Case 4 -
Hodgkin-like B-cell Lymphoproliferative Disorder
Jonathan W. Said
David Geffen School of Medicine at UCLA
Department of Pathology and Laboratory Medicine UCLA Medical Center
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This patient is a 76 year-old gentleman with a history of left supraclavicular and cervical
lymphadenopathy for at least one year without splenomegaly or constitutional 'B' symptoms. On specific
questioning he was found to have a history of rheumatoid arthritis, but was never on immunosuppressive
medication. The lymph node biopsy was from the supraclavicular lymph node. (I am grateful to Dr.
Timothy S. Braverman at the Jewish Hospital in Cincinnati OH for permission to use this case.)
Case 4 - Slide 1
Case 4 - Figure 1 - H&E original X100 - Low power photomicrograph reveals a reactive germinal center and expansion of the parafollicular region by a mixture of small lymphocytes and histiocytes giving a 'mottled' appearance.
Case 4 - Figure 2 - H&E original X100 - There is a focus of necrosis with acute inflammation.
Case 4 - Figure 3 - H&E original X100 - Mixed lymphocytic and histiocytic proliferation and scattered large cells with prominent nucleoli resembling Hodgkin cells.
Case 4 - Figure 4 - H&E original X200 - Reed Sternberg like cells with prominent nucleoli and perinucleolar clearing in a background of small lymphocytes and scattered large mononuclear cells.
Case 4 - Figure 5 - H&E original X200 - A Reed Sternberg like cell (top panel) and apoptotic mummified cell (bottom) with a mixed background which includes eosinophils.
Case 4 - Figure 6 - H&E original X200 - A Reed Sternberg like cell (top panel) and apoptotic mummified cell (bottom) with a mixed background which includes eosinophils.
Case 4 - Figure 7 - H&E original X240 - Large mononuclear cells with prominent nucleoli and amphophilic cytoplasm in a mixed background.
Case 4 - Figure 8 - H&E original X240 - Large multilobed Reed Sternberg cell with a wreath like configuration in a mixed background including mononuclear cells, lymphocytes, histiocytes, and eosinophils.
Case 4 - Figure 9 - LCA - H&E original X100 - Immunostains reveal that the large cells are positive for CD45 (LCA) and CD20, but negative for CD15.
Case 4 - Figure 10 - CD20 - H&E original X100 - Immunostains reveal that the large cells are positive for CD45 (LCA) and CD20, but negative for CD15.
Case 4 - Figure 11 - CD20 - H&E original X100 - Immunostains reveal that the large cells are positive for CD45 (LCA) and CD20, but negative for CD15.
Case 4 - Figure 12 - CD15 - H&E original X100 - Immunostains reveal that the large cells are positive for CD45 (LCA) and CD20, but negative for CD15.
Case 4 - Figure 13 - Oct 2 - H&E original X100 - Large cells are positive for both Oct2 and Bob.1
Case 4 - Figure 14 - Bob.1 - H&E original X100 - Large cells are positive for both Oct2 and Bob.1
Case 4 - Figure 15 - CD30 - H&E original X140 - Immunoblasts in the region of the germinal centers and scattered large cells are positive for CD30.
Case 4 - Figure 16 - CD30 - H&E original X140 - Immunoblasts in the region of the germinal centers and scattered large cells are positive for CD30.
Case 4 - Figure 17 - EBV EBER - H&E original X100 - Many of the large cells are positive for EBV EBER by in-situ hybridization.
Histologic and Immunohistochemical Findings:
The nodal architecture is effaced with the exception of a few foci with residual germinal centers.
There is also a focus of necrosis with numerous neutrophils and histiocyte aggregates. The majority of
the node is effaced by a proliferation of small lymphocytes, numerous histiocytes, eosinophils, plasma
cells, and large polyploid cells resembling Hodgkin (H) cells as well as Reed Sternberg (RS) cells.
Occasional apoptotic or mummified cells are also identified. The phenotype of the H-RS cells was CD45+,
CD20+, CD15-, CD30+ and EBV EBER+. The large cells were also positive for both OCT2 and BOB.1.
Classical Hodgkin Lymphoma
Hodgkin-like B-cell lymphoproliferative disorder
My diagnosis is Hodgkin-like B-cell lymphoproliferative disorder. I believe it has similarities to
cases of so-called 'Senile EBV+ B-cell lymphoproliferative disorder' as reported in Am J Surg Pathol
27:16-26, 2003, but the case is complicated by the patient's having rheumatoid arthritis, even though he
never received methotrexate or other immunosuppressive therapy.
