[CANCER RESEARCH 41, 4262-4279,
0008-5472/81
/0041-OOOOS02.00
November 1981]
Polymorphic Diffuse B-Cell Hyperplasias and Lymphomas in Renal Transplant
Recipients1
Glauco Frizzerà ,2 Douglas W. Manto, Kazimiera J. Gajl-Peczalska, Juan Rosai, Robert W. McKenna,
Richard K. Sibley, Kathleen P. Holahan,3 and Leanna L. Lindquist
Departments of Laboratory Medicine and Pathology ¡G.F., K. J. G-P., J. R., R. W. M., R. K. S., K. P. H.. L. L. L.] and Surgery ¡D.W. H.¡,University of Minnesota
Medical School. Minneapolis, Minnesota 55455
Abstract
The lymphoproliferative
processes that developed in five
renal transplant recipients were studied in an attempt to char
acterize and classify them morphologically. Nine surgical spec
imens, hematological material on all patients, and autopsy
specimens from three patients were available. Studies per
formed included: conventional histopathology; evaluation of
cell markers (immunoglobulins and sheep erythrocyte, comple
ment, and Fc receptors) and cytoplasmic immunoglobulins
(peroxidase-antiperoxidase
technique); ultrastructural exami
nation; and karyotype analysis.
The lymphoid lesions in our patients shared marked cytological polymorphism (small and large cells, of both follicular
center and "medullary" type) and polyclonal B-cell features,
which indicated a common reactive nonneoplastic origin. How
ever, other features, such as morphological atypia of the immunoblasts, extensive necrosis, chromosomal aberrations, and
an incipient monoclonal component suggested the develop
ment of lymphoma in some of these lesions. In contradistinc
tion, the abundance of typical immunoblasts was a feature that
seemed to correlate with the clinical activity of the disease
rather than with the biological malignancy.
The multiplicity of B-cell types and the presence of a follicular
center cell component with diffuse distribution, as well as the
extensive necrosis in the malignant forms, seem to differentiate
morphologically the lymphoproliferative
processes arising in
transplant recipients from both the hyperplasias and the lymphomas developing in immunologically normal hosts. For the
former, we propose the terms of "polymorphic diffuse B-cell
hyperplasias" and "polymorphic B-cell lymphomas."
Introduction
In organ transplant recipients, as in other immunologically
abnormal states such as primary immunodeficiencies, autoim
mune diseases, and postchemotherapy and postradiotherapy
states, there appears to be an increased incidence of lympho
proliferative disorders (22, 28, 35). The tendency has been to
label these as lymphomas, based on their histological appear
ance and/or their often rapidly fatal clinical course.
It has, however, become apparent that the lymphoid prolif
erations developing in these immunologically abnormal states
are not homogeneous nor do all of them carry the same
1Supported in part by USPHS Grant CA-19527.
2 To whom requests for reprints should be addressed,
at the University of
Minnesota, Box 609, Mayo Memorial Building, 420 Delaware Street, S.E.,
Minneapolis, Minn. 55455.
3 Present address: Kaiser Permanente, Sunnyside Medical Center Regional
Services Facility, 10200 S.E. Sunnyside Road, Clackamas, Ore. 97015.
Received November 20. 1980; accepted April 21, 1981.
4262
biological significance. While most of them have morphological
features compatible with lymphomas of large-cell types ("reticulum cell sarcomas," "histiocytic"
lymphomas, and "immunoblastic sarcomas") (21, 35), others fall into several different
categories (3, 16) or manifest themselves as hyperplastic pro
cesses, ranging from typical to atypical ("pseudolymphomas")
(7, 44). Immunological studies of histiocytic lymphomas or
immunoblastic sarcomas arising in dysimmune states have
shown, in some cases, a polyclonal cell population (6, 18, 21),
in others, a population negative for immunoglobulins4 (10, 33),
and more rarely, the usual monoclonicity of conventional lym
phomas (19, 45). In some of these instances, spontaneous
clinical regression, instead of the usual aggressive and fatal
course, has been reported (24, 33). The variety of these
manifestations raises fascinating pathogenetic issues, such as
the relationships of these lymphoid disorders with viral infec
tions, chemotherapeutic agents, genetic aberrations, or basic
immunological alterations, e.g., the depression of the suppres
sor T-cell system. It also points to the uncertainties of the
morphological criteria used currently to characterize and clas
sify these lymphoid disorders.
The purpose of this report is to describe in detail the mor
phological features of the lymphoid lesions that we observed in
5 renal transplant recipients, in an attempt to recognize simi
larities and differences that exist among them and with other
lymphoproliferative diseases described in the literature. The
results of this study suggest the existence of a biological
spectrum of lesions in these patients and the lack of a close
correlation between morphological appearances and clinical
behavior. However, there seems to be morphological and im
munological evidence that all of the lesions studied began as
reactive polyclonal processes. The development of true malig
nancy in some of them was surmised by the occurrence of a
number of features, not all necessarily present in the same
case: morphological atypia of the immunoblasts; extensive
necrosis; chromosomal aberrations; and monoclonality.
Materials and Methods
This study is based on 5 of the 6 patients described in the parallel
report by Manto et al. (20). The sixth patient (J. A.) has not been
included here due to the very small amount of material available for
histopathological examination. Elsewhere in this issue, Saemundsen ef
al. (40) discuss results of molecular hybridization studies which dem
onstrate the EBV genome in tissues from these patients (Patient 1 was
not studied by molecular hybridization). A summary of the clinical
histories, including all pertinent clinical and laboratory findings, is
' J. Weintraub.
Characteristics
of lymphomas
in chronically
immunosup-
pressed patients following cardiac transplantation.
Presented at the Fourth
Annual Seminar on Frontiers in Immunology, Hematology. and Neoplastia Dis
eases, Bellwood General Hospital, Bellflower, Calif., February 19-20, 1980.
CANCER
RESEARCH
VOL. 41
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Hyperplasias
provided
for brevity's
sake in tabular
form (Table 1). More clinical
details can be found in the above quoted article (20).
