Open Journal of Pathology, 2013, 3, 186-192
Published Online October 2013 (http://www.scirp.org/journal/ojpathology)
http://dx.doi.org/10.4236/ojpathology.2013.34034
Kikuchi-Fujimoto Disease Associated to th e Epstein-Barr
Virus. A Type of Rare Necrotizing Lymphadenitis and Its
Differential Diagnosis
Mónica Belinda Romero Guadarrama1,2*, Oscar Daniel Guzmán-Aguilar1,2,
Adriana Carolina López-Ugalde3, José Samuel Almeida Navarro1,2, Humberto Cruz-Ortíz1,2
1Unidad de Patología, Hospital General de México “Dr. Eduardo Liceaga”, México D.F., México; 2Facultad de Medicina,
Universidad Nacional Autónoma de México, México D.F., México; 3Unidad de Otorrinolaringología, Hospital General de México
“Dr. Eduardo Liceaga”, México D.F., México.
Received August 17th, 2013; revised September 20th, 2013; accepted September 28th, 2013
Copyright © 2013 Mónica Belinda Romero Guadarrama et al. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
ABSTRACT
Introduction: Kikuchi-Fujimoto disease (KFD), also known as histiocytic necrotizing lymphadenitis, is a specific and
self-limited disease; its etiology is unknown. Some causal microorganisms have been proposed. The objective of the
present article is to emphasize th e clinicopathological characteristics of this disease that has been associated to the Ep-
stein-Barr virus and to compare the histological changes with other types of necrotizing lymphadenopathies. Material
and Methods: We studied 32 patients of the Surgical Pathology Service with necrotizing lymphadenitis, diagnosed in
the years from 2004 to 2012 to found more cases of this rare disease in our Institutio n. Patients were 18 women and 14
men with an average age of 37 years. Results: The lymph nodes were cervical and axillary ones, so me were associated
to autoimmune diseases and no cause was identified in others. One of the cases, was diagnosed as KFD, presented
morphological changes characteristic of this disease, such as subcapsular lymphoid follicles, zones with cell debris,
epithelioid macrophages, clear-cytoplasm histiocytes, and immunoblast-reactive lymphocytes. Immunohistochemical
markers were determined, such as CD20, CD2, CD4, CD8, CD68, lysozyme, CD56, granzyme B and EBER, which
demonstrated the presence of B, T lymphocytes, histiocytes and cells positive to EBER. Histological changes in KFD
occurred in three stages: proliferative stage, necrotizing, and xanthomatous. It is important to identify the histological
stages of the disease because a differential diagnosis must be performed in regard to lymphadenopathies with necrosis
and diverse types of lymphomas. Conclusion: We present a case of necrotizing lymphadenitis (KFD) associated to the
Epstein-Barr virus and in some cases it is not possible to render a specific diagnosis based on morphologic findings,
alone, and a diagno sis of necrotizin g lymphadenitis may be used.
Keywords: Kikuchi-Fujimoto Disease; Epstein Barr Virus
1. Background
Causes of lymphadenopath y must always be identified in
each patient. The histopathological profile allows know-
ing in most cases the cause of such growth, which can be
diagnosed to a primary or secondary (metastasis) neo-
plasm, or some types of hyperplasia or inflammatory pro-
cesses, which are important to recognize, since the pa-
thologist must iden tify the changes associated to necrosis
to be able to distinguish reactive processes of any malig-
nant growth [1 -3] .
Diverse reactive symptoms can be associated to necro-
sis and polymorphous infiltrates. These can be observed
in viral infections, such as those caused by the Epstein-
Barr virus (EBV), in infectious mononucleosis where the
infiltrate is diffuse, polymorph ous, with apoptotic debris,
and zonal necrosis. In the lymphadenitis due to Herpes
simplex virus and in dermatopathic lymphadenitis pre-
dominating a T-cell hyperplasia associated with lymph
node that drains from irritated, infected or inflamed skin
sites, something similar occurs with the necrotizing lym-
phadenitis associated to systemic lupus erythematosus.
Other types of lymphadenitis of unknown etiology,
*Corresponding author.