Immunodeficiency-related Hodgkin Lymphoma and its Mimics
Classical Hodgkin lymphoma (CHL) in patients with underlying immunodeficiency disorders frequently
differs from that in the immune competent population in terms of its clinical behaviour and pathologic
features. Moreover differential from Hodgkin-like lymphoid proliferations may be problematic. Topics
under review include:
Also under consideration is the pathogenesis of these disorders with an emphasis on the role of
Epstein Barr virus (EBV).
- Classical Hodgkin lymphoma post-transplant
lymphoproliferative disorders (PTLD)
- Classical Hodgkin lymphoma in HIV/AIDS
- Hodgkin variant of Richter's syndrome in chronic
lymphocytic leukemia in association with fludarabine therapy
- Classical Hodgkin lymphoma in other
immunodeficiency states including methotrexate-associated lymphoproliferative disorder in patients with
rheumatoid arthritis (RA) and primary immune deficiencies
- Hodgkin-like lymphoid proliferations including
senile EBV+ B-cell lymphoproliferative disorder
Autoimmunity and Susceptibility to HL
The absolute lifetime risk of CHL is only 0.26% in males and 0.21% in females.  Clearly,
HL is a disease that involves the immune system and, in particular, EBV appears to be implied in the
pathogenesis. Whether the role of the EBV relates to its oncogenic potential as in many cases of HL in
South America and in immunodeficient states, or in its impact on the background milieu of HL remains not
well understood. Nodular sclerosis Hodgkin lymphoma (NSHL) in particular appears different with regard
to the demographics of the population at risk and in its relationship to EBV. There is evidence that
personal history of autoimmune diseases is consistently associated with increased risk of non-Hodgkin
lymphoma (NHL) and also with HL.  Several autoimmune conditions including rheumatoid
arthritis, systemic lupus erythematosus, sarcoidosis, and idiopathic thrombocytopenic purpura have been
implicated. Also there is increased risk with family history of autoimmune diseases such as ulcerative
colitis and sarcoidosis.  Patients with HL characteristically have defects in immunity
specifically related to impairment of T-cell function. In addition persons with genetic conditions
associated with T-lymphocyte immune dysfunction have a higher risk of HL. Excess risk is also seen with
congenital immunodeficiencies and iatrogenic immunosuppression including allogeneic bone marrow
transplantation and patients receiving methotrexate for autoimmune conditions. These findings suggest
that increased risk of HL may be directly related to immunosuppression. 
CHL and HIV/AIDS
Patients with HIV/AIDS have a 5- to 15 fold increase in HL.  Most cases are mixed
cellularity (MCHL) or lymphocyte depleted (LDHL) types, compared with NSHL in young adults without
immunosuppression  Of great interest is the finding that HL risk appears highest in AIDS
patients with moderate immunosuppression, and decreases significantly with severe immunosuppression.
This is particularly true of NSHL, which is characteristically not observed in patients with HIV/AIDS in
the most severely immunosuppressed group. In patients with HIV/AIDS most cases of HL involved lymph
nodes with some cases presenting in the bone marrow and other extranodal sites. The breakdown of
subtypes of HL in one recent report was 54% MCHL, 37% NSHL, and 54% LDHL.  This is
strikingly different from HL in the general population, in which at least 70% are of NSHL type. The
pathogenesis of NSHL appears different from that of the MCHL and LDHL subtypes in the immunosuppressed
group, since RS cells in NSHL are generally negative for EBV. The MCHL type characteristically reveals
numerous RS cells that are positive for EBV.
HL incidence has unexpectedly increased since the advent of combination antiretroviral or HAART
therapy for patients with HIV.  The incidence of NHL decreased from 29.6 per thousand
person-years to 6.5 per thousand person-years. Central nervous system lymphomas decreased from 28% pre
HAART to 17% post. Moreover in patients treated with HAART the incidence of HL is greater for patients
with relatively high CD4+ cell counts in the range of at least 150-199 CD4 cells per mL. For each HL
subtype incidence has decreased with declining CD4 counts, but this is particularly true for NSHL, which
compared with the incidence of MCHL, increasing the relative proportion of MCHL cases in patients with
HIV/AIDS. The incidence of HL is lower with severe immunosuppression than with moderate
immunosuppression, and HAART-related improvements in CD4 counts may explain increasing HL incidence since
1996. With more severe immunosuppression NSHL becomes infrequent. Paradoxically HAART may therefore
have placed AIDS patients at a higher risk for HL.
