The n e w e ng l a n d j o u r na l of
case records of the massachusetts general hospital
From the Boston Veterans Affairs Health-
care System and the Jerome Lipper Cen-
ter for Multiple Myeloma, Dana–Farber
Cancer Institute (N.C.M.); the Depart-
ments of Radiology (S.D.) and Pathology
(A.R.), Massachusetts General Hospital;
and the Departments of Medicine (N.C.M.),
Radiology (S.D.), and Pathology (A.R.),
Harvard Medical School — all in Boston.
N Engl J Med 2008;358:1838-48.
Copyright © 2008 Massachusetts Medical Society.
1838
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m e dic i n e
Founded by Richard C. Cabot
Nancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Associate Editor
Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor
Sally H. Ebeling, Assistant Editor Christine C. Peters, Assistant Editor
Case 13-2008: A 46-Year-Old Man with
Rheumatoid Arthritis and Lymphadenopathy
Nikhil C. Munshi, M.D., Subba Digumarthy, M.D., and Aliyah Rahemtullah, M.D.
Pr e sen tat ion of C a se
Viviany Taqueti (Harvard Medical School): A 46-year-old man was seen in the hema-
tology–oncology clinic of a cancer center affiliated with this hospital because of
anorexia and generalized lymphadenopathy.
The patient had a history of rheumatoid arthritis but had been otherwise well
until 1 month earlier, when diffuse lymphadenopathy gradually developed in his
neck, axillae, and groin, associated with sore throat and loss of appetite but not
with weight loss. Approximately 1 week before this evaluation, fatigue, nausea,
bloating, loose stools, and a cough productive of white sputum developed. On
examination by his primary care physician 5 days before this evaluation, the patient’s
blood pressure was 118/70 mm Hg, the pulse 108 beats per minute, the tempera-
ture 37.3°C, and the oxygen saturation 98% while he was breathing ambient air.
White lesions were present laterally on the tongue, and there were enlarged, tender
lymph nodes, up to 2 cm in diameter, in the right submandibular, bilateral anterior
cervical, left posterior cervical, and both axillary regions. The remainder of the
examination was normal. The results of laboratory tests are shown in Table 1. Oral
nystatin was prescribed. The patient returned the next day, with wheezing and
purulent nasal discharge; on examination, there was tenderness over the maxillary
sinuses and serous effusions behind the tympanic membranes. The lymphadenopa-
thy had decreased slightly. The chest was clear on auscultation. A chest radiograph
revealed prominence of the pulmonary hila and superior mediastinum, suggestive
of lymphadenopathy, and biapical pleural thickening and bibasilar parenchymal
scarring that were unchanged from a study 16 months earlier. Treatment with
levofloxacin was begun.
The next day, computed tomographic (CT) scanning of the chest, abdomen, and
pelvis after the intravenous administration of contrast material showed enlarged
lymph nodes, ranging from 5 mm to 2.5 cm in diameter, in the bilateral supracla-
vicular, axillary, hilar, internal and external iliac, and inguinal regions; the medias-
tinum; and the retroperitoneum. Some of the axillary lymph nodes contained lucent
centers, suggesting necrosis. There was basilar and biapical pulmonary fibrosis,
and two subpleural pulmonary nodules on the right side, each 9 mm in diameter,
were evident. A rounded density, 2.5 cm in diameter, was present posterior to the
n engl j med 358;17  www.nejm.org  april 24, 2008
 case records of the massachuset ts gener al hospital
stomach, and the colonic wall was thickened. The
patient was referred to a hematologist–oncologist.
The patient reported no shortness of breath or
chest pain. Rheumatoid arthritis had been diag-
nosed 31/2 years earlier, manifested as morning
stiffness, joint pain, and swelling mostly in the
hands and feet, decreased range of motion in the
hips and lumbar spine, and positive serologic
tests (Table 1). At the age of 18 years, the patient
had pain and swelling in the right elbow and
both ankles; juvenile rheumatoid arthritis was
diagnosed. The symptoms resolved spontaneously
when the patient was in his early 20s. A diagno-
sis of ankylosing spondylitis was also mentioned
to him, but he did not recall back pain, iritis,
aphthous ulcers, dysuria, or rash. At the age of
32 years, an enlarged spleen (measuring 19 cm
in length by ultrasonography) had been found in­
cidentally during evaluation for acute cholecysti-
tis; splenectomy and cholecystectomy were per-
formed. On pathological examination, the spleen
weighed 400 g, with fibrocongestive changes and
reactive lymphoid hyperplasia. Pathological exam­
ination of a biopsy specimen of the bone marrow
showed no abnormalities.
Symptoms of rheumatoid arthritis were con-
trolled with prednisone, methotrexate, folic acid,
nonsteroidal antiinflammatory medications, and
leflunomide. Nineteen months before this eval-
uation, cutaneous lesions had developed on sun-
exposed areas; examination of a biopsy specimen
showed changes consistent with subacute cutane-
ous lupus erythematosus. Methotrexate was dis-
continued, and hydroxychloroquine was added;
the skin lesions resolved. One year before this
evaluation, corticosteroids were discontinued be-
cause of recurrent oral candidiasis.
Routine laboratory monitoring revealed fluctu-
ating and intermittently low leukocyte counts
(Table 1). Three months before this evaluation,
the patient had been referred to the hematolo-
gist–oncologist for evaluation of neutropenia.
Examination of a peripheral-blood smear revealed
Howell–Jolly bodies; test results for antibodies to
the human immunodeficiency virus (HIV) and
hepatitis A, B, and C viruses were negative; serum
levels of calcium, phosphorus, protein, and albu-
min and tests of liver and renal function were
normal; other laboratory-test results from this
earlier evaluation are shown in Table 1. Flow-
cytometric analysis of peripheral-blood lympho-
cytes was normal. A scan of the liver and spleen
n engl j med 358;17  www.nejm.org  april 24, 2008
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showed no evidence of an accessory spleen. The
neutropenia was thought to be related to the pa-
tient’s medications, and he was advised to discuss
possible changes in therapy with his rheumatol­
ogist.
The patient had occasional gastroesophageal
reflux that was relieved by pantoprazole. A tonsil-
lectomy had been performed in childhood. He
had no drug allergies. He had received pneumo-
coccal vaccine after the splenectomy. He was mar-
ried, had been monogamous with his wife for
more than a decade, and did not smoke or drink
alcohol. He worked as a painter and had not
traveled recently. There was no family history of
autoimmune disease or hematologic cancer. Med-
ications included hydroxychloroquine, lefluno-
mide, meloxicam, pantoprazole, folic acid, and
levofloxacin; he had never received tumor necro-
sis factor antagonists.
On examination, the blood pressure was
120/60 mm Hg, and the weight 68.2 kg. There
were enlarged, mobile, nontender lymph nodes in
the cervical, supraclavicular, axillary, and ingui-
nal regions, which were larger on the left side
than on the right; an axillary node on the left
side was 4 cm in diameter. The remainder of the
examination was normal. The prothrombin time,
partial-thromboplastin time, and test results for
lupus anticoagulant were normal.
One week later, a diagnostic procedure was
performed.
Differ en t i a l Di agnosis
Dr. Nikhil C. Munshi: May we review the imaging
studies?
Dr. Subba Digumarthy: Axial CT studies of the
chest, abdomen, and pelvis performed after the
intravenous administration of contrast material
show enlarged lymph nodes in the supraclavicu-
lar fossae, axillae, and mediastinum, as well as
in the para-aortic, external iliac, and inguinal
regions (Fig. 1A). Small areas of decreased en-
hancement in the center of some lymph nodes
suggest necrosis. The spleen is absent. In the
splenectomy bed, there are surgical clips and an
enhancing soft-tissue nodule; the imaging fea-
tures are consistent with an accessory spleen
(Fig. 1B).
There are multiple reticular opacities in the
lung apexes, associated with architectural distor-
tion and mild bronchiectasis, and ground-glass
1839
 Table 1. Laboratory Data.

