Lymphoproliferative Lesions in the Setting of HIV Infection: A Five-Year Retrospective Case Series and Review.

Abstract

A wide variety of noninfectious lesions have been identified in association with HIV infection. Many hematolymphoid lesions are possible in this patient group, both reactive and neoplastic. Epidemiologic data suggests that lymphoid malignancies are among the most common neoplasms in patients with HIV. We present a selective case series assembled over a 5-year period from the relatively low HIV-prevalence Hamilton Regional Laboratory Medicine Program (HRLMP), a tertiary care referral centre in Southern Ontario. This series serves to demonstrate the wide variety of lymphoid lesions that may be encountered in patients with HIV. In addition to outlining the pathologic work-up necessary in these cases, we discuss characteristics that distinguish the HIV-associated lesions from the pathobiologically similar non-HIV-associated lymphoid lesions.

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SAGE-Hindawi Access to Research
Pathology Research International
Volume 2011, Article ID 618760, 12 pages
doi:10.4061/2011/618760
Review Article
LymphoproliferativeLesionsintheSetting of HIVInfection:
AFive-Year Retrospective Case Seriesand Review
EtienneMahe, CatherineRoss, and MonalisaSur
Division of Anatomical Pathology, Department of Pathology and Molecular Medicine, Juravinski Hospital and Cancer Centre,
McMaster University, 711 Concession Street, Hamilton, ON, Canada L8V 1C
Correspondence should be addressed to Monalisa Sur, surm@hhsc.ca
Received 8 December 2010; Revised 24 January 2011; Accepted 27 January 2011
Academic Editor: Liron Pantanowitz
Copyright © 2011 Etienne Mahe et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
A wide variety of noninfectious lesions have been identified in association with HIV infection. Many hematolymphoid lesions
are possible in this patient group, both reactive and neoplastic. Epidemiologic data suggests that lymphoid malignancies are
among the most common neoplasms in patients with HIV. We present a selective case series assembled over a 5-year period
from the relatively low HIV-prevalence Hamilton Regional Laboratory Medicine Program (HRLMP), a tertiary care referral centre
in Southern Ontario. This series serves to demonstrate the wide variety of lymphoid lesions that may be encountered in patients
with HIV. In addition to outlining the pathologic work-up necessary in these cases, we discuss characteristics that distinguish the
HIV-associated lesions from the pathobiologically similar non-HIV-associated lymphoid lesions.
1.Introduction
The HIV/AIDS epidemic bears the dubious distinction of
oneoftheworld’smostdevastatingyetmedicallychallenging
disease entities. Despite the rapidity of important advances
in HIV/AIDS therapies over recent decades and despite the
countlessbillions of dollars invested in researchand develop-
ment, a cure continues to elude the scientific community. So
globally profound is the HIV/AIDS epidemic that, according
to the most recent UNAIDS epidemiology update, the global
total of HIV-positive persons is nearly equal to the total
population of Canada [1, 2].
Although most of the mechanisms leading to death from
HIVinfectionarerelatedtoimmunodeficiency,neoplasiahas
long been recognized as a major contributor to morbidity
and mortality of the HIV/AIDS population [3]. Many of
the AIDS-related neoplasms are hematolymphoid; indeed,
AIDS-related lymphomas, in some current case series, have
superseded Kaposi’s sarcoma as the commonest AIDS-
related neoplasm [4].
HIV infection has been calculated to increase the like-
lihood of developing a lymphoma by 60–110 times [5,
6]. As noted by the World Health Organization (WHO),
HIV/AIDS-related lymphomas are predominantly B-cell
lymphomas [6]. A number of the common HIV-related
B-cell lymphomas are AIDS-defining illnesses [7]. It must
be noted, however, that a notable number of aggressive
peripheral T-cell lymphomas have been recognized in HIV-
positive individuals. The three most common lymphomas
associated with HIV are Burkitt’s lymphoma, diffuse large
B-cell lymphoma, and Hodgkin’s lymphoma as currently
defined in the 2008 WHO classification [6].
