Case 8-2015, A 68-Year-Old Man With Multiple Myeloma, Skin Tightness, Arthralgias and Edema

Case Records of the Massachusetts General Hospital
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EricS.Rosenberg,M.D.,Editor
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EmilyK.McDonald,Assistant Editor
Case 8-2015: A 68-Year-Old Man with

Multiple Myeloma, Skin Tightness,
Arthralgias, and Edema
FredrickWigley,M.D., RobertP.Friday,M.D., Ph.D., JoAnneO.Shepard,M.D.,
and RosalynnM.Nazarian,M.D.
Pr e sen tat ion of C a se

From the Department of Medicine, Johns
Hopkins Hospital, and the Department
of Medicine, Johns Hopkins University
School of Medicine both in Baltimore
(F.W.); and the Departments of Medicine
(R.P.F.), Radiology (J.-A.O.S.), and Pathology (R.M.N.), Massachusetts General Hospital, and the Departments of
Medicine (R.P.F.), Radiology (J.-A.O.S.),
and Pathology (R.M.N.), Harvard Medical School both in Boston.
N Engl J Med 2015;372:1056-67.
DOI: 10.1056/NEJMcpc1409840
Copyright 2015 Massachusetts Medical Society.
1056
Dr. Naina Rastalsky (Medicine): A 68-year-old man with multiple myeloma was seen
in the rheumatology clinic of this hospital because of increasing skin tightness,
joint pain, and swelling of the hands and feet.
The patient had been well until 2 years before this presentation, when anemia
was noted on routine examination at another hospital. During the next 7 months,
endoscopic and colonoscopic screening examinations were negative. Pathological
examination of a bone marrowbiopsy specimen and aspirate revealed 30% plasma
cells; flow-cytometric studies revealed an IgG lambda M component. A diagnosis
of multiple myeloma was made. Skeletal radiographs reportedly revealed multiple
lytic lesions. Lenalidomide, bortezomib, and dexamethasone were administered,
followed by cyclophosphamide. Nine months before this presentation, the patient
was admitted to this hospital; melphalan hydrochloride was administered, and
autologous stem-cell transplantation was performed. Results of follow-up studies
were consistent with complete remission.
Three months before this presentation, the patient was seen by an orthopedist
at this hospital for evaluation of low-back pain of 1 years duration. Magnetic resonance imaging (MRI) of the lumbar spine, performed after the administration of
intravenous gadolinium, revealed multilevel degenerative changes, multiple enhancing lesions in the lumbar spine and left iliac bone, and compression fractures of the
first and second lumbar vertebrae, findings consistent with the history of multiple
myeloma.
Two months before this presentation, swelling and pain in the hands occurred,
followed by pedal edema, tightening of the skin of the hands and feet, and diffuse
hyperpigmentation on the trunk, arms, and legs. Maintenance therapy with lenalidomide was begun, but it was stopped during the first cycle because of worsening
symptoms.
Diffuse joint pain occurred and hyperpigmentation increased. One month before
this presentation, on evaluation in the outpatient cancer center of this hospital,
n engl j med 372;11nejm.org March 12, 2015
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Case Records of the Massachuset ts Gener al Hospital
the red-cell indexes and results of liver-function

