Czas. Stomatol., 2007, LX, 10, 669-683
© 2007 Polish Dental Society
http://www.czas.stomat.net
Wegener’s granulomatosis in the craniofacial region
– own observations
Ziarniniakowatość Wegenera w obszarze części twarzowej czaszki
– obserwacje własne
Hubert Wanyura1, Katarzyna Życińska2, Marzena Uliasz1,
Joanna Nowak-Portalska1, Artur Kamiński1
Department of Cranio-Maxillofacial Surgery, Medical University of Warsaw, Poland1
Head: prof. H. Wanyura, MD, DDS, PhD
Department of Internal and Metabolic Diseases, Medical University of Warsaw, Primary Vasculitis
Outpatients’ Clinic, Poland2
Head: prof. K. A. Wardyn, MD, PhD
Summary
Streszczenie
Introduction: Wegener’s granulomatosis is an
uncommon systemic disease belonging to the group
of primary systemic vasculitises (PSV) of unknown
etiology. Its typical localization is the upper and lower
respiratory tract and kidneys. In a more limited form
of Wegener’s granulomatosis, necrotizing vasculitis
occurs in joints, skin and orbital tissues.
Aim of a study: To present diagnostic difficulties
and treatment methods in patients with limited
form of Wegener’s granulomatosis localized in the
craniofacial region.
Material and methods: Between 2002-2005,
Wegener’s granulomatosis was diagnosed in
3 patients. The disease was localized in the maxillary
sinus, the orbit, the skin and the muscles of the
forehead.
Conclusions: Based on our own observations we
conclude that the diagnosis of systemic vasculitis,
especially in patients with a limited form of
Wegener’s granulomatosis, is difficult, due to its rare
occurrence and unspecific clinical manifestation.
Early diagnosis of Wegener’s granulomatosis is
of significant value for therapy’s effectiveness and
poses a mulitidisciplinary problem.
Wprowadzenie: ziarniniakowatość Wegenera jest
rzadkim schorzeniem układowym należącym do grupy pierwotnych systemowych martwiczych zapaleń
naczyń krwionośnych (ang. PSV– Primary Systemic
Vasculitis) o nieznanej etiologii. Typową jej lokalizacją są górne i dolne drogi oddechowe oraz nerki.
W tzw. ograniczonej postaci ziarniniakowatości Wegenera procesy zapalno-naciekowe obejmują stawy,
skórę oraz tkanki oczodołu.
Cel pracy: przedstawienie trudności diagnostycznych oraz sposobu leczenia chorych
z ograniczoną postacią ziarniniakowatości Wegenera zlokalizowaną w obszarze części twarzowej
czaszki.
Materiał i metody: w latach 2002-2005 u 3 chorych
rozpoznano ziarniniakowatość Wegenera. Proces
chorobowy obejmował zatokę szczękową, oczodół
oraz skórę i mięśnie czoła.
Podsumowanie: z naszych obserwacji wynika, że
diagnostyka układowych zapaleń naczyń, szczególnie u chorych z ograniczoną postacią ziarniniaka
Wegenera, jest trudna z powodu ich rzadkiego występowania oraz niespecyficznych objawów klinicznych. Wczesne rozpoznawanie ziarniniakowatości
Wegenera ma bardzo istotne znaczenie dla skuteczności leczenia chorych i stanowi multidyscyplinarny
problem.
KEYWORDS:
Wegener’s granulomatosis, craniofacial region,
diagnosis
HASŁA INDEKSOWE:
ziarniniakowatość Wegenera, część twarzowa czaszki, rozpoznawanie
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H. Wanyura et al.
Czas. Stomatol.,
Introduction
– serological evaluation (determination of
the concentration of ANCA antibodies),
– histopathological examination of the
material taken during the biopsy of organs
affected by the disease [25].
Criteria (at least two) formulated in 1990
by the experts of the American Rheumatism
Association may be helpful:
1) nasopharyngitis,
2) presence of abnormal changes in the Xray examination of the lungs,
3) sediment in the urine (microscopic
hematuria or rolled erythrocytes),
4) granulomatous inflammation in the
tissue biopsy [cited after 1, 8, 14, 20, 25].
The presence of at least 2 features allows to
diagnose WG with 82.2% sensitivity and 92%
specificity [6, 8].
Antibodies detected in the serum of
patients, called anti-neutrophil cytoplasmic
antibodies (ANCA) by van der Woud et al.,
[21] react specifically with granularities of
the cytoplasm in neutrophils. Cytoplasmic
antibodies c-ANCA (PR3-ANCA) directed
against proteinase 3 (PR3) are found in about
75–80% of patients treated for Wegener’s
granulomatosis, while less characteristic
perinuclear antibodies of p-ANCA type (MPOANCA directed against myeloperoxidase)
are detected in 10–15% of patients [13, 17].