As a lentivirus, HIV shows a striking tropism for CD4
T-lymphocytes as well as dendritic cells and monocytes.
The virus exploits the host CD4 cell chemokine receptors
to gain access into the host cell wherein it self-incorporates
into the host cell genome, and engages in self-replication.
This tropism for one of the human immune system’s major
immune response modulators is believed to be the main
pathophysiologic mechanism leading to AIDS; the result
is a critically reduced number of CD4+ cells, which in
turn perturbs the intricate CD4-dependent host immune
response. In addition, its tropism for the constituent cells
of the lymph node serves to concentrate the immunologic
response in the lymph nodes, resulting in a variety of
pathologic and potentially neoplastic changes [8].

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Thecurrentparadigmsuggeststhatitistheabnormalities
of the host immune response, and not direct oncogene-
sis, that lead to the markedly increased HIV-related risk
of lymphoproliferative disease. Epidemiologic studies have
observed lower incidences of HIV-related lymphomas in
patients receiving HAART relative to those that do not
[9, 10]. Other studies noted that patients with certain HIV-
related lymphomas receiving HAART showed a relatively
improved prognosis than their untreated counterparts [11,
12].Furthermore,thewidevarietyoflymphoidmalignancies
associated with HIV argues against a direct oncogenic
influence. Other studies have noted that HIV DNA, unlike
some other known oncogenic viruses, does not seem to
incorporate itself at specific locations in the host cell genome
[13, 14] while other studies examining the gene expression
patternsinAIDS-relatedmalignancieshavenotedthat,inthe
majority, HIV DNA or proteins could not be identified in
malignant cells [15].
The combined immunosuppression and immunologic
stimulation present in HIV infection may synergize with
other infectious agents known to be oncogenic, such as EBV,
to produce lymphoproliferative disease. This is consistent
withtheobservation ofEBV positivity ingreaterproportions
in HIV-associated hematolymphoid lesions than in those in
the non-HIV population.
In the local Health Integration Network served by
HRLMP, all known HIV-positive patients are diligently
followed by the regional Special Immunology Services
clinic. Recent (2008) census data estimates a relatively low
HIV/AIDS prevalence of 91 per 100000 in the Hamilton
region [16, 17]. The HRLMP receives all tissue specimens
pertaining to HIV-positive patients in the region. We
performed a 5-year retrospective review of all pathology
reports and identified 12 cases with an HIV-associated lym-
phoproliferative disorder (Table 1). The following explores
the relevant clinical and pathological features of these
lesions, highlighting the distinguishing features they may
have relative to their non-HIV associated kindred lesions,
and some of the difficulties and pitfalls in diagnosis.
2.HIV-AssociatedLymphadenitis
HIV-associated lymphadenitis is very common in HIV-
infected individuals and was identified as a complication
of HIV infection very soon after the HIV/AIDS epidemic
was identified [18]. Lymphadenitis often accompanies the
acute phase of HIV infection, usually accompanied by
brief (sometimes barely noticeable) flu-like symptoms [19].
Even as the acute phase of HIV infection wanes, the
associated lymphadenitis can be markedly persistent [19].
This is likely due to the profound lymphotropism previously
described [8]. In cases of profound immunodeficiency,
lymphadenitis due to concurrent infection by mycobacteria
or fungi may confuse the diagnosis [20]. Clinical concern
of a lymphoproliferative disorder may also be raised in
cases of persistently enlarged groups of lymph nodes or in
cases of suddenly enlarged nodes in patients for whom a
concomitant infectious etiology has been ruled out. These
Figure 1: HIV-associated lymphadenopathy with hyperplastic
follicles taking on atypical shapes (hematoxylin and eosin, 100x).
clinical scenarios are more frequently encountered in the
HIV positive population in Ontario in whom TB and other
infections are infrequent.
