NLPHL)
This is not a variant of classic HL, but an entirely different
disorder where neoplastic cells, the so-called lymphocyte
predominant (LP) or popcorn cells, are located in nodules,
often in the context of progressively transformed lymphoid
6 PIRIS et al. Pathology (xxxx), xxx(xxx), -

Fig. 3 Lymphocyte-rich classic Hodgkin lymphoma (LRCHL). (A) Neoplastic cells surround reactive follicles. (B) This neoplasm lacked the polymorphous background
of mixed cellularity HL cases. (C) TFH-rosettes around HRS cells; (D) the HRS cells show strong CD30 expression.

follicles (Fig. 4). Diagnosis of NLPHL is facilitated by the
strong expression of B-cell markers by LP cells, particu-
larly OCT2, and the presence of rosettes of PD1-positive
TFH cells surrounding the neoplastic cells.4 CD30 stain-
ing is usually negative in LP cells, but scattered CD30-
positive immunoblasts can be found in any case. CD15 is
negative and EBV (EBER) is only exceptionally
observed.28,61 CD20 staining reveals a characteristic pattern
where CD20-positive neoplastic cells are surrounded by a
delicate rim of CD20-negative T cells but situated in the
context of reactive follicles rich in CD20-positive small
lymphocytes and fewer germinal centre cells. Advanced
stages of NLPHL cases may show a more diffuse pattern
with loss of the FDC network and progressive loss of small
B cells, thus mimicking the findings of T-cell histiocyte-
rich large B-cell lymphoma. Nevertheless, these cases
retain the presence of a TFH-rich stroma individually sur-
rounding neoplastic cells.62

Fig. 4 Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is entirely different from classic HL, distinguished by: (A) nodular architecture, (B) presence of
lymphocyte predominant (LP) cells, (C) TFH rosettes around LP cells revealed by PD1 staining, (D) OCT2 strongly highlighting the neoplastic cells.

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 HODGKIN LYMPHOMA: PATHOLOGICAL FEATURES AND PATHOGENESIS
GENETICS
Analysis of isolated single tumour cells showed that HRS
cells carry monoclonal immunoglobulin gene rearrange-
ments, associated with somatic hypermutations of the
immunoglobulin heavy-chain variable-region (VH) genes in
most cases of NLPHL and classic HL.63 Several subsequent
studies showed that HRS cells in the vast majority of classic
HL cases are derived from germinal centre B cells with
defective surface B-cell receptors, crippled immunoglobulin
transcripts, and lost B-cell programs due to epigenetic
silencing.4,11–14 The molecular pathogenesis of HL, which
shows a balance of proliferative and apoptotic effects, in-
volves TRAFs, NF-kB, STAT and cytokine pathways, and
expression of cFLIP with inhibition of caspases activities.4,15
Conventional cytogenetic analysis has shown aneuploidy
and hypertetraploidy in a subset of cases of classic HL,
consistent with centrosome overduplication and multi-
nucleation of HL tumour cells, whereas no recurrent and
specific chromosomal abnormalities were found.4,64
Comparative genomic hybridisation studies have shown
gains of subregions of chromosomes 2p, 9q, 12q, 16p, 17q
and 20q, in which the affected loci harbour genes involving
the NF-kB pathway, such as REL, CD40 and MAP3K14.4,65
It is worthy to note that classic HL has a high frequency of
genetic mutations in PDL1 and PDL2, which results in the
overexpression of both proteins, and these ligands suppress
the function of PD1-positive intratumoural T cells.66
Blockade of PD1 signalling has proven to be a highly suc-
cessful therapeutic approach for patients with refractory or
progressed HL.67
PATHOGENESIS OF HL
The oncogenic role of EBV in HL
The oncogenic role of EBV in HL is still under investigation.
