Multiple myeloma associated with diffuse osteosclerotic bone lesions: A clinical entity distinct...
Transcript of Multiple myeloma associated with diffuse osteosclerotic bone lesions: A clinical entity distinct...
Multiple Myeloma Associated With DiffuseOsteosclerotic Bone Lesions: A Clinical Entity Distinct
From Osteosclerotic Myeloma (POEMS Syndrome)
Martha Q. Lacy, 1* Morie A. Gertz, 1 Curtis A. Hanson, 2 David J. Inwards, 1 and Robert A. Kyle 1
1Division of Hematology and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota2Division of Hematopathology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota
Multiple myeloma usually is characterized by the development of lytic bone lesions.Osteosclerotic myeloma is a rare entity characterized by a single or multiple osteoscle-rotic bone lesions and often accompanied by a demyelinating polyneuropathy. Multiplemyeloma associated with widespread osteosclerotic lesions seen on radiographic stud-ies is exceedingly rare. We describe 3 such cases and review 12 other cases describedin the literature. Overall, the patients described herein had a clinical course that re-sembled multiple myeloma more than osteosclerotic myeloma. However, some patientshad features of both diseases. Although rare, multiple myeloma should be included in thedifferential diagnosis of widespread osteosclerotic bone lesions. Am. J. Hematol. 56:288–293, 1997. © 1997 Wiley-Liss, Inc.
Key words: case history; differential diagnosis; gammopathy; monoclonal protein
INTRODUCTION
Development of lytic bone lesions is a major clinicalfeature that distinguishes monoclonal gammopathy ofundetermined significance from multiple myeloma.Typically, the lesions are discrete and purely lytic. Os-teosclerotic myeloma is a rare but well-defined entitycharacterized by a demyelinating polyneuropathy asso-ciated with a single or multiple sclerotic bone lesions.The bone lesions are often modest in size and usuallyinvolve the axial skeleton [1]. POEMS syndrome (poly-neuropathy, organomegaly, endocrinopathy, monoclonalgammopathy, and skin changes) is associated with os-teosclerotic bone lesions in a majority of cases [2]. Re-cent authors find the differentiation of POEMS syndromefrom osteosclerotic myeloma to have no clinical value,but rather consider these two entities part of the clinicalspectrum of plasma cell dyscrasias with polyneuropathy[2]. Bone marrow biopsy specimens generally contain<5% plasma cells and are associated with a small mono-clonal protein, which is usually an IgA or IgGl. Malig-nant plasma cells are detected in biopsy specimens fromthe sclerotic lesions [1]. Osteosclerotic myeloma differsfrom classical multiple myeloma, which typicallypresents with lytic bone lesions, >10% plasma cells in thebone marrow, and a large monoclonal protein in the se-
rum or urine (or both). Multiple myeloma associated withwidespread osteosclerotic lesions seen on radiographicstudies is exceedingly rare. We describe three such casesand review the relevant literature.
REPORT OF CASES
Case 1
In February 1985, a 60-year-old woman had a mono-clonal gammopathy of undetermined significance(MGUS), with an IgGk monoclonal spike of 2.0 g/dL. InApril 1987, she presented with a flu-like illness. She hadno bone pain or other symptoms of myeloma. The physi-cal examination findings were normal. On laboratoryevaluation, she had a monoclonal spike of 3.11 g/dL. A24-h urine collection contained 83 mg of protein, most ofwhich was monoclonalk. Other laboratory findings in-
Contract grant sponsor: National Cancer Institute; Contract grant num-ber: CA62242.
*Correspondence to: Martha Q. Lacy, M.D., Mayo Clinic, 200 FirstStreet SW, Rochester, MN 55905.
Received for publication 29 June 1996; Accepted 9 July 1997
American Journal of Hematology 56:288–293 (1997)
© 1997 Wiley-Liss, Inc.
cluded the following: hemoglobin, 12.1 g/dL; leukocytes,6.9 × 109/L; platelets, 166 × 109/L; and the serum levelsof calcium and creatinine, 8.8 mg/dL and 1.0 mg/dL,respectively. Alkaline phosphatase was increased at 333U/L (normal, 84 to 218 U/L) and was skeletal in origin.A bone marrow biopsy specimen contained 80% plasmacells, with a plasma cell labeling index (PCLI) of 0.4%(normal, <0.8%) [3]. A metastatic bone survey showeddiffuse sclerosis involving the spine, pelvis, and proxi-mal femurs and humeri (Fig. 1).
