Chapter 9: Immunosupression-Associated Lymphoproliferative Disorders

Methotrexate-associated lymphoproliferative disorders

· Definition

o A lymphoid proliferation or lymphoma in a patient immunosuppressed with methotrexate, typically for treatment of autoimmune disease (rheumatoid arthritis, psoriasis, dermatomyositis)

o May resemble large B-cell lymphoma, Hodgkin lymphoma, or polymorphous PTLD

o These LPDs are often EBV-related, and may regress with cessation of methotrexate therapy

· Epidemiology

o Frequency of these disorders is not known

o Slightly over 100 cases have been reported in the literature

o 85% of the cases have been seen in patients with rheumatoid arthritis, 6% in dermatomyositis, and 6% in psoriasis

o Patients with RA are estimated to have a 2-20-fold increased risk of lymphoma in the absence of methotrexate therapy. It remains debated whether methotrexate per se increases the risk of lymphoma development

o A case control study of lymphoma developing in patients with and without RA demonstrated no increased frequency of EBV-positivity in the RA patients, suggesting that most lymphomas developing in RA patients are not immunosuppression-related

o The interval from the diagnosis of connective tissue disease to the development of lymphoma is approximately 15 years, which is not significantly different from that in patients not treated with methotrexate

o The mean duration of therapy with methotrexate is 3 years, with a range of 0.5-5.5 years

o The median cumulative dose of methotrexate in one study was 0.8 g (0.01-2.9g)

· Sites of involvement

o Overall approximately 40% of reported cases have been extranodal, including the gastrointestinal tract, skin, lung, kidney and soft tissue

o The frequency of extranodal involvement differs among histological types, with 50% of DLBCL, 20% of HL, 100% of lymphoplasmacytic lymphomas and atypical lymphoplasmacytic infiltrates, and 40% of follicular lymphomas being extranodal

· Clinical features

o These do not appear to differ from those of non-immunosuppressed patients with lymphomas of similar histological types

· Morphology

o The reported cases are most commonly DLBL (35%) and HL (25%) or HL-like lesions (8%)

o Less frequent cases of follicular lymphoma (10%), Burkitt lymphoma (4%), and peripheral T-cell lymphomas (4%)

o Polymorphous, small lymphocytic or lymphoplasmacytic infiltrates have been described in approximately 14% of the cases

· Etiology

o Approximately 50% of the lymphoproliferative disorders are EBV+

o The frequency of EBV infection differs among the histological types, with EBV detected in approximately 50% of DLBCL, 75% of Hodgkin lymphoma and Hodgkin-like lesions, 50% of lymphoplasmacytic infiltrates, and 40% of cases reported as follicular lymphoma

· Immunophenotype

o The immunophenotypes of the lymphomas do not appear to differ from those of similar histological types not associated with methotrexate therapy

o In cases classified as Hodgkin-like, the large cells were CD20+ and CD30+ but CD15-, while in cases classified as Hodgkin lymphoma, the large cells were CD15+

· Genetics

o The genetic features of these cases do not appear to differ from those of similar histological types not associated with methotrexate therapy

o Only a few cases of follicular lymphoma have been reported; however, these have not been studied for the BCL2 translocation t(14;18)

· Prognosis

o Overall, approximately 60% of the reported cases have shown at least partial regression in response to withdrawal of methotrexate; the majority of responses have occurred in EBV-positive cases

o In DLBCL, approximately 40% have regressed, while 60% require cytotoxic therapy; overall survival is approximately 50%

o In HL about 30% of cases regress, while of the HL-like lesions, 100% regressed; the overall survival for HL cases is about 75%

o Cases classified as lymphoplasmacytic infiltrates or lymphoplasmacytic lymphoma typically regress with withdrawal of methotrexate therapy and survival is about 75%

Post-transplant lymphoproliferative disorders

Definition

• Post-transplant lymphoproliferative disorder (PTLD) is a lymphoid proliferation or lymphoma that develops as a consequence of immunosupression in a recipient of a solid organ or bone marrow allograft

• PTLDs comprise a spectrum ranging from early EBV-driven polyclonal proliferations resembling infectious mononucleosis to EBV-positive or EBV-negative lymphomas of predominantly B-cell or less often T-cell type