Specificity of ANCA antibodies in WG reaches
92%, while sensitivity depends on the activity
of the disease [1, 2, 8, 14, 17]. Components
of the complement system activated by the
infecting agent (e.g. Staphylococcus aureus,
group A Streptococcus, Mycobacterium
tuberculosis, Parvovirus B19, Hantavirus,
Cytomegaly virus, HBV), medicines or
environmental factors, act chemotactically
mainly on neutrophils, which accumulate at
the site of aggregation of immune complexes
[13]. In normal conditions leukocytes migrate
Wegener’s granulomatosis (WG) is a rare
systemic condition belonging to the group of
diseases known as primary systemic vasculitis
(PSV) [1, 6, 13, 22, 25]. Necrotizing vasculitis
and septic inflammation of tissues with
formation of granulomas undergoing necrosis
result in limitation of blood flow to vital
organs, and makes Wegener’s granulomatosis a
disease with potentially life-threatening course
[1, 6, 23, 25]. Early diagnosis of the disease
and implementation of immunosuppressive
therapy may bring about remission in 70-80%
of patients [1, 19].
Characteristic localization of granuloma
formation: upper and lower respiratory
tract and kidneys, described by a German
pathomorphologist Friedrich Wegener [23], has
been named the “triad of Wegener” by Goodman
and Churg in 1954 [cited after 1, 22]. The study
by Abdou et al. [cited after 22] performed on a
group of 701 patients concludes that paranasal
sinusitis is diagnosed at the preliminary stage
of the disease in 68% of patients, pneumonia
in 62% of patients, and glomerulitis in 38% of
patients. On the other hand, during the advanced
phase of WG, the diagnoses account for 22%,
28%, and 30%, respectively.
The right diagnosis is difficult, and sometimes
takes months or years, especially in the case of
the limited Wegener’s granulomatosis (LWG),
deemed to be an earlier stage of generalized
multisystemic disease (classical Wegener’s
granulomatosis, CWG) [17, 20, 23]. Diversity of
clinical symptoms depends on the localization
of the inflammatory/infiltration process in the
course of WG [6].
Wegener’s granulomatosis is diagnosed on
the basis of:
– clinical advancement of the pathological
process,
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2007, LX, 10
Wegener’s granulomatosis in the craniofacial region
in order to destroy the source of inflammation
and allow the healing of tissues, while in
PSV enzymes such as proteinase 3 (PR3) or
myeloperoxidase (MPO) are expressed on the
surface of inflammation mediator-activated
granulocytes. Thanks to these enzymes ANCA
bind to the surface of neutrophils, cause their
degranulation and release of both proteolytic
enzymes and free radicals, damaging
endothelium and walls of blood vessels. An
unknown factor maintains the inflammation
process and the ongoing destruction of
tissues: necrosis, fibrosis or formation of
granulomas [6, 13, 22]. However, for the
disease to develop, a person must probably
be genetically predisposed (heterozygous
patients for PiZ variant of α1-antitrypsin
gene) [8, 13].
Focal damage to the blood vessel wall leads
to bulging and breaking of the walls, bloody
hemorrhages and perivascular necrosis.
Inflammatory lesions covering the whole
circumference of the blood vessel wall are
especially dangerous. Narrowing of the blood
Fig. 1. Male patient, 17, with the tumor of frontal area, nose and right cheek in the course of
Wegener’s granulomatosis; a – en face, b – side,
c – forehead and nose deformation.
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H. Wanyura et al.
vessel lumen and, in consequence, ischemia
of the kidneys and/or lungs, produces acute
impairment of these organs, or pulmonaryrenal syndrome [6]. Epidemiology of WG
changes as the new diagnostic methods are
being developed [6].
Aim of the study
The study aims at presenting diagnostic
problems and the method of treatment in
patients with Wegener’s granulomatosis
localized in the craniofacial region.
Czas. Stomatol.,
Materials and methods
In 2002-2005 Wegener’s granulomatosis
(WG) was diagnosed in 3 patients. One man and
two women were treated. Patients were aged 17,
23 and 64 years, respectively. The inflammatory
process in the course of WG began in the maxillary
sinus, the skin and the orbit.
Observation 1
A 17-year-old male with Asperger syndrome
was admitted to the Department of Cranio-
Fig. 2. CT scan showing a homogenous soft tissue tumor; a – axial section on the level of frontal sinuses, b
– frontal plane, abnormal mass does not infiltrate bony structures, c – intrasurgical photo, surgical access, d
– perioperative preparation.
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2007, LX, 10
Wegener’s granulomatosis in the craniofacial region
Maxillofacial Surgery in Warsaw because of
the tumor covering the frontal area, the cheeks
and the nose (Fig. 1 a-c). At the age of 6 the
patient was diagnosed with insulin-dependent
diabetes. At the moment the patient is treated
with NovoRapid insulin 24u/day, with dose
correction according to the glycemia profile,
administered by insulin pump.
The patient’s history revealed that the onset
of the disease appeared in October 2003. At that
time the swelling of the right cheek, eyelids of
the right eye and the forehead occurred. On top
of that, numerous purulent and hemorrhagic
lesions appeared on the skin of the forehead.
The lesions healed periodically after the
administration of antibiotic therapy. In 2004
the patient was hospitalized twice in the ENT
department with the complaint of obstructed
nasal ducts. Paranasal sinuses were evaluated
by means of a CT examination and were found
to be patent.