tests were normal, as were blood levels of electrolytes, calcium, phosphorus, magnesium, glucose,
thyrotropin, iron, iron-binding capacity, ferritin,
and folate; other test results are shown in Table1.
Total urine protein was 90 mg per liter (reference
range, 0 to 135). Fine-needle aspiration biopsy of
a fat pad was performed, and pathological examination of the specimen revealed no evidence
of malignant cells or amyloid. A transthoracic
echocardiogram showed trace mitral regurgitation, trace tricuspid insufficiency, and a left ventricular ejection fraction of 64% and showed that
the ascending aorta was 41 mm in diameter (reference diameter, <36 mm); there was no evidence
of amyloid or pericardial effusion. Urinalysis was
normal. The patient was referred to the rheumatology clinic of this hospital.
On presentation, the patient rated the joint
pain at 6 on a scale of 0 to 10, with 10 indicating
the most severe pain. He had hyperlipidemia, hypertension, low-back pain, and gastroesophageal
reflux disease; he had undergone colonic polypectomies and had a history of prostate cancer for
which radical prostatectomy was performed 11
years earlier. Medications included acyclovir, rosuvastatin, and omeprazole. Allopurinol caused
a rash. He lived with his wife and worked in an
office. He had stopped smoking 20 years earlier,
drank alcohol in moderation, and did not use
illicit drugs. His mother and maternal uncle had
rheumatoid arthritis.
On examination, the blood pressure was
112/63 mm Hg and the pulse 100 beats per minute; the temperature, respiratory rate, and oxygen
saturation were normal. A systolic murmur, grade
2/6, was heard at the right and left upper sternal
borders. There was swelling and tenderness in
the metacarpophalangeal and proximal interphalangeal joints bilaterally and swelling below the
knees to the toes, without erythema or warmth.
The range of motion was decreased in the metacarpophalangeal and ankle joints. The skin on the
metacarpophalangeal joints and legs below the
knees to the toes was hyperpigmented. The blood
level of C-reactive protein was 54.7 mg per liter
(reference value, <8.0); testing for antibodies to
Ro (SSA), La (SSB), Sm, RNP, Jo-1, Scl-70 (topoisomerase I), and cyclic citrullinated peptide was
negative, and the level of creatine kinase was normal. A tapering course of prednisone was administered.
Five weeks later, after returning from a vacation in Aruba, the patient was seen for follow-up
appointments at the hematology clinic of the other
hospital and the rheumatology clinic of this hospital. He reported severe fatigue, decreased exercise tolerance, and weight loss of approximately
3.5 kg. He rated the joint pain at 2 out of 10, but
substantial stiffness persisted while he was taking
prednisone. On examination, the blood pressure
was 110/70 mm Hg, the pulse 100 to 111 beats per
minute, and the oxygen saturation 96% while he
was breathing ambient air; the temperature was
normal. The metacarpophalangeal and proximal
interphalangeal joints remained swollen but were
less tender, and the wrists were slightly full.
There was 1+ pitting edema below the knees; the
skin was deeply tanned and firm in a manner that
was out of proportion to the degree of pitting
edema. Test results are shown in Table1. The
stool was dark brown and positive (3+) for blood.
The administration of omeprazole was increased
to twice daily, and an endoscopic examination was
scheduled.
One week later (six weeks after this presentation), the patient was admitted to the other hospital because of worsening anemia (Table1). The
hematocrit rose to 27.9% after leukocyte-reduced
red cells were transfused. Endoscopy revealed severe acute gastritis with marked erythema and
friability. He was discharged on the third day.
During the next 2 months, melena and anemia persisted. Colonoscopy at the other hospital
revealed a benign polyp, 5 mm in diameter, which
was excised. Multiple units of red cells were transfused, and intravenous immune globulin (IVIG)
was administered monthly, with some improvement in joint pain and stiffness. Skin tightness
persisted, and a skin biopsy was performed.
Dr. Rosalynn M. Nazarian: Examination of histologic sections of a punch-biopsy specimen from
the dorsum of the left hand revealed a fibrosing
dermopathy, with interstitial mucin deposition
and collagen expansion of the dermis extending
to the subcutaneous tissue (Fig.1A). The epidermis appeared normal. Adnexal atrophy with loss
of surrounding fat was identified. A sparse lymphoplasmacytic infiltrate was present at the
junction of the dermis and the subcutaneous fat
(Fig.1B). There were areas of marked fibroblast
hypocellularity in the middle and deep reticular
dermis, with diffuse loss of CD34 expression in
dermal spindle cells (Fig.1C). A colloidal iron

1057
1058
13.517.5
450011,000
Hematocrit (%)
Hemoglobin (g/dl)
White-cell count
(per mm3)
411
08
03
Monocytes
Eosinophils
Basophils
110210
Lactate dehydrogenase
(U/liter)
<30
8.510.5
Calcium (mg/dl)
>250
2.34.1
Globulin
Vitamin B12 (pg/ml)
3.35.0
Albumin
Rheumatoid factor
(IU/ml)
6.08.3
290
8.4
2.7
3.4
6.1
<30
172
8.8
2.4
4.0
6.4
>60
8.2
3.4
5.4
>60
0.8
20
38
364,000
0.2
12.
11.8
7.9
78.0
9300
9.4
29.3
328
305
8.0
3.1
5.1
>60
0.9
18
6.0
277,000
9600
7.6
23.8
Other
Hospital,
6 Wk after
Presentation
8.6
2.3
3.4
5.7
>60
0.82
17
321,000
0.2
2.1
14.4
7.2
75.3
13,100
9.7
30.6
This Hospital,
6 Wk 3 Days
after
Presentation
456,000
0.4
0.8
16.3
6.5
75.5
13,300
7.8
26.0
Other
Hospital,
3 Mo after
Presentation
609
277
7.8
5.0
>60
1.11
23
324,000
0.4
1.7
10.9
8.8
77.5
9500
9.4
29.3
424
7.6
2.6
2.6
5.2
36
1.87
42
224,000
0.1
1.1
12.3
4.5
81.4
11,600
9.9
30.7
452
7.2
2.5
2.5
5.0
14
4.38
86
88,000
0.1
1.1
9.1
5.7
83.1
7400
8.1
25.0
This Hospital, This Hospital, This Hospital,

