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

case records of the massachusetts general hospital

Founded by Richard C. Cabot

Eric S. Rosenberg, m.d., Editor Nancy Lee Harris, m.d., Editor
Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor
Sally H. Ebeling, Assistant Editor Emily K. McDonald, Assistant Editor

Case 38-2013: A 30-Year-Old Man

with Fever and Lymphadenopathy
Alaka Ray, M.D., Victorine V. Muse, M.D., and Daniel F. Boyer, M.D., Ph.D.

Pr e sen tat ion of C a se

Dr. Jennifer M. Rosenbluth (Medicine): A 30-year-old man was seen in an outpatient From the Departments of Medicine (A.R.),
clinic at this hospital because of fever and lymphadenopathy. Radiology (V.V.M.), and Pathology (D.F.B.),
Massachusetts General Hospital, and the
The patient had been well until approximately 2 weeks before presentation, Departments of Medicine (A.R.), Radiology
when an enlarging, tender lump developed at the posterior base of the neck on the (V.V.M.), and Pathology (D.F.B.), Harvard
right side. Two days before presentation, fever to a temperature of 39.4°C, a mild Medical School — both in Boston.

headache, myalgias, chills, and fatigue developed. He took ibuprofen, but his con- N Engl J Med 2013;369:2333-43.
dition did not improve, and he came to this hospital for evaluation. DOI: 10.1056/NEJMcpc1310002
Copyright © 2013 Massachusetts Medical Society
The patient reported no history of sore throat, coryza, or earache. He had had
a low hemoglobin level in the past but was otherwise healthy. He reportedly had
had a negative tuberculin skin test in the past, and he had not received an influ-
enza vaccine during the previous year. He took no other medications and had no
known allergies. He was born in India and came to the United States 4 years previ-
ously to attend school; his most recent visit to India was 6 months before presenta-
tion. He worked in an office and lived with a roommate. He was not sexually active
and had no known exposures to sick contacts, animals, or blood products. He had
stopped smoking 2 years before this presentation, drank alcohol occasionally, and
did not use illicit drugs. His parents had diabetes mellitus; there was no family
history of autoimmune or connective-tissue diseases.
On examination, the temperature was 38.9°C, the blood pressure 129/80 mm Hg,
and the pulse 104 beats per minute. A group of five tender lymph nodes, each
approximately 1 cm in diameter, was present in the posteroinferior cervical chain on
the right side; the lymph nodes in the posterior cervical chain on the left side and
in both inguinal regions were nontender, and there were no abnormal lymph nodes
in the supraclavicular or axillary regions. A systolic ejection murmur (grade 1 out of 6)
was heard at the cardiac base; the remainder of the examination was normal. During
evaluation, the temperature rose to 39.5°C and was associated with chills. Blood
levels of glucose, total protein, albumin, and globulin were normal, as were results
of tests of liver and renal function; testing for heterophile antibodies and rapid
tests for streptococcal pharyngitis and influenza virus were negative. Additional
test results are shown in Table 1. A blood culture was sterile. The administration
of acetaminophen alternating with ibuprofen was recommended, as were fluids

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 2334
Table 1. Laboratory Data.*

On 2 Days after 4 Days after

Reference Presentation, Presentation, Presentation, on 2nd and 3rd
Variable Range, Adults† Outpatient Outpatient Admission Hospital Days 5th Hospital Day
Hematocrit (%) 41.0–53.0 (men) 38.3 33.7 31.0 28.9 23.4
Hemoglobin (g/dl) 13.5–17.5 (men) 12.5 11.5 10.9 10.1 8.6
White-cell count (per mm 3) 4500–11,000 4300 3500 1600 1000 200
Differential count (%)
The

Neutrophils 40–70 62 63 59 47 44
Band forms 0–10 4
Lymphocytes 22–44 26 26 34 47 46
Monocytes 4–11 12 11 6 6 6
Eosinophils 0–8 0 0 1 0 0
Platelet count (per mm3) 150,000–400,000 213,000 177,000 139,000 158,000 152,000 (large forms)
Mean corpuscular volume (μm3) 80–100 56 55 53 54 53
Erythrocyte count (per mm3) 4,500,000–5,900,000 6,790,000 6,190,000 5,830,000 5,320,000 4,380,000
Mean corpuscular hemoglobin (pg/ 26.0–34.0 18.4 18.6 18.6 18.9 19.5
n e w e ng l a n d j o u r na l

red cell)