The histologic features of HIV-associated lymphadenitis
follow a well-characterized pattern of histomorphological
evolution [8]. In Grade 1, usually seen early on in the course
of HIV infection, the lymph nodes display exuberant hyper-
plastic features. Irregular enlargement of germinal centres
is noted, often with a prominent starry sky pattern due
to increased germinal centre cell apoptosis and subsequent
phagocytosisofcellulardebrisbytingible-bodymacrophages
(Figure 1). In addition, there may be focal areas of expansion
of the interfollicular zones by monocytoid cells (transformed
B lymphocytes) with an accompanying reduction of man-
tle/marginal zone lymphocytes. The exuberance with which
the latter occur leads to a distinct form of “follicular lysis”
producing atypical convoluted germinal centres (Figure 1).
Scattered multinucleated giant cells and neutrophils may
also be identified. In Grade 2, the key features are reduced
lymphoid follicles with a relative reduction in the number of
mature lymphocytes. An increased number of plasma cells
will be noted, in addition to a proliferation of perifollic-
ular blood vessels. As Grade 2 evolves into Grade 3, the
residual germinal centres become sclerotic. In some cases, a
Castleman-like pattern of hyalinized germinal centres may
be observed; Castleman’s disease is generally a non-HIV-
related disorder exhibiting a similar pattern of germinal
centre sclerosis in lymph nodes.
The patterns of HIV lymphadenitis have been identified
in other non-HIV-related conditions and are therefore not
specific to HIV. When identified in the correct clinical con-
text, however, they are reproducible and may offer valuable
clinical information relating to the natural history of HIV
infection. Grade 3, for instance, is frequently seen in HIV
patients with AIDS [21]. Kaposi’s sarcoma is frequently asso-
ciated with Grade 3 lymphadenitis [8]. Most importantly, a
statistically significant survival reduction has been identified
as HIV-associated lymphadenitis evolves from Grades 1 to 3
[21]. In addition to the recognition of the Grades of HIV-
associated lymphadenitis, it is incumbent on the surgical

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Table 1
Case
1
Age/sex
38/M
Diagnosis/primary site
Hodgkin’s lymphoma/left axillary lymph node
Polymorphic lymphoid proliferations resembling posttransplant
lymphoproliferative disease/tonsils and lymph node
Diffuse large B-cell lymphoma/liver
Burkitt’s lymphoma/liver
HIV-associated lymphadenitis/mesenteric lymph node
Burkitt’s lymphoma/tonsil
HIV-associated lymphadenitis/axillary lymph node
HIV-associated lymphadenitis/inguinal lymph node
HIV-associated lymphadenitis/inguinal lymph node
Diffuse large B-cell lymphoma/gastric mucosa
Hodgkin’s lymphoma/central nervous system
Plasmablastic lymphoma/retroperitoneal mass with concurrent
pleural effusion
Followup data
Lost to followup
2 37/M
Lost to followup
3
4
5
6
7
8
9
10
11
35/F
49/M
39/M
48/M
47/F
47/M
58/M
61/M
36/M
Alive and well
Dead of disease
Alive and well
Alive and well
Alive and well
Alive and well
Alive and well
Alive and well
Alive and well
12 42/F Dead of disease
Figure 2: HIV-associated lymphadenopathy; lymph node demon-
stratingreactivefeatures(hematoxylinandeosin,100x);insetshows
atypical EBV-infected lymphoid cells (hematoxylin & eosin, 200x).
pathologist to diligently rule out a lymphoproliferative
disorder in suspicious lymphadenopathy. The latter is of
particular importance in cases in which atypical lymphoid
cells are recognized in an otherwise typical background of
HIV lymphadenitis.