Kikuchi-Fujimoto Disease Associated to the Epstein-Barr Virus. A Type of Rare
Necrotizing Lymphadenitis and Its Differential Diagnosis 187
where a viral origin is assumed, are Kawasaki disease
and Kikuchi-Fujimoto disease (histiocytic necrotizing
lymphadenitis). The latter was described separately, al-
most simultaneously [4,5], in Japan by Kikuchi and Fu-
jimoto in young oriental females and considered as a
benign self-limited disease, characterized by cervical
lymphadenopathy and systemic symptoms. Its etiology is
still unknown, although several microorganisms, includ-
ing viruses and bacteria, have been proposed as causes of
the disease. The objectiv e of the presen t study is to repor t
a case of KFD in a 16-year-old female adolescent, with
cervical lymphadenopathy with extensive necrosis, sys-
temic manifestations, and transien affection of the skin.
Biopsy of cervical lymph node revealed zonal necrosis,
abundant cell debris, histiocytes, and a variable number
of mature lymphocytes. Immunohistochemistry tests re-
vealed polytypical proliferation of B lymphocytes, T
lymphocytes, T/cytotoxic lymphocytes, and the presence
of the EBV (Epstein-Barr-Virus) as demonstrated by in
situ hybridization. This disease is extremely rare in our
institution and the diagnosis must include such infarcts
that may be associated with lymphoma, Infectious lym-
phadenitis caused by mycobacterium, HIV (Human Im-
munodeficiency Virus) and others rare disease; we dis-
cuss its differential diagnosis from reactive lymphade-
nopaties and lymphomas with necrosis, because the treat-
ment of the patients with different types of lymphade-
nopaties is different.
2. Material and Methods
The electronic database of the Surgical Pathology Ser-
vice of the Pathology Unit of the General Hospital of
Mexico was retrospectively reviewed. We selected those
cases with the diagnosis of “necrotizing lymphadenitis”,
without any other specification, that occurred in a 8-year
period (2004 to 2012). We also reviewed the histological
sections stained with hematoxylin-eosin and with special
stains such as Shiff’s periodic stain, Groccot and Ziel-
Nelsen stains. We gathered the clinical data from the
available files and eliminated those cases with diagnosis
of necrosis by tuberculosis or another infectious agent.
From the patient with KFD diagnosis, we obtained the
clinical information, radiological images, laboratory data,
description of cutaneous injuries, excisional biopsy, and
reviewed the immunostaining was performed using the
(avidin-biotin peroxidase method) accord to the manu-
facturer´s instructions (DAKO Cytomation, Ely, United
Kingdom) and the following markers were used: CD20,
CD3, CD4, CD8, CD56, CD68, Lisozyme and Granzyme
B.
We also performed in situ hybridization for the RNA
of the EBV. For the EBER probe, we used the fluo-
rescein-labeled peptide to detect the nuclear presence of
coded RNA. Conjugated alkaline phosphatase, rabbit
antibody, and isothiocyanate-fluorescein were added, fol-
lowed by the substrate nitro-blue tetrazolium and 5-
bromo-4-chloro-3’-indolyphosphate (NBT/BCIP; Roche
Diagnostics, Indianapolis, IN, USA). Contrast was ach-
ieved wi th Hil l’s he mat oxyli n and t he fi nal pro cedure was
perform ed a s i n the desc ri bed im m unohi stoc hem i cal t ech-
nique. A nasal-type T/NK lymphoma was used as positive
external control for the EBV.
3. Results
We studied 32 patients with the diagnosis of necrotizing
lymphadenitis in th e 8-year period (2004-2012), 18 were
women (56.2%) and 14 (43.7%) were men. The youngest
patient was a 6-year-old girl and the oldest was a 74-
year-old woman. Average age was 38.7 years. Twenty
four cases (75%) corresponded to the cervical region, four
cases (12.5%) to the axillary region, three cases (9.3%)
were inguinal, and 1 (3.1%) corresponded to the retrop-
eritoneum. In three patients, it was possible to confirm
the association of necrotizing lympha denitis with autoim-
mune diseases such as lupus erythematosus (2 cases),
rheumathoid arthritis (1 case) (Table 1), only in a 16-
year-old adolescent was the KFD associated to the EBV;
clinically, she presented increased size of the cervical
lymph node of 2-month evolution, accompanied by as-
thenia, adynamia, fever, athralgia, and vesicle-shaped
cutaneous injuries in the fingers. Laboratory tests such as
blood tests and the search for antinuclear antibodies were
normal or negative. The CAT scan (computerized axial
tomography) of the neck revealed malignant-suggestive
jugular lymphadenopathy of more than 3 cm (Figure 1).