The HRS cells in EBV-positive HL have a type II latency
phenotype with expression of EBER1, EBER2, EBNA1,
LMP1, LMP2A and LMP2B.68 The HRS cells in HL are
thought to be derived from germinal centre B cells.4,21 Thus,
it is possible that EBV first infects naïve B cells, which are
activated and transformed into germinal centre B cells, and
the virus persists in these B cells by means of the default
transcription program. With the constitutive gene expression
of EBNA1, LMP1, and LMP2A in the default program,
differentiation of activated B cells is blocked and then these
cells acquire mutations that lead to neoplastic trans-
formation.20,21,69 EBV-encoded LMP1 may play an impor-
tant role in tumourigenesis.70,71 It has been shown that
germinal centre B cells with deficient B-cell receptor, which
should be destined to undergo apoptosis, can be rescued by
EBV probably through the oncogenic effect of EBV-
LMP1.72 LMP1 is a six-span transmembrane protein that is
essential for EBV-mediated growth transformation. The
biological effects of LMP1 in EBV-infected B cells are
multifaceted, such as inducing B-cell activation through C-
MYC and JUN/AP1 family members, triggering G1/S tran-
sition in B cells, activating the NF-kB pathway,73–75 and
inducing endoplasmic reticulum (ER) stress-related unfolded
protein responses.76 Constitutive activation of the NF-kB
pathway is a common feature of HL, both positive and
negative for EBV.77 However, the former is involved in
LMP1 overexpression whereas the latter is linked to IkBa
Please cite this article as: Piris MA et al., Hodgkin lymphoma: a review of pathological features and recent advances in pathogenesis, Pathology, https://
doi.org/10.1016/j.pathol.2019.09.005
7
gene mutation.77 In addition to distinct pathogenesis, there
are also some differences between EBV-positive and EBV-
negative HL. For example, the former occurs more often in
children, has a predilection for males, and may bear a worse
prognosis than that of patients with EBV-negative HL.43,44
Thus, there is value in distinguishing EBV-positive from
EBV-negative HL, especially taking therapeutic strategy into
consideration. There is compelling evidence that EBV-
positive HL is an excellent candidate for targeted cellular
immunotherapy.78–82
Since a substantial proportion of HL is EBV-negative,
especially in Western countries, two hypotheses have been
proposed to reconcile and explain the role of EBV in the
pathogenesis of HL. One is the ‘hit-and-run’ theory; that is,
the inability to detect EBV in the negative cases of HL may
be due to integrated viral fragments or a defective viral
genome.44 Another possibility is the ‘two-disease hypothesis’
which proposes that HL seen in the younger group is infec-
tious in nature, whereas HL in older persons shares similar
causes with other lymphomas.24,83 Thus, there likely exist
two pathways for HL tumourigenesis: one is EBV-associated
and the other is EBV-independent (e.g., IkB-associated). In
developing countries where EBV infection occurs earlier in
life when the immune system is relatively underdeveloped,
viral initiation of transformation may predominate in HL. In
developed areas, EBV has a lesser role in initiating trans-
formation in younger patients and instead drives trans-
formation in older patients with impaired immune status.
Thus, EBV participates in the pathogenesis of one type of HL
and the age of primary EBV infection is a potential deter-
minant of risk for EBV-positive HL.
Viral proteins, cyclin A, shelterin complex and
morphological changes in HL cells
The morphogenesis of HRS cells in HL is enigmatic. In adult
T-cell leukaemia/lymphoma, multinucleation and the for-
mation of multilobated nuclei are closely related to cell cycle
disturbances and centrosome amplification.84,85 The accu-
mulation of viral proteins in acutely or latently infected cells
may show profound morphological changes and multi-
nucleation. EBV-LMP1 transfected into HL cell lines has
been shown to promote RS cell formation.8 LMP1 expressed
in a B lymphoblastoid cell line resulted in the generation of
typical multinucleated RS-like cells.7,86 Moreover, LMP1
transfection in tonsillar germinal centre B cells can reprogram
these cells towards an RS-like phenotype.87 In the host genes
associated with cell cycle progression, aberrant expression of
cyclin A has been linked to virus-associated genomic insta-
bility and oncogenesis in virus-infected cells.88–91 Cyclin A
acts in the S phase of the cell cycle where it is required to
initiate DNA replication.92 Although cyclin A is localised
predominantly in the nucleus,88 it shuttles between the nu-
cleus and cytoplasm.93 There is mounting evidence that
cytoplasmic cyclin A expression is associated with onco-
genesis and abnormal nuclear morphogenesis. Chang and
colleagues showed differential expression of cyclin A in H
cells, RS cells, and mummified cells of HL.94 Cyclin A
tended to be expressed in the cytoplasm of RS cells, distinct
from the consistently nuclear expression in H cells in both
LMP1-positive and LMP1-negative HL cases. In vitro studies
further showed that LMP1 transfection increased the cyto-
plasmic expression of cyclin A and multinucleated RS cell
8 PIRIS et al.
formation. Therefore, the aberrant expression of cyclin A
appears to represent a common mechanism for the morpho-
genesis of RS cells in HL, in both EBV-positive and -nega-
tive cases. A model for cyclin A-associated morphogenesis of
HL is depicted in Fig. 5.
