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Lymphoid proliferations associated with human immunodeficiency virus infection.

Individuals who are immune deficient are at an increased risk for developing lymphoproliferative lesions and lymphomas. Human immunodeficiency virus (HIV) infection is 1 of 4 clinical settings associated with immunodeficiency recognized by the World Health Organization (WHO) as having an increased incidence of lymphoma and other lymphoproliferative disorders. (1) Most lymphomas that arise in patients with HIV infections are diffuse aggressive B-cell lymphomas. (2) However, individuals infected with HIV may also develop classical Hodgkin lymphoma (cHL), natural killer/T-cell neoplasms, and low-grade lymphomas. (3-7) In addition, HIV-positive persons can develop generalized lymphadenopathy, which may be mistaken clinically for lymphoma, but is reactive based on morphology, phenotype, and genotype. (8) Some of these benign lesions, such as multicentric Castleman disease (MCD) associated with Kaposi sarcoma herpesvirus/human herpesvirus 8 (KSHV/HHV8) infection, can be severely debilitating. (9,10)

As our knowledge of the pathobiology of HIV disease and as the treatment of HIV infection and its complications has evolved, the epidemiology and incidence of the HIV-associated lymphoproliferative lesions have also changed. The development and widespread use of highly active antiretroviral therapy (HAART) has been associated with a decrease in the overall occurrence of HIV-related lymphoma and a change in the morphology of benign lymph nodes. In addition, the distribution of the types of lymphoma diagnosed as well as the incidence of some of the benign lesions in these patients has also been altered. This review will examine some of the more common types of lymphomas and lymphoproliferative disorders as well as their evolution when arising in the setting of HIV infection.

HIV-RELATED BENIGN LYMPHADENOPATHY

In the early 1980s, homosexual men, many of whom had been previously diagnosed with Kaposi sarcoma or an opportunistic infection, were found to have unexplained, persistent generalized lymphadenopathy of unknown cause, which showed hyperplastic features on biopsy. (11-15) These benign lymph nodes from patients with HIV before HAART treatment did not exhibit static histologic features but, over time, progressed through a series of morphologic patterns, known as florid follicular hyperplasia (FFH), mixed follicular hyperplasia and follicular involution (MX), follicular involution (FI), and lymphocyte depletion, which paralleled the CD4 count and clinical stage of disease. (8,16-23) Furthermore, these morphologic patterns are a consequence of HIV-infection pathobiology. (8,20,24)

Florid follicular hyperplasia, the initial morphology seen in progressive HIV-related benign lymphadenopathy, is characterized by large, irregularly shaped geographic follicles, covering up to two-thirds of the cross-sectional area of the lymph node, surrounded by an attenuated to absent mantle cell zones (Figure 1). The follicles are composed of a mixed cell population, however, centroblasts are usually the predominant cell type. The germinal centers often have a starry-sky appearance because of the relatively numerous tingible-body macrophages and mitotic figures present. In some instances, the follicles are fragmented by infiltrating small lymphocytes, a phenomenon termed follicle lysis or follicular fragmentation. (8,18,20,25-27) Follicle lysis, in combination with effacement of the mantle cell zone, can obscure the normal lymph node architecture, which in light of the many centroblasts, can lead to confusion with malignant lymphoma. (28) The interfollicular area of FFH lymph nodes is composed of a mixed cell population. (18,21,28) Usually, prominent, sinusoidal monocytoid B-cell hyperplasia is present; neutrophils are often also seen within the sinuses. (25,26,29) Immunostaining shows variable disruption of the [CD21.sup.+] follicular dendritic cell (FDC) meshworks as well as p24 HIV viral particles present on the FDC processes. Many [CD8.sup.+] T cells, which are rare or absent in the germinal centers of individuals without HIV, are seen in the FFH germinal centers, sometimes in clusters in the holes" of the [CD21.sup.+] FDC meshworks. The B cells in the follicles exhibit a high proliferation rate based on Ki-67 but are negative for BCL2. The CD4:CD8 ratio in the interfollicular area may be within reference range, be decreased, or be inverted but usually it is not as low as that seen in the peripheral blood. (8,18,21,22,27,30-34)

Mixed follicular hyperplasia and follicular involution shows features of both FFH and FI. However, in MX, the size of the interfollicular area is relatively larger than that in FFH, whereas the follicles and interfollicular area are more cellular than they are in FI. Furthermore, in most patients with MX, the involuted follicles does not exceed 50%. (8,19,20,26)

The follicles in lymph nodes classified as FI are small, atrophic, and hypocellular (Figure 2). The germinal centers consist primarily of hyalinized, epithelialized, follicular dendritic cell meshworks associated with only a few germinal center B cells. Hyalinized blood vessels penetrate the involuted follicles, often at right angles. Some, but not all, of the germinal centers are surrounded by mantle cell zones. Occasionally, extracellular, hyalinized eosinophilic material is seen in association with the germinal centers. The interfollicular area is usually expanded, but may have a "washed-out" appearance because there are relatively few lymphocytes and relatively many histiocytes and polytypic plasma cells. In addition, the vascular structures are often prominent and may be hyalinized. (19-22,25-27,31) Immunophenotypically, the follicle remnants consist of a few [CD21.sup.+] FDCs and a few B cells. In the interfollicular area, there are fewer [CD3.sup.+] T cells, relatively fewer [CD4.sup.+] T cells, with increased or normal numbers of CD8~T cells. Furthermore, the density of p24 viral particles is less than that seen in the earlier stages. (8,21,22,27,31,35-37)

Lymphocyte depletion is characterized by a loss of germinal centers and a paucity of lymphocytes. These lymph nodes are composed predominately of medullary cords and sinusoids. The interfollicular area contains primarily histiocytes, plasma cells, and a few immunoblasts with only a very few lymphocytes. Focal hyaline deposits may be seen in the sites of the degenerated follicles; in addition, subcapsular and sinusoidal fibrosis may be present. (20-22,26,31) With immunostaining, virtually no FDCs are present. Most of the remaining T cells are [CD8.sup.+]; [CD4.sup.+] cells are almost completely absent, whereas B cells and polytypic plasma cells are usually present. However, the number of lymphoid cells identified by immunostaining varies partially because of the degree of lymph node fibrosis. (8,21,22,38)

The progressive stages of HIV-related benign lymphadenopathy (FFH [right arrow] MX [right arrow] FI [right arrow] lymphocyte depletion) correlate with the immune status of the patient and parallel the progressive loss of CD4+ T cells, increasing viral load, and collapse of the immune system. These temporal stages are associated with progressive loss of follicles because of the destruction of the FDC meshworks. The FDC meshworks, which trap HIV in the form of immune complexes, are the major reservoir of HIV during clinical latency. With the FFH and MX patterns, there are sufficient FDCs to effectively quarantine HIV, thereby the infected patient can be maintained with a low peripheral blood viral load and a relatively high CD4 count. The atrophic or absent follicles in FI and lymphocyte depletion, due to degeneration and death of the FDCs, results in a decreased capacity to trap virus, leading to the clinical progression of HIV disease. During these stages of progressive lymphadenopathy, the immune system collapses and the patients develop opportunistic infections and die. (20-25,39,40)

Although the FDC meshworks are nearly destroyed after prolonged, untreated HIV infection, HAART can slowly reverse this destructive pathologic process during a period of months to several years, returning the number of FDCs to the level of that in the lymph nodes of people without HIV, even with infectious virus present. (41,42) Furthermore, there may be a reversal of lymph node morphology to an earlier stage with fewer CD8+ cells in the germinal centers. (31,34,41,43-46) The mechanism of this regeneration and reversion to a more normal state is not clear; however, genetic microarray studies comparing pre-HAART and 1-month post-HAART lymph node tissues demonstrated differences in expression in a number of genes involved in trafficking, active follicle reformation, and tissue repair. (47) Furthermore, HAART decreases the amount of virus in the lymphoid tissue, thereby presumably, decreasing the rate of FDC destruction. (41,48,49) In spite of these changes with HAART, the lymph node morphology is still often abnormal. (43,44,50)

BENIGN LYMPHOEPITHELIAL CYSTIC LESIONS

Salivary gland enlargement associated with a significant lymphoid infiltrate was recognized early in the HIV epidemic. (51,52) Because the lymphoid tissue usually exhibits morphologic and immunophenotypic features similar to those seen in FFH and the lesions often occur in association with enlarged lymph nodes, benign lymphoepithelial cystic lesions are thought to represent a manifestation of persistent, generalized lymphadenopathy. (51,53,54) Known by several names, including benign lymphoepithelial lesion, benign lymphoepithelial cyst, cystic lymphoid hyperplasia, and HIV-related salivary gland disease, this lesion most commonly arises in the parotid gland where it is thought to occur in 3% to 6% of adults and 1% to 10% of children infected with HIV. (53,55) Overall, benign lymphoepithelial cystic lesions account for approximately 25% of enlarged salivary glands in the [HIV.sup.+] patient population. (56) Imaging reveals that the lesions are often cystic, bilateral, and multiple and are associated with lymphadenopathy. (51,57) Morphologically benign lymphoepithelial cystic lesions are characterized by epithelial-lined cysts, often with squamous metaplasia, follicular hyperplasia, glandular atrophy, and in some cases, epimyoepithelial islands. (53,54) In many patients, treatment with HAART results in smaller lesions or their complete resolution. (58)