The following pathological material was available on the 5 patients:
a total of 9 surgical specimens; peripheral blood smears, bone marrow
aspirates, and trephine biopsies on each patient; and complete autopsy
material from the 3 patients who died. The surgical specimens included
the following: one incisional (MR-1) and one excisional (MR-2) biopsy
from a 2.0- x 1.5-cm ulcerated lesion on the hard palate of Patient 2
and 2 incisional biopsies (MS-1 and MS-2) from an infiltrating exophytic
ulcerated 2.0- x 2.0-cm lesion at the base of the tongue of Patient 3;
biopsies of a 4.2- x 1.6- x 0.6-cm supraclavicular lymph node (JU-1)
obtained from Patient 1, a 4.0- x 3.0- x 3.0-cm cervical node (MS-3)
from Patient 3, and a 1.0- x 1.0- x 0.5-cm preauricular node (TE-1)
from Patient 4; a 2.0- x 1.5- x 1.5-cm liver wedge biopsy (MS-4) from
Patient 3; and a liver resection specimen (CS-1 ) from Patient 5. This
last specimen consisted of a portion of liver, weighing 625 g and
measuring 13.5 x 13.0 x 10.0 cm. Protruding from and clearly visible
through the capsular surface were numerous nodules of gray-white to
pink tissue. On cut section, contiguous large nodules formed a central
10.0- x 7.0- x 5.0-cm mass, surrounded by several smaller nodules of
various sizes up to 1.5 x 1.0 cm.
Most of the surgical specimens and all autopsy material had been
fixed in 10% buffered formalin; the most recent biopsies were fixed in
B6. Three-jam sections were obtained from the specimens and stained
with hematoxylin and eosin and periodic acid-Schiff. IP5 reactions for
the detection of clgs and muramidase were done according to the
methods of Sternberger (43) on 7 surgical specimens and 2 lymphoid
lesions obtained at autopsy. Due to excessive nonspecific background
stain in control sections tested with decomplemented rabbit serum or
to the lack of positive built-in controls (reactive plasma cells), the
staining reactions on 4 biopsy specimens and one autopsy specimen
were considered unsuitable for interpretation. Peripheral blood smears
were stained with Wright's-Giemsa
stain. The bone marrows were
processed for examination as described previously (9).
CM studies were performed in 3 cases (Patients 2, 3, and 4) on both
cell suspensions and cryostat tissue sections, obtained from portions
of the surgical material. In Patient 1, only cell suspensions were
studied, obtained from the lymph node biopsy (JU-1), and in Patient 5,
the liver lesion (CS-1) could not be evaluated due to an excessive
percentage of necrotic cells. Our methods for evaluation of immunological cell markers have been previously described (17). In brief, cell
suspensions and cryostat sections from the lesions were studied by
immunofluorescence
for evidence of slgs with specific antisera against
heavy and light chains and by the erythrocyte + antibody + comple
ment [19S (IgM)] rosette assay for the presence of complement recep
tors. Fc receptors were detected by immunofluorescence
with fluoresceinated aggregated human IgG in cell suspensions and by the 7S
(IgG) erythrocyte + antibody rosette assay in cryostat tissue sections.
Erythrocyte rosette-forming
cells in suspensions were detected with
unsensitized sheep erythrocytes and morphologically evaluated, as for
all other rosette assays, in cytocentrifuge
preparations stained with
Wright's-Giemsa.
Material for ultrastructural study was available from the nodal biopsy
on Patient 1, from the lymph node and liver wedge biopsy of Patient 3,
and from the liver lesion of Patient 5. All this material was fixed in 2.5%
glutaraldehyde,
postfixed in 1.5% osmium tetroxide, dehydrated in
graded ethyl alcohols, and embedded in epoxy resin. Thin sections
were stained with uranyl acetate and lead citrate and examined with a
Phillips 201 electron microscope.
For cytogenetic studies, bone marrow aspirates and/or surgical
specimens were processed immediately using the method of Hozier
and Lindquist (23). In the case of solid tissue, surgical blades were
used to finely tease apart the tissue into an even cell suspension before
'The abbreviations used are: IP, immunoperoxidase;
clg, intracytoplasmic
immunoglobulin; CM, cell marker; slg, surface immunoglobulin; FCC, tollicular
center cell.
NOVEMBER
1981
processing.
and Lymphomas in Transplant Recipients
Direct harvest, as well as 24-hr cultures,
was initiated.
Mitotic indexes were generally low, and some of the metaphases found
appeared to be in normal cells; therefore, extensive scanning of slides
was necessary. Suitable spreads were studied using Giemsa bands
and photographed with Kodax SO 115 high-contrast film.
Pathological Findings
Surgical Material
The main abnormality in all specimens consisted of a lymph
oid proliferation with polymorphic cellular composition and
marked infiltrative features. In the oral lesions (MR-1, MR-2,
MS-1, and MS-2), this proliferation was marginally covered by
normal mucosa and lamina propria and centrally extensively
ulcerated. It infiltrated deeply and disrupted minor salivary
glands, connective tissue, and bundles of striated muscle.
Small and large lymphoid cells appeared within the walls of
small blood vessels, nerves, single muscle fibers, and the lining
of epithelial structures (Fig. 1). In the lymph nodes (JU-1, MS3, and TE-1), the lymphoid proliferation completely effaced the
architecture, infiltrated the capsule, trabeculae, and blood ves
sel walls, and extended into the perinodal tissue. Vascularity
was never prominent. In JU-1 (Fig. 2), some sinuses were still
recognizable and were filled with large and small lymphoid
cells. In the same node, a "moth-eaten"
appearance was
obvious at low power, due to the presence of tingible-body
macrophages, single-cell necrosis, and large lymphoid cells
lying in lacunar spaces. In the livers (MS-4 and CS-1), a
massive cellular proliferation formed nodular areas. Adjacent
to these, infiltration of the portal triads and residual disrupted
hepatic parenchyma were seen.
At low power, extensive coagulative necrosis was a promi
nent feature in many of the lesions (Fig. 3). This largely re
placed the lymphoid proliferation (CS-1 ) or formed elongated
interconnected areas (MS-3, MS-4, and TE-1). In addition,
single-cell necrosis was consistently seen in all specimens,
with nuclear debris lying free or within the cytoplasm of mac
rophages. Also, at low power, numerous mitoses were seen in
all lesions but MS-2, in which mitotic figures were very few.