Epstein-Barr virus (EBV) seroconversion is very com-
mon in the population at large, and in the HIV-positive
population specifically. Concomitant benign EBV-associated
changes in a lymph node may produce atypical Reed-
Sternberg-like cells in a polymorphous background, as seen
in Figure 2. A basic immunohistochemical panel is often
required to identify the lesion as reactive. The prototypic
immunoprofileofthereactivelymphnodeshouldbepresent:
CD3 will highlight the mature T-cells predominant in the
interfollicular zones; CD20 will highlight the reactive B-
cells and immunoblasts of the interfollicular zones; BCL-
2 will highlight the extragerminal centre lymphocytes of a
reactive lymph node whilst BLC-6 and CD10 will be positive
within a reactive germinal centre; CD23 will highlight
the follicular dendritic cell meshwork of germinal centres
(a helpful marker in cases of questionable follicular lysis);
Ki-67 will show high proliferation index restricted to
the germinal centres. In cases in which atypical cells are
identified, as in the Reed-Sternberg-like cells of Figure 2,
a combination of LCA, CD20, EBV, CD15, and CD30 will
help to rule out Hodgkin’s lymphoma; the atypical Reed-
Sternberg-likecellswillbepositiveforLCA,CD20,EBV,with
or without positivity for CD30 (a cellularactivation marker),
and negative for CD15. EBV testing (either as immunohisto-
chemistry latent-membrane protein staining or by means of
insituhybridization)isveryhelpfulincasesoflymphadenitis
with atypical cells. In cases of Grade 2 or 3 HIV-associated
lymphadenitis, wherein the lesions are lymphocyte depleted
and may show a proliferation of fibroblasts and germinal
centre sclerosis, immunohistochemistry for HHV-8 will help
rule out Kaposi’s sarcoma. The latter entity is known to be
associated with higher-grade HIV-lymphadenitis [21].
3.Polymorphic Lymphoid Proliferations
Resembling Posttransplant
Lymphoproliferative Disease(HIV-PLP)
The WHO makes brief reference to this relatively poorly
defined entity, occurring in less than 5% of HIV patients
[6]. In our health region, this entity has been encountered
only once in the past five years. It is mentioned with
precedence in this review given the unique approach to
treatment that its diagnosis necessitates. Specifically, given
thatthemalignant natureofHIV-PLPremainsin doubt [22–
24], therapy for these patients in our institution typically
focuses on immunomodulation and not chemotherapy. The
rarity of these lesions, however, precludes rigorous trials
exploring different treatment regimens, and the current
state of the art relies heavily on inferences made from the
more thoroughly studied posttransplant lymphoproliferative
diseases. Currently, the limited available evidence suggests
that cases of HIV-PLP likely represent a spectrum of entities
spanning the reactive to the malignant [22]. In the largest

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(a)(b)
Figure 3: HIV-associated lymphadenopathy. (a) BCL-2 stain demonstrating normal immunophenotype (100x); (b) EBV stain (200x).
(a) (c)
(b)
Figure 4: PTLD-like polymorphous B-cell lymphoproliferative disorder; (a) follicular lysis (hematoxylin and eosin, 100x); (b) poly-
morphous inflammatory infiltrate (hematoxylin and eosin, 100x); (c) atypical activated lymphocytes (hematoxylin and eosin, 400x).
caseseriestodate,Nadoretal.notedthatthevastmajorityof
cases of HIV-PLP did not show the gene rearrangements of
B-cells common to other malignant lymphomas [22]. Also,
unlike most HIV-associated lymphoproliferative disorders,
HIV-PLP patients seem to present at a relatively low stage
[22].
Notsurprisingly,thehistomorphologyofHIV-PLPclose-
ly resembles posttransplant lymphoproliferative disease.
There may be a striking polymorphous infiltrate of small
lymphocytes, plasma cells, immunoblasts, histiocytes, and
eosinophils. In the single case encountered in our institution
over the course of the previous five years, prominent
reactivelymphoidfollicleswithareasoffollicularhyperplasia
and follicular lysis were encountered (Figure 4(a)). A few
scattered large atypical cells were also identified (Figures
4(b) and 4(c)), though these were not classic Reed-Sternberg
cells.
Most HIV-PLP are predominantly B-cell proliferations
and thereby show strong staining for CD20 and CD79a.
