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Suppurative necrotizing granulomatous lymphadenitis in adult-onset Still's

disease: A case report

Article in Journal of Medical Case Reports · October 2012

DOI: 10.1186/1752-1947-6-354 · Source: PubMed

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Assimakopoulos et al. Journal of Medical Case Reports 2012, 6:354
http://www.jmedicalcasereports.com/content/6/1/354 JOURNAL OF MEDICAL
CASE REPORTS

CASE REPORT Open Access

Suppurative necrotizing granulomatous

lymphadenitis in adult-onset Still’s disease:
a case report
Stelios F Assimakopoulos1*, Vassilios Karamouzos1, Christos Papakonstantinou1, Vassiliki Zolota2,
Chryssoula Labropoulou-Karatza1 and Charalambos Gogos1

Abstract
Introduction: Lymphadenopathy is found in about 65% of patients with adult-onset Still’s disease and is
histologically characterized by an intense, paracortical immunoblastic hyperplasia. Adult-onset Still’s disease has not
been previously described as an etiology of suppurative necrotizing granulomatous lymphadenitis.
Case presentation: We describe a 27-year-old Greek man who manifested prolonged fever, abdominal pain,
increased inflammatory markers, episodic skin rash and mesenteric lymphadenopathy histologically characterized by
necrotizing granulomatous adenitis with central suppuration. Disease flares were characterized by systemic
inflammatory response syndrome with immediate clinico-laboratory response to corticosteroids but the patient
required prolonged administration of methylprednisolone at a dose of above 12mg/day for disease control. After
an extensive diagnostic work-up, which ruled out any infectious, malignant, rheumatic or autoinflammatory disease
the patient was diagnosed as having adult-onset Still’s disease. The patient is currently treated with 4mg of
methylprednisolone, 100mg of anakinra daily and methotrexate 7.5mg for two consecutive days per week and
exerts full disease remission for six months.
Conclusion: To the best of our knowledge this is the first report of suppurative necrotizing granulomatous
lymphadenitis attributed to adult-onset Still’s disease. This case indicates that the finding of a suppurative
necrotizing granulomatous lymphadenitis should not deter the consideration of adult-onset Still’s disease as a
potential diagnosis in a compatible clinical context; however, the exclusion of other diagnoses is a prerequisite.
Keywords: Adult-onset Still’s disease, Granulomatous, Inflammatory, Lymphadenitis, Suppurative

Introduction hyperplasia [1-3]. To the best of our knowledge, findings

Adult-onset Still’s disease (AOSD) is a systemic inflamma- of suppurative necrotizing granulomatous lymphadenitis
tory disorder of unknown etiology and pathogenesis. have not been previously described in AOSD.
There is no single diagnostic test for AOSD; rather, the The differential diagnosis of a necrotizing granuloma-
diagnosis is based on clinical criteria, such as high daily tous lymphadenitis is wide, including: infectious diseases
fever, arthralgia, skin rash, lymphadenopathy, and hepa- (bacterial, viral, fungal or parasitic); malignant disorders,
tosplenomegaly, and exclusion of any infection, malig- mainly lymphoid malignancies; autoimmune disorders
nancy, or other rheumatic disorder known to mimic like systemic lupus erythematosus; autoinflammatory
AOSD in its clinical features [1]. Lymphadenopathy is diseases; and idiopathic causes like Kikuchi’s disease and
found in about 65% of AOSD patients and is histologically sarcoidosis [4-6]. The presence of variable degrees of
characterized by an intense, paracortical immunoblastic suppuration although being suggestive of specific diag-
noses like Yersinia pseudotuberculosis infection or tuber-
culosis (TB) does not preclude other potential causes of
* Correspondence: sassim@upatras.gr
1
Department of Internal Medicine, University Hospital of Patras, Rion-Patras
necrotizing granulomatous adenitis [4].
26504, Greece
Full list of author information is available at the end of the article

© 2012 Assimakopoulos et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the
Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.
Assimakopoulos et al. Journal of Medical Case Reports 2012, 6:354 Page 2 of 6
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Here we describe a case of suppurative necrotizing

granulomatous lymphadenitis attributed to AOSD after
an extensive diagnostic work-up, which ruled out all the
aforementioned etiologies.