1840
Reference Range
Analyte for Adults* 3.5 Yr Earlier 19 Mo Earlier 8 Mo Earlier 3 Mo Earlier 4 Days Earlier
Hematocrit (%) 41.0–53.0 40.3 42 42.9 44.5
Hemoglobin, whole blood (g/dl) 13.5–17.5 13.6 14.1 14.3 14.8
White-cell count (per mm3) 4000–11,000 5,200 2,900 3,600 8,800
Differential count (%)
Neutrophils 44–75 77 19 17 42
Band forms 0–10 0 4 21
Lymphocytes 15–45 10 47 62 16
Monocytes 0–15 12 34 14 16
Eosinophils 0–6 0 2 5
Basophils 0–2 1 0 0
The

Atypical lymphocytes 0 1
Erythrocyte sedimentation rate (mm/hr) 0–17 Normal 38 34
Platelet count (per mm3) 165,000–400,000 344,000 259,000 271,000
γ-Glutamyl transpeptidase (U/liter) 0–40 44
Lactate dehydrogenase (U/liter) 0–250 222
Herpes simplex virus
Type 1 IgG Positive
Type 1 IgM Negative
Type 2 IgG Negative
n e w e ng l a n d j o u r na l

Type 2 IgM Negative

of

Lyme IgG–IgM <0.75 (negative) <0.75 0.05

Monospot test for heterophile antibody Negative
Rheumatoid factor (IU/ml) <30.0 314 568

n engl j med 358;17  www.nejm.org  april 24, 2008

Autoantibodies
m e dic i n e

Antinuclear antibody Negative at 1:40 Positive at 1:1280, Positive at 1:320, Positive at 1:640,
speckled pattern speckled pattern speckled pattern
Anti–double-stranded DNA antibody (U) <25 3.0 Negative
Anti–Jo-1 antibody IgG (U) <20 5.6
Anti-La antibody (U) <20 5.3
Anti-Ro antibody (U) <20 6.1
Anti-RNP antibody (U) <20 250.4 Positive