3.5 Mo after 3.75 Mo after
4 Mo after
Presentation Presentation Presentation
of
Total
>60
60
0.88
19
43
2.7
285,000
0.6
4.0
9.6
16.4
69.2
9100
12.5
37.8
This Hospital,
18 Days
This Hospital,
before
5 Wk after
Presentation Presentation
n e w e ng l a n d j o u r na l
Protein (g/dl)
Estimated GFR (ml/

min/1.73 m2)
14
0.84
825
325,000
0.6
11.3
15.2
13.0
59.1
7200
12.6
38.3
This Hospital,
1 Mo before
Presentation
0.601.50
Urea nitrogen (mg/dl)
Creatinine (mg/dl)
013
0.52.5
Erythrocyte sedimentation rate

(mm/hr)
Reticulocytes (%)
150,000
400,000
2244
Lymphocytes
Platelet count (per mm
4070
Neutrophils
3)
41.053.0
Variable
Differential count (%)
Reference
Range,
Adults
Table 1. Laboratory Data.*
The
m e dic i n e

69309
53334
IgA
IgM
0.31.7
Free kappa:lambda
ratio
150400
16199
Fibrinogen (mg/dl)
Haptoglobin (mg/dl)
0.7
33.5
24.5
Normal
pattern
67
62
887
This Hospital,
1 Mo before
Presentation
0.6
26.4
16.5
Normal
pattern
50
68
1079
3.00
Negative at
1:10 dilution
Positive at
1:1280 dilution,
speckled
pattern
18.0
591
This Hospital,
18 Days
This Hospital,
before
5 Wk after
Presentation Presentation
Other
Hospital,
6 Wk after
Presentation
No M component detected
0.1
134.0
17.3
Normal
pattern
187
81
675
3.32
This Hospital,
6 Wk 3 Days
after
Presentation
0.687
58.5
40.2
Other
Hospital,
3 Mo after
Presentation
5488
0.5
62.6
34.4
Normal
pattern
57
112
1196
4.46
No M component detected
0.5
69.9
38.0
Normal
pattern
58
107
1281
7.82
13
368
25,019
This Hospital, This Hospital, This Hospital,

3.5 Mo after 3.75 Mo after
4 Mo after
Presentation Presentation Presentation
* To convert the values for urea nitrogen to millimoles per liter, multiply by 0.357. To convert the values for creatinine to micromoles per liter, multiply by 88.4. To convert the values for
calcium to millimoles per liter, multiply by 0.250. GFR denotes glomerular filtration rate, and NT-proBNP N-terminal proB-type natriuretic peptide.
Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at Massachusetts General Hospital are for adults
who are not pregnant and do not have medical conditions that could affect the results. They may therefore not be appropriate for all patients.
If the patient is black, multiply the value by 1.21.
0900 (in persons 50

75 yr of
age)
NT-proBNP (pg/ml)
C-reactive protein
(mg/liter)
<8.0
5.726.3
Free lambda light chain

(mg/liter)
Immunofixation
3.319.4
Free kappa light chain

(mg/liter)
Serum protein electrophoresis
6141295
IgG
Immunoglobulins
(mg/dl)
0.701.80
Negative at
1:10 dilution
Antibodies to doublestranded DNA
2-microglobulin
(g/ml)
Negative at
1:40 and
1:160 dilutions
Antinuclear antibodies
Variable
Reference
Range,
Adults

1059
The
of
m e dic i n e
Figure 1. Skin-Biopsy Specimen.

Hematoxylin and eosin staining of histologic sections of a skin-biopsy specimen from the dorsum of the left hand
revealed a normal epidermis with dermal collagen expansion involving the subcutaneous tissue (Panel A, asterisk);
there is adnexal atrophy with periadnexal fat loss (Panel A, arrow). A sparse lymphoplasmacytic infiltrate was identified at the junction of the dermis and the subcutaneous fat (Panel B, arrow). There were areas of reticular dermal fibroblast hypocellularity (Panel C). An immunohistochemical stain for CD34 shows a diffuse loss of CD34 expression
in dermal spindle cells (Panel C, inset). A colloidal iron stain shows interstitial mucin deposits (Panel D). An elastictissue stain shows preservation of dermal elastic fibers, with parallel arrangement and straightening (Panel E, arrow).
stain revealed finely granular mucin deposits inter- dermal elastic fibers, with straightening and parspersed between dermal collagen bundles (Fig. 1D). allel arrangement (Fig. 1E).
An elastic-tissue stain revealed preservation of
Dr. Rastalsky: Three months after this presen1060
n engl j med 372;11
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March 12, 2015