This finding causes speculation about the role of the immune system particularly the 'bystander'
mononuclear cell population in HL. An essential feature of HL is the non-neoplastic milieu of reactive
cells in the tumor mass. H-RS cells produce cytokines and chemokines resulting in an influx of
activated CD4+ cells (CD40+, CD26-), histiocytes and other cells. H-RS cells can respond to the
inflammatory cells surrounding them. The inflammatory cells may provide essential feedback signals that
stimulate proliferation or inhibit apoptosis of RS cells. HL may decline with severe immunosuppression
because RS cells are unable to recruit lymphocytes and histiocytes required for their survival.
Alternatively HL may remain occult until the immune system is sufficiently reconstituted to respond to
the RS cells, or lymphomagenesis could shift to NHL's where are independent of the inflammatory
Hodgkin Lymphoma in the Post Transplantation Setting and its Differential
In the post transplant setting patients have a fifty to 100 fold increase in the incidence of
lymphoma, mostly NHL, and the risk appears to be directly related to degree of
immunosuppression.  Most cases of PTLD are associated with EBV in the setting of decreased
T-cell surveillance, particularly cytotoxic T-cells, leading to unchecked EBV infected B-lymphocyte
proliferation and PTLD. EBV positive PTLD occurs earlier than EBV negative cases (6-10 months vs. up to
4-5 years). EBV negative cases are more likely to be monomorphic lymphomas than polymorphous lesions.
The World Health Organization (WHO) classification recognizes both HL and HL-like PTLD's. The incidence
of HL PTLD ranges from 1.8 to 3.4% of PTLD's. 
The incidence of lymphoma following transplantation is higher for solid organ than bone marrow
transplants, but paradoxically there is a relative increase in the risk of HL after bone marrow
In the case of bone marrow transplants PTLD is of donor rather than
recipient origin, and there is increased risk with T-cell depletion, severe graft versus host disease
(GVHD), anti-CD3 immunotherapy, and the degree of HLA mismatch. The time post transplant is usually
greater than 2.4 months, and there is a higher mortality than with solid organ transplants. In one
study the observed to expected incidence of HL following bone marrow transplantation was
6.2.  As in other immunosuppressed groups, MCHL type predominates, and the H-RS cells are
positive for EBV. The onset of CHL following transplantation is generally later than B-cell NHL, usually
greater than 2.5 years. Moreover there is a lack of association with established risk factors such as
T-cell depletion and HLA disparity. Patients with HL are more likely to have had GVHD
however.  Transplant patients with HL are generally treated like other Hodgkin lymphomas,
and they generally have a good prognosis. Although PTLD is usually associated with high EBV copies in
the peripheral blood, there is one reported case of HL in a renal transplant recipient with low EBV
genome copies. 
It is important to differentiate between HL and HL-like PTLD, which simulates monomorphic B-cell PTLD
both clinically and pathologically.  RS cells in cases of CHL have the typical profile of
CD15+ CD30+. RS cells are also positive for EBV EBER and EBV LMP-1. HL-like PTLD may resemble CHL in
the presence of polyploid Hodgkin cells as well as a mixed background, but there are important pathologic
differences, with clinical implications regarding treatment and prognosis. HL-like PTLD has been
described anywhere from 4 months to 6 years after transplant. There is a male predominance and
presentation may be at either nodal or extranodal sites. Unlike CHL in which the H-RS cells are
negative for common leukocyte antigen (CD45) and either negative or variably or weakly positive for CD20,
the large polyploid cells in HL-like PTLD are positive for both CD20 and CD45. They are variably
positive for CD30, but are negative for CD15. There is an important difference in the nature of the
background proliferation, in that cases of HL-like PTLD usually include a population of transformed
B-cells or B immunoblasts, which are absent from cases of CHL. An exception to this rule occurs in cases
of interfollicular CHL in which there are reactive hyperplastic lymphoid follicles, and the presence of
interfollicular immunoblasts may be 'contaminants' from the adjacent lymphoid hyperplasia. Molecular
studies may also be helpful, since the majority of cases of HL-like PTLD exhibit clonal immunoglobulin
gene rearrangements, whereas in CHL gene rearrangements are negative unless single RS cells are evaluated
individually with microdissection (this is because in CHL the Hodgkin cells typically have crippled
immunoglobulin gene rearrangements). Cases of HL-like PTLD should be treated like other types of post
transplant lymphoma, and prognosis is variable with or without combination chemotherapy including
rituximab and reduction of immunosuppression .