Detailed mechanisms for the intracellular redistribution of
cyclin A in HRS cells remain to be delineated. However,
there are some potential mechanisms that explain the cyto-
plasmic expression of cyclin A. SCAPER (S phase cyclin A-
associated protein residing in the ER), a novel protein, in-
teracts specifically with the cyclin A/CDK2 complex.
SCAPER overexpression sequesters cyclin A in the cyto-
plasm and induces cells to accumulate in the M phase of the
cell cycle.92 Alternatively, the accumulation of viral proteins
in infected cells induces alteration of calcium homeostasis via
ER stress, which results in calpain-mediated cyclin A
cleavage.95 On the other hand, LMP1, a member of the
tumour necrosis factor receptor family, activates several
signalling pathways involved in the survival of HL cells.96
The mechanisms underlying aberrant expression of cyclin
A in EBV-negative HL are currently unclear. Other hitherto
unidentified pathogens cannot be completely excluded in
EBV-undetected HL.97–99 Similar to the common activation
of NF-kB signalling in the tumourigenesis of both EBV-
positive and -negative HL,4,35 a mechanism similar to
LMP1 signalling may be involved in the aberrant expression
of cyclin A in EBV-negative HL cases. Other mechanisms
also may operate in the morphogenesis of RS cells. LMP1
downregulates CD99 in B cells, which leads to the generation
of multinucleated RS-like cells.86 Interestingly, mummified
cells more frequently express CD99, which can activate
apoptotic signaling in T cells.100 Thus, the activation of
CD99 and/or downregulation of the LMP1/cyclin A pathway
may lead to apoptosis of HL cells and hence mummified cell
formation.
Other proteins may also play an important role in the
morphogenesis of HL tumour cells. Knecht et al. have found
that multinuclear RS cells, as compared to mononuclear H
cells, are characterised by a highly significant increase of
telomere aggregates. This observation suggests that the
transition of H cells to RS cells is associated with progression
of telomere dysfunction, shelterin disruption and progression
Fig. 5 A model for the morphogenesis of Hodgkin (H), Reed–Sternberg (RS)
and mummified cells in HL. Mononuclear H cells may represent the common
dividing tumour cell type in HL, which can either transform into multinucleated
RS cells, or undergo apoptosis due to downregulation of cyclin A and/or in-
hibition of LMP1-activated NF-kB pathway. The membrane association of
LMP1 and abnormal localisation of cyclin A may alter proliferation and cell
division in HL cells, leading to centrosome duplication and multinucleation, and
multinucleated RS cell morphogenesis.
Please cite this article as: Piris MA et al., Hodgkin lymphoma: a review of pathological features and recent advances in pathogenesis, Pathology, https://
doi.org/10.1016/j.pathol.2019.09.005
Pathology (xxxx), xxx(xxx), -
of complex chromosomal rearrangements.101,102 It also has
been shown that LMP1 down-regulates the shelterin proteins,
causing shelterin disruption, telomere dysfunction, complex
chromosomal rearrangements, and finally multi-
nuclearity.103,104 Taken together, it appears that LMP1 plays
an important role in the morphogenesis of HL tumour cells.
Expression of ER stress signals in HL
LMP1 has been found to induce ER stress-related unfolded
protein responses in EBV-infected B cells.76 ER plays a
pivotal role in synthesis and modification of proteins.105
When misfolded or unfolded proteins accumulate in the
ER, cells activate appropriate genes in the nucleus to help the
ER cope with the stress, a process known as the ER stress
response or unfolded protein response.106,107 ER stress can be
provoked by a variety of pathophysiological processes, such
as viral infection and overexpression of mutant proteins.89,108
The fate of ER stress leads to either cell survival or apoptosis,
depending upon whether the rescue effort is effective or
not.106 The molecules regulating survival responses mainly
include phosphorylated protein kinase-like ER-resident
kinase (phospho-PERK), phosphorylated eukaryotic initia-
tion factor-2alpha (phospho-eIF2a), glucose-regulated pro-
tein (GRP)-78, GRP94, activating transcription factor (ATF)-
4, ATF6, inositol requiring kinase 1 (IRE1), and X-box
binding protein (XBP)-1. The major cell apoptotic molecules
include CCAAT/enhance-binding protein homologous pro-
tein (CHOP)/growth arrest DNA damage-inducible gene 153
(GADD153), caspase-12, caspase-7, and apoptosis signal-
regulating kinase (ASK) 1.106,107,109
ER stress-induced unfolded protein responses are involved
in carcinogenesis and angiogenesis and promote tumour
growth against hypoxia and chemotherapeutic resis-
tance.110,111 GRP78, also known as BiP (immunoglobulin
heavy chain binding protein), is a critical ER chaperone for
tumour survival and resistance to anticancer therapy.112,113 In
contrast, CHOP (GADD153) is a decisive effector of the
apoptotic program in the ER stress pathway.114 In a previous
study, we documented that expression of survival signals of
ER stress (GRP78 and XBP1) was a universal phenomenon
in all histological subtypes of HL and was found in both
EBV-positive and -negative cases at a similar level.69 Results
of an in vitro cell line study showed that EBV-LMP1 trans-
fection increases expression of ER stress survival signals,
GRP78 and XBP1, providing a possible mechanism ac-
counting for the expression of ER stress signals in EBV-
positive HL. This finding parallels an earlier report that
LMP1 expression in B cells at intermediate levels induces ER
stress response and promotes host cell proliferations.76
Accordingly, the survival signals triggered by ER stress
may also play a role in HL cell survival. Although ER stress
signals bear no prognostic significance in HL patients, they
potentially could be a target of novel therapy for refractory
HL patients.114–116 Figure 6 proposes a model for dominant
expression of ER stress survival signals in HL.