MULTICENTRIC CASTLEMAN DISEASE

Early in the AIDS epidemic, young, homosexual men and other people with HIV, many of whom had systemic symptoms and lymphadenopathy, had lymph node biopsies that showed features of Castleman disease. Furthermore, like HIV- patients with MCD, many of the [HIV.sup.+] patients also had or developed Kaposi sarcoma. (59-61) Because of these associations, MCD lesions were examined for KSHV/HHV8 soon after its discovery. The virus was found to be present in almost all of the [HIV.sup.+] and about one-half of the [HIV.sup.-] cases. (62,63) Furthermore, most [HIV.sup.+] cases showed the MCD-plasma cell-type morphology. (63)

The HIV-related cases of MCD morphologically show features similar to the [HIV.sup.-] cases or to the MX and FI stages of HIV-related benign lymphadenopathy. (64,65) However, in HIV-related MCD, the follicles may be more hyalinized, the vascular proliferation more prominent, and more plasma cells may be seen in the interfollicular area. Furthermore, the mantle-cell zone contains a variable number of cells with relatively abundant amphophilic cytoplasm and large vesicular nuclei with one or more nucleoli, which resemble immunoblasts (Figure 3). These cells, called plasmablasts or plasmablastic cells, are the KSHV/HHV8-infected B cells, which can be identified by immunostaining for the KSHV-associated protein, latent nuclear antigen-1 (LNA-1 or LANA). (60,65,66)

Immunophenotypically, the plasmablastic cells lack or only weakly express B-cell-associated antigens, such as CD20 and CD79a, but are positive for IRF4/MUM1, PRDM1/BLIMP1, and OCT2. The cells are negative for CD138 and CD38 and also lack evidence of infection by the Epstein-Barr virus (EBV). The plasma cells and lymphocytes in MCD lymph nodes are polytypic; however, nearly all the plasmablastic cells express cytoplasmic immunoglobulin (Ig) Mk. (64-68) Although the KSHV/HHV8-infected plasmablastic cells are monotypic, polymerase chain reaction analysis shows that they are polyclonal B cells. (67)

Patients with HIV and MCD often present with fever and other constitutional symptoms, lymphadenopathy, and cytopenias. At least some of these signs and symptoms are thought to be related to viral interleukin-6, produced by KSHV/HHV8-infected plasmablastic cells, as identified by immunostaining. (64,69) Viral interleukin-6, which has both autocrine and paracrine effects, including inducing human interleukin-6 production, activates all known human interleukin-6 signaling pathways, thereby inducing many of the latter's biologic activities. (68,70,71) Furthermore, patient symptoms correlate with serum viral interleukin-6/human interleukin-6 levels and KSHV/HHV8 viral loads, whereas treatment with anti-interleukin-6 receptor antibodies decreases symptoms, further suggesting a pathogenetic role for this cytokine in MCD. (72-75)

The incidence of MCD in the [HIV.sup.+] population has increased in the post-HAART era with the highest risk seen in older patients with HIV, with a nadir CD4 count greater than 200/[micro]L and no prior HAART therapy. (9,76,77) The risk of developing lymphoma for patients with HIV MCD is about 15 times higher than it is for the general [HIV.sup.+] patient population. The survival of patients with HIV MCD who develop lymphoma is poor. (9,78,79)

LYMPHOMAS ASSOCIATED WITH HIV INFECTION

Most HIV-related lymphomas and lymphoma-like lymphoproliferative disorders are aggressive B-cell proliferations that can be subcategorized as those occurring (1) also in immunocompetent patients (most cases), (2) more specifically in [HIV.sup.+] patients (approximately 5% of cases), and (3) in other immunodeficiency states (<5% of cases). (2) Although the incidence of non-Hodgkin lymphoma in [HIV.sup.+] individuals remains approximately 70 to 80 times greater than that of the general population, (80-83) the epidemiology of these neoplasms has changed with the institution of HAART. Although HIV-related non-Hodgkin lymphomas now accounts for most AIDS-defining cancer events, the overall incidence of them has decreased, whereas the incidence of HIV-related cHL has increased. Furthermore, evaluation of lymphomas diagnosed between 1996 and 2000, compared with those diagnosed in 2001-2007, shows that the proportion of HIV-related diffuse large B-cell lymphomas (DLBCLs) compared with all DLBCLs, has decreased, whereas the proportion of HIV-related Burkitt lymphomas (BLs) has increased. (84-86)

Lymphomas Also Occurring in Immunocompetent Patients

The main entities in this category of lymphomas also occurring in immunocompetent patients are BL (approximately 30% of HIV-related lymphomas), DLBCL (approximately 40%), and cHL (approximately 5%-15%). These neoplastic entities account for most of the HIV-related lymphomas, although only the first 2 entities are AIDS-defining diseases. (2,87,88) Other types of lymphoma, including marginal zone lymphoma, chronic lymphocytic leukemia/ small lymphocytic lymphoma, peripheral T-cell lymphoma, follicular lymphoma, natural killer cell lymphoma, and lymphoblastic leukemia/lymphoma, which occur in [HIV.sup.-] patients, may also occasionally occur in patients with HIV. (5,6,89-91) However, because most lymphomas diagnosed in patients with HIV in this category are cHL, BL, and DLBCL, only these will be discussed.

Classical Hodgkin Lymphoma.--Although not considered an AIDS-defining illness, HIV+ individuals have a 5 to 15 times greater risk of developing cHL than immunocompetent patients. The incidence of HIV cHL has increased with the advent of HAART. Furthermore, the relative risk of developing cHL is higher in patients on HAART than it is in those who are not. (92-95)

Although most patients with HIV-related cHL present with lymph node involvement, some individuals may present with disease only in the bone marrow or in extranodal sites. In comparison to immunocompetent patients, HIV-related cHL is usually widespread at presentation (stage III or IV), and many patients have B symptoms. Furthermore, in comparison to immunocompetent cHL cases, more HIV-related cases are classified as mixed cellularity (25%-55%) or lymphocyte depleted (5%-20%). (89,91,93,95-97) Morphologically and immunophenotypically, HIV-related and HIV- cHL are similar. In both patient groups, the lesions consist of Reed-Sternberg cells and variants associated with a mixed inflammatory cell infiltrate composed primarily of lymphocytes, histiocytes, plasma cells, eosinophils, and neutrophils; some HIV-related cases, however, have a distinct fibrohistiocytoid stromal background. In addition, fewer lymphocytes may be seen in the background cell infiltrate (Figure 4). Immunophenotypically, the neoplastic Reed-Sternberg cells in both [HIV.sup.-] and [HIV.sup.+] cases are [CD45.sup.-], but [PAX5.sup.+] (faint), [CD15.sup.+], and [CD30.sup.+]; in a proportion of cases, the Reed-Sternberg cells are also [CD20.sup.+]. However, in contrast to cases of cHL in immunocompetent patients, the Reed-Sternberg cells in the HIV-related cases are usually [EBV.sup.+]. In addition, there are usually many [CD8.sup.+] T cells in the accompanying microenvironment of the HIV-related cases, often resulting in an inversion in the CD4:CD8 ratio. (89,93,96,98)

Patients with HIV-related and cHL tend to have more-aggressive disease than do their immunocompetent counterparts, although the use of HAART, in addition to chemotherapy, has improved survival. However, HAART has also probably increased the incidence of HIV-related cHL. In the United States, except for the lymphocyte-depletion subtype, the incidence of cHL is highest in HIV-positive patients with an intermediate (225-249 CD4 cells/ [micro]L) CD4 count. (88,95)

Burkitt Lymphoma.--Similar to cHL in the United States, BL tends to occur more frequently in patients with intermediate to high CD4 counts, with the highest crude incidence rate in patients with a CD4 count greater than 250/[micro]L and the lowest in patients with a CD4 count less than 50/[micro]L. (99) Morphologically many lesions occurring in HIV+ patients resemble cases of BL occurring in [HIV.sup.-] patients (Figure 5, A). Some HIV-related BLs, however, are plasmacytoid," consisting of medium-sized cells with relatively abundant cytoplasm, eccentric nuclei, and central prominent nucleoli. These plasmacytoid BLs are more often EBV+ and usually express cytoplasmic immunoglobulin. Similar to BL in immunocompetent patients, HIV-related BLs are positive for pan-B-cell antigens, CD10, and BCL6 but are negative for BCL2. Nearly all cells are [Ki-67.sup.+], indicating a very high proliferation rate (Figure 5, B). (2,100-102) Variations of this classic immunophenotypic profile, however, can be seen in HIV-related BL cases. (103)

Almost all HIV-related BL cases contain a MYC rearrangement. Many cases also contain TP53 mutations, and some cases have mutations in RAS and/or BCL6 genes. (104-107) Recent genetic-expression profiling studies suggest that silencing of RBL2, a tumor suppressor gene, in conjunction with MYC overexpression, may be important in the development of BL. In HIV-infected patients, HIV may also contribute to the development of BL because the HIV TAT viral protein can physically interact with the RBL2/p130 gene product, potentially inhibiting its tumor-suppressor function.108-110 In addition, studies of primarily [HIV.sup.-] BL cases suggest that microRNAs may be involved in the pathogenesis of at least some of the [MYC.sup.-] and/or [EBV.sup.+] BLs. (111-114) Because approximately 30% of all HIV BLs, and even more of the HIV-related BL cases showing plasmacytoid differentiation, are [EBV.sup.+], microRNAs may also be important in the pathogenesis of the HIV-related BL.