Epidemiology

• The characteristics of PTLD appear to differ somewhat from one institution to another, probably as a result of different patient populations, allograft types, and immunosuppressive regimens

• The risk of lymphoma varies depending on the type of allograft and the immunosuppressive regimen

• Among solid organ recipients, patients receiving renal allograft have the lowest frequency of PTLD (<1%)

• Those with hepatic and cardiac allograft have an intermediate risk (1-2%), and those receiving heart-lung or liver-bowel allograft develop PTLD at the highest frequency (5%)

• The overall incidence of PTLD for solid organ transplant recipients is <2%. This risk is estimated to be 20 times that of the normal population for renal allograft recipients and 120 times normal for cardiac allograft recipients

• Marrow allograft recipients in general have a low risk of PTLD (1%), but those who receive HLA-mismatched or T-cell depleted BM and those who receive immunosuppressive therapy for GVHD are at the highest risk for development of lymphoma – up to 20% for patients with more than one of these risk factors

Etiology

• The majority of PTLD are associated with EBV infection, and appear to represent EBV-induced monoclonal or, less often, polyclonal B-cell or rarely T-cell proliferations that occur in setting of decreased T-cell immune surveillance

• About 20% of PTLD are EBV-negative; among renal allograft recipients up to 50%

• EBV-negative cases tend to occur later than EBV-positive cases, and the majority of cases occurring >5 years after transplant are EBV-negative

• The etiology of EBV-negative PTLD is not known

• Although these occur less frequently than EBV-positive cases, their frequency is still higher than would be expected in the normal population; in addition, some cases respond to decreased immunosupression. Thus, it is likely that they are also in some way related to decreased immune competence

• The majority of PTLD in solid organ recipients are of host origin, reflecting scope of host EBV-positive cells from immune surveillance. A minority (<10% of the cases) are of donor origin, indicating that lymphoid cells transplanted with the allograft can survive and undergo malignant transformation in some cases

• In contrast, the majority of PTLD in marrow allograft recipients are of donor origin, as would be expected, since successful allografting results in an immune system that is exclusively of donor origin

Sites of involvement

• In solid organ recipients immunosuppressed with azathioprine-based regimens, PTLDs tend to involve extranodal sites, including the allograft and the CNS

• Patients treated with cyclosporine-based or Tacrolimus-based regimens develop PTLDs that tend to involve lymph nodes and GI tract, less freq CNS

• The bone marrow, liver and lungs are often involved, but peripheral blood is rarely involved

• The allograft is involved in approx. 25% of the cases overall, and on biopsy specimens this may give rise to a differential Dx of rejection vs PTLD

• BM allograft recipients tend to present with widespread disease involving nodal
and extranodal sites, including liver, spleen, GI tract and lungs

Clinical features

• The clinical features of PTLD at presentation are variable, and correlate with the type of immunosupression, type of allograft, and with morphologically defined categories

• In solid organ recipients treated with azathioprine the mean interval to PTLD following transplantation is 48 months, cyclosporine A is 15 months

• The majority of PTLD in bone marrow allograft recipients develop within the first 5 months

• EBV-positive cases tend to occur earlier than EBV-negative cases, with a median interval of 6-10 months compared with 4-5 years for EBV-negative cases

• Plasmacytic hyperplasia (PH) and infectious-mononucleosis like (IM-like) lesions may arise at any time, most often within the first 2 years after transplantation, but some as late as 5 years

• The majority of both polymorphic and monomorphic PTLDs occur in the first
year after transplantation; pts may present with lymphadenopathy in one or
multiple sites, or with organ dysfunction, including the allograft, related to
extranodal infiltrates

• Monomorphic PTLD overlap clinically with polymorphic cases; however, late-
occurring, EBV-negative cases are more likely to be monomorphic

Morphologic categories of PTLD

• “Early” lesions: Plasmacytic hyperplasia (PH) and Infectious-mononucleosis-like PTLD:

– These lesions are defined as a lymphoid proliferation in an allograft recipient, characterized by some degree of architectural preservation of the involved tissue, with preservation of the nodal sinuses or tonsillar crypts, and residual reactive follicles in some cases

– Plasmacytic hyperplasia is characterized by numerous plasma cells and rare immunoblasts, while the IM-like lesion has the typical morphologic features of IM, with paracortical expansion and numerous immunoblasts in a background of T cells and plasma cells