It is intriguing that HL cells express survival but not death
signals of ER stress. BAX and BAK, the pro-apoptotic BCL-
2 family members, are pivotal molecules in the triggering and
mediation of ER stress-induced apoptosis.117 HL cells ex-
press both anti-apoptotic and pro-apoptotic BCL-2 family
proteins and the former counteract the latter, resulting in the
survival of HL cells.118,119 These reports are consistent with
 HODGKIN LYMPHOMA: PATHOLOGICAL FEATURES AND PATHOGENESIS
Fig. 6 A model for dominant expression of endoplasmic reticulum (ER) stress
survival signals in HL. On ER stress, PERK-eIF2a pathway mediates trans-
lational attenuation for pro-survival regulation. Alternatively, phosphorylated
eIF2a can translate ATF4, upregulate CHOP, and lead to cellular apoptosis.
Both IRE1 and ATF6 mediate transcriptional activation for survival. ATF6
upregulates transcription of XBP1 and provides XBP1 mRNA for IRE1-
mediated splicing. GRP78 is the target of both XBP1 and ATF6. In contrast,
prolonged and severe ER stress activates apoptotic signals through induction of
CHOP, caspase-12, and IRE1-ASK1 pathway. We found that HL cells express
dominant survival signals of ER stress, including GRP78, XBP1 and ATF6. The
latter is constitutively expressed in almost all cases and triggers the survival
pathway of ER stress through GRP78 (major) and XBP1 (minor) activation.
EBV-LMP1 transduction shifts ER stress signals toward the survival end by
increasing expression of GRP78 and XBP1.
our finding that survival but not apoptotic signals of ER stress
predominate in HL cells. It is likely that the expression of ER
stress survival signals is the resultant phenomenon, implying
that HL precursor cells have overcome the ER stress imposed
on tumourigenesis. EBV-encoded LMP1 possibly plays an
important role in HL tumourigenesis, since it can prevent B
cells from undergoing TNF-mediated apoptosis by activating
a variety of signalling molecules, such as NF-kB.70,71 We
also demonstrated that LMP1 transfection enhances the
expression of ER stress survival signals. In this regard, the
precursor cells of EBV-positive HL should have survived the
viral-induced ER stress and activate further oncogenic path-
ways by expressing LMP1 at a modest level.76 Thus, sur-
viving ER stress may be the essential and decision-making
step for the uncommon development of HL in a large pop-
ulation of persons with latent EBV infection.
It is noteworthy that expression of ER stress signals is
common to both EBV-positive and EBV-negative HL.
Constitutive activation of the NF-kB pathway is also
common for both EBV-positive and -negative HL cases. In
EBV-positive cases, LMP1 overexpression appears to be
critical, whereas in EBV-negative cases other un-identified
viral proteins or similar mechanisms involving NF-kB acti-
vation or ER stress may play a role. The significance of
expressing ER stress survival signals in EBV-negative HL
cases may additionally contribute to occurrence of hypoxia,
which has been found to induce expression of vascular
endothelial growth factor (VEGF) in HL cells along with
increased tumour cell density.120,121 Therefore, our results
suggest that most HL cases adapt to and survive ER stress and
that expression of ER stress survival signals may be an
alternative mechanism, in cooperation with other pathways
such as NF-kB, to prevent HL cells from stress-induced
apoptosis. In EBV-positive cases, overexpression of LMP1
may play a role in the induction of ER stress survival signals,
Please cite this article as: Piris MA et al., Hodgkin lymphoma: a review of pathological features and recent advances in pathogenesis, Pathology, https://
doi.org/10.1016/j.pathol.2019.09.005
9
which instead may be associated with hypoxia or other events
in EBV-negative cases.
