PLASMACYTOSIS
OF
BONE
MARROW
AND
HYPERGAMMA-GLOBULINEMIA
IN
ACUTE
LEUKEMIA
A Case
Report
By Gunnar B. Stickler, M.D., Ph.D., and Donald Pinkel, M.D.
Department of Pediatrics, Roswell Park Memorial Institute, Buffalo, New York
(Accepted April 7, 1958; submitted March 24.)
PRESENT ADDRESS: (G.B.S.) Section of Pediatrics, Mayo Clinic, Rochester, Minnesota.
PEDIATRICS, October 1958
P
LASMACYTOSIS of the ‘bone marrow wasobserved by Mielke’ in 11 of 120
pa-tients suffering from acute myeloblastic
leukemia. He found in these cases that 3.3
to 5% of all nucleated cells were plasma
cells. In one patient, in whom 3.6% of the
cells in the bone marrow were plasma cells,
the concentration of gamma-globulin in the
blood was increased to 4.09 gm/100 ml.
In two other patients with plasmacytosis,
only globulin was determined, and the
concentration was found to be increased to
5.21 and 4.67 gm/100 ml, respectively.
Hypogammaglobulinemia, however, is
observed more frequently in acute
leu-kemia. Wall and coworkers2 found a
de-crease in concentration of gamma-globulin
of 30% or more in 12 of 78 patients with
acute leukemia. They recorded no instances
of hypergammaglobulinemia.
The present observations concern the
de-velopment and disappearance of severe
hypergammaglobulinemia and
plasmacyto-sis during the course of acute leukemia in one patient. Plasmacytosis and
hypergam-maglobulinemia showed a high degree of
correlation.
History
CASE REPORT
A 12-year-old girl was referred to Roswell
Park Memorial Institute in March, 1957,
be-cause of acute leukemia. In February she had
begun to tire easily and in early March, fever
and cough developed. She was thought to have pneumonia and was treated with sulfonamides, penicillin, and chloramphenicol. However,
fever continued and in late March the left leg
became tender and some swelling of the left
thigh was noticed. She was hospitalized
else-where and the diagnosis of acute leukemia
was made. She received a blood transfusion and was transferred to the Institute.
Previous illnesses included chickenpox,
Ger-man measles, whooping cough, and, at age 5
years, pneumonia. Gestation, delivery, and the
development were normal; the mother had a
routine roentgenogram of the chest during the
fifth month of pregnancy. The family history
was noncontributory.
Physical Findings
Examination disclosed a well-developed,
well-nourished 12-year-old girl who appeared
acutely ill. She was pale and listless and
un-able to walk because of pain in the left thigh.
Temperature was 38.3#{176}Cand the left thigh was
swollen and tender. No organomegaly or
sig-nificant adenopathy was detected.
Laboratory Findings
The concentration of hemoglobin was 10.3
gm/100 ml, the leukocytes numbered 30,600/
mm3 with 83% blastic cells, 3% stab cells, 4%
segmented neutrophils and 10% lymphocytes.
The platelet count was 327,500/mm3 and
reticulocyte count was 5.6%. Urinalysis gave
negative results and the values for nonprotein
nitrogen and uric acid in the blood were within
the range of normal. Roentgenograms of the
chest and the skeleton disclosed no
abnormali-ties.
On aspiration of bone marrow, 95% of the
nucleated cells in the smear were myeloblasts
and many of them contained Auer bodies. The
diagnosis of acute myeloblastic leukemia was made. Treatment was begun with 6-mercapto..
purine in a dose of 100 mg/day. S
The important clinical and laboratory
find-ings during the patient’s illness are shown in
Figure 1. Electrophoretic analysis was done
with the Spinco apparatus according to the
‘F
Temperature
Blastic cells in bone marrow
Cellularity N- Normal
M-Moderately decreased
Plasma cells in bane marrow
E
\
E Tetracycline #{149} Chloramphenicol
Novobiacin #{149} Penicillin
100
Days
Fic. 1.Clinical and laboratory data during course of illness.