Hodgkin Lymphoma in Patients Treated with Methotrexate for Rheumatoid Arthritis
Methotrexate related lymphoproliferative disorders are usually associated with treatment for
rheumatoid arthritis, but can be associated with treatment for other autoimmune diseases such as
dermatomyositis and psoriasis. They are often extranodal in presentation. Although cases of CHL occur
in this setting, they must be differentiated from more common HL-like lymphoid proliferations.
Rheumatoid arthritis has a two to 20 fold increased risk of lymphoma even in the absence of
The interval between diagnosis and development of lymphoma is a mean of
15 years. The mean duration of methotrexate therapy is 3 years (0.5-5.5 years).
Immunosuppression may be related to the disease itself and therapy with methotrexate or related
agents.  Risk factors include severe disease, intensity of immunosuppression, genetic
predisposition, and latent infection with EBV. EBV is frequently found in the synovium of RA patients
and these patients may have impaired immunologic control of EBV. EBV is associated with spontaneous
regression on withdrawal of methotrexate. There is a high incidence of EBV in both HL and HL-like
lesions associated with rheumatoid disease. Most HL-like lesions regress with cessation of methotrexate
therapy, while in CHL only about 30% regress with chemotherapy. The overall survival is about 50% for
the Hodgkin-like lymphoid proliferations compared with about 75% for CHL lesions. The diagnosis of CHL
may be difficult because the HL-like proliferations often contain cells that mimic RS cells, and the
background may contain a mixture of reactive small lymphocytes and histiocytes. Diagnosis of CHL in this
setting requires application of rigid immunohistochemical, histologic, and in some cases molecular
diagnostic criteria. RS cells in cases diagnosed as CHL should be negative for common leukocyte antigen
and express characteristic staining for CD15 and CD30, whereas in the HL-like lesions the large polyploid
cells are positive for CD45, CD20, variably for CD30, and negative for CD15. Moreover, in the background
lymphoid proliferation there are frequently large transformed lymphoid cells or immunoblasts, which are
generally absent in cases of CHL. The EBV staining is restricted to H-RS cells in CHL but in the HL-like
lesion, there are usually many of the background cells staining as well. Immunoglobulin gene
rearrangement studies are usually positive in the HL-like lesions and negative in CHL.
HL Associated with Other Immunodeficiency States
HL may also occur in association with other immunodeficiency disorders including congenital immune
disorders such as ataxia telangiectasia.  There are isolated cases reports of HL in various
conditions, for example is the description of HL in a four year old girl with hyper IgE syndrome (Job's
syndrome) including severe atopic eczema, asthma, and skin infections. 
HL in Patients with Chronic Lymphocytic Leukemia/lymphoma (CLL) and Fludarabine Therapy
Richter's syndrome is the term used to describe the transformation of CLL into diffuse large B-cell
lymphoma. Rarely cases of CLL are encountered in which RS cells can be found, or in which
transformation has occurred to CHL.  This form of transformation may be a late event up to
17 years after initial diagnosis.  In these cases in addition to H and RS cells the
background milieu is typical for HL including a mixed population of background inflammatory cells. HL
transformation is usually of MCHL type and occurs most frequently in patients who have been treated with
fludarabine.  HL has more rarely been described in CLL patients treated with other regimens
including cladribine and cyclophosphamide.  In some cases molecular analysis shows a clonal
relationship between the CLL and the Hodgkin cells suggesting that HL transformation may be triggered by
Senile EBV+ B-cell Lymphoproliferative Disorders Resembling HL
Although usually encountered in well characterized immunodeficiency states, EBV+ B-cell
lymphoproliferative disorders are occasionally encountered in elderly patients (median age 75 years)
without known causes for immunodeficiency. These lymphomas are problematic in terms of diagnosis and
therapy. The histologic spectrum ranges form polymorphic B-cell lymphoproliferative disorders to
diffuse large B-cell lymphoma, but occasional cases may be indistinguishable morphologically from CHL
unless appropriate immunostains are performed. The Hodgkin and RS-like cells in these cases are positive
for CD20, CD45, and EBV and are variably positive for CD30, but are negative for CD15. 
Despite the great diversity of causes of immunodeficiency, there is a common denominator in the
spectrum of cases of Hodgkin lymphoma and Hodgkin-like lymphoproliferative disorders seen in this
setting, as well as infection of the neoplastic cells by EBV. Rarely EBV positive lymphoproliferative
disorders may even be seen in elderly patients with no known cause for immunosuppression. In many cases
the correct histologic assessment, which in turn will drive the therapeutic decisions, can only be made
by the pathologist armed with a pointed clinical history and a complete panel of immunohistochemical
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