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Case of multiple myeloma mimicking an infectious disease with fever intrahepatic cholestasis renal failure and pulmonary insufficiency.

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American Journal of Hematology 72:38–42 (2003)
Case of Multiple Myeloma Mimicking an Infectious
Disease With Fever, Intrahepatic Cholestasis, Renal
Failure, and Pulmonary Insufficiency
Francesco S. Vella,1* Barbara Simone,1 Gianluigi Giannelli,1 MariaTeresa Pesolo,1
Giuseppe Ingravallo,2 Antonia Gentile,2 and Salvatore Antonaci1
1
Dipartimento di Clinica Medica, Immunologia e Malattie Infettive, University of Bari, Policlinico, Bari, Italy
2
Dipartimento di Anatomia Patologica e di Genetica, University of Bari, Policlinico, Bari, Italy
We describe a case of multiple myeloma (MM) presenting with high fever, inflammatory
chemistry abnormalities, simultaneous acute renal failure, cholestatic hepatitis, and
acute lung failure. The extremely aggressive course and pulmonary involvement in the
form of pulmonary alveolar proteinosis (PAP) are discussed, stressing the unusual nature of the findings and the variable picture of MM. Am. J. Hematol. 72:38–42, 2003.
© 2002 Wiley-Liss, Inc.
Key words: multiple myeloma; pulmonary alveolar proteinosis (PAP); acute terminal
phase; intrahepatic cholestasis; acute-phase reaction
INTRODUCTION
Multiple myeloma (MM) is a malignant proliferation
of plasma cells usually located in the bone marrow.
High fever and inflammatory chemistry abnormalities
are rare in absence of infectious disease. Recently
Mueller et al. [1] described fever of unknown origin
caused by MM in 9 patients with no signs or data indicating infections.
Here we describe a case of fatal, diffuse MM mimicking an infectious disease, in view of multiorgan involvement and inflammatory signs.
CASE REPORT
A 64-year-old joiner was admitted with a 1-month
history of high fever, cholestasis (␥GT ⳱ 217 IU/L,
normal range ⳱ 11–49 IU/L; alkaline phosphatase ⳱
900 IU/L, normal range ⳱ 91–258 IU/L; bilirubin within
normal limits) and raised serum levels of AST (62 IU/L,
normal < 37 IU/L), ALT (96 IU/L, normal < 37 IU/L),
LDH (721 IU/L, normal range ⳱ 240–480 IU/L), acutephase reactants (fibrinogen 979 mg/dL, normal range ⳱
170–410 mg/dL; ␣2 globulin 20.9%, normal range ⳱
7–11%), especially CRP (88 mg/dL, normal < 5 mg/dL).
An accelerated erythrocyte sedimentation rate (ESR 128
mm/1st hr) and microcytic hypochromic anemia were
also observed (Table I).
© 2002 Wiley-Liss, Inc.
He had presented a similar clinical episode 1 year
before. Although no infectious agent was identified (as
assessed by culture and serological assays), excellent response was obtained to antibiotic therapy (ciprofloxacin),
with abatement of the fever and a return to normal of the
ESR and liver function tests (Table I).
On admission to our Department, physical examination revealed a palpable liver 2 cm below the costal margin but no lymphadenopathy or splenomegaly.
Direct tests with standard and Ziehl-Nielsen stains,
cultures (sputum, blood, urine, stool), and antibodies
against various infectious agents including viruses (hepatitis A, hepatitis B, and hepatitis C viruses, human immunodeficiency virus, herpesvirus group, respiratory
syncytial virus, enteroviruses, adenoviruses, and influenza and parainfluenza viruses), Legionellae, mycobacteria, mycoplasmata, chlamydiae, Rickettsias, Borreliae,
*Correspondence to: Francesco S. Vella, M.D., Viale JF Kennedy, 75
H, 70124 Bari, Italy. E-mail: diceglie@intmed.uniba.it
Received for publication 4 June 2002; Accepted 15 October 2002
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI: 10.1002/ajh.10257
Case Report: Myeloma Mimicking an Infectious Disease
39
TABLE I. Laboratory Tests Before and After Admission*
Laboratory test
Hemoglobin (g/L)
WBC (×103/mm3)
Platelets (×103/mm3)
Sideremia (␮g/L)
Ferritin (ng/mL)
ESR (mm/1st hr)
Creatinine (IU/L)
AST (IU/L)
ALT (IU/L)
GGT (IU/L)
AP (IU/L)
Bilirubin (mg/dL)
IgG (mg/dL)
IgA (mg/dL)
IgM (mg/dL)
M component
Calcium (mg/dL)
LDH (IU/L)
CRP (mg/dL)
␤2 Microglobulin (mg/dL)
