Download Reactive Plasmacytic Lesions of the Bone Marrow

Reactive Plasmacytic Lesions of the Bone Marrow
BONG HAK HYUN, M.D.,
D.Sc,
DANIEL KWA, M.D.,
AND J O H N K. ASHTON,
HERMINIA GABALDON,
M.D.,
M.D.
From the Departments of Pathology, Muhlenberg Hospital, Plainfield, New Jersey, and Rutgers Medical School,
Piscataway, New Jersey
ABSTRACT
Hyun, Bong Hak, Kwa, Daniel, Gabaldon, Herminia, and Ashton, John K.:
Reactive plasmacytic lesions of the bone marrow. Am J Clin Pathol 65: 921 —
928, 1976. A consecutive series of 1,000 bone marrow aspirates was
analyzed for percentage of plasma cells, incidence of plasmacytic satellitosis,
associated clinical disease states, lymphoid follicles, lipid granulomas, hemosiderin content, and various combinations thereof. Plasmacytosis was a common finding, and tended to parallel the presence of lymphoid follicles, lipid
granulomas and plasmacytic satellitosis. The latter is emphasized as a normal
phenomenon, may reflect morphologically a physiologic response of the B cell
system to antigenic stimulation, and is conspicuously absent in plasmacytic
neoplasia. Various secretory forms of plasma cells are illustrated. (Key words:
Plasma cells; Bone marrow; Plasmacytosis; Plasmacytic satellitosis; B cells;
Immune response.)
MUCH HAS BEEN LEARNED in recent years
concerning the functional relationships of
plasma cells to the immune reaction and
about the biochemistry of the immunoglobulins, their secretory products. Less is
known about the morphologic aspects of
the steps in the immune response.
An increase in the number of plasma cells
(plasmacytosis) in the bone marrow is of
some clinical importance, as it is found both
in malignant plasmacytic diseases and in
benign and malignant diseases other than
plasmacytic neoplasms. Morphologic evaluation of the bone marrow is still probably
Received September 2, 1975; accepted for publication September 2, 1975.
Address reprint requests to Dr. Hyun: Department
of Pathology, Muhlenberg Hospital, Plainfield, New
Jersey 07061.
Presented in part as a scientific exhibit at the annual
convention of the American Medical Association, New
York, J u n e 1973, and at the joint fall meeting of the
American Society of Clinical Pathologists and the
College of American Pathologists, Chicago, October
1973.
the most important step in the differentiation between reactive and neoplastic
plasmacytic proliferations.
The present study was undertaken to
analyze the morphologic aspects of reactive
plasmacytosis of the bone marrow and to
correlate their incidences with underlying
diseases and other bone marrow alterations, such as lipid granulomas, lymphoid
follicles and hemosiderosis. Plasmacytic
satellitosis, a morphologic unit consisting
of a central histiocyte surrounded by three
or more plasma cells, was of particular
interest to us, and was systematically
evaluated.
Materials and Methods
The analysis is based on a series of 1,000
consecutive bone marrow aspirates. T h e
specimens were obtained from the iliac
crest, sternum or tibia (in the case of infants). Films and sections were prepared in
all instances, by previously reported tech-
921
922
Table 1. Normal Values for Plasma Cells
in the Bone Marrow Differential Count 7
Berman (1949)
Custer6 (1974)
Diggs(1948)
Israels (1955)
Leitner (1945)
Lucia and Hunt (1947)
McDonald et al.a (1970)
Vaughan and Brockmyre (1947)
Whitby and Britton4 (1969)
Wintrobe20(1974)
A.J.C.P.—Vol.
HYUN, ETAL.
1%
0.1-1.2%
0-1%
0-2%
1.2%
0-4.1%
0.1-3.5%
0-1.5%
0-1%
0-3.5%
65
1+, normal; 2 + , slightly increased; 3 + ,
moderately increased; 4 + , markedly increased.
Results
Figure 1 summarizes the incidences of
plasmacytosis and plasmacytic satellitosis in
the various clinical conditions encountered.
Of 1,000 consecutive bone marrows, there
were 35 cases of multiple myeloma. Of the
remaining 965 cases, 28.6% showed reactive plasmacytosis. This finding was comnics.11 Films were stained by Wright- mon in association with infections and inGiemsa, Prussian blue and periodic acid- flammatory conditions, diabetes mellitus,
Schiff technics. Marrow particles were epithelial malignancies, cardiovascular disfixed in Zenker or B-5 solution, processed eases, and Hodgkin's disease, the highest
in the Autotechnicon, and embedded in incidence being found in association with
paraffin. Sections were cut at 6 ixm. and hepatic cirrhosis. Of interest is the relastained by hematoxylin and eosin, Giemsa, tively high incidence in Hodgkin's disease
and Prussian blue technics. T h e percentage compared with leukemias and other
of plasma cells was determined by a differ- lymphomas. In the majority of cases there
were also parallel increases in the inciential count of 500 cells on films.
dences of plasmacytic satellitosis except in
Plasmacytosis was defined for our purHodgkin's disease, hemolytic anemias and
poses as 2% or more plasma cells. A rather
diabetes mellitus, where the percentages of
wide range of normal values has been used
plasmacytic satellitosis exceeded the perby various investigators, as shown in
centages of reactive plasmacytosis.