The New England Journal of Medicine

of

Mean corpuscular hemoglobin 31.0–37.0 32.5 34.2 35.0 34.8 36.6

concentration (g/dl)
Red-cell distribution width (%) 11.5–14.5 16.3 16.2 16.2 16.3 16.2

n engl j med 369;24 nejm.org december 12, 2013

Erythrocyte sedimentation rate 0–13 5 15

Copyright © 2013 Massachusetts Medical Society. All rights reserved.

m e dic i n e

(mm/hr)
Reticulocytes (%) 0.5–2.5 1.2 (manual)
Smear description 3+ microcytes, 1+ 3+ microcytes, 1+ 3+ microcytes, 1+ 3+ microcytes, 1+ anisocy-
spherocytes, 1+ anisocytosis hypochromasia, tosis, 1+ teardrop red
anisocytosis 1+ anisocytosis cells

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Sodium (mmol/liter) 135–145 138 130 135 136
Potassium (mmol/liter) 3.4–4.8 3.8 3.9 3.4 3.7
Chloride (mmol/liter) 100–108 97 94 102 102
Carbon dioxide (mmol/liter) 23.0–31.9 23.5 24.4 22.2 23.7
 case records of the massachuset ts gener al hospital

and rest. The patient returned home but was

† 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
advised to return to the outpatient clinic if his
condition did not improve.

* To convert the values for calcium to millimoles per liter, multiply by 0.250. To convert the values for iron and iron-binding capacity to micromoles per liter, multiply by 0.1791.
Two days later, the patient returned to the
8.0

clinic. He reported decreased appetite, chills,

sweats related to fevers, mild headaches and
body aches, and a new nonproductive cough. On
examination, the lymph nodes on the right side
were slightly larger than on the previous examina-
tion and were slightly confluent; the lymph nodes

Normal pattern
on the left side and a submental lymph node were
soft and mobile. Bronchial breath sounds were
369

197
827
7.9

38
heard over the right side of the chest anteriorly,

who are not pregnant and do not have medical conditions that could affect the results. They may therefore not be appropriate for all patients.
and the remainder of the examination was un-
changed. Hemoglobin electrophoresis and DNA
sequence analysis revealed hemoglobin D Punjab,
an abnormal variant of the β-globin chain of
­hemoglobin, at a level of 91.8%, as well as a hemo-
22.6
8.8

globin A level of 0% (reference range, 95.8 to

98.0), a hemo­globin A2 level of 7.0% (reference
range, 2.0 to 3.3), and a hemoglobin F level of
1.2% (reference range, 0.0 to 0.9); other test
results are shown in Table 1. The patient de-
clined testing for the human immunodeficiency
virus (HIV).
13.4

326
153
19

Dr. Daniel F. Boyer: A fine-needle aspiration bi-

opsy of an enlarged cervical lymph node was
performed, and the aspirate showed a mixed
population of lymphocytes, histiocytes, and occa-
sional plasma cells. Some of the histiocytes con-
tained cellular debris and angular, crescentic
9.4

nuclei. The polymorphous composition of the

aspirate and the mature appearance of the lym-
phocytes were suggestive of a reactive process
Normal pattern

(Fig. 1). Gram’s and acid-fast staining of the

614–1295
8.5–10.5

230–404

110–210
45–160

30–300

69–309

53–334

aspirate revealed no organisms. Flow cytometry

<8.0

of the aspirate showed no immunophenotypic

abnormalities.
Dr. Rosenbluth: A blood culture and a culture of
the aspirate were sterile. A chest radiograph
was normal. The patient returned home again,
with instructions to return to the clinic if fevers
Total iron-binding capacity (µg/dl)

persisted.
Lactate dehydrogenase (U/liter)