The lymphoid infiltrate was very polymorphic (Fig. 4) in all
lesions except MS-2. However, variations were seen in the
cellular composition from specimen to specimen, as presented
in Table 2. Large lymphoid cells predominated, with different
numbers of them being present in different areas. Some
showed clumped chromatin, multiple prominent nucleoli at the
nuclear membrane, and a moderate amount of amphophilic
cytoplasm, features most compatible with large noncleaved
FCCs (29) (Fig. 5/1). Others showed peripheralization of the
chromatin, a central prominent nucleolus, and more abundant
and more basophilic cytoplasm, sometimes with a paranuclear
hof. These features, suggestive of plasmacytoid differentiation,
were considered most compatible with B-immunoblasts (29,
32) (Fig. 56). In both cell types, the nuclei were usually regu
larly round or oval. In some lesions, however, atypical cells
were also present in varying numbers. These cells were char
acterized by a very large size and/or irregular nuclear features,
such as bi- or multilobation, deep grooves, or contorted mar
gins (Fig. 6); due to their prominent central nucleoli and abun
dant cytoplasm, they were interpreted as atypical immunoblasts. In CS-1, these atypical forms were particularly abundant
and very often were represented by giant cells which, due to
4263
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G. Frizzerà et al.
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4264
CANCER
RESEARCH
VOL. 41
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Hyperplasias
and Lymphomas in Transplant Recipients
Table 2
Histopathological
findings
composition%
Tissue
Patient
identification1
LPLymph
studied
JU-1PM2
SLa
Pc
cells"+
+
—¿
±
±
±
+
—¿
4±
+
+
+
—¿
4- +
4-440-804-4-44-4-4-
LNC
IB
Aryp
of large
++ +
+ 4- +
—¿
4-4+
++
4+
4-4+
+
±
—¿
+
++
++
+
++
+
+
++
+
+++
++ 4++
++
++
±
-I++
++
±
+—+
—¿
+Lymphnode
+
+Liver node
TE-15
+±
+
+ ++
+
++
+
+
+
+ ++
CS-1PMTissue
+Liver mass
+
++ +
mass
—¿
-Cell
+
+
++
+ +
95Necrosis_+——-—+
+ +
a SL, small lymphocytes; LP, lymphoplasmacytoid cells; Pc, plasma cells; SC, small cleaved FCCs; LNC, large noncleaved FCCs; IB, immunoblasts; Atyp, atypical
+Lymph node
+Palatal node
MR-1MR-23
+Palatal ulcer
+Tongueulcer
MS-1MS-2MS-3MS-4PMPMPM4
+Tongue lesion
-Lymph lesion
+Liver node
+Liver mass
+Lymph
mass
+Lymph node
+
70-90+
80+
60-80±
50-70+
+
5+
70-80+
50-80+
50-80+
70-90+++
0±
80-90±
40-70±
SC
++
immunoblasts; PM, autopsy material.
" Range of values in different areas.
multiple irregular nuclei and prominent nucleoli, were similar to
Reed-Sternberg cells (Fig. 7).
The small-cell component included small round lymphocytes
with clumped chromatin, numerous mature plasma cells, and
intermediate lymphoplasmacytoid forms, showing lymphoid nu
cleus and plasmacellular cytoplasm (Fig. 8). Plasma cells were
particularly abundant in JU-1 . In addition, there were cells of
small and intermediate size, with angulated or elongated nuclei,
often traversed by a groove, and more open chromatin pattern,
features which are compatible with small cleaved FCCs (29)
(Fig. 9).
Different specimens obtained from the same patient gener
ally showed a similar cellular composition. Important variations,
however, were seen in Patient 3 (Table 2). In all specimens,
except MS-2, the infiltrate was polymorphic with a predomi
nance of large cells; lymphoplasmacytoid elements and mature
plasma cells were numerous, as were the small cleaved FCCs.
In MS-2, instead, this last cell type definitely predominated,
while the large lymphoid cells and the cells with plasmacytic
differentiation were very few in number. In addition, the large
atypical lymphoid cells were not found in the first 2 biopsies
(MS-1 and MS-2) but were present in the subsequent lymph
node (MS-3) and liver (MS-4) biopsies.
Hematological
Material
The blood and bone marrow of all 5 patients were studied at
the time of diagnosis of lymphoproliferative
disorder. Two of
the patients (Patients 1 and 4) manifested evidence of marrow
involvement by the lymphoid proliferation. Patient 1 had a
moderate anemia, normal platelet count, and a leukocyte count
of 39,000/cu
mm, consisting predominantly of immunoblasts
at various stages of transformation, plasma cells, and reactive
lymphocytes. The immunoblasts and plasma cells had been
identified in this patient's blood smears for 3 weeks prior to the
lymph node biopsy (JU-1) and had gradually increased in
number. The bone marrow in trephine biopsy sections was
normocellular; however, the normal hematopoietic elements
were decreased and replaced by a diffuse infiltration of im
munoblasts and plasma cells. These represented 37% of the
cells in the bone marrow smears and displayed a spectrum of
cell size and differentiation, with cells morphologically inter
NOVEMBER
1981
mediate between immunoblasts and mature plasma cells pre
dominating (Fig. 10). These cells had large- to medium-sized
nuclei with variably coarse nuclear chromatin and occasionally
a single prominent nucleolus. The cytoplasm was generally
abundant and basophilic in Wright's-Giemsa-stained
smears.
Numerous sharply punched out vacuoles were frequently pres
ent in the cytoplasm. Rare intracytoplasmic and/or intranuclear
pink inclusions were noted. There was an increase in mast
cells and marrow histiocytes, which showed prominent erythrophagocytosis. The erythroid and granulocytic precursors were
decreased in number, and dyserythropoiesis was observed.
Patient 4 was neutropenic at diagnosis; no abnormal cells
were seen in his peripheral blood. Occasional immunoblasts
could be identified in the bone marrow aspirate. In trephine
biopsy sections, the bone marrow was moderately hypocellular
and contained a few small scattered foci of immunoblasts. No
such foci were present in a repeat marrow biopsy obtained 3
weeks later, following therapy.
The other 3 patients did not show evidence of marrow
involvement by their lymphoproliferative
disorder. All 3 ex
hibited a postsplenectomy blood picture. Patient 3 had normal
blood counts, Patient 2 was anemic, and Patient 5 was anemic
and thrombocytopenic. In trephine biopsy sections, the first of
these patients had a normocellular and the other 2 a hypocel
lular bone marrow. In marrow smears, mild dyserythropoiesis
was observed in the 2 anemic patients, as well as a striking
increase in histiocytes and prominent hemophagocytosis
in
one of them (Patient 5).