150 200
done by one of us (D.P.) by counting 2,000
nucleated cells in the bone marrow.
Course in Hospital
Pain and swelling of the left thigh subsided,
but on the fourteenth day of antimetabolite
therapy, pharyngitis developed with a
reduc-tion of leukocytes to 8,950/mm’, only 1% of
which were neutrophils, and reduction of the platelets to 67,500/mm’. Staphylococcus
aureus (coagulase positive) and Aerobacter
aerogenes (Bacillus aerogenes) were grown on
throat culture. On the fifteenth day of
treat-ment at the Institute, the dose of
6-mercapto-purine was decreased to 50 mg daily. Use of
tetracycline having been discontinued,
chlor-amphenicol therapy was started on the same
day. On the seventeenth day, the pharyngilis
was more severe, and temperature reached
40.6#{176}C.Administration of crystalline penicillin
C, 20,000,000 units daily, was started by
con-tinuous intravenous drip. By the twenty-third
day signs of infection had subsided and
intra-venous administration of penicillin was
dis-continued.
By the twenty-seventh day, the leukocyte
count had fallen to 1,850/mm’, and no
neutro-phils were apparent on smear. A sample of
bone marrow revealed evidence of hypoplasia,
although 90% of the nucleated cells were
myelo-blasts. Treatment with 6-mercaptopurine was discontinued. On the same day the pharynx
again became severely inflamed, and a septic
temperature curve developed. Throat culture
revealed Staphylococcus aureus (coagulase
positive). Penicillin V, 0.75 gm daily, was
given orally, and transfusions of fresh blood
were administered because of decreasing
con-centration of hemoglobin and number of
platelets. On the twenty-ninth day, a
general-ized, discrete, fine papulovesicular eruption of
the skin developed, and the next day petechiae
appeared on the legs. Severe necrotic tonsillitis
and cervical adenitis ensued. On the
thrty-fourth day she began to vomit, and 2 days
31
‘41
4
4
E
Fic. 2. Bonc marrow showing marked plasinacvtosis.
Staphylococcus aureus (coagulase positive). This organism was sensitive to the penicillin and novobiocin in combination. Intravenous administration of 20,000,000 units of penicillin
G daily was restarted with 1 gm of novobiocin daily by mouth, and 1.5 gm of streptomycin daily by injection. Treatment with chloram-phenicol was d:scontinued. The skin eruption cleared, vomiting ceased, fever subsided, and the pharynx and tonsils gradually cleared. On the forty-fourth day, a sample of bone marrow again showed evidence of hypoplasia but also revealed an abundance of plasma cells and rnan- myeloblasts. On the forty-seventh day of treatment, the temperature rose to 39.7#{176}C, and a generalized, confluent, erythematous skin eruption developed, accompanied by circum-oral pallor, a deep red color to the tongue, and scattered petechiae; the eruption had some similarity to the exanthem of scarlet fever. Intravenous administration of penicillin was discontinued, and by the forty-ninth day the
temperature became normal and remained so
thereafter.
A sample of bone marrow on the fifty-first
day revealed that plasma cells were the
pre-dominant cell type (24.4%); there were fewer
myeloblasts and, for the first time, evidence
of erythropoiesis (Fig. 2). Myeloblasts
disap-peared from the peripheral blood, and
eleva-lion of platelets to safe levels and stabilizing of the concentration of hemoglobin occurred. The patient was dismissed from the hospital on
the fifty-sixth day, at which time the skin
erup-tion had disappeared.
Subsequent Course
During the 6 months after dismissal she has been under observation in the clinic and, ex-cept for one episode of sore throat and fever
which responded readily to treatment with
chloramphenicol, she has been asymptomatic
and has enjoyed normal activity and gained in
weight.
In samples of bone marrow, less than 30%
of the cells were myeloblasts, and the
per-centage of plasma cells has steadily decreased.