Serum protein electrophoresis

Two days later, the patient reported persistent

C-reactive protein (mg/liter)

Immunoglobulins (mg/dl)

fevers and a dull headache and was admitted to

the hospital. He reported no night sweats,
weight loss, rhinorrhea, neck rigidity, neck pain,
Calcium (mg/dl)

Ferritin (ng/ml)

vision changes, weakness, or numbness and no

Iron (µg/dl)

respiratory, gastrointestinal, or genitourinary

symptoms.
IgM
IgG
IgA

On examination, the blood pressure was

106/58 mm Hg, and the pulse 104 beats per

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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

Figure 1. Fine-Needle Aspirate of a Cervical Lymph Node.

Cytologic smears of the fine-needle aspirate showed a
mixed population of lymphocytes and histiocytes, includ-
ing phagocytic histiocytes with crescentic nuclei (arrow). B

minute; the respirations were 20 breaths per min-

ute, with an oxygen saturation of 98% while the
patient was breathing ambient air. There was a
superficial ulcer on the right side of the lower
lip, and the spleen tip was palpable approximately
3 cm below the costal margin; the remainder of
the examination was unchanged. Blood levels of
lactic acid, C3, C4, haptoglobin, creatine kinase,
and thyrotropin were normal; testing for rheuma-
toid factor and antinuclear antibodies was nega-
tive. Other test results are shown in Table 1.
Urinalysis revealed yellow, clear fluid, with 1+ oc-
cult blood, trace albumin, and few squamous cells
per high-power field, and was otherwise normal.
Fluids were administered intravenously, and an-
other blood sample was obtained for culture.
The maximal daily temperature was 40.7°C on
the first day. On the second day, the temperature
rose to 40.8°C.
Dr. Victorine V. Muse: Computed tomographic
(CT) scans of the neck and chest obtained after
the administration of contrast material (Fig. 2)
showed lymph nodes measuring up to 9 mm in
diameter in the submental, submandibular, and
jugular chains and at the posterior cervical level;
mediastinal and hilar lymph nodes, the largest, at
the subcarinal level, measuring 9 mm in diameter;
bilateral, clustered axillary lymph nodes measuring
up to 10 mm in diameter; a small, anterior peri-
cardial effusion; a soft-tissue nodule, 4 mm in di-
ameter, in the left lower lobe; mild centrilobular
emphysema, predominantly in the upper lobe;
Figure 2. CT Scans of the Neck and Chest.
A coronal reformatted image from a contrast-enhanced
CT scan of the neck shows multiple bilateral enhancing
cervical lymph nodes, the largest measuring 9 mm in
diameter (Panel A, arrow). A coronal reformatted image
from a CT scan of the chest (Panel B) confirms the
presence of scattered small axillary lymph nodes bilat-
erally (white arrowheads) and subcarinal lymph nodes
(black arrowhead), as well as splenomegaly (arrow).
and occasional subcentimeter cystic lucencies,
predominantly in the paramediastinal lingula
and right upper lobe. CT scans of the abdomen
and pelvis obtained after the administration of
contrast material showed splenomegaly, measur-
ing 16.5 cm in the maximal craniocaudal dimen-
sion (normal range, <14 cm); a cystic structure,
3.5 cm by 2.6 cm, in the interpolar region of the
right kidney; and no evidence of lymphadenopathy
in the abdomen or pelvis.
Dr. Rosenbluth: Additional test results are shown