In May 2005 a biopsy of a tumor visualized
by CT of the craniofacial region (Fig. 2 a, b)
was performed. The tumor progressively grew
larger; it was soft, indolent, and covered the
skin and the frontal muscles, the nose and the
right cheek. Massive swelling of the eyelids
of the right eye caused the tightening of the
crease. Normal movement of the orbits was
observed. Additionally, skin lesions resembling
acne appeared on the face. The patient was
auto– and allopsychologically oriented. Body
weight remained on the constant level of 80
kg. The patient negated pain, weakening,
elevated body temperature, micturition and
diuresis disturbances. Blood pressure was 120/
85 mm Hg, pulse regular – 12 respirations
per minute, with respiratory vesicular murmur,
Fig.3. The same patient 2 years after diagnosis; a – en face, b – side.
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H. Wanyura et al.
the liver and the spleen were of normal size,
the abdomen without pathological resistance,
no tenderness in the costovertebral angle on
either side. There were no abnormal results of
laboratory tests.
Tissue for histopathological examination
was collected under general anesthesia, by
access through superciliary arches (Fig. 2
c, d). The preparation was evaluated twice.
Histopathological examination no 4276 (1)/
2005 revealed the presence of inflammatory
infiltration of mononuclear cells and
macrophages between the muscles and
around small vessels. Diagnosis of Wegener’s
granulomatosis was made only after the
second anatomopathological examination
of the preparation in Norway (More and
Romsal County Hospital, Molde). Very active
inflammatory process resembling vasculitis
leucocytoclastica with high degree of local
destruction, necrotic lesions and focal formation
of granulomas with giant cells was described
in connective tissue and muscles. The test for
c-ANCA antibodies was negative.
Immunosuppressive
treatment
was
introduced in the Clinical Department of
Internal and Metabolic Diseases, Chair and
Department of Family Medicine, Medical
University of Warsaw: 3 pulses of SoluMedrol (500 mg in 500 ml 0.9% NaCl i.v. and
1 pulse of Endoksan (400 mg in 500 ml 5%
glucose i.v.). The patient was administered 60
mg Encortonu in ambulatory; every 14 days
the dose was reduced by 10 mg to 40 mg/day.
Additionally, the patient was taking Biseptol
– 2 times a week 960 mg, Lanzul 30 mg (1x1
tabl.), Calperos 1,0 g (2x1 tabl.), Alfakalcidol
1 µg (1x1 caps.) and insulin. Remission of the
disease was achieved (Fig. 3 a, b). The treatment
is continued; the patient is on Encorton 20 mg
and Endoxan 100 mg.
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Czas. Stomatol.,
Observation 2
A 23-year-old female was referred to the
clinic in July 2002 because of the tumor of
the soft tissues in the left cheek as well as
unhealed wound in the buccal vestibule after
the third surgery on the left maxillary sinus
in another therapeutic center. The patient
presented many hospital treatment records
documenting the progress of the disease. The
patient was frequently hospitalized in ENT,
allergological, pulmonological, neurological,
surgical and orthopedic wards. The interview
revealed that since 1995 the patient was taking
Tegretol to monitor epilepsy.
In 1997 the patient sustained an injury of the
right knee. The patient was repeatedly operated
on because of chronic, periodically exacerbating
bursitis of the right knee. Postoperative wound
required repeated drainage and long-lasting
antibiotic therapy because of the infection
with Staphylococcus aureus. The symptoms
resolved only four years after the resection of
prepatellar bursa and the application of skin
implants.
In 2001 the patient was hospitalized at the
Allergology and Pulmonology Department
because of rhinitis allergica and sinusitis
maxillaris acuta (blood test, biochemical
examination, urine test, spirometry, CT of the
chest and bronchoscopy were all within the
norm). In February and March 2002 sinuscopy
of the left maxillary sinus was performed (result
of histopathological examination no. 342826:
sinusitis chronica non-specifica and 343836:
abscessus vetus). The patient still complained
of pain, periodical swelling of the left cheek
and pyrexia. Results of laboratory tests (blood
test, coagulogram, total protein level, protein
electrophoresis, ionogram) were about the
norm. Employed conservative treatment did
not lead to amelioration of the condition.
2007, LX, 10
During subsequent hospitalizations the
scope of diagnostic methods was significantly
broadened. Antinuclear, p-ANCA and cANCA as well as anti-HIV antibodies were not
detected. Also Hbs and USR were negative. CT
examination of paranasal sinuses visualized
the presence of abnormal mass with irregular,
blurred borders and non-homogeneous structure
in the lumen of the left maxillary sinus. The
size of the tumor characterized with contrast
enhancement from 65 to 95 H.u. was 2.5 x
3 cm. Bone destruction was not noted. Other
paranasal sinuses were properly filled with air.
In June 2002 the tumor of the left cheek was
resected and revision of the left maxillary sinus
was performed (histopathological examination
no. 5749 (3)/2002: peripheral ossifying
fibroma). After the surgery, the wound healed
per secundam. No microorganisms were found
in the smear from postoperative wound.