– These are 2 possibly overlapping lymphoid proliferations that differ from typical reactive follicular hyperplasia in having a diffuse proliferation of plasma cells and immunoblasts with incomplete effacement of the involved tissue

– Some people (Nalesnik et al) described “reactive plasmacytic hyperplasia”, but they did not consider it a form of PTLD

– The same term was used by Knowles et al. and found that 3/8 cases they diagnosed as PH involved LNs, 4/8 involved Waldeyer´s ring and one involved the lung; the latter cases may correspond to what others have called IM-like lesions

– PH and IM-like lesions occur at a younger age than the other PTLDs and are often seen in children or in adult solid organ recipients who had no prior EBV infection

– They involve LNs (PH) or tonsils and adenoids (IM-like) more often than true extranodal sites, and often regress spontaneously or with reduction in immunosuppression

– However, IM-like lesions can be fatal, as can infectious mononucleosis in other settings. They may be followed by polymorphic or monomorphic PTLD in some cases

• Polymorphic PTLD

– Defined as destructive lesions composed of immunoblasts, plasma cells, and intermediate-sized lymphoid cells, that efface the architecture of LNs or form destructive extranodal masses

– In contrast to early IM-like lesions, the tissue architecture is effaced, but in contrast to most lymphomas, they show the full range of B-cell maturation, from immunoblasts to plasma cells, with small and medium-sized lymphocytes and cells with irregular nuclei resembling centrocytes

– Overall the impression is often that of “mixed small and large cell” lymphoma, resembling the “polymorphic immunocytoma” of the Kiel classification

– There may be areas of necrosis and scattered large, bizarre cells (atypical immunoblasts); numerous mitoses may be present

– This category was one time subdivided into “polymorphic B-cell hyperplasia” and “polymorphic B-cell lymphoma” based on the presence of atypical immunoblasts and necrosis, but it is now felt that attempting to distinguish between these is not practical or necessary, since both are typically monoclonal and have similar clinical features

– Some cases have areas that appear more monomorphic in the same or other tissues; thus, there may be a continuous spectrum between these lesions and the monomorphic PTLD

– The frequency of polymorphic PTLD ranges from 20% to over 80% of the cases (varies from one institution to another)

– Reduction in immunosupression leads to regression in a variable number of the cases; others may progress and require treatment for lymphoma

• Monomorphic PTLD

– Monomorphic B-cell PTLD

• These have sufficient architectural and cytologic atypia to be diagnosed as lymphoma on morphologic grounds, and have expression of B-cell associated antigens

• These tumors should be classified as B-cell lymphomas, but the term PTLD should also appear in the diagnosis

• The infiltrates are characterized by nodal architectural effacement and/or invasive, tumor growth in extranodal sites, with confluent sheets of transformed cells

• All or most cells in the infiltrate are large, transformed, blastic cells with prominent nucleoli and basophilic cytoplasm, in contrast to the full range of maturation seen in lesions characterized as polymorphic PTLD

• It is important to recognize that there may be plasmacytoid or plasmacytic differentiation. Thus, the term, monomorphic, does not mean complete cellular monotony, only that most of the cells appear to be transformed

– Diffuse large B-cell lymphoma and Burkitt lymphoma:

• The majority of monomorphic B-PTLDs fall into the category of diffuse large B-cell lymphoma

• Most would be subclassified as the immunoblastic variant, although some are centroblastic. Some cases show features of the anaplastic variant. A minority of the cases have morphologic features of Burkitt lymphoma

– Plasma cell myeloma:

• Rare transplant patients develop plasma cell myeloma. These may be EBV-positive or negative; most reported cases have failed to regress with decreased immunosuppression

– Plasmacytoma-like PTLD:

• Rare extramedullary plasmacytic neoplasms, which appear to be similar to extramedullary plasmacytoma in the non-immunocompromised host, have been reported in the post-transplant setting

• They may occur in the GI tract, LN, or other extranodal sites

• Clinical behavior not well studied

· Monomorphic T-cell PTLD

- Similarly to the monomorphic B-PTLDs, monomorphic T-PTLDs have sufficient atypia and monomorphism to be recognized as neoplastic, and should be classified in the T-cell neoplasms category

