HEMATOPATHOLOGY
Original Article
AIDS-Related Burkitt's Lymphoma
Morphologic and Immunophenotypic Study
of Biopsy Specimens
ANTONINO CARBONE, MD, 1 ANNUNZIATA GLOGHINI, BD, 1 GIANLUCA GAIDANO, MD, 2
ANNA MARIA CILIA, BD, 1 PAOLA BASSI, BD, 1 PIETRO POLITO, MD, 1
EMANUELA VACCHER, MD, 3 GIUSEPPE SAGLIO, MD, 2 AND UMBERTO TIRELLI, MD 3
In patients infected with HIV, high-grade B-cell non-Hodgkin's lymphomas (NHL), including the small noncleaved cell (SNCC) category,
exhibit pleomorphic features, which makes precise definition difficult.
Sixty-nine pathologic specimens with HIV-related systemic lymphomas, including 42 SNCC, 20 immunoblastic lymphomas (IBL), and 7
cases with features "intermediate" between SNCC and IBL were morphologically and immunophcnotypically investigated. The host immune
status was also analyzed in 57 of 69 patients. In 29 representative
SNCC lymphomas, in 9 IBL cases, and an additional 3 intermediate
lymphomas, both p53 protein overexpression and the association of Epstein-Barr virus (EBV) genetic information were assessed. Small noncleaved cell lymphomas included tumors exhibiting features of the 2
established subtypes (27 Burkitt's and 15 non-Burkitt's). In the seven
intermediate cases, cells showed features intermediate between SNCC
with plasmablastic differentiation and immunoblasts plasmacytoid. Im-
munoblast-like cells were also present. p53 protein overexpression and
EBV association were found in a proportion of SNCC (14 of 29; 7 of 29)
and intermediate (3 of 3; 2 of 3) lymphomas. Conversely, IBL cases
were consistently p53 negative, but showed a high EBV association (7
of 9). All the evaluated patients with intermediate lymphomas had a
considerably lower mean (76.6 per mm3 ± 77.4 SD) and median (54 per
mm3) number of CD4+ lymphocyte count than SNCC patients (mean
227.9 per mm3 ± 186.9 SD, median 193 per mm3), thus mirroring IBL
patients (mean 95.3 per mm3 ± 82.8 SD, median 81 per mm3). All data
provide evidence that lymphomas showing intermediate features constitute a distinct subgroup from either SNCC or IBL. (Key words:
AIDS-related lymphomas; Burkitt's lymphoma; Small noncleaved cell
lymphoma; Immunoblastic lymphoma; Lymphoma with intermediate
features; Histopathology; Immunohistochemistry) Am J Clin Pathol
1995;103:561-567.
In 1967, an experts' committee commissioned by the World
Health Organization established that "Burkitt's tumor!' 1 ' 2 was
a pathologic entity with cytologic features distinct from those
of other poorly differentiated lymphomas 3 ; it was recommended that the tumor be termed "malignant lymphoma, undifferentiated, Burkitt's type." 4 In 1982, Doll and List5 reported the first case of undifferentiated lymphoma resembling
or identical to "Burkitt's lymphoma" (BL) in a male homosexual with infections. Ziegler and colleagues6 independently reported that homosexual males (with AIDS) had an increased
incidence of BL. Currently, it is widely recognized that BL occurs: (1) in East Africa (endemic form); (2) outside Africa (spo-
radic [American] form); (3) in the setting of human immunodeficiency (HIV) infection (AIDS-associated form).