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 case records of the massachuset ts gener al hospital
in Table 1. Blood cultures remained sterile. Fevers
recurred daily. A tuberculin skin test was negative
after 48 hours.
Diagnostic tests were performed.
Differ en t i a l Di agnosis
Dr. Alaka Ray: Whenever we listen to the history of
an illness and the case presentation, whether
they are being described by another physician or
the patient, certain words and phrases seem to
carry more weight than others. In this case, my
initial impression was dominated by the patient’s
young age and previous good health, the brief
duration of his present illness, his recent travel
to India, and, of course, the fever and lymphade-
nopathy. I will construct my differential diagno-
sis around the development of lymphadenopathy
and then narrow down the list on the basis of
what we know about this patient.
Lymphadenopathy
One approach is to start with a discussion of the
causes of lymphadenopathy that focuses on the
pathological characteristics. However, I find it more
clinically relevant to focus on the size and distribu-
tion of the lymph nodes. Is the lymphadenopathy
generalized or localized? What size are the nodes,
and what other characteristics do they have?
Localized lymphadenopathy is common, and
55% of all cases involve lymph nodes in the head
and neck, including the cervical region.1 In con-
trast, 1% of all cases of lymphadenopathy are
attributed to supraclavicular lymph nodes, 5%
to axillary nodes, and 14% to inguinal nodes.1
Fortunately, the roughly 600 lymph nodes in the
human body are divided into groups that serve
particular anatomical sites; therefore, the location
can guide the initial investigation. In this pa-
tient, the presence of enlarged cervical lymph
nodes should prompt careful examination of the
head and neck, specifically the larynx, thyroid,
palate, esophagus, paranasal sinuses, tonsils, ade-
noids, posterior scalp, neck, and nose. The physical
examination and history, however, do not suggest
that the patient has such conditions as dental ab-
scesses, pharyngitis, otitis media, or otitis externa.
The presence of lymphadenopathy always raises
concern about cancer. Patients with palpable
lymph nodes in the supraclavicular region are at
high risk for cancer2,3; however, there is a ten-
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dency to overestimate the risk. Among patients
with palpable peripheral lymph nodes, the risk
of cancer is only 1 to 2% at first presentation.
This patient had cervical lymphadenopathy, and
at this point we have been given no reason to be
concerned about a cancer of the head or neck.
The lymph nodes themselves have certain
characteristics to consider, such as size, rate of
growth, tenderness, and consistency (e.g., “hard”
or “matted”). In this patient, the lymph nodes
were tender and had grown rapidly, features that
are sometimes considered to be reassuring signs
that there is not an ongoing malignant process.
However, a malignant lymph node can also be-
come enlarged and painful if it hemorrhages into
a necrotic center. Size is the most important char-
acteristic of a lymph node, and in this case, the
lymph nodes are less than 1 cm in diameter. In
general, 1 cm is the minimum diameter at which a
lymph node is designated as pathologic, since can-
cer is not typically found in smaller lymph nodes.4
Age is the most helpful variable when assessing
lymphadenopathy, and this patient’s young age is
reassuring.2,3 Patients with lymphadenopathy who
are 40 years of age or older have a 4% risk of can-
cer, whereas those younger than 40 years of age
have a 0.4% risk.2
History and Epidemiology
Before deciding whether this patient should
­undergo a lymph-node biopsy, it is important to
think about the patient as a whole and identify
any clues in his history. He presented with a
2-week history of tender lymphadenopathy, fever,
headache, myalgias, and chills, but a review of
systems was otherwise unremarkable. Some med-
ications, such as phenytoin, can cause lymphade-
nopathy; however, he was not taking any medica-
tions. The patient was of Indian origin and had
recently traveled to India. Therefore, we will need
to consider any infections, such as tuberculosis,
that he could have acquired during his visit and
that could persist for 6 months or more.
The Differential Diagnosis
On the basis of the clinical aspects of the pa-
tient’s history and pertinent laboratory data, we
can rule out most of the common causes of
lymphadenopathy 5 (Table 2). Localized infections
should have become apparent during the history
and physical examination.
2337
 The n e w e ng l a n d j o u r na l of m e dic i n e