– The frequencies reported range from 4% to 14% of the cases to be of T-cell origin

– T-PTLDs appear to span the spectrum of T-cell neoplasms, including subcutaneous panniculitis-like T-cell lymphoma, hepatosplenic gamma-delta T-cell lymphoma, NK/T-cell lymphomas, T-cell large granular lymphocyte leukemia, and peripheral T-cell lymphoma, unspecified

– Some cases may be CD30+

– The interval to lymphoma development is typically longer for the T-PTLDs than for the B-cell cases, and pts are less likely to respond to decreased immunosuppression

– Many reported cases of T-PTLD are EBV-negative, but some are EBV-positive

· Hodgkin lymphoma (HL) and HD-like PTLD

– Both classical HL and cases of HL-like PTLD have been reported in allograft recipients

– Because RS-like cells may be seen in polymorphic PTLD, the Dx of HL should be based on both classical morphologic and immunophenotypic features

– An increased incidence of classical HL has been reported after allogenic BM transplantation, with an observed-to-expected incidence ratio of 6.2

– Rarely, allograft recipients develop polymorphic, HL-like lesions in nodal or extranodal sites, similar to those that develop in pts treated with methotrexate for rheumatoid arthritis or psoriasis

– HL-like PTLD are similar to both methotrexate-related HL and HL in HIV infection in that they are virtually always EBV-positive

– Some cases have responded to therapy for HL, while others have been clinically aggressive

– Given the small number of reported cases, further study is required to determine their spectrum of clinical behavior

Immunophenotype

• Plasmacytic hyperplasia and IM-like lesions

– Immunophenotypic studies show an admixture of polyclonal B cells, plasma cells, and T cells

– Immunoblasts are typically EBV-LMP+

• Polymorphic PTLD

– Immunophenotyping shows a mixture of B and T cells, surface and cytoplasmic Ig may be either polytypic or monotypic

– EBV-LMP1 and EBNA2 are detectable in the immunoblasts in the majority of the cases

• Monomorphic B-cell PTLD

– Immunophenotypic studies show B-cell associated antigens (CD19, CD20, CD79a), with monotypic immunoglobulin (often with expression of gamma or alpha heavy chain) in 50% of the cases

– EBV-associated Ags EBNA2 and LMP1 are expressed in the majority of the cases

– Many express Ags usually associated with T cells, specifically CD43 and CD45RO, which are upregulated in EBV-infected B cells, and are expressed by some conventional B-cell lymphomas. They do not determine T lineage in this setting

– Many cases are CD30+, with or without anaplastic morphology

• Monomorphic T-cell PTLD

– T-cell cases are recognized by expression of pan-T cell Ags, may express CD4 or CD8, CD56 or CD30, and positive for T-cell receptor gene rearrangement

– They are variably EBV-positive

• HL and HL-like PTLD

– Classical HL cases have expressed CD15 and CD30

– Cases diagnosed as HL-like PTLD more often have an atypical immunophenotype with B-cell antigen expression; virtually all cases are EBV-positive

Genetics

• Antigen receptor genes and EBV
Plasmacytic hyperplasia and IM-like lesions

– Ig genes are polyclonally rearranged

– EBV is present in many but not all of the cases of nodal PH

– EBV-negative PH may represent nonspecific lymphoid hyperplasia or a reaction to an infection other than EBV, and should not be considered PTLD

– Extranodal and nodal IM-like cases are typically EBV-positive and may have small monoclonal or oligoclonal bands on Southern blots probed for episomal EBV genomes

– The significance of oligoclonality or a small clonal band is unknown

Polymorphic PTLD

– Molecular genetic studies virtually always show clonal rearrangements of Ig genes and/or EBV genomes, but CG and oncogene studies (MYC, RAS, TP53) show no mutations

– Early studies reporting polyclonality were based on Ig light chains detection in paraffin sections

– Later studies using molecular genetic analysis confirmed that most poly- and monomorphic lesions are in fact monoclonal

– In some cases tumors at different sites in the same pt may be clonally distinct

– In most cases that lack Ig gene rearrangements, clonal episomal EBV genomes can be detected