tation, prednisone was administered for persistent

stiffness. The patient reported extreme fatigue and
increasing dyspnea on exertion during the preceding 3 months. Results of tests performed at
the other hospital are shown in Table1. Chest
imaging was performed because of the worsening shortness of breath.
Dr. Jo-Anne O. Shepard: Computed tomography
(CT) of the chest revealed reticulation in the subpleural region at the lung bases and bronchiolectasis (Fig.2A). There was no evidence of pulmonary edema. These findings were suggestive of
nonspecific interstitial pneumonia. Soft-tissue
windows showed a small pleural effusion on the
right side and minimal dilatation of the main
pulmonary artery that could be correlated with
pulmonary hypertension (Fig.2B). The esophagus was diffusely dilated and contained contrast
material throughout. A representative sagittal
image showed generalized osteopenia, multiple
lytic lesions throughout the spine and ribs, and
multiple healed fractures, including one in the
sternum (Fig.2C). These skeletal findings were
consistent with the history of multiple myeloma.
Dr. Rastalsky: The patient was admitted to this
hospital 3.5 months after this presentation. On
examination, there were bilateral bronchial breath
sounds, crackles at the base of the left lung, extensive hardening of the skin from the hands to
the elbows and from the toes to above the knees,
and deep bronze discoloration on the trunk, arms,
and legs. Joint motion was limited by skin thickening. Test results are shown in Table1. An endoscopic examination was performed.
Dr. Nazarian: During the endoscopy, a gastricbiopsy specimen was obtained from the antrum;
examination of the specimen revealed expansion
of the lamina propria and prominent fibromuscular hyperplasia. Other areas showed ectatic mucosal capillaries with occasional fibrin thrombi
(Fig.3). This constellation of findings was consistent with gastric antral vascular ectasia (which
is also referred to as watermelon stomach because the condition is characterized by the parallel
arrangement of longitudinal folds containing dilated vessels that converge at the pylorus, and this
arrangement resembles the stripes on a watermelon).
Dr. Rastalsky: IVIG and bortezomib were administered. The patient was discharged on the
fourth day.
Five days later, the patient reported increased
discomfort and inability to bend his joints and

was using a wheelchair. Test results are shown
in Table1. During the next 4 days, confusion developed and he had difficulty with word-finding.
Oral intake was poor. Four months after this
presentation, he was brought to the emergency
department of this hospital; on examination, he
was alert, oriented to person only, and had difficulty with word-finding and verbal expression.
The blood pressure was 98/63 mm Hg, and there
was periorbital and facial edema; the remainder
of the examination was unchanged. Test results
are shown in Table1. The peripheral-blood smear
showed 2 to 4 schistocytes per high-power field.
Urinalysis showed 2+ albumin by dipstick, a specific gravity of 1.015, and a pH of 6.0; the urinary
sediment was packed with pigmented, coarsely
granular casts and had 10 nondysmorphic erythrocytes per high-power field and no cellular casts.
The ratio of total spot-urine protein to creatinine
was 4.0. CT of the head, performed without the
administration of contrast material, was negative.
The patient was readmitted to this hospital.
A diagnostic test result was received.
Differ en t i a l Di agnosis
Dr. Fredrick Wigley: This patient had multiple myeloma that appeared to be in remission, exposure
to several drugs, bleeding due to gastric antral
vascular ectasia, interstitial pulmonary fibrosis
with a small pleural effusion, cognitive dysfunction, and acute renal failure with associated thrombotic microangiopathic anemia. Although he had
complications involving multiple organ systems,
I will focus my differential diagnosis on his
rapidly progressive skin thickening with hyperpigmentation and associated polyarthritis. In particular, the features and distribution of the skin
disease and the degree of pigmentation are major clues in this case.
Multiple Myeloma and Systemic Amyloidosis
Are the features of this patients illness a direct

consequence of multiple myeloma? The laboratory data including the absence of the monoclonal protein, the serum free light-chain level of
less than 1500 mg per liter, and the kappa:lambda
ratio of 0.26 to 1.65 strongly suggest that the
myeloma was in remission. In addition, skin lesions associated with plasma-cell infiltration (plasmacytoma) would appear as nodules rather than

1061
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Figure 2. CT Scans of the Chest.

A CT scan of the chest with lung windows, obtained
through the lung bases with the patient in the prone
position, shows subpleural reticulation, ground-glass
opacities, and bronchiolectasis (Panel A). A scan with
soft-tissue windows, obtained with the patient in the
supine position, shows a small pleural effusion on the
right side, diffuse distention of the esophagus with air
and liquid, and dilatation of the main pulmonary artery (measuring 3.5 cm in diameter) (Panel B). A scan
with bone windows, obtained in the sagittal plane,
shows diffuse osteopenia, multiple lytic lesions in the
spine, and a healed fracture of the body of the sternum (Panel C).
ally involves proximal joints; the skin and joint

disease seen in this case were not consistent
with amyloidosis.
Toxic Effects
as the diffuse skin involvement that was described

in this case. Likewise, evidence of systemic amyloidosis was not seen on fat-pad biopsy, echocardiography, or skin biopsy. Patients with amyloidosis usually have hemorrhagic lesions due to the
fragility of infiltrated cutaneous vessels, and the
joint disease is not very inflammatory and usu1062
n engl j med 372;11
Is this patients disease a consequence of toxic