One month after revision of the left maxillary
sinus performed in another center and after
admitting the patient to our clinic (July 2002)
elastic-soft swelling of the left cheek was
observed on physical examination. Skin over
swelling was unchanged, while submandibular
lymph nodes on the left side were enlarged
and tender. Intra-orally, large oro-antral fistula
was found in the vestibule. The wound healed
through granulation. No abnormal results were
found in laboratory investigations. Another
surgery of the left maxillary sinus aimed at
both the removal of scar tissue filling the lumen
of the left maxillary sinus and the revision of
nasal cavity and buccal tissues. A fragment of
macroscopically changed inferior nasal concha
was resected. Histopathological examination of
operative preparation confirmed the presence
of scar connective tissue with inflammatory
granulation and focal purulence, granulomas
resembling the ones found around foreign
bodies, and single osteoclasts. Neoplastic
Wegener’s granulomatosis in the craniofacial region
Fig. 4. Female patient, 23, treated surgically because of knee joint inflammation and recurring inflammation of the left maxillary sinus; scars after surgeries of knee joints.
growth was not found. Normal healing was
observed postoperatively.
One year after the last surgery pain on
the left side of the face intensified. Pain
increased during chewing. Furthermore,
the patient reported limitation of lower jaw
abduction. Clinical examination revealed
palpable pain in the preauricular region as
well as clicks and irregular movement of the
left temporomandibular joint (TMJ). Magnetic
resonance imaging of TMJ revealed effusion
in the articular cavity of the TMJ, especially
intensified on the left side. No morphological
changes within bony elements of articulations
were found. On the basis of clinical and
radiological evaluation, muscular dysfunction
with pain of the left temporomandibular joint
was diagnosed. Bite splint in construction bite
was prepared; anti-inflammatory treatment
was instituted, which led to pain alleviation.
In September the patient was once again
treated orthopedically. At that time prepatellar
bursa of the left knee was removed (Fig. 4). In
January and September 2004 because of facial
paralysis of several weeks’ duration, paresthesia
of the limbs on the left side, headache, earache and dizziness with accompanying balance
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H. Wanyura et al.
Czas. Stomatol.,
Fig. 5. Female patient, 23, treated surgically because of
the left maxillary sinus; a – en face, b – CT scan showing
total shadowing of the left maxillary sinus, bone lesion in
the anterior wall after previous surgical interventions, c
– intraoral photograph.
disturbances, the patient was admitted to the
neurological department. Laesio multifocalis
systemae nervosum propter neuroinfectiam
was diagnosed. No abnormalities were found
in additional tests (radiological examination
of the chest, CT, MRI of the brain and the
cervical spine, ultrasonography of the neck
and abdomen, culture of the cerebrospinal
fluid, antibodies against boreliosis in blood
serum and cerebrospinal fluid, pharyngeal and
nasal swab). EEG recording showed discrete
changes in the left frontotemporal area, while
EMG examination confirmed damage to the
left sural nerve and partial paralysis of the
left facial nerve. Clinical evaluation has been
broadened with tests detecting systemic diseases
(antinuclear, anti-cardiolipin, anti-lupus, ANCA
antibodies) as well as virological diagnostics
(herpes virus, tick-borne encephalitis virus,
cytomegalovirus, toxoplasmosis). Results of
676
the examinations were negative. Anti-HIV1/
HIV2 antibodies and P-24 antigen were not
found. No microorganisms were found in
blood, cerebrospinal fluid or phlegm. The
patient was placed on a regimen of Encorton
45 mg, antibiotic therapy and anti-viral
medicines. Satisfactory amelioration of the
patient’s condition was not achieved.
In August 2005 the patient was re-operated
on in the Department of Cranio-Maxillofacial
Surgery of the Medical University of Warsaw
because of ulceration in the vestibule and
tumor in the left canine fossa (Fig. 5 a). CT
scan and intraoperative inspection revealed the
thickening of all walls of the left maxillary
sinus up to 5 mm and closure of the lumen
by supposedly inflammatory tissues (Fig. 5
b). The wound healed without complications
(Fig. 5 c).
Limited form of Wegener’s granulomatosis
2007, LX, 10
Wegener’s granulomatosis in the craniofacial region
was diagnosed based on histopathological
picture of the intraoperative biopsy (evaluation
no. 7494/2005). The patient was referred to the
Center for Systemic Vasculitis, Czerniakowski
Hospital, for further evaluations and treatment.
Primary systemic vasculitis, Wegener’s
granulomatosis, with infiltration into bonearticular system, paranasal sinuses, central and
peripheral nervous system (BVAS-16, DEI12) was confirmed. Concentration of c-ANCA
antibodies was 0,9 U/ml, p-ANCA 1,7 U/ml.