The patient was observed without therapy for my-eloma until September 1992, when the hemoglobin valuewas 8.9 g/dL and monoclonal protein was 5.51 g/dL. Abone survey again showed diffuse osteosclerosis but withnew lytic lesions in the skull. The initial treatment waswith erythropoietin, but there was no response to treat-ment. Beginning in April 1993, the patient received treat-ment with melphalan and prednisone. The patient had noresponse to the chemotherapy and had progressive cyto-penias. Treatment with melphalan and prednisone wasdiscontinued after 1 year. She was observed withouttreatment from April 1994 to April 1995, at which timeshe had pneumococcal pneumonia and a rising monoclo-nal spike to 7.0 g/dL. Chemotherapy with vincristine,doxorubicin, and dexamethasone was instituted, and shehad a response. At latest follow-up (November 1995), themonoclonal protein was 3.12 g/dL.
Case 2
A 53-year-old man presented in October 1992 withback pain of 1-month’s duration. Radiography revealedinnumerable small osteosclerotic lesions throughout thevertebral bodies, ribs, pelvis, and proximal femurs andhumeri (Fig. 2). Hemoglobin was 16.3 g/dL; leukocytes,4.5 × 109/L; platelets, 201 × 109/L; and the serum levelsof calcium and creatinine, 10.2 mg/dL and 1.3 mg/dL,respectively. Serum protein electrophoresis, immuno-electrophoresis, and immunofixation failed to show amonoclonal protein. On 24-h urine collection, he ex-creted 150 mg of monoclonalk light chains. Bone mar-row biopsy revealed 20% plasma cells with a PCLI of0.4%.
By January 1993, the patient’s back pain had wors-ened. The results of a bone survey were unchanged, buta computed tomographic scan showed mixed lytic andsclerotic lesions involving L-5, the sacrum, and the iliacbones (Fig. 3). The urine monoclonalk protein was 202mg/24 hr. Chemotherapy was initiated with melphalanand prednisone. There was no objective evidence of dis-ease progression, and he had no relief of his pain. After6 months, the chemotherapy was changed to a high doseof cyclophosphamide. Excessive myelosuppression andfebrile neutropenia developed, and the regimen was dis-
continued. In January 1994, he received monthly treat-ments with intravenously administered pamidronate. Atlatest follow-up (November 1995), he had a urine mono-clonal protein of 140 mg/24 hr, no new bone lesions, andno pain.
Fig. 1. Patient 1. A and B: Diffuse osteosclerosis seen onmetastatic bone survey.
Case Report: Multiple Myeloma and Bone Sclerosis 289
Case 3
A 59-year-old woman presented in February 1994with dyspnea on exertion. Laboratory findings includedthe following: hemoglobin, 6.0 g/dL, leukocytes, 4.5 ×109/L; platelets, 137 × 109/L; and serum levels of cal-cium and creatinine, 9.3 mg/dL and 1.1 mg/dL, respec-tively. Alkaline phosphatase was 369 U/L and was skel-
etal in origin. A bone marrow biopsy specimen showedthat the marrow was replaced completely with plasmacells. The physical examination findings were normal.She had a 4.08 g/dL IgAl spike in the serum. Urinestudies showed 234 mg/24 hr of protein excretion, with66% monoclonall with an IgA l fragment. The periph-eral blood labeling index showed the presence of circu-lating plasma cells. The results of a technetium bone scanwere normal. A metastatic bone survey showed diffuseosteosclerosis in the vertebral bodies, ribs, pelvis, andproximal femurs and humeri (Fig. 4).
She received treatment with melphalan and predni-sone. After 15 months of chemotherapy, the monoclonalprotein had decreased to 2.4 g/dL, and she had beentransfusion-independent for 15 months. In September1995, she again began to require transfusions. By March1996, the IgA level had increased to 5,410 mg/dL.
DISCUSSION
Osteosclerotic myeloma is a rare but well-defined en-tity. It differs from multiple myeloma in that the patientsare younger and the disease course is more indolent. Thepatients usually present with neuropathy and rarely havebone pain. Bone marrow biopsy specimens generallycontain <5% plasma cells. Erythrocytosis and thrombo-cytosis are common. Hypercalcemia and renal insuffi-ciency are rare in patients with osteosclerotic myeloma.When osteosclerotic myeloma is associated with poly-neuropathy, organomegaly, endocrinopathy, monoclonalprotein elevation, and skin changes, it is known asPOEMS syndrome [1]. The major difference betweenpatients with osteosclerotic myeloma and the ones wedescribe is the extent of bone disease seen on radio-graphic imaging. Most patients with osteosclerotic my-eloma have one or a few small isolated sclerotic bonelesions. The largest series of POEMS patients is a groupof 109 patients from Japan. Bone radiographic findingswere described in 84 patients and lesions were found in61. They included scattered osteosclerotic spots, mixedsclerotic and lytic changes, tumor formation with scle-rotic septa, periosteal calcium deposition, and a fewpurely lytic lesions [4]. None had diffuse osteoscleroticbone lesions that involved virtually all the axial skeleton,as seen in our patients.