Table 1.
Perivascular distribution of plasma cells
The numbers of examples of plasmacytic
satellitosis in at least eight films, the num- is a normal finding, and was seen occabers of lipid granulomas and lymphoid sionally in sections of bone marrows withfollicles in the sections, and the hemo- out plasmacytosis. Diffuse plasmacytosis,
siderin content as judged from both films when present in sections, was invariably
and sections were also recorded. T h e associated with an elevated percentage of
incidences of plasmacytosis and plasma- plasma cells in films.
cytic satellitosis in the different disease
T h e incidences of plasmacytic satellitosis
states were tabulated. The incidences of when the percentage of plasma cells was
plasmacytic satellitosis in cases where the normal and in reactive plasmacytosis are
percentage of plasma cells was normal and shown in Table 2. When the percentage of
in reactive plasmacytosis were compared. plasma cells was normal, the incidence of
The incidences of lymphoid follicles and plasmacytic satellitosis was 10%. A siglipid granulomas in aspirates with and with- nificant increase in incidence of plasmacytic
out reactive plasmacytosis were also com- satellitosis was found when there was repared. Last, hemosiderin content was active plasmacytosis. Plasmacytic satellitosis
evaluated in aspirates without plasma- was not encountered in sections, with one
cytosis, with plasmacytosis, and with mul- exception.
tiple myeloma. Hemosiderin content was
Figure 2 shows the correlation between
graded as follows: 0, absent or decreased; lymphoid follicles and lipid granulomas in
June 1976
PLASMACYTIC LESIONS OF BONE MARROW
Clinical
NOOf
Situations
cases 0
A. Neoplastic diseases
296 [
91
Carcinoma
Leukemia/ lymphoma
lexc. Hodgkin'sJ
10
20
30
Percent
40
50
923
60
70
151
Hodgkin's disease
24
Myeloproliferative disorders
lexc.PV, C G U
21
rnninniinnnTniiti
9
Polycythemia vera
B. Nonneoplastic hematologic diseases
221
Iron deficiency anemia
113
Megaloblastic anemia
39
Marrow hypoplasia
21
Hemolytic anemia
12
Thalassemia and sideroblastic
anemia
11
Idiopathic thrombocytopenic
purpura
25
C. Infectious and inflammatory
309
conditions
32
Fever of unknown origin
17
Viral infections
37
Bacterial infections
57
Cirrhosis
30
Granulomatous diseases
26
Collagen disorders
Nonspecific inflammatory
conditions
110
18
D. Diabetes mellitus
14
E. Cardiovascular diseases
107
F. Miscellaneous conditions
35
G. Plasma cell neoplasia
IOTAL
•IUOO
PLASMACYTOSIS
PLASMACYTIC SATELLITOSIS
MM
FIG. 1. Incidences of bone marrow plasmacytosis and plasmacytic satellitosis.
aspirates with and without reactive plasmacytosis. Clearly there were higher incidences of lymphoid follicles and lipid
granulomas in cases of reactive plasmacytosis.
The hemosiderin contents of the bone
marrow in aspirates with and without
plasmacytosis and in multiple myeloma are
shown in Table 3. A significant number of
aspirates with plasmacytosis also showed
slight to moderate hemosiderosis. Cases of
multiple myeloma showed a similar incidence of hemosiderosis. Aspirates without
plasmacytosis showed most commonly
either absent or decreased iron or a normal
amount of iron. Figure 3 illustrates their
graphic relationships.
In keeping with the secretory function of
plasma cells, a variety of cell forms was
found. Structures such as Russell bodies,
grape cells, thesaurocytes and intracellular
crystals were demonstrated. Binucleated
and multinucleated plasma cells were also
encountered. These are illustrated in
Figure 4, along with a typical example of
plasmacytic satellitosis.
924
HYUN,
A.J.C.P. —Vol. 65
ETAL.
Discussion
B cells, a major component of the immune system, are concerned with the
production of antibodies (immune globulins, immunoglobulins), in response to
appropriate antigenic stimulation. Plasma
cells are now widely accepted as the secretory form of B lymphocytes, differing
principally by the presence of abundant
protein-synthesizing equipment in the
cytoplasm. Patients who have the Bruton
form of inherited agammaglobulinemia
show an absence of plasma cells in their
tissues, in keeping with their inability to
form antibodies.