Autopsy Material
Patient 1. The main gross findings were marked hepatomeg
aly (3120 g), moderate enlargement of all lymph node groups,
and severe pulmonary congestion and edema. Microscopically,
a dense lymphoid infiltrate was present in most organs. Its
cellular composition was quite similar to that seen previously in
the lymph node biopsy (JU-1). The large cells were of the
immunoblastic type. Both large and small FCCs were absent.
Small foci of necrosis were seen in several locations within this
infiltrate. In the lymph nodes, the proliferation extended beyond
the capsule, but the nodal architecture was partially preserved;
lymphoid follicles were inconspicuous. Extensive permeation
4265
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-TT'
G. Frizzerà et al.
of the bone marrow by multiple foci of immunoblasts and
plasma cells was noted, with partial preservation of fat and
normal hematopoietic elements. In the lungs, the infiltrates
appeared as relatively well-circumscribed subpleural nodules,
which destroyed alveolar walls and reached the mesothelial
layers. The liver exhibited a dense and extensive portal infil
trate, with massive expansion and spilling of cells into the
sinusoids. Sections of the large bowel showed massive infiltra
tion of the mucosa and submucosa, resulting in wide separation
of the glands; the infiltrate stopped rather abruptly laterally, as
well as when reaching the muscularis propria. However, sec
tions of the appendix revealed widespread infiltration of the
muscularis and serosa by the same infiltrate. The adrenal gland
exhibited extensive involvement of the medulla, including a
massive infiltration of the central medullary vein; the cortex
was only focally affected. The transplanted kidney had multiple
foci of infiltration, involving cortex, medulla, pelvis, and perirenal fat. A dense diffuse interstitial infiltrate was present in the
testicles, resulting in a wide separation of the preserved semi
niferous tubules. Sections from thymus showed marked cystic
dilation of Hassall's corpuscles, which were widely separated
by a prominent lymphoid infiltrate. A random section of skin
exhibited a perivascular polymorphic lymphoid infiltrate in the
dermis and subcutaneous tissue.
Patient 3. The main gross findings were in the liver. This
weighed 3530 g and contained 2 roundish confluent tumor
masses, tan-yellowish and largely necrotic, mainly located in
the right lobe (Fig. 11). These measured 9.0 and 11.0 cm in
diameter and occupied approximately 50% of the liver mass.
One enlarged lymph node, measuring 2 cm in diameter and
having the same gross features, was seen at the porta hepatis;
the lymph nodes situated anteriorly to the head of the pancreas
were very enlarged and had a homogeneous fish-flesh appear
ance. Other gross findings included massive hemorrhage from
an acute ulcération in the distal esophagus, bilateral foci of
healing bronchopneumonia, severe atherosclerotic heart dis
ease, and a small subependymoma of the right caudate nu
cleus. Fungal and viral cultures from liver, esophagus, lung,
and kidney were negative, even though cytomegalovirus nu
clear inclusions were identified in both lungs and liver. Blood
cultures grew coagulase-negative staphylococci.
Two different types of lymphoid infiltration were observed in
this patient on histopathological examination. One was seen in
the liver and in the porta hepatis node and consisted of a
massive lymphoid proliferation that totally obliterated the ar
chitecture of the organ and was associated with extensive
areas of coagulative necrosis. In the liver, it produced discrete
tumoral masses, as well as diffuse infiltration of the portal triads
in the adjacent parenchyma. Cytologically, this lymphoid pro
liferation was identical to that seen in the lymph node and liver
biopsies (MS-3 and MS-4). The atypia of the large cells was
poorly évaluabledue to postmortem artifacts. The bone marrow
was extensively involved by focal aggregates of plasma cells
and larger cells, mostly of immunoblastic type, many with
bizarre nuclear features; however, no necrosis was present.
The second type of lymphoid lesion consisted of an infiltra
tion of mature and immature plasma cells, without obliterative
features or a necrotic component. These cells accumulated in
the peripancreatic nodes, expanding the medulla and the paracortical zone. Although germinal centers were not present,
the overall nodal architecture was well recognizable. Similar
4266
isolated cellular foci were observed in the cortex of the trans
planted kidney and in the cortex of both adrenals.
Patient 5. The only relevant gross finding was in the liver.
This weighed 2500 g and contained several well-circumscribed
largely necrotic nodules varying from 0.5 to 3.0 cm in size.
Lymph nodes in all sites were unremarkable. No localized
infectious focus was found; however, organ and blood cultures
grew Pseudomonas aeruginosa, a streptococci, coagulasenegative staphylococci, and Candida albicans.
The only significant lesions seen at microscopic examination
were in the liver. The hepatic nodules were largely composed
of necrotic tissue surrounded by an atypical cellular infiltrate.
Small and large lymphoid cells were present, but these could
not be further characterized due to autolytic phenomena; there
was also a large component of giant cells with multiple hyperchromatic and bizarre nuclei. A similar pleomorphic lymphoid
infiltrate was observed in the portal triads adjacent to the
nodules but not in the distant parenchyma. The regional and
distant lymph nodes only showed marked sinus cell hyperplasia, with obvious erythrophagocytosis
and rather depleted
lymphoid stroma. The bone marrow was hypoplastic, with
reduction of all 3 cell lines; in addition, a prominent histiocytic
component was seen, with erythrophagocytosis.
Immunological Findings
The results of the immunological studies done on all available
material are detailed in Table 3, together with our interpretation
of them. They are also summarized in Table 4, for correlation
with the histopathological and cytogenetic data. No further
mention will be made of IP-staining reactions for muramidase,
which were positive only in scattered histiocytes and negative
in all of the proliferating large cells.
In Patient 1, the cell suspension obtained from the node
biopsy (JU-1 ) contained predominantly B-cells, of both K and
\ specificity. Correspondingly, IP reactions done on one of the
autopsy nodes from this patient showed intense cytoplasmic
staining in most of the small and large cells. Equal numbers of
cells stained with anti-K and anti-A antisera; more cells con
tained IgG and IgM than IgA.
In Patient 2, CM studies demonstrated very few slg-bearing
cells in the cell suspension from the palatal lesion (MR-2) but
more numerous small and large cells with polyclonal clgs in
cryostat tissue sections. With IP methods, most of the small
and large cells stained with either anti-K or anti-A antisera (Fig.