Good Ftematopoietic activity has been present
and has been reflected by normal findings iii
the peripheral blood. Occasional myeloblasts
are still seen on blood smears, however.
Treatment with 50 mg of 6-mercaptopurine daily was resumed on the seventy-eighth day
after it was first administered. On the one
hundred twentieth day, while she was beset by
Platelet counts fell to low levels and a
speci-men of bone marrow was hypocellular. Ad-ministration of the antimetabolite, therefore,
was discontinued 2 days later. On the one
hundred thirty-fourth day, these cellular
ele-ments were normal, and a sample of marrow
was normocellular, so that administration of
50 mg of 6-mercaptopurine daily was resumed
on that day and has been continued since.
Studies of Serum Proteins
Electrophoretic patterns of serum proteins
were determined at weekly intervals from the
time of admission to this institution. The
gamma-globulin fraction rose rapidly during
the severe infection and the toxic ervthema
fol-lowing it, reaching the high point of 4.86 gm/
100 ml on the fifty-sixth day. Analysis of the
serum proteins at that time by the
ultracentri-fuge technic showed the sedimentation constant
of the gamma-globulin (S20) to be 7.1 (normal:
6.4 ± 0.7). The concentrations of albumin in
the serum were initially low (2.0 gm/100 ml)
whereas those for alpha-globulin were
ele-vated (1.1 gm/100 ml). Normal concentrations
of these elements were obtained with
hematol-ogic improvement. The other protein fractions
in the serum have remained within normal
lim-its throughout the period of observation. Re-peated tests for cryoglobulins remained
nega-tive.
COMMENT
It is difficult to determine the exact cause
of the rise in number of plasma cells in the
bone marrow and hypergammaglobulinemia
in the course of this patient’s illness. The
appearance of an exanthem may ‘be
indica-tive that the patient suffered from
hyper-sensitivity to penicillin, which was given
in high doses. However, novobiocin also
may cause erythematous eruptions.
Two cases of severe drug reactions in
which hyperglobulinemia and
plasmacyto-sis occurred were described by Robertson.3
Another case supposedly due to
hyper-sensitivity was reported by Paris and
Bakke.4 The patient was suffering from
severe depression of the bone marrow and
had staphylococcal septicemia. Both of
these conditions occurred in the case
re-ported here. The fact that plasmacytosis of
the bone marrow may occur in
agranulo-cytosis has been described by a number of
authors. Similarly, transient plasmacytosis
and hyperglobulinemia have been found in
a case of acute infection, and in
trichino-sis which was terminally complicated by
staphylococcal sepsis.9 Finally,
plasmacyto-sis and hypergammaglobulinemia may
oc-cur in the course of leukemia, as Mielke1 has
pointed out. The transient plasmacytosis and
hypergammaglobulinemia in the case
re-ported here may have been due to the
pri-mary disease process, the occurrence of
marked depression of bone marrow activity,
the severe staphylococcal infection,
hyper-sensitivity to a drug, or to any combination
of these factors. The time relationship of the
administration of penicillin, the appearance
of the rash, and the plasmacytosis, as well
as the type of exanthem observed, supports
the hypothesis that this phenomenon is best
explained on the basis of hypersensitivity
to a drug. It is doubtful that it was caused
by the depression of the bone marrow, since
the agranulocytosis continued far beyond
the period during which plasmacytosis and
hypergammaglobulinemia were present.
Paris and Bakke4 have reviewed the
ex-tensive literature regarding the highly
posi-tive correlation of plasmacytosis of the bone
marrow and hyperglobulinemia in infection,
hypersensitivity reactions, portal cirrhosis,
and rheumatic fever; this correlation
sup-ports the assumption that globulin is
pro-duced by plasma cells. Only Berlin and
co-workersbo were unable to find this correla-tion in 33 patients with rheumatoid arthri-tis, cirrhosis, or chronic infections who had
elevated concentrations of globulin in the
serum. In most publications, only the total
globulin was determined by Howe’s
method, and the gamma-globulin was not.
