Encyclopedia of Pathology

Living Edition
| Editors: J.H.J.M. van Krieken

HIV-Associated Lymphoid Disorders

  • Antonino CarboneEmail author
  • Annunziata Gloghini
Living reference work entry
DOI: https://doi.org/10.1007/978-3-319-28845-1_3840-1
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Synonyms

Definition

Lymphomas represent the most frequent malignancy among people infected with human immunodeficiency virus (HIV). Characteristically these lymphomas have high-grade malignancy and are in advanced stage, with extranodal involvement (Swerdlow et al. 2008). The most common lymphomas arising in the presence of HIV-associated immunosuppression include Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL). Classical Hodgkin lymphoma (cHL) is also increased in the setting of HIV, but it less frequent than BL and DLBCL. Additional lymphomas occurring in HIV-infected patients include primary effusion lymphoma (PEL) and its solid variants, lymphoma associated with Kaposi sarcoma herpesvirus (KSHV)-related multicentric Castleman disease (MCD), and plasmablastic lymphoma (PBL) of the oral cavity type (Table 1) (Carbone et al. 2016; Dolcetti et al. 2016; Said et al. 2017; Swerdlow et al. 2008; Yarchoan & Uldrick 2018). These three types of lymphomas rarely occur in immunocompetent patients and are more specific to HIV infection (Gloghini et al. 2013). Among HIV-associated lymphomas, the relative frequencies of the various histotypes are 50 % for DLBCL, 40 % for BL, and 10 % for all other histotypes. Among the latter, both PEL and PBL account for 3 % each.
Table 1

Categories of HIV-associated lymphoproliferative disorders

EBV-associated B-cell lymphoproliferative disorders in HIV setting

 Burkitt lymphoma-plasmacytoid

 Primary central nervous system lymphoma

 Diffuse large B-cell lymphoma, NOS, immunoblastic – plasmacytoid

 Classical Hodgkin lymphoma

 KSHV-associated PEL and its solid variant

 Plasmablastic lymphoma of the oral cavity type

 Other histotypes (rare)

  Polymorphic B-cell lymphoma (PTLD-like)

KSHV-associated lymphoproliferative disorders in HIV setting

 KSHV-associated PEL and its solid variant

  Classic PEL – in the absence of tumor masses

  Solid PEL with serous effusion

  Solid PEL without serous effusion

 MCD-associated large cell lymphoma

 MCD

Abbreviations. EBV Epstein-Barr virus, KSHV Kaposi sarcoma-associated herpesvirus, MCD multicentric Castleman disease, PEL primary effusion lymphoma, PTLD posttransplant lymphoproliferative disorder

Before highly active antiretroviral therapy (HAART), of the different histological types of lymphoma, three were AIDS-defining malignancies, by the definition of the Centers for Disease Control: DLBCL with immunoblastic features, primary central nervous system lymphoma (PCNSL), and BL (Table 2). The terminology for lymphomas has changed since then. In particular, DLBCLs have been subdivided in the germinal center subgroup or activated B-cell subgroup. Both subgroups can be considered AIDS-defining conditions.
Table 2

HIV-associated lymphomas: AIDS-defining and non-AIDS-defining

AIDS-defining lymphomas (since 1992)

 Lymphoma of the brain

 Other non-Hodgkin lymphomas of B-cell or unknown immunophenotype

  Burkitt lymphoma and diffuse large B-cell lymphoma

  Primary effusion lymphoma and its solid variant

Non-AIDS-defining lymphomas (current data)

 Classical Hodgkin lymphoma

Clinical Features

  • Incidence

    Upon the introduction of HAART, the incidence of lymphomas declined but not as dramatically as KS. The incidence of lymphomas declined by 77 % in the post-HAART era (1996–2007) as compared to the pre-HAART era (1984–1995). HAART was particularly effective at reducing the incidence of PCNSL and immunoblastic DLBCL, but it appeared to have less impact on the incidence of BL. Since the introduction of combination antiretroviral therapy (cART), a number of changes have taken place in the spectrum of cancer affecting HIV-infected individuals. However, lymphoma is still the most frequent neoplastic cause of death among HIV-infected individuals. The incidence of lymphomas initially fell in the cART era but has now stabilized. People infected with HIV display a 60–200-fold and 8–10-fold higher relative risk of developing non-Hodgkin lymphoma (NHL) and cHL, respectively, compared with HIV-uninfected people. However, the incidence of DLBCL and PCNSL has decreased, while that of BL and cHL has increased (Shiels et al. 2013; Simard et al. 2011).