A background of reactive CD3-positive T-cells will be
seen, intermixed with other inflammatory cells. To further
classify the lesion, a broad panel of immunomarkers may
be required; we recommend a preliminary panel including
CD10, BCL-2, BCL-6, CD15, and CD30. Flow cytometry
may be helpful in identifying the presence of monoclonal
B-cells, should they be present. At our institution, we also
employ polymerase chain reaction testing for B-cell gene
rearrangements to assess for the presence of a monoclonal

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(a)(b)
(c)(d)
(e) (f)
Figure5:Burkitt’slymphoma;(a)prominent“starry-sky”appearance(hematoxylinandeosin,100x);(b)CD20stain(100x);(c)CD10stain
(100x); (d) almost 100% Ki67 staining (100x); (e) BCL-2 stain (100x); BCL-6 stain (100x).
B-cell population. In contrast to the monomorphic HIV-
PLP, the polymorphic variants may or may not demonstrate
unequivocal monoclonal B-cell populations. These cases
need to be assessed and diagnosed in the proper clinical
settings. Testing for EBV, either by latent membrane protein
immunohistochemistry, or by means of the more sensitive in
situ hybridization, is also indicated since a number of HIV-
PLP are EBV positive [22].
4.HIV-AssociatedBurkitt’s
Lymphoma (HIV-BL)
In stark contrast to HIV-PLP, HIV-BL is much more
common and much more aggressive. Indeed, Burkitt’s
lymphoma is 1000-times more common in HIV patients
than the general population and accounts for up to 40%
of HIV-associated lymphomas [6, 25]. HIV-BL also presents

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1.09
525
17
04:00
MR
Figure6:CentralnervoussystemHodgkin’slymphoma.Computed
tomography image demonstrating an ill-defined ring-enhancing
intracranial lesion with peritumoural edema.
Figure 7: Central nervous system Hodgkin’s lymphoma. Brain
tissue with polymorphous inflammatory infiltrate (hematoxylin
and eosin, 100x); inset: arrow highlights Reed-Sternberg cell with
polymorphous inflammatory background (hematoxylin and eosin,
400x).
relatively early on in the course of HIV infection and, as
may be seen in the general population as well, at a relatively
young age [26]. Patients with HIV-PL will often present
with nodal disease but, relative to non-HIV-associated
Burkitt’s lymphomas, more frequently demonstrate extra-
nodal involvement [27].
The histological features of HIV-BL are identical to those
seen in other Burkitt’s lymphomas. Low power examination
typically reveals an expansile lesion diffusely effacing normal
tissues (both nodal and extra-nodal). Interspersed amongst
intermediately (∼12µ m) sized cells with basophilic cyto-
plasmandovalnucleiwithdistinctnucleoli,aremacrophages
with tangible bodies, imparting the classically described
starry-sky appearance on low power. Mitoses and apoptotic
debris are commonplace. Figure 5 demonstrates a classic
Burkitt’s morphology encountered in an HIV patient with
involvement of liver and right adrenal. The immunopheno-
type of HIV-BL is also similar to other Burkitt’s lymphomas.
Burkitt’s lymphoma cells are LCA, CD20, CD79a, PAX5,
CD10, BCL-6, and EBV positive and negative for BCL-
2, CD3, CD5, CD21, CD23, CD43, cyclin D1, and TdT.
HIV-BL also shows a virtually 100% Ki67 proliferation
index. Studies have indicated that the plasmacytoid vari-
ant is most common in HIV-BL, often highlighted with
CD138 staining [27]. Molecular testing in HIV-BL often
demonstrates the characteristic Burkitt’s C-MYC (t(8;14))
mutation; this mutation aligns the oncogenic MYC region
with the transcriptionally active immunoglobulin loci on
chromosome 14.
Treatment regimens for HIV-BL have changed since
the introduction of highly active antiretrovirals. Prior to
HAART therapy, HIV-BL was treated with the standard
cyclophosphamide, hydroxydaunorubicin, vincristine, and
prednisone (CHOP) chemotherapy (the mainstay therapy
for HIV-associated diffuse large B-cell lymphoma) with
mean survival of only 6 months [27, 28]. The literature
currently advises against the CHOP approach in HIV-BL
based on evidence that these patients fare poorly relative to
CHOP-treated cases of HIV-associated DLBCL [27, 28]. This
fact serves to underscore the weight that a correct diagnosis
of HIV-BL relative to other HIV-associated lymphomas
bears. Current regimens, such as that employed at our
institution, focus on relatively aggressive therapies including
combinations of cyclophospamide, doxorubicin, vincristine,
and methotrexate. Trials assessing the potential benefit of
rituximab are ongoing [27].
