—  SPECIALTY CONFERENCE  —

Hematopathology

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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History

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
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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.

Differential Diagnosis:
Classical Hodgkin Lymphoma

Hodgkin-like B-cell lymphoproliferative disorder

Final Diagnosis:
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.

Discussion:

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:
  • 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
Also under consideration is the pathogenesis of these disorders with an emphasis on the role of Epstein Barr virus (EBV).

Introduction:

Autoimmunity and Susceptibility to HL
The absolute lifetime risk of CHL is only 0.26% in males and 0.21% in females. [1] 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. [1] 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. [1] 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. [2]

CHL and HIV/AIDS
Patients with HIV/AIDS have a 5- to 15 fold increase in HL. [3] Most cases are mixed cellularity (MCHL) or lymphocyte depleted (LDHL) types, compared with NSHL in young adults without immunosuppression [2] 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. [2] 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. [2] 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 milieu. [2]

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. [4] 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. [5]

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 transplantation. [6, 7, 8, 9] 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. [6] 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. [6] 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. [10]

It is important to differentiate between HL and HL-like PTLD, which simulates monomorphic B-cell PTLD both clinically and pathologically. [11] 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 [5].

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 methotrexate. [12, 13, 14] 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. [15] 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. [16] 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. [17]

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. [18] This form of transformation may be a late event up to 17 years after initial diagnosis. [19] 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. [19] HL has more rarely been described in CLL patients treated with other regimens including cladribine and cyclophosphamide. [20] In some cases molecular analysis shows a clonal relationship between the CLL and the Hodgkin cells suggesting that HL transformation may be triggered by EBV.

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. [21]

Summary:

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 stains.

References:
  1. Landgren O, Engels EA, Pfeiffer RM et al. Autoimmunity and susceptibility to Hodgkin lymphoma: a population-based case-control study in Scandinavia. J Natl Cancer Inst. 2006;98:1321-30.

  2. Biggar RJ, Jaffe ES, Goedert JJ, Chaturvedi A, Pfeiffer R, Engels EA. Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS. Blood. 2006.

  3. Re A, Casari S, Cattaneo C et al. Hodgkin disease developing in patients infected by human immunodeficiency virus results in clinical features and a prognosis similar to those in patients with human immunodeficiency virus-related non-Hodgkin lymphoma. Cancer. 2001;92:2739-45.

  4. Chadburn A, Chen JM, Hsu DT et al. The morphologic and molecular genetic categories of posttransplantation lymphoproliferative disorders are clinically relevant. Cancer. 1998;82:1978-87.

  5. Nalesnik MA, Randhawa P, Demetris AJ, Casavilla A, Fung JJ, Locker J. Lymphoma resembling Hodgkin disease after posttransplant lymphoproliferative disorder in a liver transplant recipient. Cancer. 1993;72:2568-73.

  6. Rowlings PA, Curtis RE, Passweg JR et al. Increased incidence of Hodgkin's disease after allogeneic bone marrow transplantation. J Clin Oncol. 1999;17:3122-7.

  7. Curtis RE, Travis LB, Rowlings PA et al. Risk of lymphoproliferative disorders after bone marrow transplantation: a multi-institutional study. Blood. 1999;94:2208-16.

  8. Shapiro RS, McClain K, Frizzera G et al. Epstein-Barr virus associated B cell lymphoproliferative disorders following bone marrow transplantation. Blood. 1988;71:1234-43.

  9. Zutter MM, Martin PJ, Sale GE et al. Epstein-Barr virus lymphoproliferation after bone marrow transplantation. Blood. 1988;72:520-9.

  10. Craver RD, Scheer WD, Correa H, Vehaskari VM, Yu LC. Hodgkin lymphoma in a renal transplant recipient associated with low peripheral blood Epstein-Barr virus genome copies. Arch Pathol Lab Med. 2001;125:1480-2.

  11. Pitman SD, Huang Q, Zuppan CW et al. Hodgkin lymphoma-like posttransplant lymphoproliferative disorder (HL-like PTLD) simulates monomorphic B-cell PTLD both clinically and pathologically. Am J Surg Pathol. 2006;30:470-6.

  12. Mariette X, Cazals-Hatem D, Warszawki J, Liote F, Balandraud N, Sibilia J. Lymphomas in rheumatoid arthritis patients treated with methotrexate: a 3-year prospective study in France. Blood. 2002;99:3909-15.

  13. Sibilia J, Mariette X. Methotrexate treatment and mortality in rheumatoid arthritis. Lancet. 2002;360:1096-7.

  14. Mariette X. Current and potential treatments for primary Sjogren's syndrome. Joint Bone Spine . 2002;69:363-6.

  15. Georgescu L, Quinn GC, Schwartzman S, Paget SA. Lymphoma in patients with rheumatoid arthritis: association with the disease state or methotrexate treatment. Semin Arthritis Rheum. 1997;26:794-804.

  16. Boultwood J. Ataxia telangiectasia gene mutations in leukaemia and lymphoma. J Clin Pathol. 2001;54:512-6.

  17. Kashef MA, Kashef S, Handjani F, Karimi M. Hodgkin lymphoma developing in a 4.5-year-old girl with hyper-IgE syndrome. Pediatr Hematol Oncol. 2006;23:59-63.

  18. Nemets A, Ben Dor D, Barry T et al. Variant Richter's syndrome: a rare case of classical Hodgkin's lymphoma developing in a patient with chronic lymphocytic leukemia treated with fludarabine. Leuk Lymphoma. 2003;44:2151-4.

  19. Fong D, Kaiser A, Spizzo G, Gastl G, Tzankov A. Hodgkin's disease variant of Richter's syndrome in chronic lymphocytic leukaemia patients previously treated with fludarabine. Br J Haematol. 2005;129:199-205.

  20. Robak T, Szmigielska-Kaplon A, Smolewski P et al. Hodgkin's type of Richter's syndrome in familial chronic lymphocytic leukemia treated with cladribine and cyclophosphamide. Leuk Lymphoma. 2003;44:859-66.

  21. Oyama T, Ichimura K, Suzuki R et al. Senile EBV+ B-cell lymphoproliferative disorders: a clinicopathologic study of 22 patients. Am J Surg Pathol. 2003;27:16-26.