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Anti–scleroderma-70 antibody (U) <20 4.3
Anti-Smith antibody (U) <20 2.1
 case records of the massachuset ts gener al hospital

and reticular opacities in the lung bases, with

* Reference values were obtained at other laboratories and are affected by many variables, including the patient population and the laboratory methods used. They may therefore not be
2–3 ill-defined bands
architectural distortion and limited areas show-

of IgG, without
Monoclonal band
ing honeycombing (Fig. 1C). These findings are

light chains
408
2,180
104
most consistent with pulmonary fibrosis, proba-

3.6
0.4
1.0
1.5
0.6
bly related to rheumatoid arthritis. There are also
scattered pulmonary nodules, which could be
granulomas, hyperplastic intraparenchymal lymph
nodes, or tumors. These cannot be further char-
Normal pattern
acterized in a single study.
Dr. Munshi: The important clinical features of
this case are the rapid development of diffuse
generalized lymphadenopathy, without systemic
symptoms such as fever, night sweats, or weight
loss; a history of gastroesophageal reflux disease;
active autoimmune disease treated with cortico-
steroids and methotrexate; and a history of sple-
nectomy. An important laboratory result is the
presence of a monoclonal serum immunoglobu-
lin. The differential diagnosis consists of com-
plications of this patient’s autoimmune disease
or its treatment, including infections and lym-
phoproliferative disorders, as well as conditions
that may mimic or be associated with autoim-
mune disorders. It is useful to consider the dif-
ferential diagnosis in the absence of the informa-
tion provided by serum protein electrophoresis
and immunofixation and then to narrow the list of
201.1

11.5
4.8

possible diagnoses with these results in mind.

Indolent Lymphomas
The presence of generalized lymphadenopathy
without prominent systemic symptoms, a relative-
Normal pattern

ly normal complete blood count, and the relatively

694–1618

Negative

3.5–5.0
0.2–0.3
0.5–0.9
81–463

48–271

0.6–1.1
0.5–1.5
0–15
0–15
<20

low serum lactate dehydrogenase level suggest an

indolent lymphoma. The most common of these
† GPL denotes IgG phospholipid, and MPL IgM phospholipid.

disorders is follicular lymphoma. However, the

relatively rapid growth of this patient’s lymph
nodes is atypical of follicular lymphoma, and he
is also young for this disease — the median age
at onset is in the sixth decade.
This patient has a history of gastroesopha-
geal reflux disease, and he reported a loss of
appetite associated with the onset of lymphade-
Extractable nuclear antibody (U)

Serum protein electrophoresis

nopathy. Extranodal marginal-zone lymphoma of

appropriate for all patients.
Anticardiolipin antibodies†

mucosa-associated lymphoid tissue (MALT lym-

Immunoglobulin (mg/dl)

phoma) typically affects the stomach, where it is

Serum globulins (g/dl)
IgM (MPL units)
IgG (GPL units)

associated with Helicobacter pylori infection; how-

Immunofixation

ever, H. pylori infection is typically not associated

Albumin

with symptoms of gastrointestinal reflux disease,

Gamma
Alpha 1
Alpha 2

and the lymphomas that arise in the setting of

Beta
IgM
IgG
IgA

H. pylori infection are typically localized to the

stomach, rarely causing generalized lymphade-

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 The n e w e ng l a n d j o u r na l of m e dic i n e

young for Waldenström’s macroglobulinemia,

A since the median age at onset is in the seventh
decade, and this disorder is characterized by the
presence of an IgM rather than an IgG monoclo-
nal protein.

Aggressive Lymphomas
The relatively acute presentation and rapid growth
of lymphadenopathy raise the possibility of an
aggressive lymphoma, such as diffuse large-B-cell
lymphoma or classic Hodgkin’s lymphoma. These
B
diseases are more likely than indolent lympho-
mas to occur in relatively young patients, such as
the patient under discussion. The appearance of
a central area of necrosis within some of the
lymph nodes on the CT scan would be more typ-
ical of an aggressive lymphoma than an indolent
lymphoma. Patients with an autoimmune disease
— such as this patient, who has rheumatoid ar-
thritis and systemic lupus erythematosus — may
C be at increased risk for aggressive non-Hodgkin’s
lymphomas.
In addition to the risk associated with auto-
immune disease, this patient may be in an im-
munosuppressed state because of the use of drugs
such as methotrexate or tumor necrosis factor
antagonists to treat the autoimmune disorder.
Patients with iatrogenic immunodeficiency are at
increased risk for the development of aggressive
lymphomas, including both Hodgkin’s lymphoma
Figure 1. Radiologic Images. and diffuse large-B-cell lymphomas, which are
Panel A shows multiple enlarged lymph nodes (arrows) usually associated with Epstein–Barr virus infec-
in both AUTHOR: Munshi RETAKE
ICM axillae. Panel B shows an enhancing soft-tissue
1st