In the remainder 28 patients (87.5%) no associated dis-
ease could be documented.
Biopsies of patients with associated autoimmune dis-
ease revealed the presence of lymphoid cells in diverse
maturation stages, predominating small lymphocytes,
histiocytes, and necrosis. In the two cases associated to
systemic lupus erythematosus, hematoxylin bodies were
found in the paracortex zone; in the patient with rheu-
matoid arthritis the biopsy revealed periarterial and peri-
arteriolar fibrosis with zonal necrosis in most of the his-
tological section, with lymphoid infiltrate, occasional
plasmatic cells, histiocytes, abundant cell debris and lack
of hematoxilin bod ies. Large areas of zonal necro sis, cell
debris, scarce lymphocytes in diverse maturation stages
and histiocytes, and lack of polymorphonuclear cells
(Figures 2 and 3) were observed in the patient with KFD.
In the cases of reactive and unspecific necrotizing lym-
phadenitis, marked necrosis was observed in the cortical
and paracortical areas together with lymphocytes in di-
verse maturation states predominating mature lympho-
cytes, as well as abundant cell debris, scarce plasmatic

Kikuchi-Fujimoto Disease Associated to the Epstein-Barr Virus. A Type of Rare
Necrotizing Lymphadenitis and Its Differential Diagnosis
188
Table 1. Clinical changes in 32 patients with necrotizing lymphadenitis.
Sex Age Localization Clinical findings
Female (18 c as e s) 6 - 74 yo Cervical (14) Axilar (3)
Inguinale (1) LES (2) Enlargement of the Lymph node affected (18cases) and pain (7cases)
Male (14 cases) 16 - 64 yo Cervical (10) Axilar (1)
Inguinale (2) Retroperitoneal (1)RA (1) Enlargement of the Lymph node affected (14 cases) and pain (3)
Figure 3. A high magnification we can see the histiocytes
and the immunoblastic cells (40× H-E stain).
cells and histiocytes, lack of hematoxylin bodies, periar-
teriolar fibrosis, squamous histiocytes, and polymor-
phonuclear infiltrates.
Special stains in search of microorganisms were nega-
tive and immunohistochemical reactions demonstrated
scarce B cells, T cells, and some lysozyme-positive his-
tiocytes.
In the Kikuchi-Fujimoto disease case, the presence of
scarce B cells and T CD 2-positive cells was documented,
and the relation of T CD 8-positive lymphocytes with CD
4 was higher in the first.
Figure 1. Axial computari zed tomography of c ervical Lymph
node where shown enlargement of the lymph nodes with
necrosis.
Expression of T cytotoxic cells positive to Granzyme
B was observed, as well as scarce CD 56 positive cells,
scarce B cells, and nuclear expression to EBER in many
lymphoid cells (Figure 4).
4. Discussion
Necrotizing lymphadenitis is unusual and can be associ-
ated to a large variety of systemic and infectious diseases.
Among the former, autoimmune diseases like systemic
lupus erythematosus (SLE) must be considered is char-
acterized by irregularly shaped, focal or extensive, ne-
crosis sometimes accompanied by LE bodies or hema-
toxylin bodies that are heavily hematoxylin-stained ho-
mogeneous nuclear remnant of cells reacted with ANAs
(Anti-nuclear antibodies) and are strongly indicative of
SLE (Figure 5). Inmunohistochemistry would demon-
strate the lymphoid follicles are mixture of small and
Figure 2. The biopsy in a young female, where we can see
few necrosis, lymphocy tes and histiocytes (10× Hematoxilin-
eosin stain).

Kikuchi-Fujimoto Disease Associated to the Epstein-Barr Virus. A Type of Rare
Necrotizing Lymphadenitis and Its Differential Diagnosis 189
Figure 4. Eber is positive in lymphoid cells in the young
patient with KFD (40× in situ hibridization).