ally accompanied by characteristic eye and throat

Table 2. Common Causes of Lymphadenopathy.*
symptoms. Lymphoma and metastatic cancers
Infections seem unlikely in this case, given the polymor-
Dental abscess phous composition of the lymph-node aspirate,
Otitis media the patient’s young age, the relatively small size
Otitis externa of the lymph nodes, the rapid tempo of disease
Pharyngitis progression, and the presence of other symp-
Scalp infection toms (e.g., mild cough, fever, and an oral ulcer).
Toxoplasmosis Patients with unicentric Castleman’s disease
Epstein–Barr virus rarely present with peripheral lymphadenopathy;
Cytomegalovirus in 80% of these patients, the lymphadenopathy
Adenovirus is in the chest. Patients with systemic lupus ery-
Hepatitis
thematosus (SLE) can present with a variety of
Rubella
symptoms and signs, but a diagnosis of SLE is
Nodal tuberculosis
doubtful in this patient because he had a dramatic
Bartonella
presentation without detectable antinuclear anti-
Cancer bodies and with a normal complement level.
Non-Hodgkin’s lymphoma Sarcoidosis is often found during an evaluation
Hodgkin’s disease of hilar lymphadenopathy, but no bulky intra-
Head and neck cancer thoracic lymph nodes were seen on this patient’s
Unicentric Castleman’s disease CT scans. Respiratory symptoms of sarcoidosis
Autoimmune disease are usually prominent, but this patient had only
Systemic lupus erythematosus a mild cough that had developed 2 days after his
initial presentation.
Other
Kikuchi–Fujimoto disease
Using a Global Lens
Kimura’s disease
Sarcoidosis Since all the aforementioned diseases are unlikely,
only nodal tuberculosis, Kimura’s disease, and
* Data are adapted from Motyckova and Steensma.5 Kikuchi–Fujimoto disease (also known as histio-
cytic necrotizing lymphadenitis) are left for us to
consider. It may at first appear that we are focus-
Immunocompetent persons with toxoplasmo- ing on only rare diseases, but considering these
sis are rarely symptomatic, and their cervical diseases in the appropriate geographic context
lymph nodes are usually nontender bilaterally. may shift that perspective. In a North American
Abnormal results of laboratory tests are unusual or European context, cancer and benign tumors
in patients with toxoplasmosis, but occasionally would be the most likely diagnoses, followed
lymphocytosis rather than leukopenia is seen. closely by infections, SLE, and sarcoidosis.6 How-
In this patient, findings on examination of the ever, in an Asian context, nonspecific lymphade-
lymph-node aspirate were not suggestive of toxo- nitis, tuberculosis, and cancer are the most likely
plasmosis. In addition, the likelihood that the diagnoses, and rare conditions, such as Kikuchi–
patient has Epstein–Barr virus (EBV) infection is Fujimoto disease and Kimura’s disease, also make
small because of the negative test for heterophile the list.7,8
antibodies. Because this patient was of Indian origin and
Cytomegalovirus (CMV) infection is rarely symp- had traveled to India 6 months before presentation,
tomatic in immunocompetent persons, and when such conditions as nodal tuberculosis, Kimura’s
severe CMV infection is present, it is often associ- disease, and Kikuchi–Fujimoto disease are possi-
ated with ophthalmic, gastrointestinal, or neuro- ble diagnoses. India has 20% of the global bur-
logic involvement, which was not seen in this den of tuberculosis, and some estimates suggest
patient. Adenovirus is not likely to cause an ill- that up to 40% of the population may have either
ness as severe as the one seen in this patient, and active or latent tuberculosis infection.9 In one Indi­
although a pharyngoconjunctival fever might cause an hospital, roughly 64% of the cases of cervical
cervical lymphadenopathy, the syndrome is usu- lymphadenopathy were associated with tuberculo-