5.HIV-AssociatedHodgkin’s
Lymphoma (HIV-HL)
Intriguing observations regarding the incidence of HIV-
HL have been made, namely, that the incidence of HIV-
HL increases with an HIV patient’s CD4 count [29]. The
incidence of HIV-HL, however, remains low relative to the
other more common HIV-associated lymphomas (namely,
HIV-DLBCL and HIV-BL). It has been suggested that
the combination of improved CD4 counts in the context
of HIV infection causes a relatively enhanced cytokine
milieu, serving to stimulate the survival and proliferation of
neoplastic Reed-Sternberg cells [30]. The relative incidence
of the variants of HIV-HL is also intriguing, with the mixed
cellularity variant notably more common than the nodular
sclerosing, in contradistinction to the non-HIV-associated
Hodgkin’s lymphoma [29].
The morphologic features of HIV-HL are consistent with
those of non-HIV-associated Hodgkin’s lymphoma. In the
more common mixed cellularity subtype, a polymorphous
background of histiocytes, eosinophils, plasma cells, neu-
trophils, and benign small lymphoid cells may be seen.
Scattered in this infiltrate will be the large atypical binucleate
Reed-Sternberg or the mononucleate Hodgkin’s cells, some-
timessurroundedbyarosetteofsmalllymphocytes.Asinthe
non-HIV-associated Hodgkin’s cases, classic Reed-Sternberg
or Hodgkin’s cells are required; these should be large, 20–
60µm, with eosinophilic to amphophilic cytoplasm, bearing

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(a)(b)
(c)(d)
Figure 8: Hodgkin’s lymphoma; (a) Hodgkin’s cells (hematoxylin and eosin, 400x); (b) CD15-positive Hodgkin’s/Reed-Sternberg cells
(400x); (c) CD30-positive Hodgkin’s/Reed-Sternberg cells (400x); (d) EBV stain positive in Reed-Sternberg cell (400x).
Figure 9: Diffuse large B-cell lymphoma with necrotic background
(hematoxylin and eosin, 200x). Inset: large atypical cells (hema-
toxylin and eosin, 200x).
mirror image nuclear lobes with inclusion-like eosinophilic
nucleoli in the case of Reed-Sternberg cells or mononucleate
with large eosinophilic inclusion like nucleoli in the case of
Hodgkin’s cells. Figures 6 and 7 demonstrate an intriguing
case of CNS HIV-HL encountered in our institution. In
this case, the correct diagnosis was delayed given that the
initial stereotactic brain biopsies did not demonstrate Reed-
Sternberg cells and showed a polymorphous inflammatory
background with epithelioid granulomas, raising the pos-
sibility of an infectious etiology. The correct diagnosis was
arrived at after receipt of a subsequent resection specimen.
Thiscaseservesasanexampleoftheneedforampletissuefor
suspect lymphoproliferative disorders, particularly in CNS
lesions which are most commonly stereotactically biopsied
for primary diagnosis.
The HIV-HL immunophenotype is identical to that seen
innon-HIV-associatedHodgkin’s.Incaseswiththecommon
classical morphology, the Reed-Sternberg or Hodgkin’s cells
canbehighlightedwithCD15,CD30,andEBV-LMPstaining
(Figure 8). These cells are typically negative for LCA, T-
cell markers, CD20, CD79a, CD10, ALK-1, and EMA. Flow
cytometry, though not of direct diagnostic utility in HIV-
HL, can confirm the polymorphous polyclonal background
inflammatory infiltrate.
Patients with HIV-HL typically present with more
advanced-stage disease relative to non-HIV-associated
Hodgkin’s lymphoma and B-symptoms are common [28].