Chronic immunosuppressive treatment
was administered: Solu-Medrol i.v. (1 pulse
500 mg, 2 pulses 250 mg), followed by oral
cyclophosphamide and prednisolone. The
patient’s general condition improved, with
normalization of body temperature and
alleviation of articular pain. Further ambulatory
treatment was recommended (Encorton,
Endoxan, Lanzul, Calperos, Alfakalcidol,
Fig. 6. Female patient, 64, treated for Wegener’s granulomatosis, with exophthalmus, ophthalmoplegia of
the left eye and diplopia. Evaluation of eye movement; a – to the right, b – ahead, c – to the left, d – up, e
– down.
Fig. 7. Tumor of the left orbit visualized in radiological imaging; a – retro-orbital location of the tumor in CT,
b – MRI, sagittal plane, tumor located in the 2nd and 3rd zone of the orbit, c – MRI, frontal plane, the tumor
covers 3 quadrants of the orbit.
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H. Wanyura et al.
Tegretol, Biseptol). The patient remains under
ambulatory supervision of the Clinic for
Systemic Vasculitis and Department of CranioMaxillofacial Surgery in Warsaw.
Observation 3
A 64-year-old female, who was treated for
diabetes type II and rheumatoid arthritis, was
referred by an ophthalmologist to our clinic
in June 2004, with suspected tumor in the left
Czas. Stomatol.,
orbit. The first symptom connected with the
optical system was diplopia and exophthalmos
of the left eyeball gradually increasing during
the period of one year. Moreover, for the last
4 months the patient complained of headaches
and swelling of the left eyelids. Conservative
treatment brought a slight improvement of
the condition. Ophthalmological examination
revealed exophthalmos of the left eye (right
eye = 17 mm, left eye = 22 mm), decrease of
visual acuity (right eye = 1.0, left eye = 0.3),
Fig. 8. Perioperative image; a – surgical access, b – postoperative preparation.
Fig. 9. The same patient 3 years after diagnosis. Reduction of exophthalmus, remaining ptosis of the upper
eyelid. Evaluation of eye movement; a – to the right, b – forward, c – to the left, d – up, e – down.
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2007, LX, 10
Wegener’s granulomatosis in the craniofacial region
total ophthalmoplegia and edema of the disk
of the left nerve II with stasis and degenerative
changes, partial ptosis, swelling and redness of
the left eyelids. Conjunctiva of the left eye was
hyperemic, and the pupil of the left eye was
bigger than the right one (Fig. 6 a-e).
CT and MRI examinations visualized
individual angiogenic foci in both hemispheres
and inflammatory lesions in the left sphenoid
sinus and both maxillary sinuses. Analysis of
the CT and MRI of the craniofacial region
showed that the abnormal mass covered retroorbital part of the left orbit, i.e. superiomedial,
superiolateral and inferiolateral quadrants.
The infiltration covered also the structures
of temporal and infratemporal fossa, causing
sectional damage to inferiolateral wall of the
left orbit (Fig. 7 a-c). Laboratory examinations
(including TSH, T4, T3) did not show any
abnormalities. No changes were detected in
the heart or the lungs.
In June 2004 a biopsy of the tumor of the left
orbit was performed under general anesthesia,
from lateral access in the superciliary arch
(Fig. 8 a, b). Histopathological examination
of the biopsy material (8920-1/04) showed
numerous inflammatory infiltrations composed
of plasmocytes and lymphocytes, with focal
tendency to forming lymphoid nodules.
Infiltrations concentrated around the walls
of small vessels, in some places penetrated
into the vessel walls. Systemic disease was
diagnosed. No neoplastic growth was found.
The patient was referred to the Center for
Systemic Vasculitis, Czerniakowski Hospital
for further treatment. After verification of
the result of histopathological examination
(in microscopic evaluation: systemic
disease with inflammation of small vessels)
immunosuppressive treatment was employed
(methylprednisolone,
cyclophosphamide,
prednisolone). Decrease of left eye
exophthalmus was achieved on the third day.
Treatment was continued with oral medicines:
Encorton 60 mg (with systematic decrease of
the dose), Endoxan 100 mg daily, Lanzul,
Calperos, Alfakalcidol and Amaryl. For 8
months the patient has not taken any medicines.
Remission of the disease has been achieved
(Fig. 9 a-e). The patient comes systematically
for follow-up visits to the Clinic for Systemic
Vasculitis and the Department of CranioMaxillofacial Surgery in Warsaw.
Analysis of clinical cases
and discussion
Wegener’s granulomatosis (WG) is a nonneoplastic disease of hyperplastic and necrotic
nature. The disease is characterized by the
formation of granulomas in the respiratory
system and focal necrotic glomerulitis. Onset
of the disease is usually connected with
symptoms associated with the upper respiratory
tract, such as nasal secretions, cough, pleuritis,
hemoptysis. Untreated localized form of
Wegener’s granulomatosis may disseminate
into surrounding tissues and cause patient’s
death as a result of necrotic glomerulitis [2,
15].
In the area of head and neck WG may
manifest itself with e.g.: inflammation of the
mucosa of the nose and paranasal sinuses,
ulceration of nasal septum leading to saddlelike deformation of nasal dorsum, inflammation
of external auditory canal, middle ear, vocal
cords, subglottic laryngostenosis, ulceration in
the oral cavity and bilateral edema of parotid
glands [1, 7, 19]. It has been shown that
around 60-70% of patients with Wegener’s
granulomatosis are carriers of Staphylococcus
aureus [16].