The morphologic features of "endemic" African cases and
"sporadic" non-African cases do not differ. In fact, African BL,
which is considered the morphologic standard of reference for
typical monomorphic BL, may also express morphologic variations as does non-African BL.7 In the general population the
classic "small noncleaved cell" (SNCC) lymphoma category of
the Working Formulation (WF), 8 includes two main pathologic variants: Burkitt's and non-Burkitt's subtypes. The former variant was called "without plasmablastic differentiation"
by Lennert's group, 9 whereas the latter may correspond to cases
termed "with plasmablastic differentiation." Although the
boundaries between the two morphologic variants are not
sharp, the SNCC non-Burkitt's subtype may be recognized by
From the Divisions of'Pathology. Centro Regionale di Riferimento its cellular heterogeneity, variations in the size of the nucleus,
Oncologico, Istituto Nazionale di Ricovero e Cura a Carattere Scien- and presence of large nucleoli. Both SNCC subtypes have been
in HIV-infected European or American patients with
tifico, A viano. Italy; 2Dipartimento di Scienze Biomediche e Oncologia observed
10 12
Umana, Universila'di Torino, Italy;*Medical Oncology and AIDS pro- BL, " but atypical morphologic features have also been regram, Centro Regionale di Riferimento Oncologico. Istituto Nazionale ported in HIV infection. Interestingly, lymphomas mainly
di Ricovero e Cura a Carattere Scientifico, Aviano, Italy.
composed of blastic cells exhibiting features intermediate between SNCC with plasmablastic differentiation9 and immuSupported in part by the Ministero della Sanita* Istituto Superiore di
noblastic-plasmacytoid cells have been detected in patients inSanita, AIDS project 1994 (contract #8204-26, #9204-25), Rome, Italy.
fected with HIV. 1213 Concordantly, in HIV infection, an
Manuscript received September 30, 1994; revision accepted Decemimmunoblast-like (large cell) variant of SNCC can be identified
ber 14, 1994.
with cohesiveness of tumor cells.14 These atypical morphologic
Address reprint requests to Prof. Carbone: Division of Pathology,
features sometimes prevent a precise pathologic diagnosis of
Centro Regionale di Riferimento Oncologico, INRCCS, Via PedemonSNCC in individuals infected by HIV, and may bias the correct
tana Occidentale, Aviano 1-33081, Italy.
561
HEMATOPATHOLOGY
562
Original Article
TABLE 1. HISTOPATHOLOGIC, AND IMMUNOHISTOLOGIC CHARACTERISTICS OF SYSTEMIC NON-HODGKIN'S
LYMPHOMAS IN 114 PATIENTS WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION
Histologic Types (Working
Formulation Categories)
Cases
(n= 114)
Follicular large cell (D)
Diffuse large cell (G)
1
19
Immunoblastic(H)
20
Lymphoblastic (I)
Small noncleaved cell (J)
Burkitt(J)
Non-Burkitt's type
27
15
"Intermediate" features*
Anaplastic large cell
7
13
1
Extramedullary plasmacytoma
3
BM involvement by immunocytoma
"Putative histiocytic"
Unclassifiedt
Composite:):
4
2
1
Immunohistologic Markers Expression
Positive Cases/Tested Cases For
Each Histologic Category
B-cell
B-cell
Non B- non T-cell
B- and T-cell
B-cell
Non B- non T-cell
B- and T-cell
(1/1)
(10/12)
(1/12)
(1/12)
(15/16)
(1/16)
(1/D
B-cell
B-cell
Non B- and non T-cell
B-cell
CD30+, B-cell
CD30+, B- and T-cell
CD30+, non B- non T-cell
EMA+, B-cell
EMA+, non B- non T-cell
(26/26)
(14/15)
(1/15)
(5/5)
(6/12)
(1/12)
(5/12)
(2/3)
(1/3)
Histiocyte
(4/4)
B-cell
(1/0
EM A = epithelial membrane antigen.
• In seven cases, lymphoma cells showed intermediate features between small noncleaved cells with plasmablastic differentiation and
itnmunoblasts plasmacytoid.
t In both cases, the amount of tissue available for review was scarce.