12). IgG- and IgA-containing cells were more numerous than
IgM-positive cells.
In Patient 3, a good proportion of the lymphoid cells in the
node biopsy (MS-3) consisted of a polyclonal B-cell population,
showing slgs and clgs. In addition, there was a smaller com
ponent of large atypical cells that were negative for clgs but
bore Fc and complement receptors. In IP-stained sections from
the liver biopsy (MS-4), only a small polyclonal component of
small and large cells was seen, admixed with a majority of
unstained cells.
On CM studies, the lymph node from Patient 4 (TE-1 ) con
tained a polyclonal B-cell proliferation showing mostly clgs and
rarely slgs. Some of the atypical cells showed Fc and comple
ment receptors but not immunoglobulins. In sections from the
same node stained with IP methods, the polyclonal component
consisted mainly of mature plasma cells. The lymphoplasmaCANCER
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Hyperplasias
and Lvmphomas in Transplant Recipients
Table 3
Immunological
ImmunoperoxidasePasuspensions"slg
Tissue identient
tification1
JU-1PM2
Fc58
studiedLymph
clg
MR-23
nodeLymph
nodePalatal
ulcerLymph
P24
MS-3MS-44
nodeLiver
3116P
P
0
601
P
massLymph
195
TE-1Tissue
nodeCell
P
a Percentage of positive cells.
E, binding sheep erythrocytes;
polyclonal;
findings
Cell markers
E"
23
sectionsPolyC'
slg
clg
C'
Fc
9
0
10
2
0
0
64Tissue
C', binding IgM erythrocytes
proliferation±P
+P
-I-
++
tors+
P
++
+P
+
proliferation—
-HP
+
+ antibody
+
+ complement;
clonal
Negative
for clg
proliferation+
+
++
receptors±
+ ++
±
++
Monoclonal
—¿
?+
Fc, binding IgG erythrocytes
ConclusionsPolyclonal
B-cell
Polyclonal B-cell
Polyclonal
B-cells proliferation of
bearing C' and Fc recep
Polyclonal
proliferation.The
B-cell
onlybear
most atypical cells
C' and Fc
Polyclonal B-cell
Polyclonal
proliferation.Some
B-cell
bearC' atypical cells only
and Fc receptors
+ antibody
or aggregated
IgG; P,
PM, autopsy material. Empty spaces indicate not done or unsuitable for interpretation.
cytoid or immunoblastic cells were not stained with anti-K, antiG, or anti-A antisera. However, occasional isolated or loosely
aggregated cells of this type did stain with anti-X, and many
more stained with anti-M antisera.
Electron-Microscopic
Findings
Patient 1. In material from JU-1, 4 populations of cells were
observed (25, 39). A few small cleaved FCCs measuring 7 /tm
in diameter and having irregularly shaped nuclei with peripheral
heterochromatin and small central nucleoli were evident. The
cytoplasm of these cells contained monoribosomes, a few
polyribosomes, scattered mitochondria, and rare strands of
rough endoplasmic
reticulum. Also present were mature
plasma cells with round nuclei, triangular clumps of hetero
chromatin along the nuclear membrane, and numerous strands
of rough endoplasmic reticulum with dilated cisternae contain
ing granular secretory product. The predominant cells con
sisted of 2 types of immunoblasts, 12 to 13 urn in diameter
(25). The first, a nonplasmacytoid immunoblast, had sparse
rough endoplasmic reticulum but many polyribosomes, a few
mitochondria, and a small Golgi apparatus. The second, a
plasmacytoid immunoblast, had prominent serpiginous strands
of rough endoplasmic reticulum, which was often dilated and
contained granular secretory products, a conspicuous Golgi
zone, and scattered mitochondria. Both cell types had round
or oval nuclei with large nucleoli usually centrally located and
a little to moderate amount of clumped heterochromatin along
the nuclear membrane.
Patient 3. A polymorphic infiltrate of plasma cells, plasma
cytoid lymphocytes, immunoblasts, and occasional macro
phages was evident in the lymph node biopsy (MS-3) (Fig. 13).
The plasmacytoid lymphocytes measured 9 to 10 jum in diam
eter, had numerous strands of rough endoplasmic reticulum,
prominent Golgi zones, numerous polyribosomes, and a few
mitochondria. The small round eccentrically placed nuclei had
peripheral clumps of heterochromatin and a small central nucleolus. The morphology of the plasma cells and plasmacytoid
immunoblasts was similar to that seen in JU-1.
Although a polymorphic infiltrate of cells was also evident in
the liver (MS-4), here it consisted predominantly of atypical
NOVEMBER
immunoblasts and plasmacytoid and nonplasmacytoid
im
munoblasts, with a few small cleaved and large noncleaved
FCCs, plasmacytoid lymphocytes, and macrophages. The atyp
ical immunoblasts measured 12 to 13 jum in diameter and,
unlike the plasmacytoid and nonplasmacytoid immunoblasts
described above, had irregular nuclear contours with an in
crease in heterochromatin which was evenly dispersed within
the nucleus. The cytoplasm was plasmacytoid, with many elon
gated and serpiginous strands of rough endoplasmic reticulum,
a few mitochondria, and prominent Golgi zone. Aggregates of
tubular arrays with a diameter of 150 to 200 nm were found in
the cytoplasm of the immunoblasts and plasmacytoid lympho
cytes.
Patient 5. In the liver biopsy, the portal zones contained a
polymorphic infiltrate of variably sized lymphoid cells measur
ing 8 to 20 ¡urnin diameter, numerous macrophages and
polymorphonuclear leukocytes, and a few mature plasma cells.
The lymphoid cells consisted of small cleaved FCCs, nonplas
macytoid immunoblasts, and atypical plasmacytoid immuno
blasts. The small cleaved FCCs and nonplasmacytoid immuno
blasts were similar to those described in Patients 1 and 3. The
atypical immunoblasts measured 20 ¿imin diameter and had
irregularly shaped nuclei with multiple large nucleoli and irreg
ularly dispersed and prominent heterochromatin (Fig. 14).