nodule FIGURE:
REG F (arrow) in 1a-c of 4
the splenectomy bed, which is con-
2nd tion. Aggressive lymphomas most often present
sistent
CASE with a splenule. Panel C shows subpleural
Revised
3rd
with localized rather than generalized lymphade-
ground-glass
EMail opacities4-C
and reticular Line in the lungs
SIZE(ar- nopathy, and when the disease is generalized, the
ARTIST: mst H/T H/T
rows)
Enonwith architectural distortion, findings 16p6
Combo
that are lactate dehydrogenase level is often elevated, and
consistent with pulmonary fibrosis. systemic symptoms are typically more severe than
AUTHOR, PLEASE NOTE:
Figure has been redrawn and type has been reset. those in this patient, often including fevers, night
Please check carefully.
nopathy. MALT lymphoma of nongastric sites is sweats, and weight loss. This patient had received
frequently
JOB: 35817 associated with autoimmune disease,
ISSUE: 4-24-08 methotrexate but not tumor necrosis factor an-
such as Sjögren’s syndrome and Hashimoto’s tagonists, and both methotrexate and prednisone
disease; however, it is not characteristically asso- had been discontinued long before the onset of his
ciated with rheumatoid arthritis and involves symptoms; thus, an immunosuppression-related
extranodal sites, such as the salivary gland or lymphoma seems unlikely.
thyroid. Presentation with rapidly enlarging lymph-
adenopathy would be uncommon. Infections
Lymphoplasmacytic lymphoma, which is typ- Immunodeficiency due to the use of methotrexate
ically associated with Waldenström’s macroglob- and corticosteroids may predispose patients to
ulinemia, may present with generalized lymph- opportunistic infections. Tuberculosis, viral infec-
adenopathy in a patient who is otherwise tions, and fungal infections are possible in this
relatively well, and it often has a monoclonal pro- patient with generalized lymph-node enlargement
tein on serum electrophoresis. This patient is and a history of infections, including oral candi-

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 case records of the massachuset ts gener al hospital

diasis. However, the absence of fever and leuko-
cytosis argues against the presence of a systemic
infection. Although patients taking high doses of
immunosuppressive medications such as cortico-
steroids may not have fever despite severe infec-
tions, this patient had discontinued the use of
prednisone. There is no serologic evidence of an
acute viral infection.
Castleman’s Disease
Multicentric Castleman’s disease, often a result
of infection with human herpesvirus 8, can be
manifested as generalized lymphadenopathy
and can be associated with HIV infection; it may
be associated with an IgG paraprotein.1 Anemia,
thrombocytosis, an elevated erythrocyte sedimen-
tation rate, hypoalbuminemia, and polyclonal
hypergammaglobulin­emia are commonly seen;
although this patient’s erythrocyte sedimentation
rate is slightly elevated, none of the other find-
ings apply.
Monoclonal Gammopathy
The results of serum protein electrophoresis or-
dered by the patient’s primary care physician
shortly before his evaluation by a hematologist–
oncologist showed a spike in the gamma region,
which is consistent with the presence of a mono-
clonal immunoglobulin. Many conditions (Table 2)
are associated with the presence in the blood of
a monoclonal protein composed of intact immu-
noglobulin molecules, with both heavy and light
chains. Free light chains may be seen in the blood
together with intact immunoglobulin molecules
or, less commonly, alone, particularly in patients
with plasma-cell myeloma. In this case, immuno-
fixation was reported to show the presence of
gamma heavy chains, without corresponding light
chains. The presence of free heavy chains in the
blood, without light chains, is the defining fea-
ture of heavy-chain diseases.2,3
An immunoglobulin molecule is composed of
two heavy chains and two light chains, which are
joined by disulfide bonds (Fig. 2). The normal
heavy-chain constant region has three domains
(CH1-CH3); of those, CH1 is responsible for bind-
ing to the light chain. In the absence of an as-
sociated light chain, the CH1 domain binds to
heat-shock protein 78 (hsp 78) and undergoes pro-
teasomal degradation; it is thus not secreted.4
Normal heavy chains not associated with light
chains have never been detected in serum. In
heavy-chain diseases, noncontiguous deletions
in the switch–CH1 region prevent binding to the
hsp 78 protein and degradation in the absence of
a light chain (Fig. 2).2
Heavy-chain diseases (Table 3) are rare variants
of B-cell lymphomas that produce one of three
classes of immunoglobulin heavy chains: alpha,
mu, or gamma.5,6 Alpha heavy-chain disease, also
known as immunoproliferative small intestinal
disease, is a form of MALT lymphoma that devel-
ops in the small intestine in young adults living
in conditions of poor sanitation7,8; it may respond
in its early stages to treatment with antibiotics,
and Campylobacter jejuni infection has been impli-
cated in its pathogenesis.9 Mu heavy-chain disease
is an extremely rare disorder with clinical features
that resemble chronic lymphocytic leukemia and
distinctive vacuolated lymphocytes in the bone
marrow.10 Gamma heavy-chain disease, which is
intermediate in frequency between alpha and mu

Table 2. Causes of Monoclonal Proteins in Serum.