X Diffuse large cell (G) + lymphoplasmacytoid.
discrimination of SNCC from immunoblastic lymphomas
(IBL), as imposed by their different clinical and biologic characteristics in the context of HIV infection, 6 "' 2 ' 5 "' 8 For these
reasons, a recent histopathologic categorization of HIV-related
non-Hodgkin's lymphomas (NHL) has provided a provisional
separate category for cases with difficult classification such as
those with intermediate morphologic features.18
This paper focuses on our method of defining SNCC in an
HIV setting that was based on morphologic and immunophenotypic comparative data gathered by an investigation of a
large series of AIDS-related lymphomas.
MATERIALS A N D METHODS
The Centro di Riferimento Oncologico (CRO) Aviano, Italy,
is a comprehensive National Cancer Institute in Northeastern
Italy that provides health care to patients who have HIV infection and cancer, particularly lymphoid neoplasia.
From September 1984 through November 1993, 114 patients infected with HIV and systemic NHL were seen at the
CRO.
The results of histopathologic and immunophenotypic classification of the overall series of HIV-related lymphomas are
shown in Table 1. The most frequent histotype was SNCC (J
group): 42 cases, 36.8%. Other highly frequent histotypes included large cell immunoblastic (H group): 20 cases, 17.5%;
and diffuse large cell (G group): 19 cases, 16.7%. In another
seven cases, lymphoma cells showed features intermediate between SNCC with plasmablastic differentiation and plasmacytoid immunoblasts.
Clinicopathologic features and Epstein-Barr virus (EBV) serology in most of these patients were reported previously. 10 ' 3
Testing for HIV antibody was performed on all patients' sera
by ELISA and supplemental testing was done with Western
blot.19 In most patients, the CD4+ cell count at the time of
diagnosis was determined by flow cytometry.
The present study is based on 69 NHL cases (ie, 42 SNCC,
20 IBL, and 7 intermediate).
Biopsy
Specimens
All pathologic specimens were classified according to the histologic lymphoma classification of the Working Formulation
(WF).8 In the SNCC category of the WF, two histologic subtypes were distinguished: the first fulfilled the criteria of typical
BL,4'8 and the second, the non-Burkitt's subtype, showed some
plasmablastic differentiation and variation in the size and
shape of tumor cells. A provisional separate morphologic category for lymphomas showing features intermediate between
SNCC with plasmablastic differentiation and plasmacytoid immunoblasts was supported, according to the description of Raphael and colleagues12 and of our study group. 13
Forty-one SNCC, 16 IBL, and 5 intermediate were immunomorphologically characterized (Table 2) as previously reported. 1013 In the remaining cases, including two intermediate
cases, either paraffin blocks were not available for immunohistochemical analysis or tissue antigens were poorly preserved. In
frozen tissues, the expression of surface immunoglobulin (SIg),
common acute lymphoblastic leukemia antigen (CALLA)CD10, and B-cell-associated and T-cell-associated differentia-
A.J.C.P.'May 1995
CARBONE ET AL.
AIDS-Related
itt's Lymphoma
TABLE 2. IN SITU PHENOTYPIC PROFILE, P53 PROTEIN
IMMUNOHISTOCHEMICAL DETECTION, AND EBER ISH
RESULTS IN SMALL NONCLEAVED CELL AND
IMMUNOBLASTIC LYMPHOMAS, AND LYMPHOMAS
WITH "INTERMEDIATE" FEATURES
Antigen
CD20
CD45RA
CD10
CD43
CD45RO
P53
EBV(EBER)
563
nuclear fast red, dehydrated and mounted with a permanent
mounting medium. The specificity of RNA signals was ascertained by abolition of hybridization after pretreatment of sections with RNase.
Histologic Types
RESULTS
Burkitt non-Burkitt type "Intermediate" Immunoblastic
Correlation between the CD4+ cell count at the time of diagnosis and lymphoma histotypes is shown in Table 3. A CD4+
cell count was available in 57 of 69 patients. The CD4+ cell
count in patients with IBL was significantly lower (mean 95.3/
mm3 ± 82.8 standard deviation [SD], median 81 per mm3;
range 3-318) than in patients with SNCC (mean 227.9 per
mm3 ± 186.9 SD, median 193 per mm3; range 4-663). In patients with intermediate cells, the CD4+ cell count ranged from
7 per mm3 to 179 per mm3 (mean 76.6 per mm3 ± 77.4 SD,
median 54 per mm3).
