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Caso Clinico Linfadenopatias.
Caso Clinico Linfadenopatias.
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
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)
(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
Downloaded from nejm.org on December 11, 2013. For personal use only. No other uses without permission.
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
† 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
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
326
153
19
230–404
110–210
45–160
30–300
69–309
53–334
persisted.
Lactate dehydrogenase (U/liter)
Immunoglobulins (mg/dl)
Ferritin (ng/ml)
in Table 1. Blood cultures remained sterile. Fevers dency to overestimate the risk. Among patients
recurred daily. A tuberculin skin test was negative with palpable peripheral lymph nodes, the risk
after 48 hours. of cancer is only 1 to 2% at first presentation.
Diagnostic tests were performed. This patient had cervical lymphadenopathy, and
at this point we have been given no reason to be
Differ en t i a l Di agnosis concerned about a cancer of the head or neck.
The lymph nodes themselves have certain
Dr. Alaka Ray: Whenever we listen to the history of characteristics to consider, such as size, rate of
an illness and the case presentation, whether growth, tenderness, and consistency (e.g., “hard”
they are being described by another physician or or “matted”). In this patient, the lymph nodes
the patient, certain words and phrases seem to were tender and had grown rapidly, features that
carry more weight than others. In this case, my are sometimes considered to be reassuring signs
initial impression was dominated by the patient’s that there is not an ongoing malignant process.
young age and previous good health, the brief However, a malignant lymph node can also be-
duration of his present illness, his recent travel come enlarged and painful if it hemorrhages into
to India, and, of course, the fever and lymphade- a necrotic center. Size is the most important char-
nopathy. I will construct my differential diagno- acteristic of a lymph node, and in this case, the
sis around the development of lymphadenopathy lymph nodes are less than 1 cm in diameter. In
and then narrow down the list on the basis of general, 1 cm is the minimum diameter at which a
what we know about this patient. lymph node is designated as pathologic, since can-
cer is not typically found in smaller lymph nodes.4
Lymphadenopathy Age is the most helpful variable when assessing
One approach is to start with a discussion of the lymphadenopathy, and this patient’s young age is
causes of lymphadenopathy that focuses on the reassuring.2,3 Patients with lymphadenopathy who
pathological characteristics. However, I find it more are 40 years of age or older have a 4% risk of can-
clinically relevant to focus on the size and distribu- cer, whereas those younger than 40 years of age
tion of the lymph nodes. Is the lymphadenopathy have a 0.4% risk.2
generalized or localized? What size are the nodes,
and what other characteristics do they have? History and Epidemiology
Localized lymphadenopathy is common, and Before deciding whether this patient should
55% of all cases involve lymph nodes in the head undergo a lymph-node biopsy, it is important to
and neck, including the cervical region.1 In con- think about the patient as a whole and identify
trast, 1% of all cases of lymphadenopathy are any clues in his history. He presented with a
attributed to supraclavicular lymph nodes, 5% 2-week history of tender lymphadenopathy, fever,
to axillary nodes, and 14% to inguinal nodes.1 headache, myalgias, and chills, but a review of
Fortunately, the roughly 600 lymph nodes in the systems was otherwise unremarkable. Some med-
human body are divided into groups that serve ications, such as phenytoin, can cause lymphade-
particular anatomical sites; therefore, the location nopathy; however, he was not taking any medica-
can guide the initial investigation. In this pa- tions. The patient was of Indian origin and had
tient, the presence of enlarged cervical lymph recently traveled to India. Therefore, we will need
nodes should prompt careful examination of the to consider any infections, such as tuberculosis,
head and neck, specifically the larynx, thyroid, that he could have acquired during his visit and
palate, esophagus, paranasal sinuses, tonsils, ade- that could persist for 6 months or more.