Plasmacytosis of the bone marrow occurs
often, and is considered to be a reflection
of systemic antigenic stimulation. 3 ' 5 ' 8,12 Our
series of consecutive bone marrow examinations, analyzed for plasma cell percentage and several other features, is sufficiently large to permit observation of
common trends in incidence and extent of
plasmacytosis in various clinical settings.
Diseases of infectious and inflammatory
nature were commonly accompanied by
plasmacytosis of the bone marrow. T h e
highest incidence and greatest extent were
found in cirrhosis, a chronic inflammatory
state with hypergammaglobulinemia in
which the sustained high level of exposure
to antigen has been ascribed to gutderived bacteria or, in certain cases, to autoantigens. Certain malignant diseases are
associated with plasmacytosis, perhaps as a
response to new surface antigens of the
I With Plasmacytosis
1 Without
Plasmacytosis
30%
20%
10%"
Lymphoid
follicles
Lymphoid
Follicles
Lipid
Granulomas
276 with
plasmacytosis
689 without
plasmacytosis
71(25.7%)
94(13.6%)
Lipid
granulomas 34(12.3%)
25(3.6%)
FIG. 2. Incidences of lymphoid follicles and lipid
granulomas in bone marrow aspirates with and without reactive plasmacytosis.
neoplastic cell clones. The association of
other diseases with plasmacytosis is interesting but more obscure, as in the cases of
diabetes mellitus and iron-deficiency
anemia, but may be related to complications of the underlying disease state.
Lymphoid follicles and lipid granulomas
in the bone marrows were simultaneously
searched for and recorded. They were
found more commonly in those marrows
with plasmacytosis. This correlation suggests that they are reactive phenomena to
similar
stimuli. Lymphoid follicles may be
Table 2. Incidences of Plasmacytic Satellitooccasionally
found in small numbers in
sis in Bone Marrows without and
normal
bone
marrows. 15 It is not known
with Plasmacytosis
whether they are composed of B cells or T
Aspirates with cells. The exact significance of lipid granuPercentage of
Number of
Plasmacytic
lomas has not been determined. 14
Plasmacytes
Aspirates
Satellitosis
Plasmacytic satellitosis has been deNormal, < !
689
69 (10%)
scribed under several names. 1 6 - 1 9 In 1950,
2-4%
239
111 (46.4%)
Undritz, 19 in a study of histiocytes (mono5-10%
37
17 (45.9%)
cytes), observed that they were frequently
June 1976
PLASMACYTIC LESIONS OF BONE MARROW
surrounded by plasma cells. He referred to
these groupings as plasmacytic islets. In the
1960's, Thiery 17,18 confirmed Undritz's observations on lymph node suspensions and
spleen by phase contrast and electron
microscopy, and postulated a functional
cooperation of these two cellular systems in
the immune response. He suggested that
the configuration reflected a physiologic
role, but did not analyze the incidence and
significance of this interesting phenomenon in clinical material. We have called this
finding "plasmacytic satellitosis" and have
defined it as a morphologic unit consisting
of a central histiocyte surrounded by three
or more plasma cells. It appears to be a
normally occurring entity and was found in
a small percentage of bone marrows without plasmacytosis. It was present in almost
half of those bone marrows with plasmacytosis, suggesting that its appearance is
attributable to a response to similar stimuli.
Extensive studies in recent years have
shown that macrophages play an important
role in humoral antibody formation. 2,10 ' 16
An initial step in the production of antibody involves the phagocytosis and degradation of antigen in macrophages. The
antigen processed by the macrophages or
an active fraction thereof, perhaps messenger RNA or an RNA-antigen complex,
when transferred to antibody-forming
cells, results in the production of antibody. 2 Schoenberg and associates16 demonstrated by electron microscopy direct cyto-
40*
925
•••••••Without plasmacytosis
— x — W i t h plasmacytosis
—<*— Multiple myeloma
*.._
"•••._
x-—____^
30V
a
\
A
20%-
•»••••
\
\
10%-
0
0
1'
V
2'
3'
Hemosiderin Content
4
Absent or decreased
2# Slight increase
Normal
3* Moderate increase
4* Marked increase
FIG. 3. Hemosiderin contents of bone marrows
with reactive plasmacytosis and multiple myeloma.
plasmic communications between macrophages and surrounding lymphocytes and
plasma cells in lymph nodes and splenic
tissue from immunized rabbits, and observed small particles of the size of ribosomes in these cytoplasmic "bridges."