Although with the advent of HAART, intensive therapy is now possible for treating HIV-related BL, an optimal treatment approach has yet to be defined. However, based on current clinical trial data, an 85% 1-year overall survival rate for patients with HIV and BL is possible. (115,116)

Diffuse Large B-Cell Lymphoma.--Diffuse large B-cell lymphoma is the most common type of lymphoma in [HIV.sup.+] individuals. (2,88) Most HIV-related DLBCLs are composed of centroblasts, usually admixed with a small but variable number of immunoblasts (Figure 6), and are variably [EBV.sup.+], whereas fewer cases, which are usually [EBV.sup.+], consist primarily of immunoblasts and are often [EBV.sup.+] (Figure 7). (2) Most HIV-related DLBCLs are systemic, occurring in lymph nodes or extranodal sites, including the gastrointestinal tract and oral cavity. (86,100,105,117) However, many cases also occur primarily in the central nervous system (CNS; ie, primary CNS lymphomas; see below).

The HIV-related DLBCLs are characterized at the genetic level by clonal rearrangements of the immunoglobulin genes. Structural alterations involving oncogenes and tumor suppressor genes may occur, most frequently involving MYC and BCL6. In addition, TP53 mutations can be present and tend to occur in cases that contain MYC alterations. (104-106,118-120) Most (>90%) of the HIV-related DLBCLs contain somatic hypermutations in the immunoglobulin genes. In addition, approximately two-thirds of HIV-DLBCLs have BCL6 mutations, and about 50% of cases have aberrant somatic hypermutations in other proto-oncogenes, such as PIM1, PAX5, RhoH/TTF, and MYC, all of which may contribute to the development of these neoplasms. (106,107,121,122) In addition, comparison of [EBV.sup.+] and [EBV.sup.-] HIV-related DLBCLs shows that the [EBV.sup.+] cases have fewer gene copy number changes, indicating that this virus may play a pathogenetic role in [EBV.sup.+] cases. (123,124)

Diffuse large B-cell lymphomas in immunocompetent patients, as determined by gene expression profiling and by immunophenotypic expression patterns, can be divided into clinically relevant groups: germinal center and activated B cell/type 3 (nongerminal center) which are composed of approximately equal numbers of cases in each category. In contrast, using the criteria of Hans et al, HIV-related DLBCLs are more frequently of germinal center origin than those arising in [HIV.sup.-] individuals. (125-131) However, it is not clear whether classification of HIV DLBCLs as having germinal center or nongerminal center origins or expression of specific markers, which are associated with disease behavior in patients with HIV, correlate with the outcome in the [HIV.sup.+] patient population. Not unexpectedly, the CD4 count does predict outcome with distinct differences in survival between the [HIV.sup.+] patients with less than 100 and those with more than 100 [CD4.sup.+] cells/[micro]L. (125,126,132-135)

Although considered in the category of DLBCL, primary CNS lymphoma in HIV-infected patients is a relatively unique clinicopathologic entity. Most of these cases occur in patients who are severely immunosuppressed, with more than 90% of patients presenting with a CD4 count of less than 200/[micro]L and approximately 60% to 70% of those patients having a CD4 of less than 50/[micro]L. (136) Most primary CNS lymphomas exhibit immunoblastic features. Usually the neoplastic cells are [EBV.sup.+], and many express the EBV latency II gene product, latent membrane protein 1 (LMP1), suggesting that they are EBV driven. (98,136-138) Furthermore, HIV-related, primary CNS lymphoma is aggressive with a median overall survival for those treated aggressively with both chemotherapy and whole brain radiation of only 3.4 months. (136)

Lymphomas Occurring More Specifically in [HIV.sup.+] Patients

The neoplasms in this category of HIV-related lymphoma are highly associated with infection by EBV, KSHV/HHV8, or both. These lesions and their associated herpesviruses include plasmablastic lymphoma, which is often [EBV.sup.+]; large B-cell lymphoma arising in HHV8-associated MCD, a [KSHV.sup.+]/[HHV8.sup.+] neoplasm; and primary effusion lymphoma (PEL)/extracavitary PEL (EC-PEL), which are usually positive for both EBV and KSHV/HHV8. (2) Although these lesions preferentially occur in [HIV.sup.+] individuals, they all can occasionally occur in [HIV.sup.-] patients as well.

Plasmablastic Lymphoma.--The HIV-related plasmablastic lymphomas characteristically arise in the oral cavity (60% of cases); however, they can also occur in other mucosal sites, such as the sinonasal cavity and the gastrointestinal tract, and in nonmucosal sites, such as the skin, soft tissue, and lymph nodes. (139-143) Plasmablastic lymphomas exhibit a spectrum of morphologic features ranging from immunoblastic to markedly plasmacytic. In general, the malignant cells are medium to large with relatively round, often eccentrically placed nuclei, each containing a single prominent nucleolus, and a moderate to abundant amount of basophilic cytoplasm. Mitotic figures and apoptotic debris are also usually seen (Figure 8). Plasmablastic lymphomas have recently been sub-classified into morphologic categories--monomorphic plasmablastic lymphomas and plasmablastic lymphomas with plasma cell differentiation--which appear to preferentially occur in different patient populations and anatomic sites. Lesions that occur in patients with HIV tend to be monomorphic and to arise in the oral, nasal, and paranasal areas. (139,141-144)

Most plasmablastic lymphomas in [HIV.sup.+] patients express cytoplasmic immunoglobulin, CD38, CD138, and IRF4/ MUM1 and are usually negative or only weakly positive for CD45, CD20, and PAX5. Although some cases may be [CD56.sup.+], expression of this antigen should raise the possibility of a plasma-cell neoplasm warranting further workup. The plasmablastic lymphomas are frequently [EBV.sup.+] by in situ hybridization but are usually [LMP1.sup.-]. Furthermore, consistent with the number of mitotic figures seen on the routine sections, these lymphomas have a high proliferation rate based on Ki-67 immunostaining. (139,141-146) Plasmablastic lymphomas often have an MYC translocation or an MYC copy number gain. The MYC abnormalities appear to occur preferentially in the [EBV.sup.+] monomorphic cases. (144,145,147) Plasmablastic lymphomas, although they may exhibit plasmacytic differentiation, are biologically more similar to DLBCL than they are to plasma-cell myeloma, based on array comparative genomic hybridization studies. (148)

Although plasmablastic lymphomas occur primarily in patients with HIV, they can arise in [HIV.sup.-] individuals. However, the patients with HIV tend to be younger males with oral cavity-based EBV+ lesions. Furthermore, the [HIV.sup.+] individuals with plasmablastic lymphoma appear to have a better clinical outcome than do the patients without HIV. (140,143)

[KSHV.sup.+]/[HHV8.sup.+] Large B-Cell Lymphoma Associated With MCD.--The neoplastic cells in [KSHV.sup.+]/[HHV8.sup.+] large B-cell lymphoma associated with MCD, as the name implies, are KSHV/HHV8-infected B cells that are morphologically similar to those seen in KSHV/HHV8-associated MCD. In large B-cell lymphoma arising in HHV8-associated MCD, the plasmablastic cells form variably sized collections, ranging from small confluent clusters, known as microlymphomas, to sheets of neoplastic cells that obliterate the normal architecture. The neoplastic process can involve not only lymph nodes but also other sites, including the spleen, liver, gastrointestinal tract, and peripheral blood. (65,68,78,149)