Condition Paraprotein (Typical) Clinical Features

Multicentric Castleman’s disease
Monoclonal gammopathy of unknown
­significance
Plasma-cell myeloma
Chronic lymphocytic leukemia
Lymphoplasmacytic lymphoma
Splenic marginal-zone lymphoma
Heavy-chain diseases*
IgG or IgA, lambda HIV and human herpesvirus 8 infections, gen-
eralized lymphadenopathy, splenomegaly
IgG, IgA, IgM, kappa or lambda Asymptomatic
IgG, IgA, free light chains (kappa or lambda) Bone lesions, decreased normal immuno-
globulins, anemia, renal failure
IgM, low level Lymphocytosis, anemia, lymphadenopathy
IgM, often high level Anemia, hyperviscosity, lymphadenopathy
IgM, low level Splenomegaly, anemia, lymphocytosis
Free abnormal alpha, mu, or gamma heavy chains

* Clinical features of heavy-chain diseases are provided in Table 3.

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 The n e w e ng l a n d j o u r na l of m e dic i n e

systemic lupus erythematosus, Sjögren’s syndrome,

Variable size and myasthenia gravis.11,13 Autoimmune manifes-
Antigen-
deletion in HCD binding tations often precede the diagnosis of lymphoma,
H H site in some cases by up to several years. The clinical
NH2 Light-chain–
L binding site: NH2
L
course may be indolent, resembling monoclonal
R1
CD R 2 deleted VH gammopathy of unknown significance, or aggres-
CD R 3
CD in HCD D
JH H
sive, involving bone marrow and other tissues.
VL
My diagnosis is gamma heavy-chain disease,
CH1 CH1
s s– JL associated with rheumatoid arthritis. The diag-
CL s– s–s s
CL nostic procedure was probably a biopsy of an en­
s–s larged lymph node or the bone marrow, and I
s–s
predict it would show some variant of lympho-
Complement- plasmacytic lymphoma, with plasma cells produc­
CH2 binding site ing gamma heavy chains without light chains.
Dr. Nancy Lee Harris (Pathology): Are there any
questions for Dr. Munshi?
Dr. Ronald S. Weinger (Hematology–Oncology,
CH3 Fc-receptor–
binding site
North Shore Cancer Center): What do you think
COOH about the radiologist’s description of an accessory
COOH spleen?
Dr. Munshi: Splenic involvement is seen in most
Figure 2. Structure of the Immunoglobulin Molecule in Heavy-Chain Disease.
COLOR FIGURE
patients with gamma heavy-chain disease. If the
An immunoglobulin molecule is composed of two heavy chains (H) and two
Draft 7 4/8/08 accessory spleen has enlarged recently, it could
light chains (L), which are joined by disulfide bonds (S–S). The normal heavy-
chain constant region has three constant domains:FigCH1
Author Munshi
is responsible for be involved in the disease process.
# 2
binding to the light chain, CH2 for binding to complement,
Title and CH3 for
Immunoglobulin Structures
A Physician: Do you think the history of a large
binding to Fc receptors. In the absence of an associated
ME light chain, the CH1
Koopman spleen is related to this diagnosis?
Harris
domain binds to heat-shock protein 78 and undergoes DE proteasomal
Artist KMK
degrada- Dr. Munshi: Although it is theoretically possible
tion; thus, normal free heavy chains are not secreted. In heavy-chain diseases
AUTHOR PLEASE NOTE: that the history of a large spleen is related, the
(HCDs), noncontiguous deletions in the CH1 domainFigure prevent both
has been redrawn andbinding
type has been reset