Only Good and Campbell1’ found a positive
correlation between the degree of
plasma-cytosis in the bone marrow and
hyper-gammaglobulinemia in patients with
rheu-matic fever. In their series, gamma-globulin
was determined by the zinc sulfate
precipi-tati()n method of Kunkel, which may be
somewhat less accurate than
663
Of greatest importance was the
observa-tion of Good and 13 of a marked
de-ficiency of plasma cells in the bone marrow
of eight patients with so-called
agamma-globulinemia. The considerable evidence
from experimental work that antibodies are
formed by the plasma cells was reviewed
by Good and Zak13,14 as well as by Paris
and Bakke. It is also widely accepted that
most antibodies have the electrophoretic
mobility of gamma-globulin.
An observation of interest in the present
study was the correlation between plasma
cell percentages in the bone marrow and
gamma-globulin values in the serum in a
longitudinal study of one patient and not
in a series of patients who had, during
ill-ness, one examination of bone marrow and
one determination of globulin or
gamma-globulin. Also interesting was the lag of
10 or 11 days between the heights of
plas-macytosis and values of gamma-globulin.
The decreases in plasma cell counts also
seemed to anticipate the decreases in levels
of gamma-globulin by such a time interval,
and this might be related to the half-life of
gamma-globulin.
SUMMARY
Transient extreme plasmacytosis of the
bone marrow and hypergammaglobulinemia
were observed in a patient suffering from
acute leukemia. A high degree of
correla-tion was found between these two
phe-nomena. Evidence is cited from the
litera-ture supporting the thesis of a causal
rela-tionship. The reason for plasmacytosis
as-sociated with hypergainmaglobulinemia
re-mains obscure but may have been the
mani-festation of a reaction to penicillin.
REFERENCES
1. Mielke, H. C.: trber das Verhalten der
Plasmazellen im Blutbild und
Knochen-mark bel akuter myeloischer Leukamie.
Blut, 3:27, 1957.
2. Wall, R. L., Sun, L., and Picklow, F. E.: Serum proteins in diseases of the
reti-culoendothelial system: the significance
of hypogammaglobulinemia. Res. Bull.,
2:50, 1956.
3. Robertson, T.: Plasmacytosis and
hyper-globulinenua as manifestation of
hyper-sensitivity: postmortem study of 2 cases
with hypersensitivity probably due to
sulfadiazine. Am. J. Med., 9:315, 1950.
4. Paris, L., and Bakke, J. R. : Agranulocytosis with reactive bone marrow plasmacytosis.
Am.
J.
Clin. Path., 26:1044, 1956.5. Custer, R. P. : Studies on the structure and
function of bone marrow: bone marrow
in agranulocytosis. Am. J. M. Sc., 189:
507, 1935.
6. Darling, R. C., Parker, F., and Jackson, H.:
The pathological changes in the bone
marrow in agranulocytosis. Am. J. Path.,
12:1, 1936.
7. Clark, H., and Muirhead, E. E. : Plasmacy-tosis of bone marrow. Arch. Int. Med.,
94:425, 1954.
8. Goulding, A.
J.,
Rowen, M. J., and Meyer,L. M. : Transient hyperglobulinemia and
plasmacytosis of bone marrow during
an acute infection. Am. J. Clin. Path.,
20:779, 1950.
9. Carter, J. R. : Plasma cell hyperplasia and
hyperglobulinemia in trichinosis. Am. J.
Path., 25:309, 1949.
10. Berlin, I., Wallace, St. L., and Meyer,
L. M. : Studies on bone marrow in
hy-perglobulinemia. Arch.
mt.
Med., 85:144, 1950.
11. Good, R. A., and Campbell, B. :
Relation-ship of bone marrow plasmacvtosis to changes in serum gamma-globulin in
rheumatic fever. Am. J. Med., 9:330,
1950.
12. Good, R. A. : Studies on
agammaglobu-linemia: failure of plasma cell formation
in the bone marrow and lymph nodes
of patients with agammaglobulinemia.