Immunophenotypically, the neoplastic [KSHV.sup.+]/[HHV8.sup.+] plasmablastic cells are similar to the KSHV-infected cells in MCD; specifically, the neoplastic cells lack or only weakly express B-cell antigens, are [CD138.sup.-], brightly express monotypic IgM Ig-[lambda], and are positive for LANA ([KSHV.sup.+]/ [HHV8.sup.+]) but negative for EBER (Epstein-Barr virus-encoded RNA). In addition, many of the cells are [vIL6.sup.+]. PCR analysis has shown that only some of the neoplastic cases, usually those with a large number of malignant cells, are monoclonal. This neoplastic process is thought to arise from naive B cells because the immunoglobulin genes lack somatic hypermutations. (65,67,78,149)

The [KSHV.sup.+]/[HHV8.sup.+] large B-cell lymphomas associated with MCD are most frequently diagnosed in patients with HIV and KSHV/HHV8-associated MCD. The patients with [HIV.sup.+] MCD have a high risk of developing lymphoma, and the survival rate for those who develop large B-cell lymphoma MCD is poor. In general, patients live less than 1 year after diagnosis of large B-cell lymphoma MCD; however, in some studies, survival is less than 1 month. (65,78,149)

Primary Effusion Lymphoma/Extracavitary Primary Effusion Lymphoma.--In 1994, Chang et al (62) identified a fragment of DNA from what is now known as KSHV/HHV8 and showed that it was etiologically related to the development of Kaposi sarcoma. (150) Cesarman et al (151) soon found that this virus was also present in a unique type of lymphoma occurring primarily within body cavities of patients with HIV. Further characterization of these KSHV/HHV8-related PELs, showed that they are a distinct clinicopathologic entity. (151,152) A solid variant without an associated effusion, EC-PEL, has also been described. (153,154)

Primary effusion lymphoma and EC-PEL are rare accounting for less than 5% of HIV-related lymphomas. They usually occur in homosexual men with a low CD4 count and a previous AIDS diagnosis but can occur in other patient populations, including elderly individuals, transplant recipients, and [HIV.sup.+] individuals with CD4 counts within reference range. (152,153,155,156) Primary effusion lymphoma and EC-PELs are composed of large, pleomorphic neoplastic cells that sometimes appear Reed-Sternberg-like (Figure 9). Immunophenotypically, the PEL/EC-PEL cells, in general, lack B-cell-associated and T-cell-associated antigens, although a small percentage of cases may express pan-B-cell antigens, such as CD20 and CD79a, and/or immunoglobulin, usually [lambda] light chain. In addition, the neoplastic cells lack the germinal center markers CD10 and BCL6; express activation-associated antigens, such as CD30; and are positive for markers of terminal B-cell differentiation, such as CD138, IRF4/MUM1, and PRDM1/BLIMP1. The neoplastic cells are [KSHV.sup.+]/[HHV8.sup.+], as detected by immunostaining for LANA, and in approximately 90% of cases, are also [EBV.sup.+] based on in situ hybridization with an EBER probe. (68,151-154,157)

Although the neoplastic cells usually lack B-cell antigen expression, most PELs/EC-PELs have clonally rearranged immunoglobulin genes. Furthermore, the immunoglobulin genes contain somatic hypermutations. However, the neoplastic cells characteristically do not contain structural alterations in oncogenes or tumor suppressor genes. The PELs, based on gene expression profiling, exhibit an intermediate "plasmablastic" profile between that of DLBCL and plasma cells, which is distinct from non-Hodgkin lymphomas in immunocompetent patients and from other HIV-related lymphomas. * These findings, in conjunction with antigen expression, suggest that PELs/EC-PELs arise from terminally differentiated B cells that have gone through the germinal center reaction.

Both PEL and EC-PEL are aggressive disease processes. The median survival of patients with PEL/EC-PEL from 2 relatively large series was 3 and 6.2 months, with only a small percentage of patients surviving 1 year. In one of these studies, the absence of HAART before PEL diagnosis and a performance status greater than 2 were found to be predictive of shorter survival. (153,160)

Lymphomas Occurring in Other Immunodeficient States

The HIV polymorphic lymphoid proliferations, which resemble the polymorphic posttransplant-associated lymphoproliferative disorders seen in solid organ transplant recipients, comprise this category of HIV-related lymphomas/lymphoma-like lymphoproliferative disorders. (2) The HIV polymorphic lymphoid proliferations are extremely rare and have been diagnosed in both adults and children with HIV. (89,161-163) These lesions are composed of a mixture of cells, including lymphocytes, plasmacytoid lymphocytes, plasma cells, epithelioid histiocytes, and immunoblasts, which exhibit variable degrees of cytologic atypia. Foci of coagulative necrosis can also be seen. Most lesions are [EBV.sup.+]. (89,161-164) Many cases are monoclonal, based on genetic studies, but structural alterations in oncogenes and tumor suppressor genes are generally rare. (163) Although clinical outcome information is limited, at least one patient experienced regression of their polymorphic lymphoid lesion following antiviral therapy. (164)

SUMMARY

Human immunodeficiency virus infection represents one of the clinical settings recognized by the WHO in which immunodeficiency-related lymphoproliferative disorders may arise. Although most lymphomas that arise in patients infected with HIV are diffuse aggressive B-cell lesions, other lesions, which are "benign" lymphoid proliferations, may be associated with significant clinical consequences. These latter lesions can be difficult to separate either clinically and pathologically from malignant proliferations. However, the lymphoproliferations arising in the setting of HIV, although often unique, have led to greater understanding of the immune system and lymphomagenesis.

References

(1.) Jaffe ES, Harris NL, Stein H, Vardiman JW. Immunodeficiency-associated lymphoproliferative disorders. In: Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues Lyon, France: IARC Press; 2001:255. World Health Organization Classification of Tumours.

(2.) Raphael M, Said J, Dorisch B, Cesarman E, Harris N. Lymphomas associated with HIV infection. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue. 4th ed. Lyon, France: IARC Press; 2008:340-342. World Health Organization Classification of Tumours; vol 2.

(3.) Nasr SA, Brynes RK, Garrison CP, Chan WC. Peripheral T-cell lymphoma in a patient with acquired immune deficiency syndrome. Cancer. 1988;61(5):947-951.

(4.) Lust JA, Banks PM, Hooper WC, et al. T-cell non-Hodgkin lymphoma in human immunodeficiency virus-1-infected individuals. Am J Hematol. 1989;31(3):181-187.

(5.) Castillo J, Perez K, Milani C, Dezube BJ, Pantanowitz L. Peripheral T-cell lymphomas in HIV-infected individuals: a comprehensive review. J HIV Ther. 2009;14(2):34-40.

(6.) Boulanger E, Meignin V, Baia M, et al. Mucosa-associated lymphoid tissue lymphoma in patients with human immunodeficiency virus infection. Br J Haematol. 2008;140(4):470-474.

(7.) Shorrock K, Ellis IO, Finch RG. T-cell lymphoma associated with human immunodeficiency virus (HIV) infection. Histopathology. 1990;16(2):189-191.

(8.) Knowles DM, Chadburn A. Lymphadenopathy and the lymphoid neoplasms associated with the acquired immune deficiency syndrome. In: Knowles DM, ed. Neoplastic Hematopathology. Philadelphia, PA: Lippincott Williams and Wilkins; 2001:987-1089.

(9.) Mylona EE, Baraboutis IG, Lekakis LJ, Georgiou O, Papastamopoulos V, Skoutelis A. Multicentric Castleman's disease in HIV infection: a systematic review of the literature. AIDS Rev. 2008;10(1):25-35.

(10.) Oksenhendler E, Duarte M, Soulier J, et al. Multicentric Castleman's disease in HIV infection: a clinical and pathological study of 20 patients. AIDS. 1996;10(1):61-67.

(11.) Mathur-Wagh U, Enlow RW, Spigland I, et al. Longitudinal study of persistent generalised lymphadenopathy in homosexual men: relation to acquired immunodeficiency syndrome. Lancet. 1984;1(8385):1033-1038.

(12.) Guarda LA, Butler JJ, Mansell P, Hersh EM, Reuben J, Newell GR. Lymphadenopathy in homosexual men. Morbid anatomy with clinical and immunologic correlations. Am J Clin Pathol. 1983;79(5):559-568.

(13.) Metroka CE, Cunningham-Rundles S, Pollack MS, et al. Generalized lymphadenopathy in homosexual men. Ann Intern Med. 1983;99(5):585-591.

(14.) Miller B, Stansfield SK, Zack MM, et al. The syndrome of unexplained generalized lymphadenopathy in young men in New York City. Is it related to the acquired immune deficiency syndrome? JAMA. 1984;251(2):242-246.

(15.) Control CfD. Persistent, generalized lymphadenopathy among homosexual males. MMWR Morb Mortal Wkly Rep. 1982;31(19):249-251.