Case presentation
A 27-year-old Greek man, with an unremarkable past
medical history except a reported penicillin allergy, was
admitted to our department, referred from a regional hos-
pital, for investigation of fever of three months’ duration
associated with mesenteric lymphadenopathy, leukocytosis
(25.000/mm3 with polymorphonuclear predominance)
and increased erythrocyte sedimentation rate (ESR) over
100mm/h. The patient, who reported no close animal
contact, had been previously hospitalized twice in the re-
ferral hospital complaining of fever associated with rigors
and right lower guardant abdominal pain. The performed
diagnostic investigation had only shown mesenteric
lymphadenopathy and the patient was conservatively trea-
ted with intravenous antibiotic therapy consisting of cipro-
floxacin and metronidazole with temporal improvement,
followed by relapse after a short time.
On admission, the patient’s temperature was 39°C,
heart rate was 90bpm, respiratory rate was 16 breaths
per minute, blood pressure was 120/80mmHg and oxy-
gen saturation in room air was 97%. His physical exam-
ination was unremarkable except for abdominal
tenderness in his right lower guardant without rebound
tenderness. No hepatomegaly, splenomegaly or periph-
Figure 1 Computed tomography scan of the patient’s
eral lymphadenopathy was detected. abdomen (A and B): A mesenteric lymphadenopathy of 2.7cm
An initial laboratory evaluation showed a white blood maximum diameter with a hypodense center was detected
cell count of 22.3 × 109/L, with predominant neutrophils (white arrows).
(80%), hematocrit 35%, hemoglobin 11.6g/dL (mean cor-
puscular volume = 82 and mean corpuscular hemoglobin
= 26) and platelet count 51 × 109/L. Prothrombin and or hepatosplenomegaly, with normal vascular perfusion of
partial thromboplastin times were normal and d-dimers abdominal organs, absence of mediastinal lymphadenop-
were slightly increased at 0.72μg/ml. The blood biochem- athy, ascites, pleural or pericardial effusions.
istries, including serum angiotensin-converting enzyme All sets of blood cultures (at least six), urine and stool
(ACE) and protein electrophoresis were all normal. cultures and examination for ova and parasites were
Serum C-reactive protein was increased at 17.3mg/dL, negative. Antibodies for hepatitis A, B, C, coxsackie,
ESR at 80mm/h, fibrinogen at 851mg/dL and ferritin at Enteric Cytopathic Human Orphan virus, herpes simplex
663mg/dL. Thyroid function tests were normal. Urine virus, Epstein–Barr virus, cytomegalovirus, human im-
analysis and 24-hour urinary calcium and protein excre- munodeficiency virus, human T-lymphotropic virus-1
tion were normal. Electrocardiogram, chest X-ray, echo- and virus-2, Yersinia enterocolitica and Entamoeba histo-
cardiogram and arterial blood gas were also normal. A lytica, Bartonella henselae, Francisella tularensis, Leish-
detailed ophthalmologic examination including slit-lamp mania donovani, Coxiella burnetii and Rickettsia conorii
eye examination, fundoscopy, Rose Bengal test and were negative. Wright and rapid plasma reagin tests were
Schirmer’s test was unrevealing. also negative, whereas the tuberculin skin test was
An abdominal ultrasonography revealed enlarged mes- positive (15mm).
enteric lymph nodes of 2.5cm diameter. Consequent thor- The patient underwent upper and lower gastrointestinal
acic and abdominal computed tomography (CT) scans tract endoscopies, enteroclysis and capsule endoscopy
confirmed the presence of mesenteric lymphadenopathy without evidence of inflammatory bowel disease, infective
of 2.7cm maximum diameter with an hypodense center colitis or celiac disease. Examination of gastric fluid with
(Figure 1A, 1B), without evidence of bowel inflammation Ziehl–Neelsen stain detected no acid-fast bacteria; a
Assimakopoulos et al. Journal of Medical Case Reports 2012, 6:354 Page 3 of 6
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polymerase chain reaction (PCR) as well as culture for also performed without identification of sarcoid
mycobacterium TB were negative. Small bowel (jejunal granulomata.
and ileal) and colonic biopsies presented findings of non- The hematological work-up in the investigation of the
specific inflammatory reaction, the architecture of intes- patient included microscopic examination of peripheral
tinal villi was preserved and mucosal periodic acid-Schiff blood film which showed no evidence of lymphoproli-
stain for detection of Tropheryma whipplei was negative. ferative disorders. A bone marrow biopsy and immuno-