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(a)(b)
(c) (d)
(e)(f)
Figure 10: (a) Diffuse large B-cell lymphoma (hematoxylin and eosin, 200x); (b) CD20 stain (200x); (c) BCL-2 stain (200x); (d) Ki-67 stain
(200x); (e) CD10 stain (200x); (f) BCL-6 stain (200x).
Standard therapy for HIV-HL is a combination of optimized
HAART with ABVD chemotherapy, as is currently em-
ployed in our institution. In addition, several authorities
recommend the addition of G-CSF, as many HIV-HL cases
may be complicated by pancytopenias [27, 28].
6.HIV-AssociatedDiffuseLarge B-Cell
Lymphoma (HIV-DLBCL)
A number of distinct epidemiological differences between
HIV-DLBCL and non-HIV-associated DLBCL have been

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noted. DLBCL is relatively less common in the HIV popu-
lation than in the non-HIV population. In the HIV popu-
lation, DLBCL is less common than Burkitt’s lymphoma [6,
27, 31]. In HIV-positive patients, furthermore, extra-nodal
involvement is far more frequent than in non-HIV DLBCL
[15]. HIV-DLBCL cases are also more likely to present at
advanced stages than non-HIV-associated DLBCL. In our
5-year retrospective institutional review, HIV-DLBCL was
identified in only 2 of the HIV-associated lymphomas.
The histological and immunophenotypic features of
HIV-DLBCL are similar to the HIV-negative cases. The
architecture of involved tissue, either nodal or extra-nodal,
is diffusely replaced by sheets of large lymphoid cells
(Figure 9). As in the HIV-negative population, HIV-DLBCL
may show a number of morphologic variants; the charac-
teristic HIV-DLBCL variant is the immunoblastic type, in
which (as required by the WHO definition), greater than
90% of the neoplastic cells bear a morphology reminis-
cent of immunoblasts with eccentrically oriented nuclei in
basophilic cytoplasm. HIV-DLBCL is positive for pan-B cell
markersincludingCD19,CD20,CD79a,andPAX5.Differing
rates of positivity for CD10 and BLC-6 relative to MUM-
1 reflect differing germinal centre versus activated B-cell
phenotypes [32]. Typical Ki-67 staining ranges from 40–
60% (Figure 10). EBV is far more frequently positive in HIV-
DLBCL than in non-HIV-associated DLBCL [27].
The diagnosis of HIV-DLBCL has important treatment
consequences relative to non-HIV-associated DLBCL. In
particular, recent studies looking at the use of rituximab,
commonlyusedinchemotherapyregimensforDLBCLinthe
non-HIV population, noted an increased treatment-related
infection risk [27]. Currently, there are recommendations
against treating HIV-DLBCL patients also severely immuno-
compromised. Radiotherapy is generally not employed in
primarytherapyinHIV-DLBCLgiventhefrequentadvanced
stage at presentation [27]. In our institution, CHOP with
rituximab is the standard chemotherapeutic regimen with
optimization of immunostatus with HAART.
7.HIV-AssociatedPlasmablastic Lymphoma
Plasmablastic lymphoma is a rare entity with characteristic
morphologic and immunophenotypic features and is one
of the lymphomas originally considered specific to HIV-
positive patients [6]. Although it was thought to ini-
tially be restricted to the oral cavity, HIV-PBL has been
diagnosed at other extra-nodal sites [9], including one
noted in the abdominal viscera of an HIV patient in our
institution (Figure 11). Some authors consider plasmablastic
lymphomas to be a variant of DLBCL [31], though HIV-PBL
stands apart given its aggressiveness [6] and can, therefore,
be classified distinctly.
HIV-PBL at low power demonstrates diffuse effacement
of normal tissue architecture by cells that on higher power
are reminiscent of immunoblasts. The cytomorphological
features may include eccentric nuclei within eosinophilic to
amphophilic granular cytoplasm. The nuclei often demon-
strate vesicular chromatin and prominent central nucleoli.