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 case records of the massachuset ts gener al hospital
sis.10 Extrapulmonary tuberculosis affecting the
lymph nodes is commonly associated with HIV
infection. Although we do not know this pa-
tient’s HIV status, persons with HIV infection
tend to be symptomatic for a long time, with
fever, night sweats, and weight loss.11 This pa-
tient had a very sudden onset of symptoms,
which is not consistent with tuberculosis, and
his purified protein derivative tests were negative
both at this hospital and reportedly in the past.
Kimura’s disease, which is often confused with
angiolymphoid hyperplasia with eosinophilia, is
a rare, benign, chronic inflammatory disorder of
unknown cause that mainly affects young Asian
men. Patients with Kimura’s disease have an in-
dolent presentation, with painless lymphadenop-
athy in the head and neck. It is common to see
eosinophilic infiltrates in the biopsy specimens.12
A diagnosis of Kimura’s disease is not fully consis-
tent with the patient’s abrupt onset of symptoms.
Kikuchi–Fujimoto disease, which was first de-
scribed in 1972, is seen in young Asian persons.
The clinical features are consistent with this pa-
tient’s presentation, including symptom onset over
a period of 2 to 4 weeks, fevers, lymphadenopathy
(usually cervical), leukopenia (in ≤58% of cases,
according to the original description of the dis-
ease by Kikuchi), respiratory symptoms, arthral-
gias and myalgias, and skin manifestations (e.g.,
ulcers, erythematous plaques, and papules).13-17
Fine-needle aspiration biopsy of a lymph node is
not a reliable diagnostic test for Kikuchi–Fuji­moto
disease; the aspirate usually shows crescentic
histiocytes, karyorrhectic and granular debris, and
plasmacytoid monocytes.14,18 Kikuchi–Fujimoto
disease fits almost every aspect of this patient’s
presentation.
Generally, Kikuchi–Fujimoto disease resolves
without treatment in less than 6 months, although
the use of glucocorticoids and such antibiotics
as ciprofloxacin and minocycline may result in
improvement.19,20 Recurrences have been reported
but are rare, regardless of treatment modality;
death due to the disease is also rare, occurring
in approximately 2% of patients. Excisional bi-
opsy is the standard diagnostic test for Kikuchi–
Fujimoto disease and the test I would choose in
this case.
Although Kikuchi–Fujimoto disease fits almost
all aspects of the patient’s illness, the profound
anemia and signs of hemolysis remain unex-
plained. After reviewing the results of hemoglo-
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bin electrophoresis, I think the anemia is most
likely related to homozygous hemoglobin D
disease, which can result in chronic microcytic
anemia, mild hemolytic anemia, splenomegaly,
and abnormal findings on a peripheral-blood
smear, including target cells, spherocytes, and
anisocytosis. I suspect that this patient’s sudden
onset of illness affected his ability to maintain a
consistently high rate of red-cell production, and
this suspicion is supported by the abnormally
low reticulocyte count relative to his anemia.
Dr. Eric S. Rosenberg (Pathology): Dr. Rosen­
bluth, what was your impression when you eval­
uated this patient?
Dr. Rosenbluth: When we evaluated the patient,
we were initially concerned about lymphoma and
metastatic cancer. However, given the benign
nature of the lymph-node disease, we thought
either EBV infection or Kikuchi–Fujimoto disease
was most likely.
Cl inic a l Di agnosis
Epstein–Barr virus infection or Kikuchi–Fujimoto
disease.
DR . A L A K A R A Y ’S DI AGNOSE S
Kikuchi–Fujimoto disease (histiocytic necrotizing
lymphadenitis) and homozygous hemoglobin D
disease.
Pathol o gic a l Discussion
Dr. Boyer: One week after the fine-needle aspiration
biopsy, an excisional biopsy of a cervical lymph
node was performed. Microscopical examination
of the biopsy specimen showed patchy eosino-
philic areas containing necrotic and apoptotic
debris, with admixed small lymphocytes, immuno-
blasts, and phagocytic histiocytes (Fig. 3A and 3B).
The phagocytic histiocytes contained eosinophilic
proteinaceous debris and were notable for eccen-
tric, crescentic nuclei similar to those seen in the
fine-needle aspirate. Very few neutrophils and
eosinophils were present. Adjacent to the necrotic
areas, there was paracortical expansion, with
­zonation between small lymphocytes and ag-
gregates of larger lymphoid cells composed of
­immunoblasts and plasmacytoid dendritic cells
(Fig. 3C). Immunohistochemical staining for
CD123 (the interleukin-3 receptor) confirmed that
2339
 The n e w e ng l a n d j o u r na l
the lymph node contained an increased number
of plasmacytoid dendritic cells (Fig. 3D), a feature
consistent with Kikuchi–Fujimoto disease.21,22