24/26
22/25
14/16
3/22
6/20
9/16
5/16
13/13
7/14
10/12
3/13
5/14
5/13
2/13
5/5
1/2
0/3
2/3
2/5
3/3
2/3
9/15
2/11
6/12
4/12
3/12
0/9
7/9
tion antigens (Leu 12-CD19, Leul4-CD22, BA1-CD24, BA2CD9, HLA-DR, Leu 4-CD3, Leu 2a-CD8, Leu 3a- CD4, Leu
1-CD5, and Leu 8) was determined. The following antibodies
suitable for paraffin-embedded tissues (leukocyte common antigen (LCA) or CD45, BerH2-CD30, Leu Ml-CD 15, epithelial
membrane antigen (EMA), vimentin, LNl-CDw75, LN2CD74, L26-CD20, MT2-CD45RA, MB2, DNA7, DBB42,
CD3, UCHL1-CD45R0, Leu 22-CD43, MT1-CD43, KP1CD68, Ki-M6-CD68, and lysozyme) were used. In one case,
only frozen section immunophenotyping was carried out.
In 29 representative SNCC, in 9 IBL and an additional 3
intermediate cases, both p53 protein overexpression and the
association of EBV genetic information were assessed.
Lymphoma samples were tested for p53 protein overexpression with the monoclonal antibody (MoAb) DO-7 (Novocastra Laboratories, Newcastle-on-Tyne, UK), which specifically detects human p53 (wild and mutant forms) in routinely
processed specimens. Immunohistochemical analysis was carried out in Bouin-nxed, paraffin-embedded tissue sections pretreated in a microwave oven (Jet 900 W, Philips, Eindhoven,
the Netherlands) twice for 5 minutes at 650 Watts in citrate
buffer (pH 6); immunostaining was performed by using the avidin-biotin-peroxidase complex (ABC) method20 (ABC-Elite
kit, Vector, Burlingame, CA). Cases were considered positive
when at least 5% of neoplastic cells showed nuclear staining for
the DO-7 MoAb. However, almost all of the negative scoring
cases showed no stain at all. No case showed cytoplasmic positivity.
EBER in situ hybridization (ISH) studies were done on
Bouin-nxed paraffin-embedded tissue sections by using a cocktail of fluorescein isothiocyanate (FITC) labeled oligonucleotides complementary to the two nuclear EBER 1/2 RNAs encoded by EBV (Dako A/S, Glostrup, Denmark), according to
the instructions of the manufacturer, with minor modifications. After deparaffinization, the slides were treated with Proteinase K. (Sigma Chemical, St. Louis, MO) (1-3 Mg/mL), dehydrated in alcohol, air dried and incubated (2 hours at 37 °C)
with 10 to 15 /u.L hybridization buffer containing EBER 1/2
probes. After washing in Tris Buffered Saline/0.1% Triton
X100, slides were treated with RNase A (Boehringer, Mannheim, Germany) (100 jig/mL in 2X SSC) for 1 hour. Hybridization products were detected by using an FITC polyclonal
antibody conjugated with alkaline phosphatase (Dako A/S). 5Bromo-4-chloro-3-indolyl phosphate/nitroblue tetrazolium
was used as a chromogen, then slides were counterstained with
Biopsy Specimens
The general histologic pattern of the 27 SNCC Burkitt's cases
was characterized by the diffuse cellular infiltration of monomorphic small neoplastic cells with obliteration of normal tissue structure, and "starry sky" reactive histiocytes in the background. The nuclei of neoplastic cells were the same size or
smaller than those of reactive histiocytes. They were round and
uniform with distinct and prominent nuclear membranes; they
usually exhibited fine granular chromatin, two tofivesmall but
distinct nucleoli, and a large number of mitotic figures. The
cytoplasm was scant to moderate, with cohesive cell borders
(Fig. 1). The 15 SNCC non-Burkitt's lymphomas mainly contained small noncleaved cells, but large noncleaved cells with
some plasmablastic differentiation also were present. They displayed greater nuclear variability (pleomorphism and multinucleation) with nuclei containing one or two eosinophilic
nucleoli (Fig. 2).