Mature B-cell markers (e.g., CD20 or PAX5) are typically
Figure 11: Plasmablastic lymphoma (hematoxylin and eosin,
200x).Inset:plasmacytoidfeatures(largecellswitheccentric nuclei,
hematoxylin and eosin, 400x).
negative, with the exception of CD79a and MUM-1 which
showvariablepositivity(seeFigure 12foraselectionofstains
noted in our unique case of HIV-associated plasmablastic
lymphoma). Most importantly, the cells are positive for
the plasma cell markers CD38 and CD138 and often show
intracytoplasmic immunoglobulin staining. EBV is often
positive for EBER by in situ hybridization but, as we
have observed in our institution, immunohistochemistry
for latent membrane protein may not always stain positive
due to its relatively low sensitivity. Of greater importance
is the use of HHV-8 staining which is generally negative in
plasmablastic lymphoma (and usually positive in primary
effusion lymphomas, also known to occur characteristically
in the HIV population); this information will be helpful in
cases of plasmablastic lymphoma involving body cavities.
We recommend including CD56 with CD38 or CD138
stains since, in most cases, positivity for CD56 in this
context should raise concerns regarding the possibility of an
extramedullary plasmacytoma. It is prudent to also entertain
the (often more likely possibility) of a carcinoma with
plasmacytoid morphology; melanoma, often called the great
imitator,shouldalsoberuledout.Asinmostcasesofsuspect
lymphoma, flow cytometry is very helpful at demonstrating
clonality; though, in most cases of plasmablastic lymphoma,
the morphologic features are sufficient to confirm a malig-
nancy.
Outcomes in cases of HIV-PBL appear to have improved
since regular treatment with HAART was introduced [9].
Some authors advocate similar chemotherapeutic regimens
as those used in cases of HIV-BL [9]. The single case of
HIV-PBL encountered at our institution was treated with
CHOP, which needed to be rapidly discontinued due to the
development of neutropenia; the patient died only days later
due to overwhelming sepsis.
8.Discussion
HIV/AIDS creates a milieu of combined immunosup-
pression and antigenic stimulation in lymph nodes. This
environment, especially in combination with concurrent

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(a)(b)
(c)(d)
(e)(f)
Figure 12: Plasmablastic lymphoma; (a) biopsy of abdominal lesion (hematoxylin and eosin, 200x); (b) LCA stain (200x); (c) CD138 stain
(200x); (d) EMA stain (200x); (e) MUM-1 stain (200x); (f) Kappa stain (200x).
infection, creates a permissive environment for the devel-
opment of a lymphoproliferative disorder. We performed
a review of the lymphoproliferative diseases identified in
our regional pathology department over the past five years
and identified 12 cases demonstrating a lymphoproliferative
disorder (amounting to an approximate incidence of 1%
of the HIV-positive population). These entities, further-
more, were diverse and spanned much of the spectrum of
lymphoproliferative entities known to be associated with
HIV.
A number of important themes are appreciated upon
review of the literature pertaining to HIV-associated lym-
phoid lesions. The HIV positive patient population is a
unique cohort with an enhanced tendency toward devel-
oping lymphoproliferative disorders. HIV-patients are also
more prone to developing highly aggressive malignancies
than the general population. The use of HAART improves
both the risk of and the outcomes in many HIV-associated
lymphoproliferative disorders. The inherently immunosup-
pressed state of HIV makes the choice of chemotherapy

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Pathology Research International 11
difficult and often complicated by infection. The heterogene-
ity of HIV-associated lymphoproliferative disorders often
necessitates extensive ancillary testing, including immuno-
histochemistry, flow cytometry, and molecular testing as
they are often diagnostically challenging. The highly vari-
able prognosis ascribed to the spectrum of HIV-associated
lymphoproliferative diseases necessitates diligence and speed
in the diagnostic work-up. Finally, clear communication
between clinicians and consultant pathologists is paramount
at ensuring correct diagnosis and proper patient manage-
ment.
Acknowledgment
The authors thank Dr. Fiona Smaill, Professor, Division of
Medical Microbiology and Infectious Disease, Department
of Pathology and Molecular Medicine, McMaster University,
for providing important epidemiologic data regarding the
HIV-infected patient population of Southern Ontario.
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