A full immunologic screening with rheumatoid factor, phenotypic analysis revealed no pathologic findings. A
antinuclear antibodies, antibodies to double-stranded DNA, peripheral blood immunophenotypic analysis revealed
anti-Sm, anti-Ro/SSA, anti-La/SSB, anti-RNP, anti-Jo-1, lymphopenia due to simultaneous decrease of B-, T- and
anti-Scl-70, anti-histones, anti-mitochondrial antibodies, NK-cells. Serum beta-2-microglobulin levels were within
anti-smooth muscle antibodies, cytoplasmic-antineutrophil normal limits.
cytoplasmic antibody (ANCA), perinuclear-ANCA, anti- After an extensive diagnostic work-up no definite diag-
transglutaminase, anti-cardiolipin, and lupus anticoagulant nosis was available for our patient. During hospitalization
was negative. Serum complement and levels of immunoglo- the patient was empirically treated with combined anti-
bulins (Igs, IgA, IgG, IgM, IgE, IgD) were normal. The microbial therapy that consisted of ciprofloxacin and
results of genetic testing for mutation of the familial metronidazole without response, while episodic disease
Mediterranean fever gene (Μ694V, V726A, M694I, flares characterized by a systemic inflammatory response
M680I, and E148Q) were negative. In addition, the syndrome (SIRS) and spikes of increased markers of in-
results of a full tumor marker profile were also normal. flammation were recorded. Sporadically, fever spikes
The patient underwent laparotomy with mesenteric were associated with a transient maculopapular skin rash
lymph node excision for microbiological and histological in his upper extremities. Of note, the patient experienced
examination. Histology revealed a granulomatous lymph- a dramatic clinical improvement after administration of
adenitis with central suppurative necrosis (Figure 2A). corticosteroids for a short time; the corticosteroids were
Gram, Giemsa, Ziehl–Neelsen and Grocott methenamine administered due to his history of allergy in order to
silver stains for detection of common bacteria, mycobac- administer intravenous contrast media for CT perform-
teria and fungi were all negative. Immunohistochemical ance. This temporal improvement was shortly followed
studies for lymphoproliferative disease were unrevealing. by disease relapse. Based on the therapeutic criterion
In addition, the patient’s lymph node was examined with of response to corticosteroids and taking into consider-
a PCR and cultures for mycobacterium TB, atypical ation the significantly positive tuberculin skin test in
mycobacteria (Mycobacterium africanum I and/or II, conjunction with the histology of the mesenteric
M. microti, M. carnetti, M. bovis, and M. avium com- lymph node, which showed a granulomatous necrotizing
plex), fungi and Tropheryma whipplei without detection lymphadenitis with central suppuration, we decided to
of any pathogen. A gastrocnemius muscle biopsy was administer a combination empiric therapy. The therapy
consisted of corticosteroids (methylprednisolone 16mg)
and anti-TB drugs (isoniazide 150mg/d, pyrazinamide
30mg/kg, ethambutol 20mg/kg and moxifloxacin
400mg/d). Rifampicin 300mg/d, which was included in
our initial scheme, was later discontinued due to in-
duction of rifampicin-associated pancreatitis. He
received the anti-TB therapy for one year and discon-
tinued corticosteroids after a very slow tapering at 11
months. During this period the patient was asymptom-
atic with normal values of inflammatory markers and
he had a total resolution of mesenteric lymphadenop-
athy at abdominal CT re-examination on completion
of the anti-TB therapy. Unfortunately, 20 days after
stopping the corticosteroids the disease relapsed, and
the patient had fever, abdominal pain, increased markers
of inflammation and reappearance of mesenteric lymph-
adenopathy on abdominal MRI. The patient’s symptoms
Figure 2 Mesenteric lymph node biopsy from the presented were controlled with 16mg methylprednisolone; however,
patient: formation of histiocytic granulomas with central while attempting to taper the methylprednisolone to
suppurative necrosis (hematoxylin and eosin stain, A: ×100,
12mg after about two months of treatment, his symp-
insert ×200).
toms relapsed forcing us to reinstitute a higher
Assimakopoulos et al. Journal of Medical Case Reports 2012, 6:354 Page 4 of 6
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Table 1 Causes of granulomatous and/or necrotizing Table 1 Causes of granulomatous and/or necrotizing
lymphadenitis, with or without suppuration lymphadenitis, with or without suppuration (Continued)
Granulomas Necrosis Suppuration D. Idiopathic diseases
A. Infections Sarcoidosis + – –