of the heavy chain to the light chain and degradationIssueindate

Please check carefully
the proteasome,
4/24/08
free heavy chains are secreted. Variable-sized deletions also occur in the
heavy-chain diversity region (DH), the heavy-chain joining region (JH), and
the heavy-chain variable region (VH). CDR denotes complementarity-deter-
mining region, CL light-chain constant region, COOH carboxyl terminal, JL light-
chain joining region, NH2 amino terminal, and VL light-chain variable region.
heavy-chain diseases, is typically associated with
a systemic lymphoma. 11
Gamma Heavy-Chain Disease
In this patient, the presence of gamma heavy
chains without light chains strongly suggests the
diagnosis of gamma heavy-chain disease. Since
it was first reported in 1964 by Franklin12 (it is
also known as Franklin’s disease), only about 130
cases have been reported in the literature. Patients
typically present with generalized lymphadenop-
athy, splenomegaly, and anemia and occasionally
with palatal and uvular swelling. Almost one
third of patients have a history of autoimmune
disease. The most common is rheumatoid arthri-
tis; others include autoimmune hemolytic anemia,
idiopathic thrombocytopenic purpura, vasculitis,
and time from splenectomy to the current diagnosis
(14 years) argues against this possibility.
Dr. Hasan Bazari (Medicine): Is there any asso-
ciation between hepatitis C virus, Epstein–Barr
virus, or human herpesvirus 8 and gamma heavy-
chain disease?
Dr. Munshi: Not that I am aware of. The major-
ity of the reports of heavy-chain disease were
before 1980, when the role of hepatitis C virus
in lymphoproliferative disorders was not under-
stood and human herpesvirus 8 had not yet been
described; in reports since that time, I am not
aware of the results of testing for these viruses.
Dr. Harris: Dr. Weinger, would you summarize
your thinking at the time you saw the patient?
Dr. Weinger: I thought his persistent neutrope-
nia might be due to autoimmune neutropenia,
associated with his rheumatoid arthritis, despite
the fact that his spleen had been removed. When
he returned with generalized lymphadenopathy,
I believed that he probably had a lymphoma.
When I saw him in the office, I did not have the
results of the serum protein electrophoresis and
immunofixation. I requested an excisional biopsy

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 case records of the massachuset ts gener al hospital

Table 3. Heavy-Chain Diseases.*

Heavy-Chain Disease Associated Lymphoma Features

Alpha (immuno­ Extranodal marginal-zone B-cell
proliferative small lymphoma of mucosa-associat-
intestinal disease) ed lymphoid tissue (MALT
lymphoma)
Gamma Lymphoplasmacytic lymphoma
Mu Chronic lymphocytic leukemia
Most common of the three heavy-chain diseases, com-
mon in Mediterranean regions, involvement of small
intestine, associated with intestinal parasites and
Campylobacter jejuni infection, may be responsive to
antibiotics early in course, may progress to diffuse
large-B-cell lymphoma
Widespread involvement of bone marrow, lymph nodes,
and spleen; associated with constitutional symptoms,
anemia, eosinophilia, and autoimmune conditions
Rarest of the three heavy-chain diseases, systemic lym-
phoma with hepatosplenomegaly and vacuolated
bone marrow plasma cells, free urinary light chains
produced in addition to abnormal serum mu chain

* Data are from Grogan et al.5 and Fermand et al.6

of one of the enlarged lymph nodes. When the nuclei — somewhat higher than would be expect-
results of the serum protein analysis became ed for a low-grade B-cell lymphoma.
available, it was clear that the likely diagnosis A bone marrow biopsy, performed approxi-
was gamma heavy-chain disease. mately 1 month after the lymph-node biopsy, re-
vealed normal overall cellularity, with a few small
Cl inic a l Di agnosis lymphoplasmacytic aggregates (Fig. 3E). In areas
away from aggregates, small, subtle plasma-cell
Gamma heavy-chain disease. clusters could be seen. Immunohistochemical
stains showed that the plasma cells were positive
dr . nik hil c . munshi’s Di agnosis for IgG but negative for both kappa and lambda
light chains (Fig. 3F).
Gamma heavy-chain disease. Four days before the patient saw the hema-
tologist–oncologist, Dr. Weinger, serum protein
Pathol o gic a l Dis cus sion electrophoresis revealed a distinct band in the
immunoglobulin region that was anodal with
Dr. Aliyah Rahemtullah: The diagnostic procedure respect to the point of origin, which was typed
was a biopsy of an enlarged 2-cm right cervical on immunofixation as IgG without a correspond-
lymph node; the specimen was sent to this hos- ing light chain (Fig. 4A). Urinary protein electro-
pital for pathological evaluation. The lymph-node phoresis performed at the time of the bone mar-
architecture was effaced by a diffuse, polymor- row biopsy revealed a dense monoclonal band,
phous proliferation of small and medium-sized which was also typed as IgG without an associ-
lymphoid cells, some with plasmacytic differenti- ated light chain (Fig. 4B). Gamma heavy chains
ation, plasma cells, and scattered large immuno- are too large to pass into the urinary space, even
blasts (Fig. 3A). Immunohistochemical stains dem­ in patients with elevated serum levels; this find-
onstrated a mixture of CD20-positive B cells and ing suggests either impairment of renal function
CD3-positive T cells (Fig. 3B); many cells were or alteration of the heavy-chain structure, such
negative for CD20 but expressed the plasma-cell– that it is truncated and able to pass into the uri-
associated antigens CD138 and multiple myeloma nary space.
oncogene 1 (MUM1) (Fig. 3C). Staining for im- The lymphoma associated with gamma heavy-
munoglobulin heavy chains showed that the vast chain disease typically involves hematopoietic
majority of plasma cells contained cytoplasmic tissues, including bone marrow, the spleen, and
IgG, whereas in situ hybridization for immuno- lymph nodes, as in this case,5 but it may be lo-
globulin light chains showed only scattered poly- calized and involve extrahematopoietic sites, in-
typic plasma cells (Fig. 3D). Ki-67, a proliferation cluding those often involved in MALT lymphoma,
marker, was positive in approximately 40% of such as the skin, thyroid, salivary glands, and

n engl j med 358;17  www.nejm.org  april 24, 2008 1845

Downloaded from www.nejm.org on June 13, 2010 . Copyright © 2008 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