    Although the incidence of HIV-associated DLBCL declined after the introduction of HAART and cART, DLBCL remains the main type of cancer in HIV-infected people. The incidence of other HIV-associated lymphomas such as BL, PEL, and PBL of the oral cavity type still remains high. At the present HIV-infected individuals continue to present virus-associated NHL (Carbone and Gloghini 2018; Yarchoan and Uldrick 2018) (Table 3) and are at a 23-fold increased risk compared to the general population (Shiels et al. 2013; Simard et al. 2011).

    Of note, in the cART era, people with HIV seem to be at greater risk of cHL than those who do not have HIV infection. Patients with HIV with modest immunocompromised systems, owing to the improvement in CD4 counts associated with cART, are at higher risk of developing the nodular sclerosis subtype of classic HL (cHL). It has been postulated that with an increase of the CD4+ T-cell population as a result of cART therapy, the appropriate cellular milieu of cHL surrounding the Reed-Sternberg (RS) cells might be available to support tumor development. In patients with HIV with improved immunity, CD4+ T cells provide adequate antiapoptotic pathways and mechanisms of immune evasion for tumor cells, which enable the expansion and maintenance of full expression of concomitant disease, as occurs in cHL among people without AIDS. Alternatively, cHL can arise as part of an immune reconstitution syndrome. Hypothetically, the RS cell might already be present in severe immunosuppressed patients, and partial restoration of the immune system may enable recruitment of surrounding immune cells and hence the manifestation of these tumors. Immunosuppression and poor viral control can increase cHL risk, specifically during the immune reconstitution interval immediately after the initiation of cART (IARC monograph 2012; Carbone et al. 2014).

  • Age

    Young and middle-aged people are affected. Age of lymphoma occurrence is dependent on the age of HIV infection. In comparison to patients naive to cART, patients on cART at cHL diagnosis were older, had less B symptoms, and better bone marrow reserve.

  • Sex

    There is an apparently lower risk of lymphomas in women than men.

  • Site

    Lymphomas that develop in HIV-infected patients are predominantly aggressive nodal and extranodal B-cell malignancies. These lymphomas display a marked propensity to involve the gastrointestinal tract, central nervous system (less frequent after HAART), liver and bone marrow, and perinodal soft tissue.

    At diagnosis, most patients with HIV-associated cHL present with B symptoms and advanced stages of disease with involvement of extranodal sites, including the bone marrow, liver, and spleen.

  • Treatment

    The combination of cART and chemotherapy treatment has resulted in a remarkable prolongation of long-term, disease-free survival and overall survival among HIV-infected patients with lymphoma. However, there is a need for further improvement and wider dissemination of the best treatment protocols because the survival in these patients still lags behind that of patients with lymphoma who are not infected with HIV.

    For patients with HIV and B-cell NHL, solid evidence points to the safety and efficacy of combined treatment including rituximab plus chemotherapy (R-CT), in agreement with corresponding findings in NHL in the general population. Immunotherapy and/or standard-intensive chemotherapy is now feasible in patients receiving cART and supportive care that includes hematopoietic growth factors (such as granulocyte colony-stimulating factor [G-CSF]) and prophylaxis for opportunistic infection (Carbone et al. 2014; Dunleavy and Wilson 2012).

    HIV-associated cHL shows unusually aggressive clinical behavior, which mandates the use of specific therapeutic strategies. The combination of cART with better supportive therapy (such as G-CSF use and prophylaxis of major opportunistic infections) has made standard ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) and intensive chemotherapy regimens feasible also in patients with HIV-associated cHL (Carbone et al. 2014).

  • Outcome

    The outcome of HIV-associated lymphomas including NHL and cHL has dramatically improved since the introduction of cART and survival is now approaching that of HIV-uninfected patients.

Table 3

Lymphoid proliferations in people with HIV/AIDS carry infection by other viral agents

 

HIV

EBV

KSHV

Hodgkin lymphoma

+

+

Burkitt lymphoma-plasmacytoid

+

−/+

DLBCL-IBL plasmacytoid

+

+

PEL and its solid variants

+

+

+

PBL of the oral cavity type

+

+/−

MCD-associated LBCL

+

+

MCD

+

+

Abbreviations: DLBCL diffuse large B-cell lymphoma, EBV Epstein-Barr virus, HIV human immunodeficiency virus, KSHV Kaposi sarcoma-associated herpesvirus, IBL immunoblastic lymphoma, PEL primary effusion lymphoma, MCD multicentric Castleman disease, PBL plasmablastic lymphoma, LBCL large B-cell lymphoma

+, positive in 100 % of cases; −, negative in 100 % of cases; −/+, positive in less than 50 % of cases; +/−, positive in more than 50 % of cases

Macroscopy

Most lymphomas present with tumor masses and large lymphadenopathies with necrosis.