effects associated with medications or with the
recent MRI examination? During the course of
this patients treatment, he received several drugs
that may have caused a secondary process. Lenalidomide can cause a diffuse rash, but the rash
is usually an eczematous eruption without clinically significant skin thickening. Cyclophosphamide or melphalan hydrochloride can induce a
second cancer, and thus it is possible that a paraneoplastic process such as the palmar fasciitis
and polyarthritis syndrome could explain some
of the features in this case. IVIG can cause renal
toxic effects that could in part account for the
acute renal failure.
Could this patients rapidly progressive skin
thickening and hyperpigmentation be caused by
exposure to gadolinium? In rare cases, exposure
to gadolinium during an MRI examination can
result in nephrogenic systemic fibrosis, a fibrotic
process that mainly affects the skin but also affects internal organs; lung fibrosis, heart infiltration, and neuropathy have been reported.1 Nephrogenic systemic fibrosis typically occurs in
patients with severe impairment of renal function
(with a glomerular filtration rate of <15 ml per
minute). Skin changes can develop rapidly after
exposure to gadolinium and are associated with
burning, pruritus, and hyperpigmentation. The
acute phase evolves into progressive fibrosis involving the dermis and deep soft tissue. The skin
feels marblelike, and large plaques are present that
usually involve the legs, less commonly involve
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March 12, 2015

the arms and trunk, and spare the face. Severe

flexion contractures of joints result from fibrosis
of deep soft tissue. Dermal fibrosis and interstitial mucin deposition with little or no inflammatory infiltrate are seen on biopsy. This patient
may have an increased risk of gadolinium-induced
renal disease because of his older age and history
of myeloma; however, he had relatively normal
results of renal-function tests at the time of the
imaging study, and furthermore, his inflammatory joint disease was not consistent with nephrogenic systemic fibrosis.
Myeloma-Related Skin Disorders
Scleredema is a disorder that is characterized by

mucin deposition in the dermis.2 It can be associated with a previous infection, diabetes, or monoclonal gammopathy of undetermined significance
(MGUS); it has also been associated with multiple myeloma. Scleredema is characterized by nonpitting doughy or woody induration of skin of
the neck, back (especially the middle of the back),
and shoulders, with sparing of the distal limbs.
The distribution of skin involvement in this patient is not typical of scleredema.
Scleromyxedema is a form of lichen myxedematosus (papular mucinosis) that is almost always
associated with IgG MGUS. Several cases of scleromyxedema have been associated with multiple
myeloma.3 This rare disorder has four diagnostic
criteria: a generalized papular and sclerodermoid
eruption, a triad of findings on microscopic examination of skin-biopsy specimens (mucin deposition, fibroblast proliferation, and fibrosis), a
monoclonal gammopathy, and absence of a thyroid disorder. Involvement of the skin of the face,
including papules on the neck, glabella, and
postauricular area, is almost always present; the
limbs and back can also be affected. Linear
streaks of papules are characteristic of scleromyxedema, and hyperpigmentation is rare and mild.
Unlike patients with nephrogenic systemic fibrosis, patients with scleromyxedema can have a slight
superficial, perivascular, lymphoplasmacytic inflammatory-cell infiltrate.4 Systemic disease is
common and can have neurologic, musculoskeletal, cardiac, gastrointestinal, pulmonary, and hematologic manifestations (including myeloma).5,6
Inflammatory polyarthritis may also occur. In
addition, acute renal crisis has been reported in
patients with scleromyxedema; in such cases, findings consistent with thrombotic microangiopathic
n engl j med 372;11
anemia, including narrowed glomerular capillaries, endothelial proliferation, and microthrombi,

are seen.7-9 Many of the features described in this
case could be explained by scleromyxedema; however, the absence of skin papules, one of the four
diagnostic criteria, makes this diagnosis unlikely.
Eosinophilic fasciitis (Shulmans syndrome)
should also be considered because it has been
associated with hematologic diseases, including
multiple myeloma. In patients with this disorder,
there is a rapid onset of skin changes on the arms
and legs and sometimes the trunk, with sparing
of the face and hands.10 Fibrosis of deep soft tissue in the fascia leads to contractures; dimpling
of the skin (peau dorange), particularly of the
upper inner arms and forearms, is typical. Systemic disease is uncommon, but an inflammatory rheumatoid-like arthritis can be seen. Eosinophilia is present in approximately 80% of cases,
and testing for antinuclear antibodies is negative.
The clinical features in this case are not suggestive of eosinophilic fasciitis.
Scleroderma
Systemic sclerosis, or scleroderma, is an autoimmune disease associated with skin fibrosis and
multisystem involvement.11 Obliterative vascular
disease can lead to scleroderma renal crisis, with
manifestations such as thrombotic microangio-
Figure 3. Gastric-Biopsy Specimen (Hematoxylin and

Eosin).
Examination of a gastric-biopsy specimen from the
antrum reveals expansion of the lamina propria and
prominent fibromuscular hyperplasia. There were ectatic mucosal capillaries with occasional fibrin thrombi (inset). This constellation of findings is consistent
with gastric antral vascular ectasia (watermelon
stomach).
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March 12, 2015