Cytogenetic Findings
In Patient 2, the palatal biopsy (MR-2) yielded only 2 metaphases, both of which contained a long marker chromosome
identified as a 6q + . In addition, there was an extra Chromo
some 11, which appeared structurally normal, whereas one
Chromosome 9 was missing (Fig. 15). Chromosomes 14 ap
peared normal. Patient 3 had successful cytogenetic analysis
from both bone marrow and lymph node specimens. The bone
marrow yielded predominantly normal cells but also revealed
an abnormal hyperdiploid cell clone of 47 chromosomes. The
extra chromosome, which was consistent in size and morphol
ogy from cell to cell, could not be identified due to its small
size and "ring" configuration. No other structural abnormalities
were observed. The lymph node from this patient (MS-3) also
demonstrated an abnormal hyperdiploid cell clone, but the
1981
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4267
G. Frizzerà et al.
Table 4
Correlation and interpretation
Atypi-cells,
cal imMono-slg
but C'6 and
Necro-Tissue
typimuñoidentifi
Pa
sisLymphstudied
cal"
blasts
Interpretation+
clg
Fc-positive
tient12345Tissue
cationJU-1MR-1MR-2MS-1MS-2MS-3MS-4TE-1CS-1HistologyLarge
—¿Palatal
node
+ + ±
±Palatal
ulcer
+
-Tongueulcer
+ ±
±Tonguelesion
+
±Lymphlesion
+Liver node
+Lymph
mass
+Liver node
mass
++
+ ±
++
+
—¿
clonal
Polymorphic
hyperplasia.very
diffuse B-cell
activePolymorphic
hyperplasia.moderately
diffuse (B-cell)c
active±
++
+
+
+
+++
-
hyperplasia+
lymphoma+
+
+
+
lymphoma±
±
++
+
+
+
+ + +ImmunologyPolyclonalclg-negative
interpretation.
c Terms in parentheses, probable but not proven immunological
Fc, binding IgG erythrocytes
?+
46,hyperplasia.—
XX, 6q+,
Polymorphic diffuse B-cell
9, +11
activePolymorphic
moderately
hyperplasia,moderately
diffuse, (B-cell)
activeNonspecific
reactive lymphoid
47, XY, +14
Polymorphic B-cell
Polymorphic B-cell
Polymorphic B-cell
lymphomaPolymorphic
(B-cell) lymphoma
+ antibody.
Empty spaces indicate
not done or unsuitable
for
nature.
extra chromosome appeared to be a structurally normal Chro
mosome 14 (Fig. 16). Again, no other abnormalities were
noted.
Discussion
Summary of Findings. The lymphoid lesions that developed
in the 5 patients in this study share several features. They are
B-cell proliferations, have a very polymorphic cellular compo
sition, and display histological evidence of "aggressiveness"
towards normal tissue structures. Their B-cell nature was sug
gested by histological and ultrastructural characteristics and
was documented in 4 of the 5 cases with immunological meth
ods. Their polymorphism was due to the mixture of small cells
and large proliferating cells, as well as to the presence of 2
different morphofunctional types of lymphoid cells, which could
be designated as "follicular"
(small cleaved and large noncleaved FCCs) and "medullary" (lymphoplasmacytoid lympho
cytes, plasma cells, and immunoblasts).
However, in addition to these similarities, there were distinc
tive differential features among these lesions. The number of
large cells, especially immunoblasts, varied; nuclear atypia of
the immunoblasts and extensive coagulative necrosis was ob
served only in some of the cases; and the immunological
characteristics were not homogeneous. Even though all spec
imens tested contained a polyclonal B-cell component, in 2
lesions (MS-3 and TE-1), a component of large cells was also
present that did not contain clgs but bore complement and Fc
receptors; in one of them (TE-1), IP findings suggested the
possibility of a monoclonal population emerging amidst the
polyclonal proliferation.
Significance of Findings (Table 4). The significance of some
of these findings is not completely clear. The presence in all
cases of a FCC component, often prominent, was rather sur
prising at first. The main function of germinal centers, accord
ing to a prevalent view, is the production of precursors of
immunoglobulin-secreting
cells (32) or, as Nienwenhuis and
Kenning (34) put it, that of an "amplification system for the Bcell population." The dissolution of the germinal centers as
discrete aggregates is one characteristic
Cytogenetics
+
Include large noncleaved FCCs and immunoblasts.
* C', binding IgM erythrocytes + antibody + complement;
4268
of findings
of stimulated nodes
in experimental animals (2) and can be observed in many
intense ¡mmunological reactions of nodes in humans, such as
infectious mononucleosis (41), hypersensitivity to drugs (11),
angioimmunoblastic
lymphadenopathy (15), and multicentric
angiolymphoid follicular hyperplasia.6 Therefore, even if ger
minal centers as such were not seen in any of the lymphoid
lesions of transplant recipients, we feel that the presence of
sparse nonaggregated cells of follicular center types may well
represent the evidence of an actively operating "amplification
system."
The existence of such an amplification system of the B-cells,
in addition to the polymorphism of the cell population, including
all stages of maturation to the plasma cells, and the polyclonal
nature of it in immunological studies, strongly suggests a
reactive process as the initial common denominator for all of
these lesions. The serological evidence of primary or reacti
vated EBV infection in 4 of the 5 patients, the presence of the
viral genome within the lesions (20), and the apparent predi
lection of these processes for the organs typically involved in
infectious mononucleosis (oral cavity, lymph nodes, and liver)
obviously make EBV a likely causative factor.
While these common features suggest that all the lesions we
studied are, at least initially, reactive, the morphological varia
tions among them could well indicate a different biological
evolution. Indeed, some of these differential features may man
ifest an emerging or fully developed lymphoid malignancy.
A monoclonal component, which would, by definition, indi
cate malignancy (14, 27), was suspected to be developing in
one of the lesions (TE-1 ) with IP techniques. In 2 instances
(MS-4 and TE-1), clg-negative large lymphoid cells were de
tected by IP within the predominantly polyclonal B-cell prolif
eration. A similar finding in the context of angioimmunoblastic
lymphadenopathy has been considered indicative of either
neoplastic dedifferentiation or lack of plasmacytic differentia
tion (33). Other cases of posttransplant lymphoma, in which
the component cells were negative for immunoglobulins and T8 G. Frizzerà , B. A. Peterson, P. M. Banks. J. Rosai, E. D. Bayrd, and G.
Massarelli. A multicentric lymphoproliferative
disorder
features of Castleman's disease. A clinico-pathologic
with the morphologic
study of 14 patients,
manuscript in preparation.