The constellation of histologic features was
most consistent with Kikuchi–Fujimoto disease,
and the differential diagnosis included lymphoma,
SLE-related lymphadenitis, and infectious lymph-
adenopathy. Immunohistochemical stains for
T cells (CD3) and B cells (CD20) revealed that the
necrotic areas were virtually devoid of B cells
and the large lymphocytes were predominantly
T cells (Fig. 3E and 3F). These results, taken to-
gether with the observation of polytypic light-chain
expression on flow cytometry, argued strongly
against a diagnosis of B-cell lymphoma. The
expanded population of large T cells suggested
that the possible diagnosis of peripheral T-cell
lymphoma should be investigated. T-cell lymphoma
usually involves effacement of the lymph-node
architecture by atypical T cells, but in this lymph
node, the architecture was mostly preserved, and
the extent of necrosis was disproportionate to
the level of T-cell proliferation. In most patients
with peripheral T-cell lymphoma, the large T cells
are uniformly CD4+ T cells, but in this patient,
the immunoblasts consisted of CD8+ T cells and
CD4+ T cells, a mixture more typical of Kikuchi–
Fujimoto disease and other reactive processes
than of lymphoma.13,23 The presence of abun-
dant crescentic histiocytes is also more typical
of Kikuchi–Fujimoto disease than of lymphoma.
In patients with Kikuchi–Fujimoto disease,
as compared with patients who have other non-
neoplastic causes of necrotizing lymphadenitis,
the lymph nodes usually contain a paucity of
neutrophils, eosinophils, plasma cells, and gran-
ulomas and an abundance of crescentic histio-
cytes.24-26 In this patient, staining of the biopsy
specimen for fungi and mycobacteria was nega-
tive. In situ hybridization for EBV-encoded RNA
was positive in a few scattered small and large
lymphoid cells, suggesting latent infection. The
results of serologic testing for EBV were consis-
tent with past infection. The extent of EBV infec-
tion in the lymph nodes was limited and was
judged to be insufficient to account for the se-
verity of the necrotizing lymphadenitis.
SLE-related lymphadenitis is the condition his-
tologically closest to Kikuchi–Fujimoto disease.
Hematoxylin bodies (basophilic condensations of
nuclear and cytoplasmic debris) and the Azzopardi
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of m e dic i n e
effect (which occurs when nuclear debris adheres
to the surface of blood vessels) are findings spe-
cific to SLE-related lymphadenitis, but they are
uncommon.13,27 In patients with SLE-related
lymphadenitis, the lymph nodes tend to contain
more neutrophils and plasma cells than do those
in patients with Kikuchi–Fujimoto disease; the
presence of vasculitis outside necrotic areas is
also more common in patients with SLE-related
lymphadenitis. None of these features were pres-
ent in this patient; however, serologic testing for
SLE is recommended for all patients with biopsy
results suggestive of Kikuchi–Fujimoto disease,
because it is difficult to distinguish between the
two diseases on the basis of histologic features
alone. In this patient, serologic testing for SLE
was negative. There are a few reported cases of
SLE diagnosed months to years after results of a
lymph-node biopsy suggested Kikuchi–Fujimoto
disease, and it is likely that some patients who
receive an initial diagnosis of Kikuchi–Fujimoto
disease actually have an early form of SLE. How­
ever, SLE rarely develops in patients who have auto­
antibody titers within the normal range when the
results of a lymph-node biopsy suggest Kikuchi–
Fujimoto disease.16
On the basis of the findings on examination
of the lymph node–biopsy specimen and the fine-
needle aspirate, as well as the serologic studies,
the final diagnosis was necrotizing lymphadenitis,
with features consistent with histiocytic necro-
tizing lymphadenitis (Kikuchi–Fujimoto disease).
Dr. Rosenberg: Dr. Rosenbluth, would you tell
us what happened with this patient?
Dr. Rosenbluth: We treated this patient support-
ively and did not give him antibiotics or gluco-
corticoids. Acetaminophen, ibuprofen, and me-
peridine were administered to treat his fever and
chills. He spent 1.5 weeks in the hospital, and
eventually his fever resolved.
After the patient was discharged, he was seen
at a follow-up visit 3 weeks later, and by that
time, his neutrophil count had recovered, his
lymphadenopathy had nearly resolved, and he was
feeling well and had returned to work. However,
his primary care physician was concerned about
the decreased range of motion of the right arm
during abduction, given that he had undergone
an excisional biopsy of a cervical lymph node.
The patient was evaluated in the orthopedic
clinic. A nerve-conduction study was performed,
 case records of the massachuset ts gener al hospital