1063
The
pathic anemia, pulmonary hypertension, cardiac

disease, and gastrointestinal bleeding due to gastric antral vascular ectasia; all these features were
seen in this case. Interstitial lung disease is common in patients with scleroderma, particularly in
those with antibodies to Scl-70 (topoisomerase
I). There is an increased risk of cancer among
patients with scleroderma.12 Skin disease associated with scleroderma has a highly variable course,
but a subset of patients present with rapidly advancing, widespread disease that usually affects
the distal limbs first, spreads proximally to the
trunk and face, and spares the back. Scleroderma begins as an inflammatory process that is
commonly characterized by pitting edema and
then transforms into a fibrotic skin disease that
is often associated with intense hyperpigmentation, inflammatory joint disease, and eventually,
joint contractures. Examination of skin-biopsy
specimens often reveals dermal fibrosis with dense
extracellular matrix, a mild perivascular inflammatory infiltrate, and no excess mucin. This patient
had many features of scleroderma; however, the
mucin deposition that was seen on histopathologic
examination would be atypical of this diagnosis.
Summary
of
m e dic i n e
mary scleroderma-related heart disease and are

at increased risk for concomitant cancer and
scleroderma.23
I suspect that a diagnostic test for the detection of anti-RNA polymerase III antibodies was
performed in this case; a positive test would confirm the clinical diagnosis of scleroderma. It is
possible that examination of a tissue-biopsy specimen revealed the presence of gadolinium, the
cause of nephrogenic systemic fibrosis, but this
is doubtful. I considered thrombotic thrombocytopenic purpura as an explanation of the patients
central nervous system and renal disease, but this
diagnosis would not explain the previous findings of the skin, joints, and other organ systems.
In making a diagnosis of scleromyxedema, it
would be necessary to perform a kidney biopsy
to look for mucin deposition in renal vessels. My
diagnosis in this patient with multiple myeloma
that has been previously treated and is in remission is scleroderma.
Dr. Eric S. Rosenberg (Pathology): Dr. Friday, what
was your impression when you evaluated this
patient?
Dr. Robert P. Friday: The patient had a history of
multiple myeloma and had multisystem disease
with prominent and rapidly progressive skin fibrosis, and these factors guided the initial decision to
administer IVIG for suspected scleromyxedema.
However, there were a number of competing diagnostic considerations. The detection of interstitial fibrosis on lung imaging in a patient with
progressive dyspnea and bleeding due to gastric
antral vascular ectasia increased our suspicion
for scleroderma. At the time of admission, the
findings in the urinary sediment and the relative
hypotension in the presence of altered mental
status and acute kidney injury supported a diagnosis of acute tubular necrosis, but the presence
of schistocytes and thrombocytopenia on the
peripheral-blood smear raised concerns about
scleroderma renal crisis. The patient had also
received prednisone, and the administration of
prednisone is a known risk factor for scleroderma renal crisis, including normotensive scleroderma renal crisis.24
I think the differential diagnosis narrows to two

similar but discrete clinical syndromes: scleroderma and scleromyxedema (Table2). The finding of mucin deposition on examination of the
skin-biopsy specimen argues against a diagnosis
of scleroderma. However, I think scleroderma is
likely, given the overall clinical features (including
interstitial lung disease, bleeding due to gastric
antral vascular ectasia, inflammatory joint disease
with limitations of motion, and rapidly emerging
diffuse, hyperpigmented, fibrotic skin disease
without papules). The event that led to his last
presentation to the hospital was probably scleroderma renal crisis. Normotensive scleroderma renal crisis has been reported, but this patient was
probably dehydrated, and cardiac dysfunction
could have accounted in part for his hypotension. A subset of patients with scleroderma and
anti-RNA polymerase III antibodies present with
rapid diffuse skin disease, fibrosis of deep soft
tissue, friction rubs, and joint contractures. They
Cl inic a l Di agnosis
are unlikely to have clinically significant interstitial lung disease but are at high risk for sclero- Diffuse systemic sclerosis (scleroderma), with
derma renal crisis (20%).22 They often have pri- scleroderma renal crisis.
1064

Table 2. Clinical, Laboratory, and Histologic Features of Scleroderma, Scleromyxedema, and This Case.*
Feature
Scleroderma
Scleromyxedema
This Case
Distal, pigmented
Papular, facial
Distal, pigmented
Arthritis
Common
Common
Lung, heart, and gastrointestinal manifestations
Common
Common
Monoclonal gammopathy of undetermined

significance
Reported
Clinical and laboratory

Skin disease
Multiple myeloma
Present
Interstitial lung disease and
gastric antral vascular
ectasia
Present in almost every case