A B C

D E F

Figure 3. Biopsy Specimens of the Right Cervical Lymph Node and Bone Marrow.
The lymph-node architecture is effaced by a polymorphous lymphoid population with a diffuse pattern of growth
(Panel A, hematoxylin and eosin). Lymphocytes include small, mature-appearing forms, plasmacytoid lymphocytes
with moderately abundant cytoplasm AUTHOR: Munshi RETAKE 1st
ICM and eccentric nuclei, and medium-sized cells with dispersed chromatin and
2nd
slight nuclear irregularities (PanelREG
A, Finset). Numerous
FIGURE: 3a-f of 4plasma cells (arrows in inset) and scattered large immuno-
3rd
blasts are also present. Immunohistochemical
CASE stains show that most of the lymphoid infiltrate is composed of
Revised
CD20-positive B cells, including the immunoblasts (PanelLine
EMail B, arrow),
4-Cwith fewer
SIZECD3-positive T cells (Panel B, inset).
The numerous plasma cells scattered ARTIST: mst
throughout the lymphH/Tnode H/T
are highlighted by the plasma-cell marker CD138
Enon 33p9
(Panel C). Immunohistochemical staining for heavy chainsCombo shows that the majority of plasma cells are IgG-positive
AUTHOR, PLEASE NOTE:
(Panel D), whereas in situ hybridization for immunoglobulin kappa light chains (left inset) and lambda light chains
Figure has been redrawn and type has been reset.
(right inset) shows only scattered polytypic plasma cells. The total number of cells staining for kappa and lambda
Please check carefully.
together appeared fewer than the number of IgG-positive plasma cells. The bone marrow–biopsy specimen has an
overall cellularity of 50%, whichJOB:
is appropriate
35817
for the patient’s age, with maturing trilineage hematopoiesis (Panel
ISSUE: 4-24-08
E, Giemsa stain). A few small aggregates composed of plasma cells and lymphocytes have displaced normal hema-
topoietic elements (arrow), accounting for approximately 5% of the overall marrow cellularity. Some plasma cells are
mature, whereas others are atypical with open chromatin (Panel E, inset). Immunohistochemical staining of the
specimen from the bone marrow core biopsy shows that the atypical plasmacytic aggregates are positive for CD138
and IgG (Panel F). Only scattered IgM-positive plasma cells are present. In situ hybridization for kappa and lambda
light chains showed scattered polytypic plasma cells, but the IgG-positive plasma cells within the small aggregates
were negative for both kappa and lambda light chains.

gastrointestinal tract.6 Skeletal involvement is
rare, and amyloid deposits are not found because
of the absence of light-chain production; gamma
heavy-chain disease, therefore, almost never
mimics multiple myeloma clinically.6
Pathological examination most commonly
demonstrates a mixed proliferation of lympho-
cytes, plasmacytoid lymphocytes, plasma cells,
and scattered immunoblasts, as were seen in this
case.6 These findings resemble those of lympho-
plasmacytic lymphoma; however, the infiltrate is
often more polymorphous, with more numerous
immunoblasts and medium-sized cells. Occasion-
ally, mature plasma cells predominate, or patients
may present with peripheral-blood lymphocyto-
sis.6,14 Unusual features, such as the presence of
cells resembling Reed–Sternberg cells, increased
eosinophils and histiocytes, and vascular prolif-
eration may give rise to the histologic differen-
tial diagnosis of Hodgkin’s lymphoma or certain
forms of T-cell lymphoma.6 Unlike alpha heavy-
chain disease, gamma heavy-chain disease only
rarely progresses to diffuse large-B-cell lympho-
ma.5,6,14 Because of the association of gamma
heavy-chain disease with rheumatoid arthri-
tis,6,14,15 the differential diagnosis may include

1846 n engl j med 358;17  www.nejm.org  april 24, 2008

Downloaded from www.nejm.org on June 13, 2010 . Copyright © 2008 Massachusetts Medical Society. All rights reserved.
 case records of the massachuset ts gener al hospital

the more common entity of rheumatoid-arthritis– A Serum

associated reactive lymphadenopathy, which may +
be generalized or located near the site of an in-
flamed joint and is characterized by follicular
hyperplasia.16
After the diagnosis was made, we reviewed the
prior splenectomy specimen, which revealed reac-
tive follicular hyperplasia, without morphologic
evidence of lymphoma; tissue was no longer O
available to assess immunoglobulin heavy-chain
and light-chain expression. A specimen from a
bone marrow biopsy at that time showed normal −
SPE IgG IgA IgM κ λ
hematopoiesis, without morphologic evidence of
lymphoma. The biopsy specimen of the skin ob- B Urine
tained 19 months earlier revealed dermatitis with +
features that were compatible with subacute cu-
taneous lupus erythematosus; however, the find-
ings were morphologically indistinguishable from
a drug hypersensitivity reaction.
In summary, several findings confirmed the
diagnosis of gamma heavy-chain disease. These
were the presence of free gamma heavy chains O
without corresponding light chains in serum and
urine and the involvement of lymph nodes and
bone marrow by a B-cell lymphoma with plasma- −
cytic differentiation, expressing gamma heavy UPE IgG IgA IgM κ λ

chains without light chains.