– EBV in PTLD is reported to be exclusively of type A

– Detection of EBV by EBER by ISH is a useful tool in the differential Dx of PTLD vs rejection in allografts

– Most cases of polymorphic PTLD contain numerous EBER positive cells; Rare positive cells should not be considered diagnostic of PTLD

Monomorphic B-PTLD

– Ig gene rearrangement in virtually all cases, and the majority contain EBV genomes. When present, are in clonal episomal form

Monomorphic T-PTLD

– Most reported cases show clonal T-cell receptor gene rearrangement

– About 25% have clonal episomal EBV genomes

• Oncogenes

– In polymorphic PTLD, one study showed no mutations of the RAS or TP53 genes, and no rearrangement of the MYC gene. Monomorphic B-PTLD frequently shows such abnormalities, similar to de novo DLBCL

– Mutations of the BCL6 gene were described in 40% of polymorphic cases and 90% of monomorphic cases; were a/w failure to respond to decreased immunosuppression

Prognosis

- Early and IM-like lesions tend to regress with reduction of immune suppression, and if this can be accomplished without graft rejection, prognosis is excellent, particularly in children

- Polymorphic and less often monomorphic PTLD may regress with reduction in immune suppression. The proportion of cases that do not regress require cytotoxic chemotherapy

– Overall the mortality of PTLD in solid organ allograft recipients is approx 60%, while that of marrow allograft recipients with PTLD is 80%

– Anti-CD20 therapy has been useful in abrogating PTLD development in some cases, particularly in the marrow allograft setting

– Monitoring for evidence of reactivation of EBV infection may provide an early warning of PTLD development

– With an early Dx, prompt reduction of immune suppression, and careful administration of chemotherapy or radiation therapy, the prognosis for all types of PTLD has improved

Lymphomas associated with infection by the human immune deficiency virus (HIV)

Definition

· Lymphomas that develop in HIV+ pts are predominantly aggressive B-cell lymphomas

· Most common HIV-associated lymphomas:

- BL

- DLBCL (often involve CNS)

- PEL

- Plasmablastic lymphoma of the oral cavity

· HL also increased in the setting of HIV

Epidemiology

· Incidence of all subtypes of NHL increased 60-200 fold in HIV+ pts

· Before highly active antiretroviral therapy (HAART) available, primary CNS lymphoma and BL were increased approx 1000 fold compared to general population

· Incidence of HL may be increased up to 8 fold

Etiology

· Lymphomas in HIV pts are heterogenous with several pathogenetic mechanisms:

- Chronic antigen stimulation

- Genetic abnormalities

- Cytokine dysregulation

- Role of herpes virus: EBV and KSHV/HHV8

· HIV-related lymphomas are consistently monoclonal, and are characterized by a number of common genetic abnormalities of oncogenes involving the MYC and BCL6 oncogenes, as well as tumor suppressor genes

· Disruption of the cytokine network leading to high levels of IL6 and IL10 is a feature of HIV-related lymphomas a/w EBV or KSHV/HHV8

· EBV is identified in the neoplastic cells of approx 60% of HIV-related lymphomas

· EBV infection occurs in almost all cases of primary CNS lymphoma and PEL, 80% of DLBC with immunoblastic features, and 30-50% of BL

· Nearly all cases of HL in the HIV-setting are a/w EBV

· KSHV/HHV8 is specifically a/w PEL

Sites of Involvement

· Marked propensity to involve extranodal sites, in particular the GI tract, CNS (less frequent since HAART), liver, and BM

· PB rarely involved except in occasional cases of BL presenting as acute leukemia

· Unusual sites such as oral cavity, jaw, and body cavities often involved

· Many other extranodal sites, e.g., lung, skin, testis, heart, breast can be involved

· LNs involved about 1/3 of pts at presentation

Clinical Features

· Most pts present with advanced clinical stage

· Bulky disease with a high tumor burden is frequent

· LDH is usually markedly elevated

· DLBCL more often occurs in the setting of long-standing AIDS before the diagnosis of lymphoma, with a trend towards higher rates of opportunistic infections and lower CD4+ T-cell counts (mean below 100 x 10⁶/L)

Lymphomas also occurring in immunocompetent pts

· Should be classified according to usual criteria for these diseases

· BL

- Classical

§ Shows morphologic features of classical BL with a monomorphous, medium-sized cell proliferation