IL-6 (pg/mL)
PT-INR
APTT-R
Fibrinogen (mg/dL)
ATIII (%)
D-dimer (␮g/L)
Factor X (%)
Normal values
February 2000
April 2000
February 2001
(on admission)
March 2001
12–16
4–10
150–500
35–150
10–258
<15
0.6–1
<37
<37
11–49
91–258
<1
700–1,600
70–400
40–230
NE
8.5–10.1
240–480
<5
0.8–2
<4
<1.2
<1.16
170–410
75–125
<150
70–130
10.6
7.120
200
18
872
113
0.8
120
160
105
400
0.9
1,000
501
90
NE
NE
NE
41
NE
NE
0.98
0.9
630
NE
NE
NE
12
6.850
270
NE
NE
10
NE
30
35
40
170
0.8
NE
NE
NE
NE
NE
NE
3.2
NE
NE
NE
NE
250
NE
NE
NE
10.2
7.620
290
15
2,386
128
0.98
62
96
217
900
0.68
892
419
31
B-J proteinuria (␭)
9.1
721
88
7.5
450
1.01
0.99
979
102
123
NE
9.5
9.920
180
NE
3,170
132
7.19
37
72
350
1,100
1.24
896
276
50
NE
9.2
820
100
NE
NE
0.89
1
470
NE
NE
114
*WBC, white blood cells; ESR, erythrocyte sedimentation rate; AST, aspartate-aminotransferase; ALT, alanine-aminotransferase; GGT, ␥-glutamyl
transpeptidase; AP, alkaline phosphatase; Ig, immunoglobulins; B-J, Bence-Jones; LDH, lactate dehydrogenase; CRP, C-reactive protein; IL-6, interleukin
6; PT-INR, prothrombin time-international normalized rate; aPTT-R, activated partial thromboplastin time-ratio; ATIII, antithrombin III; NE, not
evaluated.
Brucella, Salmonellae, Toxoplasma, Pneumocystis carinii, and fungi were negative, as were specific tests for
autoimmune diseases.
There was proteinuria (2 g/24 hr), consisting exclusively of ␭ light chains, with no M component in the
serum. These findings and the marrow results (50%
plasma cells) led to the diagnosis of MM. Circulating
plasma cells were not found. The levels of ␤2 microglobulin and IL 6 were 7.5 mg/dL (normal range ⳱
0.8–2 mg/dL) and 450 pg/mL (normal < 4.0 pg/mL),
respectively. A plain radiographic skeletal survey
showed no lytic lesion.
Because of the increasing levels of cholestatic markers
with hepatomegaly, liver biopsy was performed, revealing sinusoidal plasmacytic infiltrates (Fig. 1A). Congo
red was negative for amyloid. Plasma cells stained positive for ␭ light chains (Fig. 1B).
Renal failure developed in a few days (Table I), requiring hemodialysis. Renal biopsy documented myeloma cast nephropathy.
Subsequently, the fever persisted, and he developed
dyspnea and a dry cough. Chest roentgenography revealed reticulonodular opacities of both lungs; a diffuse
reticulonodular infiltrate was visualized by thoracic CT
scan, rapidly complicated by pulmonary insufficiency.
The inflammatory status and interstitial lung disease suggested an infectious disease, and MM complicated with
acute respiratory failure induced by opportunistic infection was hypothesized. Although no infectious etiological agent was identified, he was given antibiotic treatment (cotrimoxazole, sulbactam-ampicillin, ceftriaxone,
ciprofloxacin), to no effect. Antiviral and antifungal
therapies were not administered.
A successive lung CT scan was compatible with pulmonary alveolar proteinosis (PAP) (Fig. 2A), confirmed
later by autopsy.
Cor pulmonale supervened, and shortly afterward, before chemotherapy could be started, the patient died.
Autopsy disclosed plasmacytic infiltration of the liver,
kidneys, and spleen; the lungs were congested, and the
alveoli were filled with protein that stained positive for ␭
light chains (Fig. 2B) while Congo red stain was negative. A thrombus in the right atrium was detected, causing the tricuspid valve obstruction; this was probably the
terminal cause of death.
DISCUSSION
To our knowledge, this is the first case report in the
English-language medical literature describing high fe-
40
Case Report: Vella et al.
Fig. 1. Liver biopsy specimen showing sinusoidal infiltration by atypical lymphoid cells in Indian file manner, some with
plasmacytic features (A, hematoxylin–eosin, original magnification ×400). Immunoperoxidase staining for ␭ light chains of
monoclonal plasmacytoid cells within sinusoidal spaces (B, diaminobenzidine and hematoxylin, original magnification
×400). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
Fig. 2. Thoracic computed tomogram revealing diffuse symmetric reticulonodular pulmonary infiltrate in both lungs (A).
