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Multiple Myeloma
in
a
Child
SHELLY
C.
BERNSTEIN, MD, PHD, ANTONIO
R.
PEREZ-ATAYDE, MD, AND HOWARD J. WEINSTEIN,
MD
A 12-year-old
girl
with the
diagaosi
of multiple myeloma is described. She presented with
a
nasopharyngeal
mass which was histologically found to
be
a
plrsmacytoma. Serum immunoelectrophoresis revealed
an
IgA-kappa M-protein
(4.9
g/dl). There were approximately 20% atypical plasma
cells
in
a
bone marrow
biopsy specimen. The diagnosis
was
further supported by immunohistochemical demonstration of
cyto-
plasmic monoclonal IgA-kappa in the tumor
cells
of both the nasopharyngeal and
bone
marrow biopsies.
The patient was treated with chemotherapy for
1
year, at which time she became refractory to treatment,
based on serum
IgA
levels. Five months after cessation of therapy, she continues to exhibit
a
significant
objective response, remaining clinically well with
a
stable,
elevated serum
IgA
level.
Cancer
56:2 143-2 147, 1985.
ULTIPLE
MYELOMA
(plasma
cell
myeloma) is the
M
most common
form
of plasma cell neoplasm. The
incidence
of
myeloma increases progressively with age; it
is extremely rare in the pediatric age group. While a num-
ber
of
cases
have been reported that lacked convincing
evidence for the diagnosis,'" only
two
reports
of
well-
documented patients with myeloma have been described
younger than age
30
years.'**
This report describes a 12-year-old girl
with
the diag-
nosis
of
multiple myeloma, based on the presence
of
a
nasopharyngeal plasmacytoma on tissue biopsy, bone
marrow
plasmacytosis
of
2096,
and IgA-kappa monoclonal
immunoglobulin in the cytoplasm
of
the tumor cells and
in the patient's serum (4.9 g/dl).
Case
Report
A
12-year-old Chinese
girl
complained of inability to breathe
through her nose and stuffiness of her
ears
for
I
month. There
was no response to decongestants and antibiotics and she was
referred to an otolaryngologist, who noted
a
mass in the
posterior
pharynx. She was otherwise completely asymptomatic, without
weakness, fatigue, or bone pain.
No
other abnormalities were
noted on exam.
Routine histologic sections of the biopsied mass revealed a
diffuse, monotonous infiltration of immature plasma
cells
(Fig.
From the Division of Pediatric Hematology and Oncology, Dana-
Farber
Cancer
Institute and The Children's Hospital, and the Department
of
Pediatrics, Harvard Medical School, Boston, Massachusetts.
Address for reprints: Shelly
C.
Eemstein,
MD,
PhD, Dana-Farber
Cancer Institute, Room
1842.44
Binney Stnet, Boston,
MA
021
15.
The authors thank Donald L. Gantz and Elizabeth Beaumont
for
technical assistance in electron microscopy
and
Ruth
Trow
Coughlin
for
her excellent work in the preparation
of
the manuscript.
Accepted for publication December
4,
1984.
I).
Initial laboratory data showed
a
hemoglobin of 12.9
g/dl.
Serum viscosity was 2.5 (normal,
1.5-1.9).
Serum calcium, blood
urea nitrogen (BUN), albumin, uric acid, and creatinine
clear-
ance were normal. lmmunoelectrophoresis showed an IgA-kappa
M-protein to be present, with quantitative immunoglobulin lev-
els for
IgA
of
4900
mg/dl (normal, 60-290 mg/dl), for
IgG
of
6
10
mudl (normal, 600-
I500
mg/dl), and for
IgM
of
20
rng/dl
(normal, 50-200 mg/dl). There was
no
evidence
of
Bence Jones
protein
on
electrophoresis of the urine. Skeletal survey did not
reveal any lytic bone lesions or other abnormalities.
A
posterior
iliac bone marrow aspirate contained
20%
plasma cells, with
dysplastic nuclei, some binucleate, and
1
%
to 2% plasmablasts.
Biopsy study
of
the marrow indicated some
of
the
cells
to
be
arranged in small and large clusters. Chromosome analysis of
the bone marrow showed no abnormalities. Immunohisto-
chemical studies
of
the nasopharyngeal tumor and bone marrow
biopsy specimen were performed on buffered formalin-fixed,
paraffin-embedded tissue using the avidin-biotin complex tech-
nique (Vectastain
ABC
Kit,
Vector
Laboratories, Burlingame,
CA). Tumor
cells
were strongly positive
for
IgA
and kappa light
chain, and negative for
I&,
lgM, and lambda (Figs. 2A, 2B,
and
3).