noids, posterior scalp, neck, and nose. The physical
examination and history, however, do not suggest The Differential Diagnosis
that the patient has such conditions as dental ab- On the basis of the clinical aspects of the pa-
scesses, pharyngitis, otitis media, or otitis externa. tient’s history and pertinent laboratory data, we
The presence of lymphadenopathy always raises can rule out most of the common causes of
concern about cancer. Patients with palpable lymphadenopathy 5 (Table 2). Localized infections
lymph nodes in the supraclavicular region are at should have become apparent during the history
high risk for cancer2,3; however, there is a ten- and physical examination.
sis.10 Extrapulmonary tuberculosis affecting the bin electrophoresis, I think the anemia is most
lymph nodes is commonly associated with HIV likely related to homozygous hemoglobin D
infection. Although we do not know this pa- disease, which can result in chronic microcytic
tient’s HIV status, persons with HIV infection anemia, mild hemolytic anemia, splenomegaly,
tend to be symptomatic for a long time, with and abnormal findings on a peripheral-blood
fever, night sweats, and weight loss.11 This pa- smear, including target cells, spherocytes, and
tient had a very sudden onset of symptoms, anisocytosis. I suspect that this patient’s sudden
which is not consistent with tuberculosis, and onset of illness affected his ability to maintain a
his purified protein derivative tests were negative consistently high rate of red-cell production, and
both at this hospital and reportedly in the past. this suspicion is supported by the abnormally
Kimura’s disease, which is often confused with low reticulocyte count relative to his anemia.
angiolymphoid hyperplasia with eosinophilia, is Dr. Eric S. Rosenberg (Pathology): Dr. Rosen
a rare, benign, chronic inflammatory disorder of bluth, what was your impression when you eval
unknown cause that mainly affects young Asian uated this patient?
men. Patients with Kimura’s disease have an in- Dr. Rosenbluth: When we evaluated the patient,
dolent presentation, with painless lymphadenop- we were initially concerned about lymphoma and
athy in the head and neck. It is common to see metastatic cancer. However, given the benign
eosinophilic infiltrates in the biopsy specimens.12 nature of the lymph-node disease, we thought
A diagnosis of Kimura’s disease is not fully consis- either EBV infection or Kikuchi–Fujimoto disease
tent with the patient’s abrupt onset of symptoms. was most likely.
Kikuchi–Fujimoto disease, which was first de-
scribed in 1972, is seen in young Asian persons. Cl inic a l Di agnosis
The clinical features are consistent with this pa-
tient’s presentation, including symptom onset over Epstein–Barr virus infection or Kikuchi–Fujimoto
a period of 2 to 4 weeks, fevers, lymphadenopathy disease.
(usually cervical), leukopenia (in ≤58% of cases,
according to the original description of the dis- DR . A L A K A R A Y ’S DI AGNOSE S
ease by Kikuchi), respiratory symptoms, arthral-
gias and myalgias, and skin manifestations (e.g., Kikuchi–Fujimoto disease (histiocytic necrotizing
ulcers, erythematous plaques, and papules).13-17 lymphadenitis) and homozygous hemoglobin D
Fine-needle aspiration biopsy of a lymph node is disease.
not a reliable diagnostic test for Kikuchi–Fujimoto
disease; the aspirate usually shows crescentic Pathol o gic a l Discussion
histiocytes, karyorrhectic and granular debris, and
plasmacytoid monocytes.14,18 Kikuchi–Fujimoto Dr. Boyer: One week after the fine-needle aspiration
disease fits almost every aspect of this patient’s biopsy, an excisional biopsy of a cervical lymph
presentation. node was performed. Microscopical examination
Generally, Kikuchi–Fujimoto disease resolves of the biopsy specimen showed patchy eosino-
without treatment in less than 6 months, although philic areas containing necrotic and apoptotic
the use of glucocorticoids and such antibiotics debris, with admixed small lymphocytes, immuno-
as ciprofloxacin and minocycline may result in blasts, and phagocytic histiocytes (Fig. 3A and 3B).