TREATMENT AND PROGNOSIS
The impact of EBV status on the clinical outcome of HL
patients has been controversial which may be attributable to
the inclusion of different study populations (especially age),
small sample size, or different EBV detection methods.122
Substantial evidence from population-based studies has
shown that the impact of EBV infection on patient outcome is
age-dependent and that older patients with EBV-positive HL
have a significantly poorer prognosis than those who have
EBV-negative HL.122–124 In addition to older age, Chang
et al. found that higher expression and secretion of cytokines
may be a culprit explaining poorer prognosis.43 Cytokines
play a pivotal role in the pathogenesis of HL.125,126 The
production of cytokines by HRS cells likely attracts inflam-
matory cells and is responsible for the characteristic inflam-
matory cell-rich morphology.126 In addition, HRS cells may
secrete cytokines that recruit regulatory T cells (Treg) thereby
facilitating immune evasion by HRS cells.125 The poorer
prognosis of patients with EBV-positive HL may be attrib-
utable to virus-associated cytokine effects rather than tumour
proliferation. In addition, combined rather than single
expression of the cytokines correlated with a poorer outcome
suggesting that various cytokines can have a synergistic
effect on patient survival. The constellation of cytokines
triggered by EBV in classic HL may explain the presence of
B symptoms.43 Several studies have described the association
of high cytokine levels with the presence of B symp-
toms,127,128 which is a known poor prognosticator along with
older age (>50 years).129
Mutational studies in classic HL are also starting to reveal
molecular markers associated with treatment failure. Thus,
genomic analyses of microdissected HRS cells have shown
that mutations in epigenetic regulators and p53 are more
frequent in cases of refractory classic HL.130
CONCLUSION
HL, an enigmatic disease, usually affects young patients with
a localised nodal disease. Its clinical course is typically
indolent and most patients with HL respond well to chemo-
therapy with a high cure rate. The recent finding of PD-L1
expression, an immune checkpoint, warrants the use of
immunotherapy for those patients with recurrent and/or re-
fractory disease. Pathologically, two entities are recognised,
nodular lymphocyte predominant HL and classic HL, the
latter including nodular sclerosis, mixed cellularity,
lymphocyte-rich classic and lymphocyte-depleted subtypes.
The neoplastic cells of HL are of B-cell lineage in virtually all
cases.
The neoplastic HRS and mummified cells in HL have
puzzled pathologists for decades. The viral inclusion-like
morphology parallels an association with EBV, which is
intriguingly variable in different geographic regions and in
pathological subtypes, and correlates with socioeconomic
status, indicating that environmental factors are likely
involved in HL pathogenesis. Virus-related LMP1 and ER
stress also may contribute to mechanisms underlying the
characteristic morphogenesis of HRS cells, which are asso-
ciated with aberrant subcellular localisation of cyclin A
expression and/or shelterin downregulation. Interestingly, all
10 PIRIS et al.
histological subtypes of HL, irrespective of EBV-positive or
-negative status, express survival but not death signals of ER
stress at similar levels, suggesting that surviving ER stress
may be involved in the pathogenesis of HL.
The differential diagnosis of HL includes anaplastic large
cell lymphoma, T-cell/histiocyte-rich large B-cell lymphoma,
peripheral T-cell lymphoma with RS-like cells (EBV-positive
or -negative) and some benign diseases such as infectious
mononucleosis. Classic HL diagnosis requires the combina-
tion of HRS cells with the polymorphic infiltrate that char-
acterises this disease and benefits from the integration of
clinical data with morphology and immunophenotype.
Conflicts of interest and sources of funding: This article
was supported by grants from the Ministry of Science and
Technology, Taiwan (MOST-106-2320-B-006-037-MY3) to
Dr K. C. Chang. The authors state that there are no conflicts
of interest to disclose.
Address for correspondence: Kung-Chao Chang, MD, PhD, Department of
Pathology, National Cheng Kung University Hospital, 138 Sheng-Li Road,
Tainan, 704 Taiwan. E-mail: changkc@mail.ncku.edu.tw
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