By ultrastructure, tumor
cells
had features of immature plasma
cells
in different stages of differentiation.
A
few tumor
cells
had
large irregular nuclei with abundant euchromatin, and scant
cy-
toplasm containing numerous free ribosomes, few mitochondria,
and few cisternae of
rough
endoplasmic reticulum. The majority
of tumor cells, however, displayed more differentiation with a
well developed
rough
endoplasmic reticulum with frequent con-
centric arrangement (Fig.
4).
The nuclei in these
cells
resembled
those
of
normal plasma
cells
but with larger nucleoli,
less
abun-
dant heterochromatin, and increased nuclear/cytoplasmic ratio.
The patient
was
initially
treated
with one
course
of vincristine,
1.5
mg/m2,
2
mg maximum dose, Adriamycin (doxorubicin),
75
mg/m2, and prednisone,
40
mg/rn2 daily for 21 days, for a
nasopharyngeal non-Hodgkin's lymphoma. After
3
weeks
the
2143
2144
CANCER
October
15
1985
Vol.
56
diagnosis of multiple myeloma was made, and her treatment
was then changed to the
M-2
proto~ol.~ consisting of vincristine.
0.03
mg/kg,
2
mg
maximum dose; BCNU,
0.05
mg/kg;
cyclo-
phosphamide,
10
mg/kg;
melphalan,
0.25
rng/kg daily
for
4
days:
and prednisone,
I
mg/kg daily
for
28
days during the first
cycle
and
for
I4
days during subsequent cycles. Chemotherapy was
administered at 5-week intervals, with minimal side effects.
Dosages of cyclophosphamide and melphalan were increased
until mild myelosuppression was evident.
After
I
year of treatment. the patient's serum
IgA
level reached
a nadir of
984
mg/dl. Subsequent
IgA
levels gradually
rose
to
a
maximum of
2707
mg/dl
5
months later, at which time che-
motherapy was electively discontinued. She remained clinically
well at the time. Over the next
5
months, her
IgA
remained
stable between
1978
and
2206
mg/dl
without further treatment.
The patient continues
to
exhibit
a
significant objective response
with decrease
of
her presenting serum
IgA
by greater than
50%
complete absence
of
plasmacytoma
by
CT
scan, maintenance
of normal hemoglobin,
serum
albumin and serum calcium levels,
and lack
of
bone pain
or
bony lesions.
Discussion
Multiple myeloma accounts for about
1%
of all types
of malignant disease and slightly more than
10%
of
he-
matologic malignancies. The primary abnormality is a
progressive and uncontrolled proliferation of immature
and mature plasma cells in the bone marrow. This pop-
ulation
of
cells is believed to
be
monoclonal with a ho-
mogeneous production
of
immunoglobulin composed of
FIG.
I.
Light microscopic overview
of
nasopharyngeal plasmacytoma showing
diffuse infiltration by a monotonous popu-
lation
of
small
cells.
Respiratory epithelium
(arrow) is preserved and is surrounded by
small residual lymphocytes
(*)
and tumor
cells
(H
&
E,
X130)
Inset:
At
higher mag-
nification tumor
cells
have the character-
istics
of
immature plasma cells
(H
&
E,
XSOO).
a single class
of
heavy chain and one type of light chain,
often referred to as an M-protein.
The incidence of myeloma increases progressively with
age, with the highest rates being observed in men older
than age
80
years, and in women older than age
70
years.
The mean age at diagnosis has been reported at 62 to
64
years in several large Less than
1%
to 2%
of
patients are younger than
40
years of age at diagnosis.'
This report presents the case of a 12-year-old Chinese
girl with multiple myeloma. Few well-documented pa-
tients with multiple myeloma have been previously de-
scribed younger than age 30 years. One report describes
a 13-year-old girl with breast tumors,
IgA
monoclonal
gammopathy, and extensive bone marrow plasmacyt~sis.~
Another report documents three young men, aged
I7
to
22 years, with plasmacytomas and multiple lytic bone
lesions;' two of the three had an M-protein. Bone marrow
examination of all three revealed
5%
morphologically
normal plasma cells. In our patient, the diagnosis
of
mul-
tiple myeloma was established on the basis of marrow
plasmacytosis associated with a high magnitude mono-
clonal immunoglobulin spike and an extramedullary
plasmacytoma, as well
as
immunohistochemical evidence
of cytoplasmic monoclonal IgA-kappa in the tumor cells
of the nasopharyngeal mass and bone marrow. The ab-
sence
of
lytic bone lesions
does
not exclude the diagnosis
of multiple myeloma. As many as
21%
of patients with
myeloma have negative roentgenographic findings.