The IBL group of tumors was characterized by marked polymorphism. They were classified into two histologic subsets. In
the first subset (14 cases), lymphomas consisted of a dominant
population of medium-sized immunoblasts with plasmacytic
features. This subtype is probably identical to the "large cell"
plasmacytoid immunoblastic variant of the WF.8 In the second
subset (six cases), the neoplastic cell population was more polymorphic with larger immunoblasts and large multinucleated
Reed-Sternberg-like cells.
In the seven intermediate cases, the tumors exhibited some
of the features of the SNCC non-Burkitt's subtype, but the gen-
TABLE 3. IMMUNE STATUS OF PATIENTS AT THE TIME
OF DIAGNOSIS
Histotypes
Patients
(n)
CD4 cell count (mm3)
Mean (+ SD)*f
Small noncleaved cell
"Intermediate"
Immunoblastic
35
5
17
227.9 (± 186.9)
76.6 (±77.4)
95.3 (± 82.8)
SD = standard deviation.
Data were available in 57 out of 69 patients.
* Mann-Whitney test: small noncleaved cell vs "intermediate" P = .06; small noncleaved
cell v.i- immunoblastic P = .008: "intermediate" vs immunoblastic P = .82.
t Kruskal-Wallis test: small noncleaved cell vs "intermediate" vs immunoblastic P = .01.
Vol. 11 •No. 5
564
HEMATOPATHOLOGY
Original Article
was
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FlG. 1. (Left) Small noncleaved cell lymphoma, Burkitt's subtype. The tumor consists of small to medium-sized monomorphic cells interspersed
with large phagocytizing histiocytes ("starry sky" pattern) (hematoxylin and eosin, X400).
FIG. 2. (Right) Small noncleaved cell lymphoma, non-Burkitt's subtype. Tumor cells have round or irregular, frequently eccentric nuclei containing
randomly located small nucleoli. Larger cells with one or two larger nucleoli are recognizable (hematoxylin and eosin, X400).
eral histologic pattern was mainly composed of large cohesive
cells and of reactive histiocytes in the background giving rise to
a "starry sky" pattern. The size of the tumor cells was variable
with small cells also present. Several large cells exhibited a large
single nucleolus, and abundant basophilic cytoplasm as seen in
immunoblastic-plasmacytoid lymphomas (Fig. 3).
By means of immunophenotypic characterization, 40 of 41
evaluated HIV-related SNCC cases expressed B-cell-associated
markers. The most common phenotype was IgMx-l-, CD10+,
CD19+, CD22+, CDw75+, CD74+, CD20+, CD45RA+,
MB2+. No substantial differences were found between the two
SNCC histologic subtypes. In particular, CD 10 expression was
consistently found in both subtypes. Fifteen of 16 IBL cases
that were evaluated expressed B-cell associated markers. The
most common phenotype was CDw75+, CD74+, DBA44+,
DNA7+, CD20+. Two cases—one SNCC and one IBL—were
negative with all B- and T-cell associated antibodies, and were
classified immunologically as being of the non-B, non-T phenotype. The five evaluated intermediate lymphomas expressed
the CD 19, CD20, CDw75, and CD74 B-cell associated markers, but lacked CD 10 expression, and had EM A positivity (2 of
3) (Tables 2 and 4). Interestingly, CD45RO was expressed by a
fraction of tumor cells in 11 of 34 SNCC lymphomas, in 2 of 5
intermediate and in 3 of 12 IBL cases. In three SNCC Burkitt's
cases, tumor cells expressed both CD45RA and CD45RO.