In our material the presence of Staphylococcus
aureus has been confirmed in one patient.
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H. Wanyura et al.
Paralysis of cranial nerves is observed in 2-4%
cases [1, 18]. Edema of eyelids, redness of
conjunctiva, exophthalmus and pain of the
eyeball suggest involvement of orbital tissues.
The so-called “red eye symptom” is caused by
inflammation of the vessels in conjunctiva and
sclera of the eye in the course of WG [1, 6].
The first symptom of a disease from the group
of PSV may be lesions in the oral cavity, e.g.:
ulceration, gingivitis and delayed healing of
dental alveoli following tooth extraction [12, 20,
22]. They occur a few weeks or months before
systemic complications. Gingivae are tender,
edematous and bleed easily [20]. Hypertrophic
gingivitis co-existing with an acute inflammatory
process and multiple granulomatous exophitic
nodules resembling pyogenic granuloma have
the characteristic colour of a ripe strawberry
(hyperplastic granulomatous strawberry-like
gingiva). Another characteristic symptom
within the oral cavity is ulceration of the palate
[8, 20, 22].
The comparison of symptoms of Wegener’s
granulomatosis as manifested by our patients
with corresponding descriptions of the disease
in literature confirms that early diagnosis of
the condition is difficult, especially when
antibodies against proteinase 3 are absent
and characteristic Wegener triad cannot be
observed [5, 7, 8, 21, 24]. On the basis of
literature, localization of pathologies in the
course of WG is as follows: joints (56%), skin
(44%), orbit (39%), middle ear (39%), heart
and pericardium (28%) and nervous system
(22%) [13, 17, 22, 24]. The condition may
occur at any age. Peak morbidity is observed
in the 4th and 5th decade of life [19]. Mean time
from the onset of symptoms to WG diagnosis
is 5 months [24], while in our material it was
about 2 years.
Clinical picture of WG may be diverse: with
mild or acute onset of the disease [1]. In our
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Czas. Stomatol.,
material the patients complained of headache,
nasal obstruction with mucopurulent secretion,
skin lesions in the form of rash, purpura
and ulcerations (observation 1), persistent
inflammation of paranasal sinuses without
neuralgia of nerve V, otitis media, symmetrical
joint inflammation without bone destruction,
involvement of central (epilepsy) and peripheral
nerve system (paralysis of nerve VII, sural
nerve), in spite of normal cerebrospinal fluid
(observation 2) and unilateral exophthalmus,
ptosis, eyeball inflammation, polyneuropathy,
transient cerebral or retinal ischemia
(observation 3) [1, 2, 3, 6, 10, 11, 15, 19, 22,
24]. Paralysis of the facial nerve in the course
of WG may be a result of nerve compression
in its intraosseal part or damage to arterioles in
the epineurium [3, 6]. Decompression of nerve
VII, as well as exploration of mastoid bone
area are ineffective and worsen the prognosis
[3].
Detection of c-ANCA antibodies in blood
serum facilitates diagnosis of Wegener’s
granulomatosis [1, 17, 18]. Their presence is
a specific and sensitive marker, which can
also be used to evaluate the intensity of the
disease, response to treatment and prognosis of
relapse [1, 6, 17, 22]. Diagnostic efficiency of
ANCA for active generalized disease (classical
Wegener’s granulomatosis, CWG) reaches
93%, while in the case of localized form
(limited Wegener’s granulomatosis, LWG) it
decreases to 60% [1, 3, 17].
At the early stage of the disease immunological
determinations for the presence of antibodies
may give negative results. Negative result of
c-ANCA does not exclude the disease, especially
that in 35% of patients with histopathologically
confirmed diagnosis of a PSV disease ANCA
antibodies are not found [17]. This necessitates
repeated determination of antibodies in the
case of suspected Wegener’s granulomatosis
2007, LX, 10
Wegener’s granulomatosis in the craniofacial region
(observation 2) [3, 7]. Occurrence of ANCA
may suggest that LWG form progresses to CWG
[17]. Laboratory investigations may detect
moderate anemia, leukocytosis with decreased
ratio of neutrophils, thrombocytosis, faster ESR,
hyper-α2-globulinemia, hypoalbuminemia,
hypergammaglobulinemia, low complement
concentration, presence of cryoglobulins,
HBs antigen and/or anti-HCV antibodies,
proteinuria, abnormal urine sediment, abnormal
liver tests, laboratory characteristics of renal
impairment [6]. Detection of the disease in
the lungs and kidneys in people with LWG
suggests generalization of WG [8]. The most
frequent cause of death is renal and respiratory
failure [23, 25].
An early symptom of Wegener’s
granulomatosis is the presence of thickened
and inflammatorily-changed mucosa of the
nasal cavity and paranasal sinuses in CT and
MRI evaluation. In further stages of the disease
the formation of granulomas and ulcerations is
observed. In MRI aggregates of granulomas
occur as places of low intensity in T1– and
T2-dependent images. CT examination may
reveal bone destruction or its formation [19].