'*
Our
No.
8
MULTIPLE MYELOMA
IN
A
CHILD
Bernstein ef
a/.
2145
FIGS.
2A
AND
28.
(A,
top) Immunoperoxi-
dase studies of nasopharyngeal plasmacytoma
reveals strongly positive staining for kappa light
chain in the cytoplasm
of
tumor cells. Residual
lymphocytes
(*)
show only few positive cells
(X
130).
her:
At
higher magnification the cy-
toplasmic staining is better seen
(XSOO).
Iden-
tical results were obtained for
IgA
(not shown
here).
(B,
bottom) Identical area of tumor
seen
in Fig.
2A,
now stained
for
I@,
is shown here
for comparison. Notice negative staining of tu-
mor cells. Residual lymphocytes
(*)
show
some
positive cells
(X130).
her:
At higher
magni-
fication the absence
of
cytoplasmic
lgG
is
better
observed
(XSOO).
Negative results were
also
ob
tained for
IgM
and lambda light chain (not
shown here) (Hematoxylin used
as
counter-
stain).
patient was classified
as
Stage
11,
indicating an interme-
diate tumor cell mass, by the criteria of Dune and
Salmon.
l3
While
our
patient's illness fulfills the criteria for the
diagnosis of multiple myeloma, it also closely resembles
extramedullary plasmacytoma with subclinical dissemi-
nati~n.'~,'~ Extramedullary plasmacytoma most com-
monly occurs in the upper respiratory tract and
oral
cavity
(82%
of recently published cases"). Of
272
cases
reported,
9
were diagnosed before the age of
20
years,
32
were
be-
tween
2
1
and
40
years, and the majority of patients were
5
I
to
70
years of age.I4
Extramedullary plasmacytoma differs from solitary
plasmacytoma of bone and from multiple myeloma in
FIG.
3.
lmmunoperoxidase study of
the
bone
marrow biopsy shows strongly positive staining
for lgA in a large clusta of tumor
cells.
Staining
for kappa light chain gave identical results (not
shown) (Hematoxylin
used
as
counterstain,
XS00).
FIG.
4.
By electron microscopy, tumor cells have features of immature plasma cells
with
large irregular nuclei containing thin heterochromatic
rim and prominent nucleoli. The cytoplasm has numerous rough endoplasmic reticulum cisternae containing amorphous proteinaceous material.
A
collapsed capillary is
also
present
(C)
(Uranyl acetate and
lead
citrate,
X5300).
NO.
a
MULTIPLE
MYELOMA
IN
A
CHILD
-
Bernstein et
al.
2147
terms of clinical features, pattern
of
spread, and survival.
Subsequent dissemination of extramedullary plasmacy-
toma in the form of typical multiple myeloma occurs
rarely.14 We cannot determine whether our patient’s dis-
ease arose within the bone marrow
or
if the marrow in-
volvement was a final phase in the natural history
of
ex-
tramedullary plasmacytoma. However, it is clear that ex-
tramedullary plasmacytoma gives
rise
to a different
disseminated picture of multiple metastatic lesions to soft
tissue sites and to bones, usually without diffuse bone
marrow inv01vement.l~ Therefore, we prefer to designate
our patient as a case
of
multiple myeloma.
Because
of
our patient’s high M-protein and marrow
involvement, it was decided to treat her with chemother-
apy in an effort to control both
local
and systemic disease.
Although the patient became refractory
to
treatment with
the
M-2
protocol after
1
year, as manifested by a
rise
in
her serum
IgA,
she continues to exhibit a significant
ob-
jective response, with a stable elevation of
IgA
of
less than
50%
of her presenting
IgA
level and remaining clinically
well. Long-term survival among patients with multiple
myeloma is uncommon. Kyle reports that the major dif-
ference between the long-term survivors and the larger
group is response to therapy.I6 In addition, long-term sur-
vivors had a younger median age and a lower incidence
of renal insufficiency and hypercalcemia. Because
of
the
continued elevation of
our
patient’s serum
IgA
level, it
is
difficult to predict the expected length of remission, in
spite
of
her relatively favorable prognostic factors, espe-
cially her young age.
ADDENDUM
One
year
after the cessation of therapy, the patient developed a re-
currence of her nasopharyngeal plasmacytoma. This was treated with
local radiation. Her serum
IgA
has increased
to
5
102
mg/dl. She remains
clinically well without lytic bone lesions and without clinical evidence
of bone marrow replacement.
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Waldenstrom
J.
Diagnosis and Treatment of Multiple Myeloma.
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Multiple myeloma in a child.
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