CANCER
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41
Hyperplasias
cell antisera but bore la-like antigens, were interpreted as
possible pre-B-cell malignancies4 or "a B-immunoblastic lymphoma which has lost immunoglobulin expression" (10). In one
of our 2 cases (Patient 4), the finding of clg-negative cells in IP
corresponded to the presence of clg-negative but complementand Fc-positive cells in CM studies (Table 3). Since these are
marker characteristics of FCCs, as opposed to immunoblasts
(42), we prefer to interpret these data as being indicative of
the presence of a FCC component, rather than of an immunoblastic malignancy. This correlates well with the cytological
findings and is in keeping with the concept of an "amplification
system" being present in these lesions.
The presence of great numbers of large lymphoid cells was
associated with rapidly evolving disease (Patient 1) or an
accelerated tempo of the disease (Patient 3, MS-3 and MS-4),
and vice versa, paucity of these cells was a feature of the only
self-limited lesion in our series (Patient 2). A similar correlation
between abundance of large lymphoid cells and clinical ag
gressiveness of the disease has been observed in other atypical
immunoproliferative
processes, such as angioimmunoblastic
lymphadenopathy (33) and multicentric angiolymphoid hyperplasia.6 The variable severity of the lymphoid reaction, as
expressed by the number of "transformed lymphocytes, ' ' could
be due to biological characteristics of the etiological agent (8),
to the host immunological abnormalities (1, 6), or to both (36).
Nuclear atypias of the immunoblasts were associated with
chromosomal abnormalities in one lesion (MS-3), possible monoclonality in another lesion (TE-1 ), and tumoral mass formation
in the liver in 2 instances (MS-4 and CS-1 ); conversely, they
were absent in the only patient (Patient 2) still surviving after 2
years and in Patient 1, who died with primary Epstein-Barr
virus infection. Based on these findings, we feel that the pres
ence of evident nuclear atypias is strongly suggestive of true
lymphoid malignancy developing in these transplant recipients.
However, the lack of morphological atypia does not necessarily
exclude the presence of an incipient malignancy, since, for
instance, atypia was not observed in a lesion (MR-2) in which
chromosomal abnormalities were detected, nor should it by
itself assure a good prognosis, since atypia was conspicuously
absent in the lesion of Patient 1 who died very rapidly. Exten
sive coagulative necrosis in the biopsy material was consis
tently associated with nuclear atypia and has perhaps the same
significance.
Interpretation and Classification of Cases. Based on the
above analysis of their common and differential features, we
interpret the lymphoproliferative
disorders arising in these 5
patients as being different expressions of a morphological and
biological spectrum of abnormal B-cell proliferations (Table 4).
The process in Patient 1 appears to represent a disseminated
extremely active B-cell proliferation in responses to EpsteinBarr virus infection. The widespread organ involvement, also
seen in reported cases of fatal infectious mononucleosis (4, 8,
12), and the obliteration of the nodal architecture may certainly
suggest a malignancy. However, the reactive cellular compo
sition without atypia, as defined above, and the definite polyclonal nature of the proliferation on immunological evaluation
argue strongly against such an interpretation (38) and rather
support the concept of a B-cell hyperplasia, that has proceeded
unrestrained, possibly due to iatrogenic depression of the Tcell system (13).
Patient 2 had a localized reactive (polyclonal) process of
NOVEMBER
1981
and Lymphomas in Transplant Recipients
moderate severity. Morphological atypia was not seen, but the
presence of a chromosomal aberration possibly pointed to a
malignant cellular component, not yet recognizable morpholog
ically or ¡mmunologically. Patient 3 presented with a similar
reactive oral lesion (MS-1 ) which showed moderate activity and
later regressed (MS-2). This was followed by disseminated
disease, characterized by an extremely active lymphoid prolif
eration. Besides a reactive (polyclonal) population, the com
bined findings of cellular atypia, extensive necrosis, and chro
mosomal abnormalities (MS-3) appear to indicate the emer
gence of a true malignancy, not yet detectable ¡mmunologi
cally. This is, indeed, the most logical interpretation in view of
the autopsy findings (Fig. 11). Similarly, the lymphoid process
in Patient 4 was an active lesion that, although still definable as
polyclonal by CM analysis, showed histopathological features
(nuclear atypia and extensive necrosis) and IP reactions (pre
dominant juA population), strongly suggestive of malignancy.
Finally, Patient 5 developed exclusively in the liver a lymphoid
process that can be interpreted as malignant by virtue of its
histopathological features and the gross findings at operation
and autopsy. In the absence of immunological data, the B-cell
nature of the proliferation is only suspected based on histological and ultrastructural similarities with the other lesions.
The terminology we use to define these different lesions
(Table 4) was chosen to stress their salient features: their Bcell nature; polymorphic cellular composition; and diffuse pat
tern of growth. The term hyperplasia is reserved for reactive
processes without evidence of atypia or monoclonality, and the
addition to it of "moderately active" or "very active" refers to
the number of immunoblasts, a feature which is possibly pre
dictive of the degree of clinical aggressiveness. For the reasons
given in the previous section, we chose to diagnose as "lymphomas" only lesions that showed nuclear atypias and exten
sive necrosis, even if no monoclonal component
strated.
"Polymorphic B-cell lymphoma" seems to us
term to both "histiocytic"
(large-cell) lymphoma
"immunoblastic sarcoma" (6, 10, 18, 19, 30),
was demon
a preferable
(1, 21) and
designations
which are frequently used to label these processes. Neither of
these terms does justice to the complex cellular composition of
the lesions described here, especially to their prominent FCC
component. In particular, this component is not a feature of the
immunoblastic sarcomas as described by Lukes ef al. (29) or
Lennert and Mohri (26). Of the categories of lymphomas de
scribed in the literature, the one that best corresponds to the
cytology of these polymorphic B-cell lymphomas is that of the
"blastic (sarcomatous) variants of immunocytomas"
(26). In
terestingly enough, it is in these types of tumors that hetero
geneity and difficulties of immunological characterization are
encountered similar to those with which we contended in our
polymorphic B-cell lymphomas (31, 42).
Conclusion
The study of the morphological features of the lymphoid
lesions arising in this group of patients, correlated with immu
nological, chromosomal, and clinical data, suggests that: (a) all
of them are polymorphic B-cell proliferations, involving both
FCCs (B-cell amplification system) and immunoblasts and
showing some indication of plasmacytic differentiation; these
features and the polyclonality of these lesions seem to reflect
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G. Frizzerà et al.