Figure 4. Results of Serum Protein Electrophoresis and Immunofixation
Dr. Harris: Dr. Munshi, what treatment would Performed 4 Days before Evaluation and Urinary Protein Electrophoresis
you recommend? and Immunofixation Performed
AUTHOR: at the Time of the Bone
Munshi Marrow
RETAKE 1st Biopsy.
ICM
Dr. Munshi: In some patients, the disease is Protein electrophoresis
REG F relies
FIGURE: 4 on
of the
4 separation of proteins 2nd
according to
3rd
indolent, and the patient can be followed with- properties of charge
CASE and size at pH 8.6 when a sampleRevised is applied at the ori-
out specific intervention. In a patient such as this gin (o) of an agarose
EMail gel. Most proteins are negatively
Line 4-C charged
SIZE at this pH
and migrate toward ARTIST:
the ts charged
positively H/T electrode
H/T (anode). The band in
one, with overt lymphoma, therapeutic interven- Enon
Combo
22p3
the most anodal position is albumin. Immunoglobulins are largely uncharged
tion may include cyclophosphamide, vincristine, at this pH and either remainAUTHOR,
around PLEASE NOTE:
the point of origin or migrate toward
and prednisone, with or without doxorubicin, Figure electrode
the negatively charged has been redrawn and type
(cathode) haswith
along beenthe
reset.
bulk flow of the
Please check carefully.
which have been used with some success.10,13 If buffer. In a patient who does not have a serum monoclonal component
the lymphoma cells express CD20, the anti-CD20 (M component), the expected polyclonal immunoglobulin pattern would
JOB: 35817 ISSUE: 4-24-08
be a faint, even smear across this region of the gel, without distinct bands.
monoclonal antibody, rituximab, may be useful;
However, in this patient, a distinct band was identified by serum protein
in one case, it appeared to be effective.14 The electrophoresis (SPE) in the immunoglobulin region anodal to the point of
prognosis is highly variable; in one review, sur- origin (Panel A, arrow). M components are characterized further by immuno-
vival ranged from 1 month to more than 21 years, fixation to identify the heavy and light chains that make up the paraprotein.
with a median of 7.4 years.14 In this patient, the M component typed as IgG (denoted by the band seen
in the IgG lane in Panel A), but without a corresponding light chain (only
Dr. Harris: Dr. Weinger, would you tell us how
faint polyclonal patterns can be seen in the kappa and lambda lanes in
you treated the patient? Panel A). Urinary protein electrophoresis (UPE) performed approximately
Dr. Weinger: I treated him with four weekly 1 month later revealed similar results (Panel B), with a broad monoclonal
doses of rituximab; within 2 weeks, the lymph- band corresponding to IgG, without a corresponding light chain. Calculated
adenopathy had disappeared and he felt better; total urinary IgG was approximately 225 mg per deciliter.
in retrospect, he felt he had been much sicker

n engl j med 358;17  www.nejm.org  april 24, 2008 1847

Downloaded from www.nejm.org on June 13, 2010 . Copyright © 2008 Massachusetts Medical Society. All rights reserved.
 case records of the massachuset ts gener al hospital

than we appreciated at the time of his presenta-
tion. I gave him four additional doses of ritux-
imab, ending 1 year after the diagnosis. Ten
months after the last dose of rituximab, both
the lymphoma and the rheumatoid arthritis were
in clinical remission. Repeated serum protein
electrophoresis showed a very faint band of free
gamma heavy chains. Testing for antibodies to
hepatitis C virus and human herpesvirus 8 was
negative.
Dr. Mandakolathur R. Murali (Medicine, Allergy):
The rheumatoid factor in this patient could be a
polyclonal IgM antibody directed at the abnormal
monoclonal heavy chain. It would be interesting
to look for anticyclic citrullinated peptide anti-
body, which is the hallmark of rheumatoid arthri-
tis. If that test is negative, he could actually have
a form of vasculitic rheumatoid-like arthritis.
Dr. Weinger: The test for anticyclic citrullinated
peptide IgG antibody was positive (at 34 U per
liter; normal range, 0 to 19) 6 months after his
last dose of rituximab.
A nat omic a l Di agnosis
Gamma heavy-chain disease and rheumatoid
arthritis.
Dr. Munshi reports receiving lecture fees from Celgene, Millen-
nium, and Novartis. No other potential conflict of interest relevant
to this article was reported.

References
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