(16.) Chan WC, Brynes RK, Spira TJ, et al. Lymphocyte subsets in lymph nodes of homosexual men with generalized unexplained lymphadenopathy: correlation with morphology and blood changes. Arch Pathol Lab Med. 1985;109(2):133-137.

(17.) Fernandez R, Mouradian J, Metroka C, Davis J. The prognostic value of histopathology in persistent generalized lymphadenopathy in homosexual men. N Engl J Med. 1983;309(3):185-186.

(18.) Pileri S, Rivano MT, Raise E, et al. The value of lymph node biopsy in patients with the acquired immunodeficiency syndrome (AIDS) and the AIDS-related complex (ARC): a morphological and immunohistochemical study of 90 cases. Histopathology. 1986;10(11):1107-1129.

(19.) Ioachim HL, Cronin W, Roy M, Maya M. Persistent lymphadenopathies in people at high risk for HIV infection: clinicopathologic correlations and long term follow-up in 79 cases. Am J Clin Pathol. 1990;93(2):208-218.

(20.) Chadburn A, Metroka C, Mouradian J. Progressive lymph node histology and its prognostic value in patients with acquired immunodeficiency syndrome and AIDS-related complex. Hum Pathol. 1989;20(6):579-587.

(21.) Biberfeld P, OstA, Porwit A, et al. Histopathology and immunohistology of HTLV-III/LAV related lymphadenopathy and AIDS. Acta Pathol Microbiol Immunol Scand A. 1987;95(1):47-65.

(22.) Schuurman HJ, Kluin PM, Gmelig Meijling FH, Van Unnik JA, Kater L. Lymphocyte status of lymph node and blood in acquired immunodeficiency syndrome (AIDS) and AIDS-related complex disease. J Pathol. 1985;147(4):269-280.

(23.) Gerstoft J, Pallesen G, Mathiesen L, et al. Stages in LAV/HTLV-III lymphadenitis, II: correlation with clinical and immunological findings. Scand J Immunol. 1987;25(1):93-99.

(24.) Burton GF, Keele BF, Estes JD, Thacker TC, Gartner S. Follicular dendritic cell contributions to HIV pathogenesis. Semin Immunol. 2002;14(4):275-284.

(25.) Burns BF, Wood GS, Dorfman RF. The varied histopathology of lymphadenopathy in the homosexual male. Am J Surg Pathol. 1985;9(4):287-297.

(26.) Turner RR, Levine AM, Gill PS, Parker JW, Meyer PR. Progressive histopathologic abnormalities in the persistent generalized lymphadenopathy syndrome. Am J Surg Pathol. 1987;11(8):625-632.

(27.) Pallesen G, Gerstoft J, Mathiesen L. Stages in LAV/HTLV-III lymphadenitis, I: histological and immunohistological classification. Scand J Immunol. 25(1):83-91.

(28.) Said JW. AIDS-related lymphadenopathies. Semin Diagn Pathol. Nov 1988;5(4):365-375.

(29.) Sohn CC, Sheibani K, Winberg CD, Rappaport H. Monocytoid B lymphocytes: their relation to the patterns of the acquired immunodeficiency syndrome (AIDS) and AIDS-related lymphadenopathy. Hum Pathol. 1985;16(10):979-985.

(30.) Wood GS, Garcia CF, Dorfman RF, Warnke RA. The immunohistology of follicle lysis in lymph node biopsies from homosexual men. Blood. 1985;66(5):1092-1097.

(31.) Diebold J, Marche C, Audouin J, et al. Lymph node modification in patients with the acquired immunodeficiency syndrome (AIDS) or with AIDS related complex (ARC). A histological, immuno-histopathological and ultrastructural study of 45 cases. Pathol Res Pract. 1985;180(6):590-611.

(32.) Raphael M, Pouletty P, Cavaille-Coll M, et al. Lymphadenopathyin patients at risk for acquired immunodeficiency syndrome. Histopathology and histochemistry. Arch Pathol Lab Med. 1985;109(2):128-132.

(33.) Said JW, Shintaku IP, Teitelbaum A, Chien K, Sassoon AF. Distribution of T cell phenotypic subsets and surface immunoglobulin-bearing lymphocytes in lymph nodes from male homosexuals with persistent generalized adenopathy: an immunohistochemical and ultrastructural study. Hum Pathol. 1984;15(8):785-790.

(34.) Baroni CD, Vitolo D, Uccini S. Immunohistopathogenesis of persistent generalized lymphadenopathy in HIV-positive patients. Ric Clin Lab. 1990;20(1):1-10.

(35.) Schuurman HJ, Krone WJ, Broekhuizen R, Goudsmit J. Expression of RNA and antigens of human immunodeficiency virus type-1 (HIV-1) in lymph nodes from HIV-1 infected individuals. Am J Pathol. 1988;133(3):516-524.

(36.) Wood GS, Burns BF, Dorfman RF, Warnke RA. Fatal post-transfusion acquired immunodeficiency in a heterosexual man: quantitative lymph node immunopathology. Hum Pathol. 1988;19(2):236-238.

(37.) Porwit A, Bottiger B, Pallesen G, Bodner A, Biberfeld P. Follicular involution in HIV lymphadenopathy: a morphometric study. APMIS. 1989;97(2):153-165.

(38.) Walewska-Zielecka B, Nowoslawski A. HIV lymphadenopathy--a histopathological and immunomorphological study of 65 cases. Pol J Pathol. 1995;46(4):211-217.

(39.) Grouard G, Clark EA. Roleofdendritic and follicular dendritic cellsin HIV infection and pathogenesis. Curr Opin Immunol. 1997;9(4):563-567.

(40.) Pantaleo G, Fauci AS. Immunopathogenesis of HIV infection. Annu Rev Microbiol. 1996;50:825-854.

(41.) Zhang ZQ, Schuler T, Cavert W, et al. Reversibility of the pathological changes in the follicular dendritic cell network with treatment of HIV-1 infection. Proc Natl Acad Sci USA. 1999;96(9):5169-5172.

(42.) Huber G, Banki Z, Lengauer S, Stoiber H. Emerging role for complement in HIV infection. Curr Opin HIVAIDS. 2011;6(5):419-426.

(43.) Orenstein JM, Feinberg M, Yoder C, et al. Lymph node architecture preceding and following 6 months of potent antiviral therapy: follicular hyperplasia persists in parallel with p24 antigen restoration after involution and CD4 cell depletion in an AIDS patient. AIDS. 1999;13(16):2219-2229.

(44.) Mueller BU, Sei S, Anderson B, et al. Comparison of virus burden in blood and sequential lymph node biopsy specimens from children infected with human immunodeficiency virus. J Pediatr. 1996;129(3):410-418.

(45.) Ehrhard S, Wernli M, Kaufmann G, et al. Effect of antiretroviral therapy on apoptosis markers and morphology in peripheral lymph nodes of HIV-infected individuals. Infection. 2008;36(2):120-129.

(46.) Laman JD, Claassen E, Van Rooijen N, Boersma WJ. Immune complexes on follicular dendritic cells as a target for cytolytic cells in AIDS. AIDS. 1989;3(8):543-544.

(47.) Li Q, Schacker T, Carlis J, Beilman G, Nguyen P, Haase AT. Functional genomic analysis of the response of HIV-1-infected lymphatic tissue to antiretroviral therapy. J Infect Dis. 2004;189(4):572-582.

(48.) Bart PA, Rizzardi GP, Tambussi G, et al. Immunological and virological responses in HIV-1-infected adults at early stage of established infection treated with highly active antiretroviral therapy. AIDS. 2000;14(13):1887-1897.

(49.) Cavert W, Notermans DW, Staskus K, et al. Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection. Science. 1997;276(5314):960-964.

(50.) Schacker TW, Nguyen PL, Martinez E, et al. Persistent abnormalities in lymphoid tissues of human immunodeficiency virus-infected patients successfully treated with highly active antiretroviral therapy. J Infect Dis. 2002;186(8):1092-1097.

(51.) Shugar JM, Som PM, Jacobson AL, Ryan JR, Bernard PJ, Dickman SH. Multicentric parotid cysts and cervical adenopathy in AIDS patients: a newly recognized entity: CT and MR manifestations. Laryngoscope. 1988;98(7):772-775.

(52.) Finfer MD, Schinella RA, Rothstein SG, Persky MS. Cysticparotid lesionsin patients at risk for the acquired immunodeficiency syndrome. Arch Otolaryngol Head Neck Surg. 1988;114(11):1290-1294.

(53.) DiGiuseppe JA, Corio RL, Westra WH. Lymphoid infiltrates of the salivary glands: pathology, biology and clinical significance. Curr Opin Oncol. 1996;8(3):232-237.

(54.) Kreisel FH, Frater JL, Hassan A, El-Mofty SK. Cystic lymphoid hyperplasia of the parotid gland in HIV-positive and HIV-negative patients: quantitative immunopathology. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010;109(4):567-574.