Lung autopsy specimen (B, diaminobenzidine and hematoxylin, original magnification ×400): immunohistochemical demonstration of proteinaceous material within the alveolar spaces staining intense positive immunoreactivity for ␭ light
chains (black arrows) and slight infiltration of cells with plasmacytoid features mildly positive for ␭ light chains (white
arrows). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
ver, simultaneous acute renal failure, cholestatic hepatitis, and acute lung failure at the onset of MM. Our patient
was also remarkable because of the extremely aggressive
course and the pulmonary involvement in the form of
PAP. The unusual nature of our case, emphasizing the
variable picture of MM, can be summarized as follows:
1. diffuse multiorgan manifestations (liver, lung, kidneys, spleen);
2. inflammatory data (with no apparent underlying infection) and cholestatic laboratory abnormalities;
3. extremely aggressive course.
Extramedullary spread of myeloma is rare at diagnosis, and in this context, a clinical picture with predomi-
nant hepatic involvement is an exceptional form of presentation [2–6].
The most common clinical manifestation of liver disease is hepatomegaly, which is not always related to
plasma cell infiltration [7–9]. Symptomatic liver disease
is extremely rare although jaundice is occasionally seen
[8], almost always in association with hepatic amyloid
deposits [9–11].
Serum alkaline phosphatase, the only biochemical
marker that correlates with plasmacytic infiltrates of the
liver, is mildly raised in 25–40% of cases [7,8].
Nodular liver involvement is a very uncommon feature
in MM [2,3,5,12,13]. Post mortem series show a higher
percentage of liver involvement, demonstrating infiltra-
Case Report: Myeloma Mimicking an Infectious Disease
tion in 26–46% of MM cases [7,14,15], with nodular,
sinusoidal (the most common), portal, and mixed patterns [8,9,14].
Among the various organs potentially affected, pulmonary parenchyma involvement is rare, and, in the few
cases described, usually secondary to an infectious process or extending from primary bone involvement, highly
variable lung manifestations have been reported [16]. In
practice, however, lung involvement is so rare that no
attention has been paid to lung investigations in several
large MM series [7,17].
Three types of roentgenographic manifestations of
myeloma pulmonary involvement are described: nodular
mass lesion, diffuse reticulonodular pulmonary infiltrate,
and pleural effusion [15,18].
Direct myeloma cell infiltration of the lung and amyloid deposits need to be differentiated from diffuse pulmonary inflammatory processes, pulmonary edema [16],
and from another exceptional infiltrating form, PAP, first
described in the course of MM in 1966 by Proks et al.
[19].
In 1994, Meijer [20] reported another case of PAP
secondary to MM with no chest X-ray abnormalities,
high CRP and LDH, low-grade fever, and kidney and
liver infiltrations.
In this case, as in ours and in other series, pulmonary
involvement was associated with the aggressive terminal
phase of MM or plasma cell leukemia [21–23]. In accordance with these authors’ findings and our patient’s features, we hypothesize a link between multi-organ involvement, acute-phase response, and the terminal phase
of MM.
The high serum levels of LDH, CRP, IL-6, and the
high fever documented in our case have already been
reported in the course of MM [24,25] and have been
recognized as poor prognostic factors, indicating the terminal phase [24,26].
Many researchers agree that large amounts of IL-6 are
produced by the tumoral microenvironment in response
to stimulating myeloma cells, causing high fever and
high serum levels of CRP and inducing the terminal fulminant phase [24,27,28].
A critical point to remember is that CRP is highly
influenced by infections (via IL-6 overproduction). Our
patient had clinical and laboratory features mimicking
infectious disease, consisting of
1. previous episode of fever and intrahepatic cholestasis
with transient complete normalization of all laboratory tests after antibiotic therapy;
2. spectrum of organs involved with typical patterns (intrahepatic cholestasis and reticulonodular pulmonary
involvement) of infectious diseases;
3. high fever and CRP levels.
Secondary PAP also enters the differential diagnosis.
41
The demonstration of the same ␭ light chains paraprotein
in the alveolar spaces as was found in the blood yielded
the diagnosis of PAP with neoplastic pathogenesis rather
than PAP secondary to an infectious disease. We also
demonstrated the neoplastic pathogenesis of our patient’s
features for the remainder of extramedullary locations
(liver, kidney). Pulmonary Congo red negative ␭ light
chain deposits suggested a systemic light chain deposition disease (LCDD). Such cases are usually ␬ subtype
[29]; moreover, histology of liver and kidney ruled out
finally this unifying hypothesis.
Nevertheless, on the bases of clinical features strongly
resembling an infectious disease, the suggestion remains
whether the acute terminal phase of MM, now known to
be a “cytokine-mediated phase,” could in fact be a supervening manifestation of the time-honored infectious
disease.
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