improvement.19,20 Recurrences have been reported The phagocytic histiocytes contained eosinophilic
but are rare, regardless of treatment modality; proteinaceous debris and were notable for eccen-
death due to the disease is also rare, occurring tric, crescentic nuclei similar to those seen in the
in approximately 2% of patients. Excisional bi- fine-needle aspirate. Very few neutrophils and
opsy is the standard diagnostic test for Kikuchi– eosinophils were present. Adjacent to the necrotic
Fujimoto disease and the test I would choose in areas, there was paracortical expansion, with
this case. zonation between small lymphocytes and ag-
Although Kikuchi–Fujimoto disease fits almost gregates of larger lymphoid cells composed of
all aspects of the patient’s illness, the profound immunoblasts and plasmacytoid dendritic cells
anemia and signs of hemolysis remain unex- (Fig. 3C). Immunohistochemical staining for
plained. After reviewing the results of hemoglo- CD123 (the interleukin-3 receptor) confirmed that
the lymph node contained an increased number effect (which occurs when nuclear debris adheres
of plasmacytoid dendritic cells (Fig. 3D), a feature to the surface of blood vessels) are findings spe-
consistent with Kikuchi–Fujimoto disease.21,22 cific to SLE-related lymphadenitis, but they are
The constellation of histologic features was uncommon.13,27 In patients with SLE-related
most consistent with Kikuchi–Fujimoto disease, lymphadenitis, the lymph nodes tend to contain
and the differential diagnosis included lymphoma, more neutrophils and plasma cells than do those
SLE-related lymphadenitis, and infectious lymph- in patients with Kikuchi–Fujimoto disease; the
adenopathy. Immunohistochemical stains for presence of vasculitis outside necrotic areas is
T cells (CD3) and B cells (CD20) revealed that the also more common in patients with SLE-related
necrotic areas were virtually devoid of B cells lymphadenitis. None of these features were pres-
and the large lymphocytes were predominantly ent in this patient; however, serologic testing for
T cells (Fig. 3E and 3F). These results, taken to- SLE is recommended for all patients with biopsy
gether with the observation of polytypic light-chain results suggestive of Kikuchi–Fujimoto disease,
expression on flow cytometry, argued strongly because it is difficult to distinguish between the
against a diagnosis of B-cell lymphoma. The two diseases on the basis of histologic features
expanded population of large T cells suggested alone. In this patient, serologic testing for SLE
that the possible diagnosis of peripheral T-cell was negative. There are a few reported cases of
lymphoma should be investigated. T-cell lymphoma SLE diagnosed months to years after results of a
usually involves effacement of the lymph-node lymph-node biopsy suggested Kikuchi–Fujimoto
architecture by atypical T cells, but in this lymph disease, and it is likely that some patients who
node, the architecture was mostly preserved, and receive an initial diagnosis of Kikuchi–Fujimoto
the extent of necrosis was disproportionate to disease actually have an early form of SLE. How
the level of T-cell proliferation. In most patients ever, SLE rarely develops in patients who have auto
with peripheral T-cell lymphoma, the large T cells antibody titers within the normal range when the
are uniformly CD4+ T cells, but in this patient, results of a lymph-node biopsy suggest Kikuchi–
the immunoblasts consisted of CD8+ T cells and Fujimoto disease.16
CD4+ T cells, a mixture more typical of Kikuchi– On the basis of the findings on examination
Fujimoto disease and other reactive processes of the lymph node–biopsy specimen and the fine-
than of lymphoma.13,23 The presence of abun- needle aspirate, as well as the serologic studies,
dant crescentic histiocytes is also more typical the final diagnosis was necrotizing lymphadenitis,
of Kikuchi–Fujimoto disease than of lymphoma. with features consistent with histiocytic necro-
In patients with Kikuchi–Fujimoto disease, tizing lymphadenitis (Kikuchi–Fujimoto disease).