Microscopy

BL. HIV-associated BL includes cases that exhibit classic BL features, as well as cases that show plasmacytoid differentiation or greater nuclear polymorphism, which in the past was referred to as atypical Burkitt or Burkitt-like lymphoma. Morphologically HIV-associated BL can resemble those occurring in HIV-uninfected patients. However, many HIV-associated BL cases show plasmacytoid features that are characterized by pleomorphism in nuclear size and shape, abundant eccentric cytoplasm, and nuclei with a centrally located prominent nucleolus (Fig. 1). Interestingly, BL with plasmacytoid differentiation is seen almost exclusively in patients with HIV (Gloghini et al. 2013).
Fig. 1

Burkitt lymphoma with plasmacytoid differentiation involving (a, b, el) lymph node, (c) extracapsular and (d) extranodal tissues. (ab) Tumor consists of a homogeneous proliferation of medium-sized cells displaying a cohesive pattern. Tumor cells have round nuclei, multiple nucleoli, and limited cytoplasm. (eg) Tumor cells typically express CD20 (membranous staining), CD10 (membranous staining), and BCL6 (nuclear staining). (h) EBV is detected in almost all tumor cells as demonstrated by EBER in situ hybridization. (i) The tumor cells carry rearrangement of MYC as detected by a double-staining chromogenic in situ hybridization assay. (l) Proliferation rate is close to 100 % as shown by MIB1 immunohistochemistry. (a, c, d) Hematoxylin-eosin stain. (b) Giemsa stain. (eg, l) Immunohistochemistry, hematoxylin counterstain. (h, i) Bright field in situ hybridization, hematoxylin counterstain. Abbreviations: EBER Epstein-Barr RNA, EBV Epstein-Barr virus

DLBCL. DLBCLs are morphologically and clinically heterogeneous. The different morphological variants of DLBCL include the centroblastic variant (composed of centroblasts with multiple nucleoli), the immunoblastic variant (composed of immunoblasts with a single, prominent nucleolus) (Fig. 2), and the anaplastic variant (with large tumor cells having anaplastic nucleus). In general, immunoblastic lymphoma tends to occur in patients with more advanced HIV disease compared with centroblastic lymphoma. Primary DLBCL of the central nervous system associated with HIV infection usually belongs to the immunoblastic type (Fig. 2). In HIV-associated DLBCL with immunoblastic features, tumor cells contain over 90 % of immunoblasts with plasmacytoid features (Swerdlow et al. 2008).
Fig. 2

HIV-associated diffuse large B-cell lymphoma with immunoblastic-plasmacytoid features. These lymphomas can be either (ac) systemic or (d, e) primary central nervous system lymphomas. (a-b) Tumor cells contain abundant plasmacytoid cytoplasm and round, oval, or ovoid nuclei with prominent nucleoli. (d) In primary diffuse large B-cell lymphoma of the central nervous system, tumor cells are present in the perivascular space. (c, e) EBV is detected in almost all tumor cells as demonstrated by EBER in situ hybridization. (a, b, d) Hematoxylin-eosin stain. (c, e) Bright field in situ hybridization, hematoxylin counterstain. Abbreviations: EBER Epstein-Barr RNA, EBV Epstein-Barr virus

cHL. Classic HL is currently the most common type of non-AIDS-defining cancers. Three common histological subtypes of HIV-associated cHL have been distinguished based on the characteristics of the reactive infiltrate, and these include a nodular sclerosis cHL, a mixed cellularity cHL, and a lymphocyte depletion cHL. The pathological spectrum of HIV-associated cHL differs from that of cHL nonrelated to HIV. In particular, the aggressive histological subtypes of cHL – mainly mixed cellularity and lymphocyte depletion – predominate among HIV-associated cHL. As observed in cHL in patients not infected by HIV, the so-called RS cell is the diagnostic key for assessing this lymphoma owing to its typical morphology, a giant cell with binucleation or multinucleation and huge nucleoli (Fig. 3) (Carbone et al. 2014).
Fig. 3

(a, c) Involvement of lymph node and (b) bone marrow by HIV-associated classic Hodgkin lymphoma (cHL) of the lymphocyte depletion subtype. (a, b, c) The background is rich in fibrohistiocytoid cells and is depleted of lymphocytes. Rare large Reed-Sternberg (RS) cells with multiple nuclei and prominent nucleoli are present. (df) Lymph node involved by cHL with several RS cells expressing the typical phenotype with intense staining for (d) CD30, (e) CD15, and (b) CD40. (g) RS cells are EBV-infected as demonstrated by EBER in situ hybridization. (h) The EBV carry a latency II phenotype as demonstrated by latent membrane protein 1 expression. (ac) Hematoxylin-eosin stain. (df, h) Immunohistochemistry, hematoxylin counterstain. (g) Bright field in situ hybridization, hematoxylin counterstain. Abbreviations: EBER Epstein-Barr RNA, EBV Epstein-Barr virus

Immunophenotype

BL. HIV-associated Burkitt lymphoma variants have a homogeneous immunophenotype, with expression of CD20, CD10, BCL6, absence of BCL2, and a proliferation rate close to 100 % (Fig. 1).