(usually IgG)
Reported
Absent
Reported
Present (in remission)
Raynauds phenomenon
Present in 95% of cases
Reported
Absent
Renal crisis with thrombotic microangiopathic anemia
Scleroderma renal crisis in

710% of cases
Reported
Present
Antinuclear antibodies
Present in 95% of cases
Reported
Positive at 1:1280
Anti-RNA polymerase III antibodies
Present in 425% of cases,

highly specific
Absent
Present
Present
Present
Histologic
Dermal expansion
Present
Periadnexal fat loss
Present
Absent
Present
Fibroblast cellularity
Decreased
Increased
Decreased
Present (in pools)
Present
Mucin deposition
None (usually) or mild
Epidermis
Normal or atrophic
Normal
Normal
Present
Absent
Present
Lymphoplasmacytic
Lymphoplasmacytic
Involvement of subcutaneous tissue

Inflammation
Lymphoplasmacytic histiocytes
Elastic fibers
Straight, parallel
CD34+ dermal cells
Fragmented, reduced in
number
Loss
Straight, parallel
Mild increase
Loss
* Data are from Boin and Hummers,10 Kucher et al.,13 Nashel and Steen,14 Rongioletti et al.,15 Walters et al.,16 Aiba et al.,17 Khandpur et al.,18
Stone,19 Steen,20 and Chung and Utz.21
Dr . Fr edr ick W igl e y s Di agnosis

Systemic sclerosis (scleroderma) in a patient with
multiple myeloma that has been treated and is in
remission.
Pathol o gic a l Discussion

Dr. Nazarian: Fibrosing dermopathies are a group
of diseases with overlapping clinicopathological
features.10,13-15,25-27 Assessment of subcutaneous
involvement and dermal fibroblast cellularity on
routine histologic examination can help to differentiate among these conditions. Useful ancillary studies (which were performed in this case)
include colloidal iron staining to assess for mucin deposition, elastic-tissue staining to assess
the quality and quantity of elastic fibers, and

immunohistochemical staining to assess for
CD34 expression in dermal spindle cells.16,17
In this case, serologic studies were remarkable
for the presence of a high titer of antinuclear
antibodies (1:1280), a positive titer of anti-RNA
polymerase III antibodies (>80; normal titer, <20)
and negative titers of antibodies to Scl-70 (topoisomerase I) and RNP. In addition to these serologic test results, key findings were a fibrosing
dermopathy with subcutaneous involvement, areas of dermal hypocellularity, and periadnexal
fat loss, all in the presence of diffuse skin tightening involving the arms and legs, renal crisis,
and gastric antral vascular ectasia (Table2). A
few atypical features, including a paraproteinemia and mucin deposition with no evidence of

1065
The
of
m e dic i n e
Raynauds phenomenon or nailfold capillary abnormalities, led to some diagnostic confusion

and underscored the multidisciplinary diagnostic challenge in this case. Ultimately, correlation
of the histopathological features with clinical history and laboratory findings established the final anatomical diagnosis of scleroderma.
the patient was found unresponsive and pulseless.

No resuscitation efforts were pursued, in accordance with the patients wishes.
Dr. John H. Stone (Medicine): Why did pharyngeal dysfunction develop very late in the course
of this patients disease?
Dr. Wigley: Swallowing difficulties can be seen
in a subset of patients with scleroderma with very
rapid, diffuse involvement of the head, neck, and
Discussion of M a nagemen t
face. There are two problems: one is difficulty with
a nd Fol l ow-up
initiation of swallowing, and the other is dysphaDr. Rosenberg: Dr. Friday, would you tell us what gia due to esophageal dysfunction. Patients who
happened with this patient?
have trouble with initiation of swallowing have
Dr. Friday: The patient was initially treated pharyngeal involvement due to either inflammawith intravenous fluids. Renal biopsy was con- tory myositis or fibrosis of soft tissue.
sidered, but it was decided that the results would
probably not influence therapy and the proceFina l Di agnosis
dure would expose this critically ill patient to
unnecessary risk. Hemodialysis was initiated, Scleroderma.
and low doses of enalapril were administered.
This case was presented at the Medical Case Conference.
Dr. Wigley reports receiving consulting fees from Eiger BioThe patients mental status improved dramatically
pharmaceuticals and grant support from Actelion Pharmaceutiwith hemodialysis, but over a period of several cals, MedImmune, Novartis, United Therapeutics, CSL Behring,
days there was no meaningful recovery of renal Sanofi Aventis, and HoffmannLa Roche; and Dr. Shepard, refunction. Despite having clearer mentation, the ceiving consulting fees for providing expert testimony in a legal
case regarding thoracic imaging. No other potential conflict of
patient had severe swallowing difficulties; on video interest relevant to this article was reported.
fluoroscopic evaluation, marked pharyngeal dysDisclosure forms provided by the authors are available with
function was present, and thus a gastric tube was the full text of this article at NEJM.org.
We thank Dr. John H. Stone for his help in organizing this
placed. He was transferred to a rehabilitation fa- conference and with the preparation and editing of the case
cility for further care. Four days after discharge, history.
References
1. Piera-Velzquez S, Sandorfi N, Jimnez SA. Nephrogenic systemic fibrosis/
nephrogenic fibrosing dermopathy: clinical aspects. Skinmed 2007;6:24-7.
2. Yaqub A, Chung L, Rieger KE, Fiorentino DF. Localized cutaneous fibrosing
disorders. Rheum Dis Clin North Am
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3. Muldrow ML, Bailin PL. Scleromyxedema associated with IgG lambda multiple myeloma. Cleve Clin Q 1983;50:189-95.
4. Rongioletti F, Rebora A. Updated
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5. Rongioletti F, Merlo G, Cinotti E, et
al. Scleromyxedema: a multicenter study
of characteristics, comorbidities, course,
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6. Blum M, Wigley FM, Hummers LK.
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intravenous immunoglobulin (IVIG).
Medicine (Baltimore) 2008;87:10-20.
7. Kantor GR, Bergfeld WF, Katzin WE,
et al. Scleromyxedema associated with
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scleroderma renal disease and acute psychosis. J Am Acad Dermatol 1986;14:87988.