A B

C D

E F

Figure 3. Excisional-Biopsy Specimen of a Cervical Lymph Node.

The lymph node–biopsy specimen contains patchy eosinophilic areas alternating with areas of paracortical expan-
sion (Panel A, hematoxylin and eosin). At high magnification (Panel B, hematoxylin and eosin), the eosinophilic
areas contain necrotic and apoptotic debris, with admixed small lymphocytes, immunoblasts (arrows), and crescen-
tic histiocytes (arrowheads). At high magnification (Panel C, hematoxylin and eosin), the paracortex contains sev-
eral immunoblasts (arrows) and clusters of medium-sized cells with eccentric nuclei and pale chromatin, features
consistent with plasmacytoid dendritic cells. Immunohistochemical analysis of the lymph node–biopsy specimen
was also performed. Staining for CD123 (Panel D) confirms the presence of aggregates of plasmacytoid dendritic
cells. CD3 staining for T cells (Panel E) shows that the lymphoid-cell population, including the majority of the im-
munoblasts (inset, arrows), consists predominantly of T cells in the necrotic and paracortical regions of the lymph
node. CD20 staining for B cells (Panel F) shows that the necrotic areas are virtually devoid of B cells, and very few
B-cell immunoblasts can be identified in the paracortex (inset, arrow).

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 case records of the massachuset ts gener al hospital

and an injury of the spinal accessory nerve was
diagnosed. He underwent a repair of the right
spinal accessory nerve and afterward noted im-
provement in the strength in his right arm.
Dr. Nancy Lee Harris (Pathology): I would like to
congratulate the patient’s caregivers both in the
outpatient clinic and in the hospital for resisting
the temptation to give antibiotics to this acutely
ill patient who had cervical lymphadenopathy.
Almost every biopsy specimen of a cervical
lymph node that I see in my work as a hemato-
pathologist comes from a patient who has been
treated with one course or more of antibiotics
that were administered on the assumption that
the patient had a bacterial infection.
I want to make two points about the pathologi-
cal diagnosis of Kikuchi–Fujimoto disease. First,
Kikuchi–Fujimoto disease can be misdiagnosed as
T-cell lymphoma. This is an important pitfall for
the pathologist that an astute clinician can fore-
stall. Peripheral T-cell lymphomas are most com-
monly seen in patients older than 50 years of age.
The diagnosis of a T-cell lymphoma — other than
lymphoblastic lymphoma, anaplastic lymphoma
kinase–positive anaplastic large-cell lymphoma, or
(in rare cases) hepatosplenic T-cell lymphoma —
in a patient younger than 35 years of age should
be viewed with utmost suspicion by clinicians.
Second, it is virtually impossible to distinguish
Kikuchi–Fujimoto disease from SLE on a biopsy
specimen of a lymph node. SLE may occasion-
ally develop in patients months or years after the
findings on a lymph-node biopsy suggested
Kikuchi–Fujimoto disease. Such patients and
their caregivers should be aware that if new
symptoms develop, reassessment of the serologic
tests for SLE and repeat serologic testing may be
indicated.
A nat omic a l Di agnosis
Necrotizing lymphadenitis, with features consis-
tent with histiocytic necrotizing lymphadenitis
(Kikuchi–Fujimoto disease) and scattered EBV-
positive cells.
This case was presented at the Medical Case Conference. Dr.
Muse reports receiving payment for expert testimony on behalf
of patients in cases of asbestos exposure. No other potential
conflict of interest relevant to this article was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Dr. Andrew Lundquist for assistance with the case
history, and Dr. David Sykes for assistance with the differential
diagnosis.

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