Figure 5. Necrotizing lymphadenitis by Erithematosus Lu-
pus, is evident the hemathoxifilic bodies (15× H-E stain).
medium-size lymphocytes and immunoblasts that are
positive for B-cell or T-cell markers CD4 and CD8 stains
would show a mixed nature of the interfollicular T lym-
phocytes. In many occasions it is not possible to docu-
ment the cause or causes of lymphadenitis associated
with necrosis, therefore, clinical information and labora-
tory tests are needed to identify the probable etiology,
and the different morphological patterns of lymph node
must always be taken into account, as these will vary
depending on the etiological agent; the most common
lymph node growth corresponds to hyperplasias, of which
the following varieties are known: follicular hyperplasia,
hyperplasia of marginal B zone, paracortical lymphoid
hyperplasia, sinusal hyperplasia and their combination,
although in these hyperplasia patterns, it is not common
to find zo n es of necrosi s [1 ].
In the case of acute lymphadenitis, it is common to
find some type of infectious agent and the clinical symp-
toms are very suggestive of an infectious process associ-
ated to the increase in lymph node volume [2,3]. KFD,
the cause is unknown until now, infectious and autoim-
mune causes have been suggested, viral infections like,
EBV has been shown by some authors to be linked to the
disease, but the studies are not conclusive, another asso-
ciation is with the hemophagocytic syn drome [4,5].
Most authors agree that KFD patients present leuko-
penia, elevation of transaminases, dehydrogenase lactate
and erythrocyte sedimentation [6,7]. In our patient, no
alterations were observed in the laboratory tests. Before
the lymphadenopathy, the patient presented cutaneous
alterations characterized by vesicles in the fingers of both
hands, which disappeared spontaneously, these cutaneous
manifestations have already been documented. Reck et al.
[8] reported in their study that dermatological alterations
occur in 27% of patients. KFD is more common in Asi-
atic individuals than in the remainder world population.
The ultrastructural histological changes and those re-
vealed by histochemistry imply a hyperimmune reaction
mediated by T cells in patients su sceptible to a variety of
non-specific stimuli. Some HLA class II (major histo-
compatibility co mplex) genes h ave been demonstrated in
patients with the disease [9]. In Mexico, the disease is
rare, the first two cases, in two women were reported in
our institution in 1987 [10]. In 2006 , Gutiérrez-Castro, et
al. [11] reported a series of 14 cases, 11 women and 3
men, median age was of 37 years. The necrotizing type
was the predominant histological pattern that predomi-
nated in these patients, and no association with the EBV
was reported. Other cases have been reported as isolated
cases in diverse national medical journals, even in pedi-
atric age patients and in adolescents [12-14].
Diagnosis must be performed in correlation with
clinical, morphological, and Immunohistochemistry data;
CD 68 and lysozyme are the markers that confirm the
presence of macrophages in lymphoid tissue [10]. Imag-
ing studies such as CAT (Computarized Axial Tomo-
graphy) and MRN (Magnetic Resonance Nuclear) do not
help to differentiate this disease from other diseases in-
volving lymph node, such as lymphoma, metastases, or
tuberculosis; hence, excisional biopsy of affected lymph
node must be done, particularly when necrotic areas are
evidenced by imaging studies. In the excisional biopsy it
is necessary to discard diseases that course with exten-
sive necrosis such as hyporeactive and non-reactive tu-
berculosis, where poorly defined granulomas, rare giant
cells, caseous necrosis and karyorrhexis are identified
[15]. The presence of tuberculosis bacilli demonstrated
with special stains confirm this disease, and KFD is dis-
carded, as done in this report.
Necrotizing lymphadenitis is characterized by pre-
senting necrotic areas with a cartographic aspect, as well
as reactive lymphoid cells of immature aspect (immuno-
blasts), numerous histiocytes, and absence of polymor-

Kikuchi-Fujimoto Disease Associated to the Epstein-Barr Virus. A Type of Rare
Necrotizing Lymphadenitis and Its Differential Diagnosis
190
phonuclear cells. Other lymphadenopathies, in some
cases, can resemble slightly KFD, such as cat scratch
disease, tularemia, venereal lymphogranuloma, other
bacterial or even viral infections; in some cases it is not
possible to establish a definite KFD diagnosis based only
on the morphological changes, and the diagnosis of ne-
crotizing lymphadenitis can be used when a characteristic
pattern is shown with lack of polymor phonuclear cells
[16].