§ Represents 30% of all HIV-associated lymphomas

§ EBV+ in about 30% of cases

- BL with plasmacytoid differentiation

§ Relatively unique to AIDS pts

§ Represents ~20% of NHL cases

§ Medium-sized cells with abundant basophilic cytoplasm, an eccentric nucleus, often with one centrally located prominent nucleolus

§ Cells often contain cytoplasmic immunoglobulin

§ EBV+ in ~50-70% of cases

- Atypical Burkitt/Burkitt-like

§ Less frequent

§ Nuclear features similar to classical BL, but greater pleomorphism in size and shape of cells

§ Nuclei may contain more prominent nucleoli

§ EBV present in 30-50% of cases

· DLBCL

- Majority contain numerous centroblasts admixed with a variable component of immunoblasts, c/w centroblastic variant; represents ~25% of HIV-associated lymphomas; EBV present in 30% of cases

- Cases containing more than 90% immunoblasts and usually exhibiting plasmacytoid features are classified as immunoblastic variant; EBV in 90%, and often occur late in the course of HIV disease

- Primary CNS lymphomas are usually immunoblastic type

· HL

- Most cases either mixed cellularity or lymphocyte depeleted forms of classical HL

- Some cases of NSHL also seen

- a/w EBV in nearly all cases; cells express latent membrane protein (LMP1) and are EBER+

· Other lymphomas (rare)

- Rare cases of MALT described in both pediatric and adult pts with HIV infection

- Rare cases of PTCL and NK-lymphoma can also occur

Lymphomas occurring more specifically in HIV+ pts

· Primary effusion lymphoma (PEL)

- Synonym: body cavity based lymphoma

- Rare representing less than 5% of NHL

- Not fully characterized until after the discovery of the KSHV/HHV8 virus

- Usually presents as lymphomatous effusions

- Can present as a solid tumor mass, most commonly affecting the GI tract or soft tissue

- a/w KS and multicentric Castleman disease in HIV+ pts

- Cells exhibit wide range of appearances, from large immunoblastic or plasmablastic cells to cells with more anaplastic morphology

- Nuclei are large, round to more irregular in shape, with prominent nucleoli

- Cytoplasm can be very abundant and deeply basophilic with presence of vacuoles in some cells

- Perinuclear hof c/w plasmacytoid differentiation may be seen

- Some cells resemble RS cells

- Cells often appear more uniform in histologic sections than cytospin preparations

· Plasmablastic lymphoma of the oral cavity

- Localized in the oral cavity or jaw

- Rapidly growing with a high mitotic index

- Display a diffuse growth pattern interspersed by macrophages

- Tumor cells are large with eccentrically located nuclei, and usually single, centrally located prominent nucleoli

- Cytoplasm deeply basophilic with a perinuclear hof

- Some cells display cytoplasmic immunoglobulins

- EBV present in >50% of cases, but no association with KSHV/HHV8 detected

Lymphomas occurring in other immunodeficient states

· Polymorphic lymphoid proliferations resembling PTLD may be seen in adults and also in children but are much less common than in post-transplant setting (<5% of HIV-associated lymphomas)

· Conform to the criteria of polymorphic B-cell PTLD

· Infiltrates contain a range of lymphoid cells from small cells, often with plasmacytoid features of immunoblasts, with scattered large bizarre cells expressing CD30

· EBV often present, but some cases negative

Immunophenotype

· Varies according to histological subtype of lymphoma

· Vast majority are B-cell origin

· CD19, CD20, and CD79a and CD10 expressed in virtually all tumors in BL

· DLBCL- more variable phenotype

· Tumor cells lose CD20 in immunoblastic lymphomas with plasmacytic differentiation, plasmablastic lymphoma of the oral cavity, and PEL

· In PEL and plasmablastic lymphomas, other markers of plasmacytic differentiation are also present such as CD138 and VS38c

· CD45 expressed in most cases of PEL, despite a null cell or aberrant phenotype with other markers

· Activation-associated antigens expressed in some DLC lymphomas, esp in the immunoblastic subtype, and PEL include EMA, CD30, CD38, and CD71

· PEL may aberrantly express cytoplasmic CD3

· True T-cell lymphomas are infrequent

· Mature T-cell lymphomas, when they exist, express CD2, CD3, CD5, CD4 or CD8, CD16 or CD56