(55.) Dave SP, Pernas FG, Roy S. The benign lymphoepithelial cyst and a classification system for lymphocytic parotid gland enlargement in the pediatric HIV population. Laryngoscope. 2007;117(1):106-113.

(56.) Michelow P, Dezube BJ, Pantanowitz L. Fine needle aspiration of salivary gland masses in HIV-infected patients [published online ahead of print January 6, 2011]. Diagn Cytopathol. doi:10.1002/dc.21597.

(57.) Terry JH, Loree TR, Thomas MD, Marti JR. Major salivary gland lymphoepithelial lesions and the acquired immunodeficiency syndrome. Am J Surg. 1991;162(4):324-329.

(58.) Syebele K, Butow KW. Comparative study of the effect of antiretroviral therapy on benign lymphoepithelial cyst of parotid glands and ranulas in HIV-positive patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011;111(2):205-210.

(59.) Lowenthal DA, Filippa DA, Richardson ME, Bertoni M, Straus DJ. Generalized lymphadenopathy with morphologic features of Castleman's disease in an HIV-positive man. Cancer. 1987;60(10):2454-2458.

(60.) Lachant NA, Sun NC, Leong LA, Oseas RS, Prince HE. Multicentric angiofollicular lymph node hyperplasia (Castleman's disease) followed by Kaposi's sarcoma in two homosexual males with the acquired immunodeficiency syndrome (AIDS). Am J Clin Pathol. 1985;83(1):27-33.

(61.) Perlow LS, Taff ML, Orsini JM, et al. Kaposi's sarcoma in a young homosexual man: association with angiofollicular lymphoid hyperplasia and a malignant lymphoproliferative disorder. Arch Pathol Lab Med. 1983;107(10):510-513.

(62.) Chang Y, Cesarman E, Pessin MS, et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science. 1994;266(5192):1865-1869.

(63.) Soulier J, Grollet L, Oksenhendler E, et al. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease. Blood. 1995;86(4):1276-1280.

(64.) Chadburn A, Hyjek EM, Tam W, et al. Immunophenotypic analysis of the Kaposi sarcoma herpesvirus (KSHV; HHV-8)-infected B cells in HIV+ multicentric Castleman disease (MCD). Histopathology. 2008;53(5):513-524.

(65.) Dupin N, Diss TL, Kellam P, et al. HHV-8 is associated with a plasmablastic variant of Castleman disease that is linked to HHV-8-positive plasmablastic lymphoma. Blood. 2000;95(4):1406-1412.

(66.) Dupin N, Fisher C, Kellam P, et al. Distribution of human herpesvirus-8 latently infected cells in Kaposi's sarcoma, multicentric Castleman's disease, and primary effusion lymphoma. Proc Natl Acad Sci U S A. 1999;96(8):4546-4551.

(67.) Du MQ, Liu H, Diss TC, et al. Kaposi sarcoma-associated herpesvirus infects monotypic (IgMk) but polyclonal naive B cells in Castleman disease and associated lymphoproliferative disorders. Blood. 2001;97(7):2130-2136.

(68.) Du MQ, Bacon CM, Isaacson PG. Kaposi sarcoma-associated herpesvirus/ human herpesvirus 8 and lymphoproliferative disorders. J Clin Pathol. 2007;60(12):1350-1357.

(69.) Parravicini C, Chandran B, Corbellino M, et al. Differential viral protein expression in Kaposi's sarcoma-associated herpesvirus-infected diseases: Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. Am J Pathol. 2000;156(3):743-749.

(70.) Molden J, Chang Y, You Y, Moore PS, Goldsmith MA. A Kaposi's sarcoma-associated herpesvirus-encoded cytokine homolog (vIL-6) activates signaling through the shared gp130 receptor subunit. J Biol Chem. 1997;272(31):19625-19631.

(71.) Aoki Y, Jaffe ES, Chang Y, et al. Angiogenesis and hematopoiesis induced by Kaposi's sarcoma-associated herpesvirus-encoded interleukin-6. Blood. 1999;93(12):4034-4043.

(72.) Song SN, Tomosugi N, Kawabata H, Ishikawa T, Nishikawa T, Yoshizaki K. Down-regulation of hepcidin resulting from long-term treatment with an anti-IL-6 receptor antibody (tocilizumab) improves anemia of inflammation in multicentric Castleman disease. Blood. 2010;116(18):3627-3634.

(73.) Matsuyama M, Suzuki T, Tsuboi H, et al. Anti-interleukin-6 receptor antibody (tocilizumab) treatment of multicentric Castleman's disease. Intern Med. 2007;46(11):771-774.

(74.) Oksenhendler E, Carcelain G, Aoki Y, et al. High levels of human herpesvirus 8 viral load, human interleukin-6, interleukin-10, and C reactive protein correlate with exacerbation of multicentric Castleman disease in HIV infected patients. Blood. 2000;96(6):2069-2073.

(75.) Aoki Y, Tosato G, Fonville TW, Pittaluga S. Serum viral interleukin-6 in AIDS-related multicentric Castleman disease. Blood. 2001;97(8):2526-2527.

(76.) Powles T, Stebbing J, Bazeos A, et al. The role of immune suppression and HHV-8 in the increasing incidence of HIV-associated multicentric Castleman's disease. Ann Oncol. 2009;20(4):775-779.

(77.) Oksenhendler E. HIV-associated multicentric Castleman disease. Curr Opin HIV AIDS. 2009;4(1):16-21.

(78.) Oksenhendler E, Boulanger E, Galicier L, et al. High incidence of Kaposi sarcoma-associated herpesvirus-related non-Hodgkin lymphoma in patients with HIV infection and multicentric Castleman disease. Blood. 2002;99(7):2331-2336.

(79.) Matthews GV, Bower M, Mandalia S, Powles T, Nelson MR, Gazzard BG. Changes in acquired immunodeficiency syndrome-related lymphoma since the introduction of highly active antiretroviral therapy. Blood. 2000;96(8):2730-2734.

(80.) Seaberg EC, Wiley D, Martinez-Maza O, et al. Cancer incidence in the multicenter AIDS CohortStudy before and during the HAAR Tera: 1984 to 2007. Cancer. 2010;116(23):5507-5516.

(81.) Stebbing J, Duru O, Bower M. Non-AIDS-defining cancers. Curr Opin Infect Dis. 2009;22(1):7-10.

(82.) Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet. 2007;370(9581):59-67.

(83.) Mbulaiteye SM, Biggar RJ, Goedert JJ, Engels EA. Immune deficiency and risk for malignancy among persons with AIDS. J Acquir Immune Defic Syndr. 2003;32(5):527-533.

(84.) Shiels MS, Pfeiffer RM, Hall HI, et al. Proportions of Kaposi sarcoma, selected non-Hodgkin lymphomas, and cervical cancer in the United States occurring in persons with AIDS, 1980-2007. JAMA. 2011;305(14):1450-1459.

(85.) Simard EP, Pfeiffer RM, Engels EA. Cumulative incidence of cancer among individuals with acquired immunodeficiency syndrome in the United States. Cancer. 2011;117(5):1089-1096.

(86.) Shiels MS, Pfeiffer RM, Gail MH, et al. Cancer burden in the HIV-infected population in the United States. J Natl Cancer Inst. 2011;103(9):753-762.

(87.) Centers for Disease Control and Prevention. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep. 1992;41(RR-17):1-19.

(88.) Engels EA, Biggar RJ, Hall HI, et al. Cancer risk in people infected with human immunodeficiency virus in the United States. Int J Cancer. 2008;123(1):187-194.

(89.) Grogg KL, Miller RF, Dogan A. HIV infection and lymphoma. J Clin Pathol. 2007;60(12):1365-1372.

(90.) Panarelli NC, Furman RR, Wang YL, Elstrom R, Cohen JA, Chadburn A. NK/T cell non-Hodgkin lymphoma in a HIV-positive patient. J Hematop. 2010;3(1):35-40.

(91.) Mantina H, Wiggill TM, Carmona S, Perner Y, Stevens WS. Characterization of Lymphomas in a high prevalence HIV setting. J Acquir Immune Defic Syndr. 2010;53(5):656-660.

(92.) Hessol NA, Pipkin S, Schwarcz S, Cress RD, Bacchetti P, Scheer S. The impact of highly active antiretroviral therapy on non-AIDS-defining cancers among adults with AIDS. Am J Epidemiol. 2007;165(10):1143-1153.

(93.) Carbone A, Spina M, Gloghini A, Tirelli U. Classical Hodgkin's lymphoma arising in different host's conditions: pathobiology parameters, therapeutic options, and outcome. Am J Hematol. 2011;86(2):170-179.

(94.) Clifford GM, Rickenbach M, Lise M, et al. Hodgkin lymphomain the Swiss HIV Cohort Study. Blood. 2009;113(23):5737-5742.