Histopathological
characteristics
differentiating
Table 5
posttransplant
from "spontaneous"
lymphoproliferative
PlasmacyType of lesion
"Nonspecific"
reactive lymphoid
FCCs
+ +(GCa)
lesions
"Inva-
tic differentiation
Large lymphoid cells
Atypical immunoblasts
siveness"
Necrosis
hyperplasia
Polymorphic diffuse B-cell
hyperplasia
Polymorphic diffuse B-cell
lymphoma
Immunoblastic sarcoma of B-cells
GC, germinal centers; D, diffuse.
their original reactive nature; (o) the nuclear atypias and exten
sive necrosis appearing in some of the lesions denote the
development, on this background, of a true malignancy; and
(c) the number of large lymphoid cells may be indicative of the
clinical severity and tempo of the disease, rather than of a
malignant growth.
The morphological features of these lesions seem to be
distinctive enough to separate them from other known lymphoid
processes, benign or malignant (Table 5). On one hand, the
lesions we labeled as polymorphic diffuse B-cell hyperplasias
differ from nonspecific lymphoid hyperplasias, including infec
tious mononucleosis in immunologically normal hosts, in their
histological "invasiveness,"
diffuse distribution of the FCCs,
and very prominent large-cell component, closely mimicking a
malignant lymphoma. On the other hand, the lesions we labeled
as polymorphic B-cell lymphomas differ from the immunoblastic
sarcomas, as described in the literature (26, 29) and observed
by us (5), in the abundance of a FCC component and the
presence of extensive necrosis, as well as in the residual
evidence of a polyclonal origin.
According to this interpretation, the immunoblastic sarcomas
can be thought of as morphologically and immunologically pure
neoplasias of the immunoblasts, while the polymorphic B-cell
lymphomas arising in transplant recipients, and very possibly
in other dysimmune states as well, would represent immuno
blastic malignancies that still bear morphological and immunological evidence of their origin from a reactive lymphoid
process.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
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Fig. 1. Biopsy MS-1. The lymphoid proliferation
H & E, x 160.
4272
extensively infiltrates normal structures: A, striated muscle; B, salivary duct epithelium; C, small artery; D, nerve.
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VOL. 41
Hyperplasias
Fig. 2. Biopsy JU-1. Despite diffuse architectural
obliteration,
and Lymphomas in Transplant Recipients
a portion of the peripheral sinus is still recognizable
(arrows). A "moth-eaten"
noted. H & E, x 160.
Fig. 3. Biopsy TE-1. Extensive necrosis of the lymphoid proliferation. H & E, x 82.
Fig. 4. Biopsy MS-3 In this infiltrate, several lymphoid cell types can be identified: small and large, of follicular center, and "medullary"
NOVEMBER 1981
appearance
is also
type. H & E, x 400.
4273
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G. Frizzerà et al.
r 4 **
l
i';-- A.-8
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9 Ã ' **
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Fig. 5. Biopsy MS-3. Smaller peripheral nucleoli and lesser cytoplasm characterize the largì
large noncleaved
non
plasmacytoid cytoplasm characterize the B-immunoblasts (B). H & E. x 820.
Fig. 6. Biopsies TE-1 (A, B. and D) and MS-4 (Q. Atypical forms of immunoblasts (arrows). . H
H&
& E,
E, xx 820.
FCCs (A), while larger more central nucleoli and
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VOL. 41
Hyperplasias
and Lymphomas in Transplant Recipients
«*é
3. <Mr^* s)^«3bV
^ ^v
,.*\.
-,»X
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Fig. 7. Biopsy CS-1. Predominance of atypical immunoblasts. H & E, x 640.
Fig. 8. Biopsy MS-1. Small-cell component of "medullary" type (lymphoplasmacytoid
forms and plasma cells). H & E, x 640.
Fig. 9. Biopsy TE-1. Small-cell component of FCC type. H & E, x 400.
NOVEMBER
1981
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4275
G. Frizzerà et al.
ft." f»
?>o
*r
«1*
« *
.*.
Fig. 10. Patient 1. bone marrow smear. Spectrum of cellular differentiation between plasma cells and immunoblasts.
out cytoplasmic vacuoles and prominent nucleoli (arrows). Wright's-Giemsa, x 1,200.
Fig. 11. Patient 3. Gross features of the liver tumor at autopsy.
Fig. 12. Biopsy MR-2. Polyclonal cytoplasmic staining of the lymphoid proliferation,
method, x 512.
4276
Many of the latter contain sharply punched
showing both K (At- and A (BJ-positive cells. Peroxidase-antiperoxidase
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Hyperplasias
and Lymphomas in Transplant Recipients
": V--'
Fig. 13. Biopsy MS-3. Ultrastructural features of the pleomorphic lymphoid infiltrate, consisting of small lymphocytes,
and 2 nonplasmacytoid immunoblasts (left and right lower corners). Uranyl acetate and lead citrate, x 6.980.
"*^
•¿
*^
large noncleaved lymphoid cell, plasma cell,
NOVEMBER 1981
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4277
G. Frizzerà et al.
Fig. 14. Biopsy CS-1. This atypical plasmacytoid immunoblast has an abundant amount of cytoplasm containing strands ot granular cisternae. irregularly shaped
nucleus with clumps of peripheral heterochromatin, and prominent nucleolus. Uranyl acetate and lead citrate, x 12.670.
4278
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41
Hyperplasias
fe le \(
H fi
123
\\\l
8
9
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45
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6*7
41
and Lymphomas in Transplant Recipients
10
11
12
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(I
it
14
16
17
15
It
t »
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20
21
22
19
18
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15
Fig. 15. Patient 2. Karyotype from biopsy MR-2, showing a marker chromosome
6q + , a missing Chromosome 9, and an extra Chromosome
U
11. Giemsa.
u If
M H t( n^ot ti f
16
6
7
II
Ili
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8
14
9
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15
10
11
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16
17
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Fig. 16. Patient 3. Karyotype from biopsy MS-3, showing 3 structurally
NOVEMBER
12
normal Chromosomes
X
ti
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1981
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4279
Polymorphic Diffuse B-Cell Hyperplasias and Lymphomas in
Renal Transplant Recipients
Glauco Frizzera, Douglas W. Hanto, Kazimiera J. Gajl-Peczalska, et al.
Cancer Res 1981;41:4262-4279.
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