8. Gwinner W, Erdbruegger U, Mengel
M, et al. Scleroderma-like acute renal crisis in a patient with scleromyxedema.
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9. Lee YH, Sahu J, OBrien MS, DAgati
VD, Jimenez SA. Scleroderma renal crisislike acute renal failure associated with
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10. Boin F, Hummers LK. Sclerodermalike fibrosing disorders. Rheum Dis Clin
North Am 2008;34:199-220.
11. Boin F, Wigley F. Clinical features and
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Budd R, Gabriel S, McInnes I, ODell J,
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12. Bonifazi M, Tramacere I, Pomponio
G, et al. Systemic sclerosis (scleroderma)
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17. Aiba S, Tabata N, Ohtani H, Tagami
H. CD34+ spindle-shaped cells selectively
disappear from the skin lesion of scleroderma. Arch Dermatol 1994;130:593-7.
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Gupta R, Singh MK. Linear morphea with
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Medsger TA Jr. Normotensive renal failure
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Copyright 2015 Massachusetts Medical Society.
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Case 8-2015, A 68-Year-Old Man With Multiple Myeloma, Skin Tightness, Arthralgias and Edema

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Case Records of the Massachusetts General Hospital

Case 8-2015: A 68-Year-Old Man with

Pr e sen tat ion of C a se

n engl j med 372;11nejm.org March 12, 2015

The New England Journal of Medicine

Case Records of the Massachuset ts Gener al Hospital

the red-cell indexes and results of liver-function

n engl j med 372;11nejm.org March 12, 2015

The New England Journal of Medicine

Vitamin B12 (pg/ml)

This Hospital, This Hospital, This Hospital,

Estimated GFR (ml/

Urea nitrogen (mg/dl)

Erythrocyte sedimentation rate

Platelet count (per mm

Differential count (%)

Table 1. Laboratory Data.*

n engl j med 372;11nejm.org March 12, 2015

The New England Journal of Medicine

This Hospital, This Hospital, This Hospital,

0900 (in persons 50

Free lambda light chain

Free kappa light chain

Serum protein electrophoresis

Antibodies to doublestranded DNA

Case Records of the Massachuset ts Gener al Hospital

n engl j med 372;11nejm.org March 12, 2015

The New England Journal of Medicine

Figure 1. Skin-Biopsy Specimen.

n engl j med 372;11

March 12, 2015

The New England Journal of Medicine

Case Records of the Massachuset ts Gener al Hospital

tation, prednisone was administered for persistent

discomfort and inability to bend his joints and

Are the features of this patients illness a direct

n engl j med 372;11nejm.org March 12, 2015

The New England Journal of Medicine

Figure 2. CT Scans of the Chest.

ally involves proximal joints; the skin and joint

as the diffuse skin involvement that was described

n engl j med 372;11

Is this patients disease a consequence of toxic

March 12, 2015

The New England Journal of Medicine

Case Records of the Massachuset ts Gener al Hospital

the arms and trunk, and spare the face. Severe

Scleredema is a disorder that is characterized by

anemia, including narrowed glomerular capillaries, endothelial proliferation, and microthrombi,

Figure 3. Gastric-Biopsy Specimen (Hematoxylin and

March 12, 2015

The New England Journal of Medicine

pathic anemia, pulmonary hypertension, cardiac

mary scleroderma-related heart disease and are

I think the differential diagnosis narrows to two

n engl j med 372;11nejm.org March 12, 2015

The New England Journal of Medicine

Case Records of the Massachuset ts Gener al Hospital

Lung, heart, and gastrointestinal manifestations

Monoclonal gammopathy of undetermined

Clinical and laboratory

Present in almost every case

Present (in remission)

Present in 95% of cases