Recurring pyrexia, loss of body weight,
myalgia and arthralgia as well as anesthesia
observed in our patient (observation 2) may
suggest generalization of WG [16, 19]. These
are caused by mass production of cytokines in
pathological vessels [6]. In acute and advanced
cases there occurs the involvement of orbit
walls and other facial bones [14, 19].
None of our patients manifested the presence
of ANCA antibodies in the early phase of the
disease (ANCA concentration ≤ 1:80). In our
material the diagnosis was made on the basis
of histopathological evaluation of the tumor
and the clinical picture. Each preparation was
verified by several anatomopathologists. There
are problems with differentiating Wegener’s
granulomatosis from granulomatous infection,
lymphoid
granulomatosis,
idiopathic
granuloma of the maxillofacial region, allergic
granulomatous vasculitis, sarcoidosis and tissue
reaction to foreign bodies [7, 12, 24]. Three
characteristic features of WG (inflammation
of blood vessel walls, granuloma and necrosis)
occur in only 16% of histopathologically
evaluated preparations, while two of these
features are present in 23% of preparations
[7].
Our observations confirm that in patients
with suspected WG localized in the area of
head and neck, only non-specific inflammatory
reactions are found in histopathological
examination of biopsies. Described in literature
secondary and less specific microscopic
features of WG in the form of microulcerations
and microulcerations with granulomas, as well
as scarification of tissues, imitate ulcerative
inflammatory process [4, 24]. This picture,
characteristic also of the chronic inflammation
of paranasal sinuses, made WG diagnosis in
our 23-year-old patient more difficult. In spite
of very detailed examinations lasting many
years, as well as numerous surgical procedures
connected with histopathological evaluation
of tissues removed during the surgery of knee
joints, maxillary sinus, unequivocal diagnosis
could only be made after 7 years from the first
orthopedic surgery.
In the 64-year-old patient with orbit tumor,
the microscopic picture (first histopathological
evaluation) was not characteristic (pseudotumor
– systemic disease); ANCA determination was
negative. Only complex analysis of clinical
signs, results of additional tests and positive
response to immunosuppressive treatment
resembling the one employed in case report
by Kaufmann et al. [9], allowed making
the diagnosis of Wegener’s granulomatosis.
Authors dealing with the diagnostics of primary
681
H. Wanyura et al.
systemic necrotizing vasculitis stress the
importance of arteriography, when performing
biopsy is difficult, or there is a high risk of
postoperative complications [6].
Treatment is long and complex and begins
with inductive treatment with cytostatics and
glucocorticoids aiming at remission of the
disease. Maintenance treatment enables longterm retention of achieved therapeutic effect
with concurrent avoidance of unwanted sideeffects of immunosuppressive drugs [11, 22,
24, 25].
Patients with renal impairment undergo
dialysis or organ transplantation; in the case of
orbit involvement and subglottic laryngostenosis
local injections of glucocorticoids are
used. Additionally, Staphylococcus aureus
carriers, because of suspected pathogenic
role of this bacterium in the development
of pathologies occurring in the course of
Wegener’s granulomatosis, are administered
Biseptol, and in the case of resistance, other
chemotherapeutics [6].
Conclusions
Our experience shows that diagnostics of
systemic vasculitis, especially in patients with
limited form of Wegener’s granulomatosis, is
difficult because of rare occurrence of primary
systemic necrotizing vasculitis, non-specific
clinical picture and equivocal microscopic
picture.
Early diagnosis of Wegener’s granulomatosis
is very important for the efficacy of treatment
and becomes an multidisciplinary problem.
Although immunosuppressive treatment
significantly improves prognosis, the mortality
of patients in the group of serious forms of
primary systemic necrotizing vasculitis is
high, while prognosis after remission remains
uncertain.
682
Czas. Stomatol.,
References
1. Benendo-Kapuścińska B, Święcicka D,
WojciechowskiA, Decker E: Ziarniniakowatość
Wegenera – obraz kliniczny, rozpoznanie,
metody diagnostyczne. Pol Przegl Radiol
2000, 65, 1: 57-61.
2. Benoudiba F, Marsot-Dupuch K, Hadj
Rabia M, Cabanne J, Bobin S, Lasjaunias
P: Sinonasal Wegener’s granulomatosis: CT
characteristics. Neuroradiology 2003, 45, 2:
95-99.
3. Bibas A, Fahy C, Sneddon L, Bowdler D:
Facial paralysis in Wegener’s granulomatosis
of the middle ear. J Laryngol Otol 2001, 115,
4: 304-306.
4. Devaney KO, Ferlito A, Hunter BC, Devaney
SL, Rinaldo A: Wegener’s Granulomatosis
of The Head and Neck. Ann Otol Rhinol
Laryngol 1998, 107, 5: 439-445.
5. Ghosh A, Bandyopadhyay D, Basu S,
Majumdar A, Dutta S: ANCA-negative
limited Wegener’s granulomatosis. Indian J
Dermatol Venerol Leprol 2004, 70, 2: 102103.