Viruses – + – Necrotic sarcoid granulomatosis + + –
(EBV, CMV, HBV, HCV, Herpes simplex, Adenovirus, HIV) Kikuchi-Fujimoto disease + + –
Bacteria E. Autoinflammatory diseases
Yersinia pseudotuberculosis + + + Familial Mediterranean fever – + –
Bartonella + + + Hyperimmunoglobulinemia-D no data no data no data
syndrome
Tropheryma whipplei + – –
PFAPA syndrome – ± ±
Francisella tularensis + + +
Note: ± indicates the potential existence of the corresponding histological
Brucella + + + feature, which is however non-typical for this disease.
Spirochaetes CMV, Cytomegalovirus; EBV, Epstein–Barr virus; HBV, Hepatitis B; HCV, Hepatitis
C; HIV, Human immunodeficiency virus; PFAPA, Periodic fever, aphthous
Treponema pallidum + + + stomatitis, pharyngitis and adenitis.
Chlamydia
Lymphogranuloma + + + corticosteroid dose. Our second effort to gradually re-
venereum duce the corticosteroid dose, after control of the patient’s
Rickettsia symptoms and total remission of mesenteric lymphaden-
Coxiella burnetii + – – opathy on abdominal MRI, led to disease relapse when
Mycobacteria the dose of methylprednisolone was reduced to 12mg/
day. Disease relapse was controlled by increasing methyl-
Mycobacterium tuberculosis + + +
prednisolone dose to 16mg, while additional immuno-
Atypical mycobacterial + + +
infection
modulatory drugs (anakinra and methotrexate) were
added in order to prevent disease relapse during methyl-
Mycobacterium leprae + + +
prednisolone tapering. The patient is currently treated
Parasites with 4mg of methylprednisolone, 100mg of anakinra
Toxoplasmosis + ± + daily and methotrexate 7.5mg for two consecutive days
Leishmaniasis + – – per week and has experienced full disease remission for
Fungi six months.
Histoplasmosis + + +
Aspergillosis + – –
Discussion
Coccidioidomycosis + + + Here we describe a previously healthy young man who
Cryptococcosis + + + presented with prolonged fever, abdominal pain,
B. Neoplastic diseases increased inflammatory markers, episodic skin rash and
Hodgkin disease + + ± mesenteric lymphadenopathy histologically characterized
by necrotizing granulomatous adenitis with central sup-
Non-Hodgkin disease ± + ±
puration. Disease flares were characterized by SIRS with
Metastatic carcinoma + + ±
immediate clinico-laboratory response to corticosteroids
Langerhans cell histiocytosis + – – but the patient required prolonged administration of
Seminoma + – – methylprednisolone at a dose of above 12mg/day for dis-
Dysgerminoma + – – ease control.
C. Autoimmune diseases In Table 1 we present an extensive differential diagno-
sis of granulomatous necrotizing and suppurative
Systemic lupus erythematosus – + –
lymphadenitis [4,5,7]. As shown in Table 1, histological
Granulomatosis with polyangiitis + + +
overlapping of the formation, necrosis and suppuration
Churg–Strauss syndrome + + – of granulomas, in variable degrees, may exist in diverse
Celiac disease + – – lymphadenopathies. Therefore, when a suppurative nec-
Crohn’s disease + – – rotizing granulomatous lymphadenitis cannot be asso-
Primary biliary cirrhosis + + – ciated with any of its typical causes, our diagnostic
consideration should encompass all the potential causes
Kawasaki disease – + +
of granulomatous and necrotizing lymphadenitis.
Assimakopoulos et al. Journal of Medical Case Reports 2012, 6:354 Page 5 of 6
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In our patient, no infectious etiology could be detected diagnostic consideration. Disease presentation in the pa-
by serological, microbiological, histological and molecular tient was atypical for AOSD because it lacked common
methods. Whipple’s disease, which was a serious diagnostic features such as arthralgias, sore throat, abnormal liver
consideration, was thoroughly investigated and excluded. function tests and significant serum hyperferritinemia
Lymph node histology in conjunction with positive Man- [14]. However, diagnosis of AOSD was based on fulfill-
toux reaction, compatible clinical picture, and absence of ment of the commonly used high sensitive Yamaguchi
an alternative confirmed diagnosis led to institution of criteria (93.5% sensitivity) and exclusion of any other
empiric anti-TB therapy. Disease relapse after completion diagnostic consideration including any infectious, malig-
of one year’s anti-TB therapy was the strongest criterion nant, or rheumatic disorder known to mimic AOSD in
for exclusion of tuberculous lymphadenitis. its clinical features (Table 2) [1,15]. Although a lymph
Lymphoid malignancies, either non-Hodgkin or Hodg- node biopsy is not necessary for the diagnosis of AOSD