J. Lab. & Clin. Med., 46:167, 1955.
13. Good, R. A., and Zak, S.
J.
: Disturbancesin gamma-globulin synthesis as
“experi-ments of nature.” PEDIATRICS, 18:109,
1956.
14. Good, R. A. : Morphological basis of the
immune response and hypersensitivity,
in Felton, H. M., ed. : Host-parasite
Re-lationships in Living Cells. Springfield,
Thomas, 1957, pp. 78-160.
SUMMARIO IN INTERLINGUA
Plasmacytose
Del
Medulla
Ossee
E
Hypergammaglobulinemja
In
Leucemia
Acute
Plasmacytose e hypergammaglobulinemia ha
previemente esite observate per Mielke in
casos de leucemia acute. Nos observava Ic
de etate qui suffreva de leucemia acute. Post
que le diagnose de acute leucemia myeloblastic
esseva establite, le patiente esseva tractate con 6-mercaptopurina. Vinti-sex dies post le
initia-tion de iste tractamento, sever agranulocvtose e acute tonsillitis causate per Staphylococcus
aureus (positive a coagulase) se disveloppava.
Le puera esseva tractate con doses massive de
antibioticos, e 3 dies plus tarde un generalisate,
discrete, e fin eruption papulovesicular del pelle
insimul con petechias se disveloppava in su
gambas. Iste phenomeno se clarificava
gradual-mente, sed 14 dies post le apparition del
erup-tion cutanee, le patiente comenciava haber marcate grados de plasmacytose del medulla
ossee e signos de hvpergammaglobulinemia. Le
concentration maximal de globulina gamma in
le sero esseva 4,86 g per 100 ml. Plasmacytose
e hypergammaglobulinemia monstrava un alte
grado de correlation con un retardo de tempore
de circa 10 dies. Datos citate ab le litteratura
supporta le these de un relation causal inter le
duo. Le ration del occurrentia de plasmacvtose
con hyperglobulinemia remane obscur, sed il
es possibile que il se tracta de un manifestation de sensibilitate a penicillina.
DIAGNOSTIC VALUE OF SERUM-TRANSAMINASE ACTIVITY IN HEPATIC AND
GASTRO-INTESTINAL DIsEAsEs,
J.
Pryse-Davies et al. (Lancet, 1 : 1249, June 14, 1958.)Glutamic-oxaloacetic transaminase is increased in the serum following damage to
either liver or muscle cells. Glutamic-pyruvic transaminase is found in relatively
high concentration in the liver. In this investigation of an assortment of liver and gastrointestinal diseases, it was found that both enzymes became elevated following
damage to liver cells. Damage to muscle cells alone, as in myocardial infarction, did not produce a significant elevation of glutamic-pyruvic transaminase. Thus the simul-taneous determinations of glutamic-oxaloacetic transaminase and glutamic-pyruvic
transaminase may be of value in differentiation between diseases with damage to liver
cells and diseases causing necrosis of muscle.
PLASMA-TRANSAMINASE ACTIVITY AS AN INDEX OF THE EFFECTIVENESS OF CORTISONE
IN CiusoNlc HEPATITIS, E. N. O’Brien at al. ( Lancet, 1 :1245, June 14, 1958.)
The use of cortisone in the treatment of active hepatitis has been advocated without
logical reasons. Evaluations of the clinical results have been equivocal. In the present
paper, the effect of cortisone therapy on the activity of glutamic-oxaloacetic
trans-aminase in the plasma was observed in 10 cases. The level of this enzyme in the plasma
reflects the degree of damage in liver cells. Within 48 hours after the administration
of cortisone, the activity of the enzyme in the plasma decreased markedly in five
patients who were suffering from what was presumed to be active infectious hepatitis. Cortisone had little or no effect in the remaining five patients, in whom various causes
other than infectious hepatitis were responsible for the liver disease. The index of the
effect of cortisone may prove useful for more critical evaluation of the place of