as compared with patients who have other non- Dr. Rosenberg: Dr. Rosenbluth, would you tell
neoplastic causes of necrotizing lymphadenitis, us what happened with this patient?
the lymph nodes usually contain a paucity of Dr. Rosenbluth: We treated this patient support-
neutrophils, eosinophils, plasma cells, and gran- ively and did not give him antibiotics or gluco-
ulomas and an abundance of crescentic histio- corticoids. Acetaminophen, ibuprofen, and me-
cytes.24-26 In this patient, staining of the biopsy peridine were administered to treat his fever and
specimen for fungi and mycobacteria was nega- chills. He spent 1.5 weeks in the hospital, and
tive. In situ hybridization for EBV-encoded RNA eventually his fever resolved.
was positive in a few scattered small and large After the patient was discharged, he was seen
lymphoid cells, suggesting latent infection. The at a follow-up visit 3 weeks later, and by that
results of serologic testing for EBV were consis- time, his neutrophil count had recovered, his
tent with past infection. The extent of EBV infec- lymphadenopathy had nearly resolved, and he was
tion in the lymph nodes was limited and was feeling well and had returned to work. However,
judged to be insufficient to account for the se- his primary care physician was concerned about
verity of the necrotizing lymphadenitis. the decreased range of motion of the right arm
SLE-related lymphadenitis is the condition his- during abduction, given that he had undergone
tologically closest to Kikuchi–Fujimoto disease. an excisional biopsy of a cervical lymph node.
Hematoxylin bodies (basophilic condensations of The patient was evaluated in the orthopedic
nuclear and cytoplasmic debris) and the Azzopardi clinic. A nerve-conduction study was performed,
A B
C D
E F
and an injury of the spinal accessory nerve was in a patient younger than 35 years of age should
diagnosed. He underwent a repair of the right be viewed with utmost suspicion by clinicians.
spinal accessory nerve and afterward noted im- Second, it is virtually impossible to distinguish
provement in the strength in his right arm. Kikuchi–Fujimoto disease from SLE on a biopsy
Dr. Nancy Lee Harris (Pathology): I would like to specimen of a lymph node. SLE may occasion-
congratulate the patient’s caregivers both in the ally develop in patients months or years after the
outpatient clinic and in the hospital for resisting findings on a lymph-node biopsy suggested
the temptation to give antibiotics to this acutely Kikuchi–Fujimoto disease. Such patients and
ill patient who had cervical lymphadenopathy. their caregivers should be aware that if new
Almost every biopsy specimen of a cervical symptoms develop, reassessment of the serologic
lymph node that I see in my work as a hemato- tests for SLE and repeat serologic testing may be
pathologist comes from a patient who has been indicated.
treated with one course or more of antibiotics
that were administered on the assumption that A nat omic a l Di agnosis
the patient had a bacterial infection.
I want to make two points about the pathologi- Necrotizing lymphadenitis, with features consis-
cal diagnosis of Kikuchi–Fujimoto disease. First, tent with histiocytic necrotizing lymphadenitis
Kikuchi–Fujimoto disease can be misdiagnosed as (Kikuchi–Fujimoto disease) and scattered EBV-
T-cell lymphoma. This is an important pitfall for positive cells.
the pathologist that an astute clinician can fore- This case was presented at the Medical Case Conference. Dr.
stall. Peripheral T-cell lymphomas are most com- Muse reports receiving payment for expert testimony on behalf
of patients in cases of asbestos exposure. No other potential
monly seen in patients older than 50 years of age. conflict of interest relevant to this article was reported.
The diagnosis of a T-cell lymphoma — other than Disclosure forms provided by the authors are available with
lymphoblastic lymphoma, anaplastic lymphoma the full text of this article at NEJM.org.
We thank Dr. Andrew Lundquist for assistance with the case
kinase–positive anaplastic large-cell lymphoma, or history, and Dr. David Sykes for assistance with the differential
(in rare cases) hepatosplenic T-cell lymphoma — diagnosis.
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