kin disease, were excluded based on lymph node histo- it is often performed to rule out other potential diag-
logic and immunohistochemical studies, bone marrow nostic thoughts, like lymphomas. Lymphadenopathy in
aspiration, biopsy and immunophenotypic analysis, and AOSD patients is histologically characterized by an in-
peripheral blood smear examination and immunopheno- tense, paracortical immunoblastic hyperplasia, whereas
typic analysis. the finding of a suppurative necrotizing granuloma-
Crohn’s disease was another important diagnostic pos- tous lymphadenitis has not been previously described
sibility. Normal upper and lower gastrointestinal tract [1-3].
endoscopies, enteroclysis, capsule endoscopy and small
and large intestinal biopsies excluded this diagnosis.
Sarcoidosis was also considered to be a diagnostic pos- Conclusion
sibility in our patient. The typical histological feature of To the best of our knowledge this is the first report of
sarcoidosis is the formation of non-necrotizing granu- suppurative necrotizing granulomatous lymphadenitis
lomata [8]; however, the existence of necrotizing sarcoid attributed to AOSD. The presented case demonstrates
granulomatosis has also been described since 1973 [9]. that the finding of a suppurative necrotizing granuloma-
Normal serum ACE levels, absence of hypercalciuria, tous lymphadenitis should not deter the consideration of
normal pulmonary function tests, slit-lamp eye examin-
ation, CD4 to CD8 ratio in bronchoalveolar lavage, and Table 2 Accordance of the presented patient with the
no detection of sarcoid granulomata in gastrocnemius Yamaguchi criteria for the diagnosis of adult-onset Still’s
muscle biopsy [10], made this diagnosis unlikely. disease
Regarding autoimmune diseases, systemic lupus erythe- Yamaguchi criteria (require the presence Patient’s
of five features, with at least two being characteristics
matosus was excluded by the absence of autoantibodies. major diagnostic criteria):
The possibility of granulomatosis with polyangiitis and
Major Yamaguchi criteria:
Churg–Strauss syndrome was ruled out based mainly on
1. Fever of at least 39°C lasting at least one week. +
clinical criteria combined with negative ANCAs. Kawasaki
disease, which occurs rarely in adults, was excluded by 2. Arthralgias or arthritis lasting two weeks or longer. –
incompatible clinical course because it is typically a 3. Typical rash (maculopapular, nonpruritic) +
self-limited condition, while its associated necrotizing during febrile episodes.
lymphadenitis is typically non-granulomatous [11]. 4. Leukocytosis (10,000/μL or greater), +
with at least 80% granulocytes.
Kikuchi-Fujimoto disease was excluded based on the
prolonged and relapsing clinical course of our patient Minor Yamaguchi criteria:
and the histological features of affected lymph nodes 1. Sore throat –
with significant infiltration by neutrophils [12]. Among 2. Lymphadenopathy +
autoinflammatory diseases, the familial Mediterranean 3. Hepatomegaly or splenomegaly –
fever was excluded by appropriate genetic testing, the
4. Abnormal liver function studies –
hyper-IgD syndrome by normal serum IgD and IgA
5. Negative antinuclear antibodies +
levels and periodic fever with aphthous stomatitis, pha- and rheumatoid factor.
ryngitis, and adenitis syndrome by clinical criteria [13].
Exclusions
After the aforementioned extensive diagnostic work-
up and ruling out all potential alternative diagnostic 1. Infection, especially sepsis and infectious ✓
mononucleosis
considerations, AOSD, an inflammatory disorder which
2. Malignancies, especially lymphomas ✓
could be expressed with daily fevers, increased inflam-
matory markers and lymphadenopathy, in the absence of 3. Rheumatic diseases known to mimic adult ✓
Still’s disease
positive autoantibodies, came into play as an important
 Assimakopoulos et al. Journal of Medical Case Reports 2012, 6:354 Page 6 of 6
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AOSD as a potential diagnosis when the clinical features 14. Lian F, Wang Y, Yang X, Xu H, Liang L: Clinical features and
are compatible; however, exclusion of a wide range of hyperferritinemia diagnostic cutoff points for AOSD based on ROC
curve: a Chinese experience. Rheumatol Int 2012, 32:189–192.
infections, malignancies and other rheumatologic condi- 15. Masson C, Le Loet X, Liote F, Dubost JJ, Boissier MC, Perroux-Goumy L,
tions should always be performed. Bregeon C, Audran M: Comparative study of 6 types of criteria in adult
Still’s disease. J Rheumatol 1996, 23:495–497.