Myeloma associated with widespread osteosclerosisseen on radiologic examinations was first described bySharnoff et al. in 1954 [5]. In addition to this first report,we have identified 11 other reports in the English-language literature [6–15]. The clinical features of thepatients reported in the literature and those of our threepatients are summarized in Table I.
Overall, the 12 patients described in the literature andthe 3 we describe had a clinical course that resembledmultiple myeloma more than osteosclerotic myeloma.
Fig. 2. Patient 2. Innumerable small osteosclerotic bonelesions seen on metastatic bone survey.
Fig. 3. Patient 2. Mixed lytic and sclerotic lesions seen oncomputed tomographic scan of vertebral body L-5.
290 Case Report: Lacy et al.
TA
BLE
I.C
ompa
rison
ofR
epor
tsof
Pat
ient
sW
ithM
yelo
ma
Ass
ocia
ted
With
Wid
espr
ead
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eosc
lero
ticLe
sion
s*
Aut
hor
Age
,yr
/sex
Ser
umM
-pro
tein
(g/d
L)
Urin
em
onoc
lona
lpr
otei
n(g
/24
hr)
Hgb
(g/d
L)
No.
ofpl
atel
ets
×10
9/L
Cal
cium
(mg/
dL)
Cre
atin
ine
(mg/
dL)
Phy
sica
lex
amfin
ding
sB
one/
mar
row
path
olog
yR
adio
logi
cfin
ding
sS
urvi
val
Clin
ical
pres
enta
tion
Sha
rnof
fet
al.,
1954
[5]
68/M
8.0
Aty
pica
lPC
Diff
use
oste
oscl
eros
is
Vid
ebæ
k,19
56[6
]68
/F5.
4S
plen
omeg
aly
Mye
lofib
rosi
s/m
yelo
scle
rosi
sD
iffus
eos
teos
cler
osis
16m
onth
sA
nem
ia
Eng
els
etal
.,19
60[7
]40
/M9.
5T
hick
ened
trab
ecul
aear
ound
grou
psof
PC
Innu
mer
able
oste
oscl
erot
icle
sion
sS
ubcu
tane
ous
plas
mac
ytom
as
65/M
Not
give
nS
tern
alas
pira
tew
ith35
%P
CD
iffus
eos
teos
cler
osis
Ano
rexi
a,R
UQ
pain
Fai
rley
etal
.,19
64[8
]61
/F1.
97B
ence
Jone
s3.
830
Spl
enom
egal
yM
yelo
fibro
sis,
mye
losc
lero
sis
mar
row
PC
infil
trat
ion
Diff
use
oste
oscl
eros
is;
late
rde
velo
ped
lytic
lesi
ons
20m
oA
nem
ia
Cla
risse
and
Sta
ple,
1971
[9]
68/F
k10
.1N
orm
alIn
crea
sed
PC
Diff
use
oste
oscl
eros
isA
nem
ia
Hei
tzm
anan
dM
arka
rian,
1973
[10]
80/F
IgA
8.7
300.
9H
epat
omeg
aly
She
ets
ofP
C,
scle
rotic
trab
ecul
aeD
iffus
eos
teos
cler
osis
Ane
mia
Bro
wn
and
Pat
erso
n,19
73[1
1]
65/F
2.92
/IgA
kF
ree
k8.
611
.5F
orm
atio
nof
new
bone
arou
ndpo
cket
sof
PC
Diff
use
oste
oscl
eros
is;
fem
oral
lytic
lesi
ons
Hip
pain
Him
mel
farb
etal
.,19
74[1
2]
74/M
7.0/
IgA
Hep
atom
egal
yT
hick
ened
bony
trab
ecul
aead
jace
ntto
grou
psof
PC
Diff
use
oste
oscl
eros
is11
mon
ths
Bac
kpa
in,
anem
ia
Mac
Cal
lum
etal
.,19
88[1
3]
40/M
3.1/
IgD
l19
.8/fr
eel
7.7
130
2.4
mm
ol/L
791m
mol
/LS
plen
omeg
aly,
aden
opat
hyIn
filtr
ated
with
PC
,in
crea
sed
trab
ecul
ae,
incr
ease
dre
ticul
in
Diff
use
oste
oscl
eros
is14
mon
ths
Ane
mia
and
bone
pain
McC
lugg
age
etal
.,19
95[1
4]
51/F
4.6/
IgA
l4.
6/Ig
Al
8.0
165
2.49
mm
ol/L
Nor
mal
Thi
cken
edbo
nytr
abec
ulae
,gr
ade
4co
llage
nfib
rosi
s,cl
umps
ofP
C
Diff
use
oste
oscl
eros
is,
late
rde
velo
ped
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ons
60m
onth
sA
nem
iaan
dba
ckpa
in
Kuo
and
Shi
h,19
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5]71
/M2.