· The loss of one or more antigens can be observed

Genetic Features

· Antigen receptor genes

- Most are monoclonal B-cell neoplasms, with clonal rearrangement of immunoglobulin genes detected by Southern blot or PCR techniques

- Most cases have somatically mutated immunoglobulin genes

- T-cell cases have clonal rearrangements of TCR genes

· Oncogenes and tumor suppressor genes

- HIV-associated BL, like other BL, have genetic abnormalities affecting band 8q24 (the location of the MYC locus)

- The classical t(8;14)(q24q32) or its variants affecting the light chain genes at 2p11 and 22q11 been described

- Rearrangement of BCL6, a proto-oncogene located at band 3q27 and belonging to the family of transcription factors containing zinc finger domains, is confined to DLBCL and absent in BL

- Frequent mutations of the 5’ noncoding region of the BCL6 gene occurring independently of BCL6 rearrangements are detected in BL and DLBCL and represent the most common genetic alteration in HIV-related lymphomas

- Mutations of the RAS family proto-oncogenes are present, although in a small number of cases (15%)

- RAS mutation peculiar in HIV-related lymphomas; there is no significant detection of RAS abnormalities in lymphoma occurring in immunocompetent hosts

- Point mutations and deletions of the TP53 tumor suppressor gene are detected in 50-60% of BL and in 40% of DLBCL, leading to inactivation of this gene and overexpression of p53 protein

- Deletions of the long arm of chromosome 6 clustering of 6q27 and other recurrent genetic abnormalities occur in 25% cases may implicate other tumor suppressor genes

Prognosis and Predictive Factors

· Rate of remission ~50%

· However, 2-year survival significantly lower in DLBCL than in BL in univariate analysis

· Degree of immunodeficiency correlates positively with the IPI score (International Prognostic Index)

· Other adverse prognostic factors, age >35 yrs, IVDU, stage III/IV, and CD4 counts less than 100 x 10⁶/L

· Long term survival achieved in approx 1/3 of pts with HIV-associated lymphoma with favorable prognostic characteristics

· PEL usually have very poor prognosis with a low complete remission rate

Lymphoproliferative diseases associated with primary immune disorders

Definition

· A lymphoproliferative disease (LPD) arising in the setting of a primary immunodeficiency or a primary immunoregulatory disorder

· Highly variable

· PIDs (primary immune disorders) most commonly associated with lymphoproliferative disorders are ataxia-telangiectasia (AT), Wiskott-Aldrich syndrome (WAS), common variable immunodeficiency (CVID), SCID, X-linked lymphoproliferative disorder (XLP), Nijmegen breakage syndrome (NBS), hyper-IgM syndrome, and autoimmune lymphoproliferative syndrome (ALPS)

Epidemiology

· Risk of developing lymphoma is highly related to the type of the underlying PID

· Primarily present in the pediatric age group

· CVID more common in adults

· More common in males, because many of the primary genetic abnormalities are X-linked, e.g. Duncan syndrome, XLP, SCID, and hyper-IgM syndrome

Sites of Involvement

· Most cases extranodal sites; most common GI tract and CNS

· Lung and kidney frequently involved in lymphomatoid granulomatosis

Clinical Features

· Often present with symptoms resembling infection or neoplasia (fever, fatigue, infectious mononucleosis-like syndromes)

Etiology

· Cause of LPD related to underlying PID

· EBV involved in the majority of PID-associated lymphoid proliferations

· In ALPS the presence of FAS gene mutations may contribute directly to the LPD through the accumulation of lymphoid cells

· FAS blocks apoptosis, and in ALPS the severity of the apoptotic defect is an important risk factor for the development of lymphoma

· In AT, an abnormal DNA repair mechanism secondary to mutations of the ATM gene can contribute to the development of lymphoma, leukemia, as well as other neoplasms

· Chronic antigenic stimulation may predispose to the development of lymphoma in some pts

· Intestinal lymphangiectasia and protein losing enteropathy lead to hypogammaglobulinemia and late-occurring lymphomas

Precursor Lesions

· Underlying primary immune disorder is the principal precursor lesion leading to the development of LPD