Consent doi:10.1186/1752-1947-6-354
Cite this article as: Assimakopoulos et al.: Suppurative necrotizing
Written informed consent was obtained from the patient granulomatous lymphadenitis in adult-onset Still’s disease: a case report.
for publication of this case report and accompanying Journal of Medical Case Reports 2012 6:354.
images. A copy of the written consent is available for re-
view by the Editor-in-Chief of this journal.

Abbreviations
ACE: angiotensin-converting enzyme; ANCA: antineutrophil cytoplasmic
antibody; AOSD: Adult-onset Still’s disease; CT: computed tomography;
ESR: erythrocyte sedimentation rate; Ig: immunoglobulin, PCR, polymerase
chain reaction; SIRS: systemic inflammatory response syndrome;
TB: tuberculosis.

Competing interests
The authors declare that they have no competing interests.

Authors’ contributions
SFA wrote this case report; SFA, VK and CP, were the patient’s doctors; VZ
performed the histological diagnosis; CL-K and CG critically revised the
manuscript. All authors have read and approved the final version of this
manuscript.

Author details
1
Department of Internal Medicine, University Hospital of Patras, Rion-Patras
26504, Greece. 2Department of Pathology, University Hospital of Patras,
Rion-Patras 26504, Greece.

Received: 25 June 2012 Accepted: 19 September 2012

Published: 18 October 2012

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