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Gl
4.1
617.
81.
2T
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ened
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trab
ecul
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pack
edw
ithP
C
Diff
use
oste
oscl
eros
is22
+m
onth
sA
nem
iaan
dw
eigh
tlo
ss
Thi
sst
udy,
patie
nt1
60/F
3.11
/IgG
k0.
083/
IgG
k12
.116
68.
81.
0S
heet
sof
PC
;S
cler
otic
bone
form
atio
n;ne
wbo
nefo
rmat
ion
with
foca
lpa
ratr
abec
ular
mye
lofib
rosi
s
Diff
use
oste
oscl
eros
is,
late
rde
velo
ped
lytic
lesi
ons
10ye
ars
Initi
ally
asym
ptom
atic
,an
emia
whe
ntr
eatm
ent
inst
itute
d
Thi
sst
udy,
patie
nt2
53/M
Non
e0.
15/fr
eek
16.3
201
10.2
1.3
Sm
allf
ocio
fat
ypic
alP
Cth
atar
eno
tdi
rect
lyas
soci
ated
with
fibro
sis;
scle
rotic
bone
form
atio
n;fo
cal
para
trab
ecul
arm
yelo
fibro
sis
Innu
mer
able
oste
oscl
erot
icle
sion
s;la
ter
deve
lope
dm
ixed
lytic
/scl
erot
icle
sion
s
37+
mon
ths
Sev
ere
back
pain
Thi
sst
udy,
patie
nt3
59/F
4.08
/IgA
l0.
234/
IgA
l6.
013
79.
31.
1S
cler
otic
bone
form
atio
n;sh
eets
ofP
C;
nofib
rosi
sD
iffus
eos
teos
cler
osis
18+
mon
ths
Ane
mia
*PC
,pl
asm
ace
lls;
RU
Q,
right
uppe
rqu
adra
nt.
All the patients had osteosclerotic lesions that were moreextensive than those of osteosclerotic myeloma. Present-ing symptoms consisted of bone pain in 5 patients andsymptoms of anemia in 10, symptoms that rarely are seenin conjunction with osteosclerotic myeloma. Patientswith osteosclerotic myeloma frequently present withsymptoms of peripheral neuropathy. None of our patientshad evidence of neuropathy. Several patients initiallypresented with diffuse osteosclerosis but subsequentlyhad lytic lesions. Lytic lesions are unusual with osteo-sclerotic myeloma. None of the patients we reviewed hadthe laboratory abnormalities that are found with osteo-sclerotic myeloma, such as thrombocytosis or erythrocy-tosis. The literature suggests that the monoclonal proteinsassociated with POEMS are almost exclusively IgAl orIgG l [2,4]. This was not seen in the patients we describeand further supports the observation that these patientshave a clinical course more like multiple myeloma thanlike POEMS.
The median survival after diagnosis for patients withmultiple myeloma is 36 months [16]. Only eight of thereports in the literature included information about long-term follow-up. Initial reports suggested a poor prognosisfor this group of patients, with most patients dying lessthan 2 years after diagnosis. Two of our patients had amore indolent course than that described in the literature.McCluggage et al. [14] described a patient who survived
for 5 years after diagnosis. Kuo and Shih [15] reported ona patient with plasma cell leukemia who achieved a com-plete remission and was still alive and in remission 22months after the diagnosis. Whether these cases indicatea better prognosis for patients with this variant remains tobe determined.
The pathogenesis of diffuse osteosclerosis in myelomais not clear. It is known that the lytic lesions of myelomalikely are mediated through the stimulation of osteoclastsby several cytokines, including IL-1b and tumor necrosisfactor [17]. Osteosclerotic lesions likely result from anuncoupling of osteoblast and osteoclast cell activities.Prostate cancer cells, a malignancy often associated withosteosclerotic bone lesions, synthesize platelet-derivedgrowth factor and transforming growth factorb, cyto-kines known to stimulate osteoblasts [18]. Platelet-derived growth factors also are thought to be responsiblefor the diffuse fibrosis and osteosclerosis found in agno-genic myeloid metaplasia and other myeloproliferativediseases [19]. A similar mechanism possibly accounts forthe sclerotic bone lesions in patients with myeloma.
ACKNOWLEDGMENTS
Funded in part by a grant from the National CancerInstitute (CA 62242).
Fig. 4. Patient 3. A and B: Diffuse osteosclerosis seen on metastatic bone survey.
292 Case Report: Lacy et al.
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Case Report: Multiple Myeloma and Bone Sclerosis 293