DLBCL. DLBCL with plasmacytoid features display a plasma cell differentiation-related phenotype while retaining features of the immunoblastic stage of B-cell development. Specifically, plasma cell surface markers, such as CD138, are upregulated, whereas markers of mature B cells, such as CD20 and CD45, are usually downregulated. Similarly, transcription factors associated with B cells in general (such as PAX5 and BCL6) are downregulated, and the fact that the transcriptional program has transitioned to that of plasma cells can be demonstrated by the expression of PRDM1(also known as BLIMP1), XBP1, and IRF4 proteins. The prognostic implications of such immunophenotype is still unclear

cHL. Phenotypically, RS cells of cHL are consistently positive for CD30, CD15, CD40 (Fig. 3), and IRF4.

Molecular Features

BL. Almost all HIV-associated BL cases contain a MYC rearrangement (Fig. 1). Translocation of MYC into one of the immunoglobulin (Ig) loci occurs in all BL. The most common translocation is t(8;14)(q24;q32), which involves the MYC and Ig heavy chain genes, but in 10 % of the cases, it can involve MYC and one of the Ig light chain genes. Many BL cases also contain mutations in TP53, and some tumors have mutations in RAS and/or BCL6 genes. EBV is present in about 50–70 % of BL cases (Fig. 1), especially in the plasmacytoid variant, with a restricted expression pattern of latent genes (EBNA1 only), although heterogeneous expression of EBNA3 and LMP1 in a small proportion of cases has also been reported (IARC monograph 2012). In addition, studies of HIV-associated BL cases suggest that microRNAs might be involved in the pathogenesis of at least some of the EBV-associated lymphomas.

DLBCL. Gene-expression profiling studies have identified at least two major molecular subgroups of DLBCL arising in HIV-uninfected patients. They resemble either germinal center B cells or activated B cells, establishing a putative “cell of origin.” These DLBCL subgroups correlate with prognosis and may have relevance for treatment. The role of molecular subgroups in predicting outcome in HIV-associated DLBCL is still uncertain. By contrast, IHC analysis of HIV-associated DLBCL may predict a better overall survival in the germinal center than in the post-germinal center subgroup. Most (>90 %) HIV-associated DLBCL contain somatic hypermutations in the immunoglobulin genes. In addition, approximately two-thirds of these tumors have BCL6 mutations, and about 50 % of cases have aberrant somatic hypermutations in other proto-oncogenes such as PIM1, PAX5, RHOH, and MYC, all of which may contribute to lymphomagenesis. Structural alterations (gene rearrangements or point mutations) involving oncogenes and tumor suppressor genes can occur, most frequently involving MYC and BCL6. HIV-associated DLBCL are closely linked to EBV infection (Fig. 2). In EBV-associated DLBCL, immunoblastic tumor cells express EBV-encoded LMP1 (indicating a type II latency pattern). A subset of DLBCL has a type III latency pattern as proved by the additional expression of the EBNA2 protein. HIV-associated DLBCL is highly angiogenic with markedly higher blood vessel density than sporadic DLBCL cases. Preclinical studies are currently underway to examine the role of EBV in angiogenesis and to test agents that target antiangiogenic processes in these HIV-associated lymphomas (IARC monograph 2012).

cHL. In HIV-infected patients, nearly all cases of cHL are associated with EBV infection and express a type II latency (Fig. 2). HIV-associated cHL displays biological peculiarities when compared with cHL of patients not infected by HIV. In particular, tumor tissue is characterized by an unusually large proportion of RS cells infected by EBV. Moreover, the fact that LMP1 is expressed in virtually all HIV-associated cHL cases suggests that EBV has an etiological role in their pathogenesis (IARC monograph 2012).

Differential Diagnosis

INT. In HIV setting unclassifiable lymphomas with features intermediate between DLBCL and BL may occur (Fig. 4). These lymphomas, which have been reported in Africa and in Western countries, have also been observed in HIV-uninfected people (Swerdlow et al. 2008).
Fig. 4

Unclassifiable lymphomas with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (at low and high magnification). Neoplastic cells show a microimmunoblastic morphology. They are medium-sized and show clear nucleus containing a large nucleolus. (a, b) Hematoxylin-eosin stain

References

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Authors and Affiliations

  1. 1.Department of PathologyCentro di Riferimento Oncologico Aviano, Istituto Nazionale Tumori, IRCCSAvianoItaly
  2. 2.Department of Diagnostic Pathology and Laboratory MedicineFondazione IRCCS, Istituto Nazionale TumoriMilanItaly