Andre-Schwartz 1 studied the cellular
changes in the regional lymph nodes
following homografts in rabbits. By electron microscopy an extensive interdigitation between the cytoplasmic membranes
of both young and mature plasma cells
and adjacent "reticulum cells" was ob-
Table 3. Hemosiderin Content in Bone Marrow
276 Aspirates
with
Plasmacytosis
689 Aspirates
without
Plas macytosis
3 : Aspirates
Multiple
Myeloma
Fe Content
No.
%
No.
ft
No.
ft
Decreased or absent
Normal
Slight increase
Moderate increase
Marked increase
76
82
39
72
7
27.5
29.7
14.1
26.1
2.5
267
237
79
93
13
38.8
34.4
11.5
13.5
1.9
11
10
5
8
1
31.4
28.6
14.3
22.9
2.9
926
HYUN, ETAL.
A.J.C.P.—Vol.
65
FIG. 4. A (upper, left). Bone marrow film. Plasmacytic satellitosis. Six plasma cells surround a central
histiocyte, from a patient with chronic pelvic inflammatory disease. Wright-Giemsa. X 1,500.
B (upper, right). Bone marrow section. Plasmacytosis with three Russell bodies, from a patient with alcoholic
cirrhosis. Hematoxylin and eosin. X 1,500.
C (middle, left). Bone marrow film. Grape cell, a giant plasma cell filled with protein globules, from a patient
with anemia of chronic renal failure. Wright-Giemsa. x 1,500.
D (middle, right). Bone marrow film. Thesaurocyte, a large plasma cell with finely vacuolated cytoplasm, from
a patient with iron-deficiency anemia associated with carcinoma of the colon. Wright-Giemsa. x 1,500.
E (lower, left). Bone marrow film. Intracellular crystal in a plasma cell, from a patient with iron-deficiency
anemia, without bone marrow plasmacytosis. Wright-Giemsa. x 1,500.
F (lower, right). Bone marrow film. A multinucleated plasma cell, from a patient with bronchopneumonia
and refractory anemia. Wright-Giemsa. x 1,500.
June 1976
PLASMACYTIC LESIONS OF BONE MARROW
927
served, a picture of active pinocytosis. The cyte surrounded by three or more plasma
appearance of plasma cells was a distinct cells, appears to be a normally occurring
entity, and was seen in 10% of our bone
feature of the second-set reaction.
On the basis of these considerations, we marrows without plasmacytosis. Its incisuggest that plasmacytic satellitosis repre- dence increased to 46.4% in those marrows
sents the morphologic manifestation of with plasmacytosis, suggesting that it reantigen processing by the macrophage and flects a reaction to similar stimuli. We have
transfer of information required for anti- not observed this phenomenon in any of
body production to the effector cells, the our 35 cases of plasmacytic neoplasia.
plasma cells. It is interesting that satellitosis Plasmacytic satellitosis may represent a
by lymphocytes was a rare finding in our stage in antigen handling; the configuraexperience, although theoretically this tion raises speculation that information or
might be expected to occur commonly. Per- coding destined for antibody production is
haps plasmacytic satellitosis represents the being transferred from the histiocyte to
anamnestic response of sensitized B cells, the plasma cells.
although no direct evidence is available to
In keeping with the secretory function of
clarify this point.
plasma cells, a variety of cell forms is found.
We did not observe plasmacytic satellito- Structures such as Russell bodies, grape
sis in any of the 35 cases of plasmacytic cells, thesaurocytes and intracellular crysneoplasia encountered in this series of bone tals are illustrated.
marrow examinations, and this negative
feature may prove to be a differential
Note: Fifteen additional cases of multiple myeloma
point of some usefulness. This failure of were reviewed following completion of this study.
Plasmacytic satellitosis was found in one case.
physiologic responsiveness may correlate
with the fact that patients with multiple
myeloma have impairment of antibody
Acknowledgments: Dr. Joon Seuck Lee helped in the
production 9 (apart from the monoclonal accumulation of data.
immunoglobulin) with resulting increased
susceptibility to infection.
References
Conclusions
Plasmacytosis, defined as 2% plasma cells
or more in the differential count, occurred
in 28.6% of a series of 1,000 bone marrow
aspirates, apart from 35 cases of multiple
myeloma. This finding was particularly
common in association with inflammatory
and infectious diseases, diabetes mellitus,
epithelial malignancies, Hodgkin's disease,
and iron-deficiency anemia. T h e highest
incidence was in cirrhosis.
Bone marrows with plasmacytosis
showed increased lymphoid follicles and
lipid granulomas more commonly than did
marrows without plasmacytosis. These
findings are probably reactive phenomena
in a general sense.
Plasmacytic satellitosis, defined as a morphologic unit consisting of a central histio-
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