(95.) Biggar RJ, Jaffe ES, Goedert JJ, Chaturvedi A, Pfeiffer R, Engels EA. Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS. Blood. 2006;108(12):3786-3791.

(96.) Spina M, Berretta M, Tirelli U. Hodgkin's disease in HIV. Hematol Oncol Clin North Am. 2003;17(3):843-858.

(97.) Tirelli U, Errante D, Dolcetti R, et al. Hodgkin's disease and human immunodeficiency virus infection: clinicopathologic and virologic features of 114 patients from the Italian Cooperative Group on AIDS and Tumors. J Clin Oncol. 1995;13(7):1758-1767.

(98.) Hamilton-Dutoit SJ, Raphael M, Audouin J, et al. In situ demonstration of Epstein-Barr virus small RNAs (EBER 1) in acquired immunodeficiency syndrome related lymphomas: correlation with tumor morphology and primary site. Blood. 1993;82(2):619-624.

(99.) Guech-Ongey M, Simard EP, Anderson WF, et al. AIDS-related Burkitt lymphomain the United States: what do age and CD4 lymphocyte patterns tell us about etiology and/or biology? Blood. 2010;116(25):5600-5604.

(100.) Raphael M, Gentilhomme O, Tulliez M, Byron PA, Diebold J; French Study Group of Pathology for Human Immunodeficiency Virus-Associated Tumors. Histopathologic features of high-grade non-Hodgkin's lymphomas in acquired immunodeficiency syndrome. Arch Pathol Lab Med. 1991;115(1):15-20.

(101.) Leoncini L, Raphael M, Stein H, Harris NL, Jaffe ES, Kluin PM. Burkitt lymphoma. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissue. 4th ed. Lyon, France: IARC Press; 2008:262-264. World Health Organization Classification of Tumours; vol 2.

(102.) Davi F, Delecluse HJ, Guiet P, et al; Burkitt's Lymphoma Study Group. Burkitt-like lymphomas in AIDS patients: characterization within a series of 103 human immunodeficiency virus-associated non-Hodgkin's lymphomas. J Clin Oncol. 1998;16(12):3788-3795.

(103.) Kelemen K, Braziel RM, Gatter K, Bakke TC, Olson S, Fan G. Immunophenotypic variations of Burkitt lymphoma. Am J Clin Pathol. 2010;134(1):127-138.

(104.) Ballerini P, Gaidano G, Gong JZ, et al. Multiple genetic lesions in acquired immunodeficiency syndrome-related non-Hodgkin's lymphoma. Blood. 1993;81(1):166-176.

(105.) Knowles DM. Etiology and pathogenesis of AIDS-related non-Hodgkin's lymphoma. Hematol Oncol Clin North Am. 2003;17(3):785-820.

(106.) Carbone A, Gaidano G, Gloghini A, et al. Differential expression of BCL-6, CD138/syndecan-1, and Epstein-Barr virus-encoded latent membrane protein-1 identifies distinct histogenetic subsets of acquired immunodeficiency syndrome-related non-Hodgkin's lymphomas. Blood. 1998;91(3):747-755.

(107.) Gaidano G, Carbone A, Pastore C, et al. Frequent mutation of the 5' noncoding region of the BCL-6 gene in acquired immunodeficiency syndrome related non-Hodgkin's lymphomas. Blood. 1997;89(10):3755-3762.

(108.) Bellan C, De Falco G, Lazzi S, Leoncini L. Pathologic aspects of AIDS malignancies. Oncogene. 2003;22(42):6639-6645.

(109.) De Falco G, Bellan C, Lazzi S, et al. Interaction between HIV-1 Tat and pRb2/p130: a possible mechanism in the pathogenesis of AIDS-related neoplasms. Oncogene. 2003;22(40):6214-6219.

(110.) Piccaluga PP, De Falco G, Kustagi M, et al. Gene expression analysis uncovers similarity and differences among Burkitt lymphoma subtypes. Blood. 2011;117(13):3596-3608.

(111.) De Falco G, Antonicelli G, Onnis A, Lazzi S, Bellan C, Leoncini L. Role of EBV in microRNA dysregulation in Burkitt lymphoma. Semin Cancer Biol. 2009;19(6):401-406.

(112.) Leucci E, Onnis A, Cocco M, et al. B-cell differentiation in EBV-positive Burkitt lymphoma is impaired at posttranscriptional level by miRNA-altered expression. Int J Cancer. 2010;126(6):1316-1326.

(113.) Leucci E, Cocco M, Onnis A, et al. MYC translocation-negative classical Burkitt lymphoma cases: an alternative pathogenetic mechanism involving miRNA deregulation. J Pathol. 2008;216(4):440-450.

(114.) Onnis A, De Falco G, Antonicelli G, et al. Alteration of microRNAs regulated by c-Myc in Burkitt lymphoma. PLoS One. 2010;5(9):e12960. doi:10. 1371/journal.pone.0012960.

(115.) Blinder VS, Chadburn A, Furman RR, Mathew S, Leonard JP. Improving outcomes for patients with Burkitt lymphoma and HIV. AIDS Patient Care STDS. 2008;22(3):175-187.

(116.) Noy A. Controversies in the treatment of Burkitt lymphoma in AIDS. Curr Opin Oncol. 2010;22(5):443-448.

(117.) Knowles DM, Chamulak GA, Subar M, et al. Lymphoid neoplasia associated with the acquired immunodeficiency syndrome (AIDS). The New York University Medical Center experience with 105 patients (1981-1986). Ann Intern Med. 1988;108(5):744-753.

(118.) Gaidano G, LoCoco F, Ye BH, et al. Rearrangements of the BCL-6 gene in acquired immunodeficiency syndrome-associated non-Hodgkin's lymphoma: association with diffuse large-cell subtype. Blood. 1994;84(2):397-402.

(119.) Mathew S, Gogineni S, Cesarman E, Knowles DM, Chadburn A. MYC, BCL6 and BCL2 genetic alterations and associated phenotypes of AIDS-related (AR) diffuse large B cell lymphomas (DLBCLs) suggest biologic differences with immunocompetent (IC) DLBCLs. Mod Pathol. 2010;23(suppl 1s):377A; doi:10. 1038/modpathol.2010.23.

(120.) Subar M, Neri A, Inghirami G, Knowles DM, Dalla-Favera R. Frequent cmyc oncogene activation and infrequent presence of Epstein-Barr virus genome in AIDS-associated lymphoma. Blood. 1988;72(2):667-671.

(121.) Gaidano G, Pasqualucci L, Capello D, et al. Aberrant somatic hypermutation in multiple subtypes of AIDS-associated non-Hodgkin lymphoma. Blood. 2003;102(5):1833-1841.

(122.) Capello D, Martini M, Gloghini A, et al. Molecular analysis of immunoglobulin variable genes in human immunodeficiency virus-related non-Hodgkin's lymphoma reveals implications for disease pathogenesis and histogenesis. Haematologica. 2008;93(8):1178-1185.

(123.) Capello D, Scandurra M, Poretti G, et al. Genome wide DNA-profiling of HIV-related B-cell lymphomas. Br J Haematol. 2010;148(2):245-255.

(124.) Deffenbacher KE, Iqbal J, Liu Z, Fu K, Chan WC. Recurrent chromosomal alterations in molecularly classified AIDS-related lymphomas: an integrated analysis of DNA copy number and gene expression. J Acquir Immune Defic Syndr. 2010;54(1):18-26.

(125.) Chadburn A, Silver S, Pasqualucci L, et al. Comparison of AIDS-related diffuse large B cell lymphomas (AR-DLBCLs) and Immunocompetent (IC) DLBCLs suggest biologic differences. Mod Pathol. 2009;22:257A.

(126.) Little RF, Pittaluga S, Grant N, et al. Highly effective treatment of acquired immunodeficiency syndrome-related lymphoma with dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology. Blood. 2003;101(12):4653-4659.

(127.) Alacacioglu I, Ozcan MA, Ozkal S, et al. Prognostic significance of immunohistochemical classification of diffuse large B-cell lymphoma. Hematology. 2009;14(2):84-89.

(128.) Hong J, Park S, Park J, et al. Evaluation of prognostic values of clinical and histopathologic characteristics in diffuse large B-cell lymphoma treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone therapy. Leuk Lymphoma. 2011;52(10):1904-1912.

(129.) Choi WW, Weisenburger DD, Greiner TC, et al. A new immunostain algorithm classifies diffuse large B-cell lymphoma into molecular subtypes with high accuracy. Clin Cancer Res. 2009;15(17):5494-5502.

(130.) Hans CP, Weisenburger DD, Greiner TC, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103(1):275-282.

(131.) Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B cell lymphoma identified by gene expression profiling. Nature. 2000;403(6769):503-511.