The results of the immunohistochemical analysis for p53
protein and the distribution of EBER positivity within the
SNCC histologic subtypes, the IBL group and the intermediate
cases are shown in Tables 2 and 4. The overall frequency of p53
positive samples among the SNCC studied was 48% (14 of 29).
No substantial differences concerning immunohistochemical
reactivity for p53 were found between the two SNCC histologic
subtypes. p53 positivity was observed in the three intermediate
lymphomas tested. Conversely, the nine IBL cases investigated
were p53 negative.
EBER ISH studies identified EBV RNA in 5 of 16 SNCC
Burkitt's subtypes, in 2 of 13 SNCC non-Burkitt's subtypes, in
7 of 9 IBL, and in 2 of 3 intermediate lymphomas (Fig. 4).
Three of 14 p53 positive SNCC lymphomas, all Burkitt's subtype, were EBV associated, as demonstrated by the expression
of EBER RNA, whereas among the three p53 positive intermediate lymphomas, two cases were EBV positive.
DISCUSSION
The NHLs that develop in patients with HIV infection are
commonly of high grade histology with many being SNCC
lymphoma. 10-1214 " 16 In addition to classic SNCC lymphoma
with its pathologic subtypes, lymphomas "resembling" the
SNCC histotype have been described in the setting of HIV infection.14 They include lymphomas with blastic cells showing
features intermediate between SNCC and plasmacytoid immunoblasts. 1213
In this study, the SNCC category included tumors exhibiting
classic features of the two established subtypes (27 Burkitt's and
15 non-Burkitt's) (Table 1). The most frequent immunophenotypic profile, which was substantially similar in both SNCC
subtypes, corresponded with a recently reported one. 14,21 However, expression of CD45RO by a relevant number (11 of 34,
32%) of SNCC lymphomas was an unexpected finding because
it is known that the monoclonal antibody UCHL1 reacts with
only 5% to 10% of all B-cell NHL occurring in the general population.22"23 CD45RO expression, which was also found in IBL
(25%) and intermediate (40%) cases (Tables 2 and 4), was often
A.J.C.P.- May 1995
565
CARBONE ET AL.
AIDS-Related Burkitt's Lymphoma
FIG. 3. (Top) Non-Hodgkin's lymphoma with
"intermediate" features between small noncleaved cells with plasmablastic differentiation and immunoblasts. Medium-sized tumor
cells with several small or medium-sized
nucleoli are interspersed with larger cells. The
latter have large solitary nucleoli, being indistinguishable from immunoblasts. Inset: Plasmablastic-like cells are also present (hematoxylin and eosin, X400).
Sb&*fc
FIG. 4. (Bottom) EBER in situ hybridization
signal is present as dense grains over the nuclei
of tumor cells of a lymphoma with features
"intermediate" between small noncleaved
cells with plasmablastic differentiation and
immunoblasts. (In situ hybridization; nuclear
fast red counterstain; paraffin-embedded tissue section; X400).
TABLE 4. IN SITU PHENOTYPIC PROFILE, P53 PROTEIN IMMUNOHISTOCHEMICAL DETECTION, EBER ISH RESULTS
AND CD4+ CELL COUNT AT THE TIME OF DIAGNOSIS, IN SMALL NONCLEAVED CELL AND IMMUNOBLASTIC
LYMPHOMAS, AND LYMPHOMAS WITH "INTERMEDIATE" FEATURES
Percentages of Positive Cases
Histologic Types
CD 10*
CD45RO
EMAf
P53±
EBV§
Burkitt
Non-Burkitt's type
"Intermediate"
Immunoblastic
87
83
0
50
30
36
40
25
5
0
67
40
56
38
100
0
31
15
67
78
P values were given only for significance differences.
Chi-squarc test (df = 3): * P = .006; t P = .002; %P- .007; § P•=
Kruskal-Wallis: II />=.03.