It is important to keep in mind the different histologi-
cal aspects of KFD, particularly for the necrotizing stage,
when cells of the proliferative stage are observed [17-19]
and can be confused with malignant lymphoid cells,
hence, the most important differential diagnosis is with
respect to lymphomas especially if abundant immuno-
blasts and necrosis are observed. Within this group, we
have to consider B diffuse lymphomas of large cells
(Figure 6), if faced with the suspicion of this disease,
other malignant cells must be searched for such as cen-
troblasts, immunohistochemical reactions like CD20,
CD4, CD8, CD68, lysozyme, and Ki 67 can help to es-
tablish the correct diagnosis [11,18-20].
The T lymphomas are rare, it is important to consider
always the primary nasal-type T/NK lymphoma of lymph
node, in this lymphoma it is possible to observe angio-
centricity of neoplastic cells, marked necrosis, and pleo-
morphism of neoplastic cells; immunohistochemical re-
actions are very useful [21] (Figure 7). Other rare types
of neoplasms that have to be included in the differential
diagnosis are the T cells plasmacytoid leukemia, a clini-
copathological entity recently described in older men. If
the histiocytes of the KFD resemble sealed ring cells,
scarcely differentiated metastatic adenocarcinomas must
be include d [11,18] ( Table 2).
Table 2. Differential diagnosis of Kikuchi-Fujimoto lymphadenitis.
Disease Morphologic changes Immunohistochemistry
Autoimmune diseases
SLE/RA CD8 Necrosis, nuclear basophilic smearing of vessels, Hematoxylin bodies, plasma cells, neutrophils and
plasmacytoid cells, plasmacytic immunoblastic proliferation
Mixture of T and B cells,
CD8 increased. Eber negative.
Infectious disease
Herpes simplex Viral inclusions must be demonstrate in tissue sections. Anti-HSV antibody
Tuberculosis Granulomas with necrosis and microorganisms may show on
special stains.
Non-Hodgkin lym p h omas
Diffuse large B-cell lymphoma Identification of centroblasts, immunoblasts and necrosi s Antibodies are positives for CD20, CD10, Bcl2,
Bcl6, MumKi-67 o r Mib-1 high.
NK/T cell Lymphoma of
Nasal type in lymph node
Extensive necrosis, pleomorphic cells, cellular detritus,
apoptotic cells, and inflammatory backgrown cells with
clear cytoplasm and cytoplasm positive for PAS-stain
Mucicarmin and others.
Antibodies positives for: CD2, CD3, CD56,
Granzime B, TIA-1 and Eber in neoplastic cells.
Metastasic carcinoma Antibodies positives for: Cytoqueratin
and others epithelial stains.
Figure 7. Ly mphoma T/NK–Nasal Type of the lymph node,
where we can see angioinvasion for pleomorphic tumor cells
(40×, H-E stain).
Figure 6. Large B cell with necrosis (15×, H-E stain).

Kikuchi-Fujimoto Disease Associated to the Epstein-Barr Virus. A Type of Rare
Necrotizing Lymphadenitis and Its Differential Diagnosis 191
5. Conclusion
In conclusion, we present a rare case of KFD, in a
16-year-old adolescent, with unspecific cutaneous mani-
festations and cervical lymphadenopathy, with KFD-
characteristic changes, where the presence of EBV was
evidenced by in situ hybridization and she’s healthy two
years after the diagnosis. This is the third case reported in
our institution and all the previously cases diagnosed as
necrotizing lymphadenitis were excluded due to the
presence of polymorphonuclear leukocytes. It is impor-
tant to know this rare disease in Mexico, because it is
generally confused with highly malignant lymphomas or
infectious processes. Necrotizing lymphadenitis is a rare
finding and in some cases it is not possible to render a
specific diagnosis based on morphologic findings alone
and a diagnosis of necrotizing lymphadenitis alone or
unspecific may be used.
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