· Lymphoid hyperplasia may precede the development of LPD in some diseases, such as ALPS and WAS

· Pts with WAS often have serum monoclonal gammopathy

· LNs may contain plasmacytosis, and may be monoclonal in some cases (may not necessarily progress to lymphoma)

Morphology

· In PID pts diverse types of lymphoma and LPD may occur

· DLBCL is by far the most common LPD in the setting of PID

· HL and polymorphic lymphoproliferations resembling PTLD may also occur

B-cell Neoplasms

· Fatal infectious mononucleosis (FIM)

- Characterized by a highly polymorphous proliferation of lymphoid cells showing evidence of plasmacytoid and immunoblastic differentiation

- RS cells may be seen

- This condition primarily seen in XLP (Duncan syndrome) and SCID

- FIM results from the proliferation of EBV+ B-cells in the absence of effective immune surveillance

- The abnormal B-cell proliferation is systemic, involving both lymphoid and non-lymphoid organs, most commonly the terminal ileum

- Hemophagocytosis commonly seen; most readily identified in the BM

- Hemophagocytic syndrome may be the primary cause of death, usually a/w marked pancytopenia and further infectious complications

· DLBCL

- Most common LPD in pts with PID

- Increased in AT, WAS, Job syndrome, CVID, and NBS

- Centroblastic and immunoblastic variants seen, but immunoblastic variants predominate

· Lymphomatoid granulomatosis (LYG)

- An EBV-driven proliferation of B-cells a/w T-cell infiltration

- Increased in frequency in pts with WAS

- WAS is a complex immune disorder, with defects in function of T cells, B cells, neutrophils, and macrophages

- T-cell dysfunction is significant, and tends to increase in severity during the course of the disease

- LYG is characterized by an angiocentric and angiodestructive infiltrate, often with extensive necrosis

- The most common sites of involvement are lung, skin, brain, and kidney

- LYG is not considered a lymphoma, since the EBV-driven B-cell expansion is often not autonomous, and may respond to immunoregulatory therapy using interferon alfa-2b

- Variations in histological grade are seen and tend to correlate with prognosis

- Moreover, LYG may progress to DLBCL

· Burkitt lymphoma

- may occur in XLP and AT pts

T-cell Neoplasms

· AT is the one PID in which T-cell lymphomas and leukemias are more common than B-cell neoplasms

· Both pre-T ALL/LBL and T-PLL been reported

· Rare cases of peripheral T-cell lymphoma seen in pts with ALPS

· However, benign T-cell expansions of double-negative (CD4-/CD8-) alpha beta T-cells are much more common than T-cell lymphomas

· Because the T-cell expansion is very marked, use caution in the diagnosis of T-cell lymphoma in pts with ALPS

· Clonal T-cell expansions and rare cases of T-cell lymphoma also reported in CVID

Hodgkin lymphoma

· Classical HL reported in pts with WAS, ALPS, and AT

· Hodgkin-like lymphoproliferations resembling those seen in setting of methotrexate treatment also seen

· NLPHL reported in a/w ALPS

Immunophenotype

· Most LPDs are of B-cell lineage; thus, carry B-cell markers

· EBV infection of B-cells often lead to down-regulation of B-cell antigens

· Thus, CD20, CD19, and CD79a may be negative

· EBV leads to expression of CD30+ in most cases

Genetics

· FIM may be polyclonal at the genetic level

· Because many PIDs are a/w atypical lymphoid hyperplasia, the absence of clonality at the genetic level is helpful in ruling out progression to lymphoma

· In AT, in addition to mutations of the ATM gene, inversions and transpositions of the TCR genes on chromosomes 7 and 14 are common; these often show breakpoints at 14q11-12, 7q32-35, and 7p15

· These translocations may involve the TCL1 gene, leading to T-cell lymphoproliferative disease including both pre-T ALL/LBL as well as T-cell PLL

Prognosis and Predictive Factors

· Prognosis is related to both the underlying PID as well as type of lymphoma

· The immunologic status of the host is an important risk factor

· Most of the lymphomas and leukemias in pts with PID are aggressive

· Treatment is based on the nature of the neoplastic process, as well as the underlying genetic defect

· Allogeneic BM transplantation has been used in pts with WAS, SCID, and hyper IgM syndrome