Vol. 103-No. 5
Mean (± SD) CD4
Count ||
237.5
211.5
76.6
95.3
(±181.9)
(±201.4)
(±77.4)
(±82.8)
566
HEMATOPATHOLOGY
Original Article
detected in lymphoma cases that were associated with EBV
(data not shown). Whether this unusual expression of
CD45RO by HIV-related lymphomas may reflect their high
correlation with EBV remains to be elucidated. The significance of both CD45RO expression and CD45RA and RO
coexpression, which were observed in this series of HI V-related
lymphomas, deserves further investigation.
Despite the fact that SNCC and intermediate lymphomas exhibited some morphologic and immunophenotypic differences
(CD10+ vsCDlO-), immunohistochemistry forp53 revealed
similarities between these groups of NHL (Table 4). p53 protein overexpression was found either in a proportion (48%) of
SNCC or in intermediate lymphomas, and it was consistently
negative in IBL cases. It is known that among genetic lesions
detectable in AIDS-NHL, p53 inactivation is associated with a
proportion of SNCC lymphomas, while it is consistently absent
in all other types of NHL.24"26 Thus, it appeared that the intermediate cases mirrored classic SNCC histologic subtypes.
However, the differential expression of p53 distinguished IBL
from intermediate lymphomas.
Our data were in accordance with previousfindingsshowing
a higher EBV association with IBL than with AIDS-related
SNCC lymphomas.161727'28 Furthermore, EBV association was
found in two of the three intermediate lymphomas. In this regard, it is worth noting that a recent study reporting an AIDSrelated NHL with a morphology intermediate between SNCC
and immunoblastic showed that the tumor was associated with
EBV, and harbored a c-myc rearrangement.29 In the authors'
opinion, such a tumor could represent a SNCC lymphoma that
had adopted an immunoblastic morphotype in the context of
AIDS.29 This view is supported by molecular data demonstrating that the activation of c-myc oncogene could be detected
in 100% AIDS-SNCC lymphomas, whereas in immunoblasticplasmacytoid lymphomas it was restricted to a minority of tumors.2430
Concerning the immune status, CD4+ cell count at the time
of diagnosis was available in 57 of 69 patients. Low numbers
of CD4+ cells were found in several patients regardless of the
lymphoma histotype. However, between the two established
histotypes, IBL and SNCC, the IBL was associated with lower
numbers of CD4+ cells (Table 3). All the evaluated patients
with intermediate lymphomas had numbers of CD4+ cells
lower than 200 per mm3 with a considerably lower mean and
median number of CD4+ lymphocytes than in SNCC patients,
thus mirroring IBL patients.
These data provide evidence that intermediate lymphomas
can constitute a subgroup distinct from either SNCC or IBL.
Although the explanation for their pronounced polymorphism
still remains to be assessed, the influence of EBV, as in the case
of post-transplant lymphomas,31 and/or other AIDS-related biologic events in the tumor cells, may be hypothesized. Remarkably, three intermediate lymphomas developed in highly immunosuppressed patients. They had an extremely low count of
CD4+ peripheral blood lymphocytes (<54 per mm3). Two of
these tumors were evaluated by EBER ISH and both were
found to be positive. Thus, an influence of EBV on the morphology of lymphomas in these severely immunocompromised
patients may not be excluded.
In conclusion, pathologic categorization of HIV-related
SNCC lymphomas, which is primarily based on the recognition
of the Burkitt's and non-Burkitt's subtypes, should also give
proper consideration to a possible separate variant, provisionally termed "intermediate," between SNCC and IBL. This vari-
ant is pleomorphic and shows small and large SNCC with plasmablastic features and immunoblast-like plasmacytoid cells.
Whether such tumors may represent cases of SNCC lymphoma
remains to be elucidated. However, they seem to be more
closely related to SNCC than to IBL because of immunohistochemical data concerning p53 overexpression and the morphologic resemblance of their polymorphic morphotype to AIDSrelated SNCC lymphomas observed in culture.32 However, because the clinical and biologic features of these tumors are still
to be defined, a proposed provisionally separate category for
these lymphomas18 should be maintained.
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