(132.) Dunleavy K, Little RF, Pittaluga S, et al. The role of tumor histogenesis, FDG-PET, and short-course EPOCH with dose-dense rituximab (SC-EPOCH-RR) in HIV-associated diffuse large B-cell lymphoma. Blood. 2010;115(15):3017-3024.

(133.) Xicoy B, Ribera JM, Mate JL, et al. Immunohistochemical expression profile and prognosis in patients with diffuse large B-cell lymphoma with or without human immunodeficiency virus infection. Leuk Lymphoma. 2010;51(11):2063-2069.

(134.) Straus DJ, Huang J, Testa MA, Levine AM, Kaplan LD; National Institute of Allergy and Infectious Diseases. Prognostic factors in the treatment of human immunodeficiency virus-associated non-Hodgkin's lymphoma: analysis of AIDS Clinical Trials Group protocol 142--low-dose versus standard-dose m-BACOD plus granulocyte-macrophage colony-stimulating factor. J Clin Oncol. 1998;16(11):3601-3606.

(135.) Bohlius J, Schmidlin K, Costagliola D, et al. Prognosis of HIV-associated non-Hodgkin lymphoma in patients starting combination antiretroviral therapy. AIDS. 2009;23(15):2029-2037.

(136.) Bayraktar S, Bayraktar UD, Ramos JC, Stefanovic A, Lossos IS. Primary CNS lymphoma in HIV positive and negative patients: comparison of clinical characteristics, outcome and prognostic factors. J Neurooncol. 2011;101(2):257 265.

(137.) Camilleri-Broet S, Davi F, Feuillard J, et al; The French Study Group for HIV-Associated Tumors. AIDS-related primary brain lymphomas: histopathologic and immunohistochemical study of 51 cases. Hum Pathol. 1997;28(3):367-374.

(138.) MacMahon EM, Glass JD, Hayward SD, et al. Epstein-Barr virus in AIDS-related primary central nervous system lymphoma. Lancet. 1991;338(8773):969 973.

(139.) Delecluse HJ, Anagnostopoulos I, Dallenbach F, et al. Plasmablastic lymphomas of the oral cavity: a new entity associated with the human immunodeficiency virus infection. Blood. 1997;89(4):1413-1420.

(140.) Castillo JJ, Winer ES, Stachurski D, et al. Clinical and pathological differences between human immunodeficiency virus-positive and human immunodeficiency virus-negative patients with plasmablastic lymphoma. Leuk Lymphoma. 2010;51(11):2047-2053.

(141.) Stein H, Harris N, Campo E. Plasmablastic lymphoma. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue. 4th ed. Lyon, France: IARC Press; 2008:256-257. World Health Organization Classification of Tumours; vol 2.

(142.) Dong HY, Scadden DT, de Leval L, Tang Z, Isaacson PG, Harris NL. Plasmablastic lymphoma in HIV-positive patients: an aggressive Epstein-Barr virus-associated extramedullary plasmacytic neoplasm. Am J Surg Pathol. 2005;29(12):1633-1641.

(143.) Hansra D, Montague N, Stefanovic A, et al. Oral and extraoral plasmablastic lymphoma: similarities and differences in clinicopathologic characteristics. Am J Clin Pathol. 2010;134(5):710-719.

(144.) Taddesse-Heath L, Meloni-Ehrig A, Scheerle J, Kelly JC, Jaffe ES. Plasmablastic lymphoma with MYC translocation: evidence for a common pathway in the generation of plasmablastic features. Mod Pathol. 2010;23(7):991-999.

(145.) Valera A, Balague O, Colomo L, et al. IG/MYC rearrangements are the main cytogenetic alteration in plasmablastic lymphomas. Am J Surg Pathol. 2010;34(11):1686-1694.

(146.) Gaidano G, Cerri M, Capello D, et al. Molecular histogenesis of plasmablastic lymphoma of the oral cavity. Br J Haematol. 2002;119(3):622-628.

(147.) Bogusz AM, Seegmiller AC, Garcia R, Shang P, Ashfaq R, Chen W. Plasmablastic lymphomas with MYC/IgH rearrangement: report of three cases and review of the literature. Am J Clin Pathol. 2009;132(4):597-605.

(148.) Chang CC, Zhou X, Taylor JJ, et al. Genomic profiling of plasmablastic lymphoma using array comparative genomic hybridization (aCGH): revealing significant overlapping genomic lesions with diffuse large B-cell lymphoma. J Hematol Oncol. 2009;2:47.

(149.) Isaacson PG, Campo E, Harris NL. Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008:258-259. World Health Organization Classification of Tumours; vol 2.

(150.) Moore PS, Chang Y. Detection of herpesvirus-like DNA sequences in Kaposi's sarcoma in patients with and without HIV infection. N Engl J Med. 1995;332(18):1181-1185.

(151.) Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in AIDS-related body cavity-based lymphomas. N EnglJMed. 1995;332(18):1186-1191.

(152.) Nador RG, Cesarman E, Chadburn A, et al. Primary effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi's sarcoma-associated herpes virus. Blood. 1996;88(2):645-656.

(153.) Chadburn A, Hyjek E, Mathew S, Cesarman E, Said J, Knowles DM. KSHV-positive solid lymphomas represent an extra-cavitary variant of primary effusion lymphoma. Am J Surg Pathol. 2004;28(11):1401-1416.

(154.) Carbone A, Gloghini A, Vaccher E, et al. Kaposi's sarcoma-associated herpesvirus/human herpesvirus type 8-positive solid lymphomas: a tissue-based variant of primary effusion lymphoma. J Mol Diagn. 2005;7(1):17-27.

(155.) Boulanger E, Afonso PV, Yahiaoui Y, Adle-Biassette H, Gabarre J, Agbalika F. Human herpesvirus-8 (HHV-8)-associated primary effusion lymphoma in two renal transplant recipients receiving rapamycin. Am J Transplant. 2008;8(3):707-710.

(156.) Dotti G, Fiocchi R, Motta T, et al. Primary effusion lymphoma after heart transplantation: a new entity associated with human herpesvirus-8. Leukemia. 1999;13(5):664-670.

(157.) Said J, Cesarman E. Primary effusion lymphoma. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue. 4th ed. Lyon, France: IARC Press; 2008:260-261. World Health Organization Classification of Tumours; vol 2.

(158.) Klein U, Gloghini A, GaidanoG, et al. Gene expression profile analysis of AIDS-related primary effusion lymphoma (PEL) suggests a plasmablastic derivation and identifies PEL-specific transcripts. Blood. 2003;101(10):4115-4121.

(159.) Fais F, Gaidano G, Capello D, et al. Immunoglobulin V region gene use and structure suggest antigen selection in AIDS-related primary effusion lymphomas. Leukemia. 1999;13(7):1093-1099.

(160.) Boulanger E, Gerard L, Gabarre J, et al. Prognostic factors and outcome of human herpesvirus 8-associated primary effusion lymphoma in patients with AIDS. J Clin Oncol. 2005;23(19):4372-4380.

(161.) Wang X, Nathan S, Catchatourian R, Richter H, 3rd, Kovarik P. Polymorphic lymphoid proliferation presenting as ileocecal intussusception. Ann Hematol. 2007;86(6):453-454.

(162.) Tao J, Valderrama E. Epstein-Barr virus-associated polymorphic B-cell lymphoproliferative disorders in the lungs of children with AIDS: a report of two cases. Am J Surg Pathol. 1999;23(5):560-566.

(163.) Nador RG, Chadburn A, Gundappa G, Cesarman E, Said JW, Knowles DM. Human immunodeficiency virus (HIV)-associated polymorphic lymphoproliferative disorders. Am J Surg Pathol. 2003;27(3):293-302.

(164.) Martin SI, Zukerberg L, Robbins GK. Reactive Epstein-Barr virus-related polyclonal lymphoproliferative disorder in a patient with AIDS. Clin Infect Dis. 2005;41(8):e76-79.

Amy Chadburn, MD; Anmaar M. Abdul-Nabi, MD; Bryan Scott Teruya, MD; Amy A. Lo, MD

Accepted for publication March 30, 2012.

From the Department of Pathology, Northwestern University-Feinberg School of Medicine, Chicago, Illinois (Drs Chadburn, Abdul-Nabi, Teruya, and Lo).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Amy Chadburn, MD, Department of Pathology, Northwestern University-Feinberg School of Medicine, 251 E Huron, Feinberg 7-210, Chicago, IL 6061 1 (e-mail: achadburn@ northwestern.edu).

* References 122, 151, 153, 154, 158, 159.

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Author:Chadburn, Amy; Abdul-Nabi, Anmaar M.; Teruya, Bryan Scott; Lo, Amy A.
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Report
Geographic Code:1USA
Date:Mar 1, 2013
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