6. Jakubicz D: Układowe zapalenia naczyń.
Probl Lek 2006, 45, 2: 65–73.
7. Jones GL, Lukaris AD, Prabhu H V, Brown
M, Bondeson J: Wegener’s granulomatosis
mimicking a parotid abscess. J Laryngol Otol
2005, 119, 9: 746-749.
8. Jóźwiakowska M, Tuszkiewicz-Misztal E,
Górnicka G: Ziarniniakowatość Wegenera –
opis przypadku. Przegl Pediatr 2005, 35, 4:
234-240.
9. Kaufmann J, Schulze E, Voigt U, Strobel J,
Hein G, Stein G: Orbital inflammatory
pseudotumor due to hypersensitivity vasculitis
and mononeuritis multiplex in a patient
with atypical, cANCA-positive Wegener’s
granulomatosis. Rheumatol Int 2003, 23, 3:
138-142.
10. Lim IGS, Spira PJ, McNeil HP: Headache
as the initial presentation of Wegener’s
granulomatosis. Ann Rheum Dis 2002, 61, 6:
2007, LX, 10
11.
12.
13.
14.
15.
16.
17.
18.
19.
571-572.
Lim KS, Lee GA, Pavesio C E, Ficker LA:
Wegener’s granulomatosis. Br J Ophthalmol
2003, 87, 4: 500.
Łangowska-Adamczyk H, Niedzielska I,
Mykała–Cieśla
J,
Mochalski
M:
Trudności w rozpoznawaniu ziarniniaka
Wegenera ujawnionego podczas leczenia
stomatologicznego. Czas Stomatol 1997, L,
10: 681-688.
Maj J, Reich A, Baran E: Pierwotne systemowe
zapalenie naczyń. Postępy Dermatol Alergol
2004, 21, 5: 247–254.
Muhle C, Reinhold-Keller E, Richter Ch,
Duncker G, Beigel A, Brinkmann G, Gross
WL, Heller M: MRI of the nasal cavity, the
paranasal sinuses and orbits inWegener’s
granulomatosis. Eur Radiol 1997, 7: 566–
570.
Pakrou N, Selva D, Leibovitch I: Wegener’s
Granulomatosis: Ophthalmic Manifestations
and Management. Semin Arthritis Rheum
2006, 35, 5: 284-292.
Pitsh T, Grzanka A, Legaszewski T, Rogala
B: Ziarniniakowatość Wegenera maskowana
objawami przewlekłego alergicznego nieżytu
nosa. Allerg Astma Immunol 2004, 9, 4: 209212.
Pradhan V, Badakere S, Gnos K, Almeida A:
ANCA: Serology in Wegener’s granulomatosis. Indian J Med Sci 2005, 59, 7: 292299.
Puszczewicz M: Przeciwciała przeciw cytoplazmie granulocytów obojętnochłonnych
(ANCA). Reumatologia 2005, 43, 6: 341348.
Restrepo S, Rojas IC, Villamil MA, Palacios
E: Wegener’s granulomatosis of the nasal
cavity. Ear Nose Throat J 2003, 82, 2: 100-
Wegener’s granulomatosis in the craniofacial region
20.
21.
22.
23.
24.
25.
101.
Sadlak-Nowicka J, Łaska M, Bochniak M, Weber-Dubaniewicz M: Aspekty stomatologiczne ziarniniaka Wegenera. Dent Med Probl
2003, 40, 2: 417–422.
Van der Woude FJ, Rasmussen N, Lobatto S,
Wiik A, Permin H, van Es LA, van der Giessen
M, van der Hem GK, The TH: Autoantibodies
against neutrophils and monocytes: tool for
diagnosis and marker of disease activity in
Wegener’s granulomatosis. Lancet 1985, 23,
1: 425-429.
Wardyn KA, Życińska K, Olędzka-Oręziak M:
Ziarniniakowatość Wegenera. Red. K. A.
Wardyn, K. Życińska w: Pierwotne układowe
zapalenia naczyń. Urban & Partner, Wrocław
2004, str. 229-276.
Wegener F: Über eine eigenartige
Granulomatose mit besonderee Beteilligung
das Arteriensystem und der Nieren. Beitr Path
Anat 1939, 102: 36.
Wiatr E, Decker E, Siekierzyńska–Czarnecka
A, Billip–Tomecka Z, Gellert R, Rowińska–
Zakrzewska E: Ziarniniakowatość Wegenera
– problem diagnostyczny i postęp w leczeniu
na podstawie przeglądu 54 przypadków
opublikowanych w latach 1959-1990 w
Polsce. Pol Arch Med Wewn 1991, 86, 3:
198-207.
Życińska K, Wardyn KA: Ocena czasu
przeżycia i ryzyka nawrotów u pacjentów z
ziarniniakowatością Wegenera z dominującym
zajęciem nerek. Pol Arch Med Wewn 2007,
117, 4: 136-144.
Paper received 17 July 2007
Accepted 28 September 2007
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