Localized Tongue Amyloidosis in a Patient
with Neurofibromatosis Type II
Dimitrios Andreadis•Athanasios Poulopoulos•
Petros Papadopoulos•Apostolos Epivatianos
Received: 16 January 2011/Accepted: 8 February 2011/Published online: 22 February 2011
? Springer Science+Business Media, LLC 2011
involve oral mucosa. This is the first known reported case
describing the development of tongue AL in a 30-year-old
patient with Neurofibromatosis (NF) type-2.
A female patient presented with a painless, well-cir-
cumscribed nodule of the tongue. Her medical history inclu-
ded NF type-2 with chromosome-22 abnormal karyotype
(mosaicism), multiple intracranial and spinal meningiomas/
schwannomas and unilateral blindness/deafness. The biopsy
of the excised lesion of the tongue revealed subepithelial
accumulation of an amorphous, nodular, fibrillar material
positive for Congo red. Blood examination showed increased
Thyroxine-T4 due to thyroid multinodular colloid goiter, but
excludedany other hematological/immunologicaldisorderor
organ dysfunction. No recurrence was observed after a six-
This case highlights the possibility of oral
manifestations as the only sign of AL and reveals the
unexpected co-existence of AL and NF 2, for the first time.
Localized Amyloidosis (AL) may rarely
Oral amyloidosis ? Neurofibromatosis type II
Amyloidosis results from the continuous, excessive pro-
duction and accumulation of an extracellular, insoluble,
fibrillar proteinaceous material, called amyloid . This
disease can be acquired or hereditary, limited in a tissue/
organ with benign prognosis (localized form) or may affect
multiple tissues/organs (kidneys, heart, liver, gastrointes-
tinal tract, bladder etc.) leading to significant morbidity and
at times mortality (systemic form) [2–4].
The main subtypes of systemic amyloidosis are AL
(amyloid light chain-AL) and AA (amyloid A-AA). AL as
form. AA (amyloid A-AA) is the secondary form of amy-
loidosis associated with chronic infectious or inflammatory
diseases such as rheumatoid arthritis, connective tissue dis-
eases, Crohns or other inflammatory bowel disease [5, 6].
There is also the b2 microglobulin amyloidosis in chronic
renal failure/hemodialysis patients and the autosomal-dom-
inant hereditary/familial form including Mediterranean
fever (AA-type) and familial amyloidosis accompanied by
polyneuropathy with transthyretin/light chain-related amy-
loid (ATTR) depositions [4, 7, 8].
The secondary form of amyloidosis can affect the head
and neck area including orbit, sinuses, salivary glands,
pharynx/larynx and oral cavity in 10–40% of the cases.
Potential sites of oral lesions are buccal, palatal and gin-
gival mucosa and tongue [6, 8–12].
of localized tongue amyloidosis in a patient with Neurofi-
bromatosis type II (NF2) a genetic disorder related to chro-
mosome 22 alterations, characterized by bilateral vestibular
schwannomas, meningiomas, gliomas, and schwannomas of
cranial/spinal nerves with related consequences .
A 30-year-old female with mild mental retardation pre-
sented to the Department of Oral Medicine/Pathology,
D. Andreadis (&) ? A. Poulopoulos ? P. Papadopoulos ?
Department of Oral Medicine/Pathology, School of Dentistry,
Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
e-mail: email@example.com; firstname.lastname@example.org
Head and Neck Pathol (2011) 5:302–305
School of Dentistry of Aristotle University of Thessaloniki,
Greece with a painless, nodular mass on the midline dorsal
tongue, covered by normal mucosa (Fig. 1).
The onset/duration of the tongue lesion was unclear.
Medical history reported no weight loss, fever, chest pain,
nausea, vomiting, or arthritis, but 10 years previously a
diagnosis of NF2 with characteristic karyotype including
the existence of ring-type or the absence of chromosome 22
(mosaicism), multiple cranial (cerebellum/parietal) (Fig. 2)
and spinal (thoracic) meningiomas and schwannomas
(orbital/inner ear), as confirmed by imaging and micros-
copy of the excised lesions. These lesions caused mild
imbalance, right eye blindness and left ear hearing loss.
Laboratory tests revealed elevated thyroxine T4 which
was due to a thyroid multinodular colloid goiter. Serum
and urine protein electrophoresis did not reveal any
monoclonal immunoglobulin proteins. Furthermore, renal,
heart, liver and spleen morphology and function were
normal based on laboratory tests and imaging analysis.
showed a subepithelial, multinodular amorphous, fibrillar
for Congo-Red, exhibiting a reddish color under light
microscopy (Fig. 3) and apple green birefringence under
polarized light (Fig. 4). Correlating the pathologic, labora-
tory and imaging findings with the medical history, a diag-
nosis of a localized form of amyloidosis without systemic
involvement was established. In a 6-month follow-up no
recurrence or systemic complication was detected but
afterwards the patient was lost to follow up.
In contrast to Neurofibromatosis type 1 (NF1), a genetic
disorder, with gene mutations in chromosomes 17 and
multiple cutaneous and CNS neurofibromas and pigmen-
tation, NF2 is a dominantly inherited, tumor prone disorder
with pathogenic mutations or mosaicism in the NF2 gene
on chromosome 22 characterized by the development of
multiple schwannomas, meningiomas, ependymomas, and
only infrequently, neurofibromas . Its prevalence is
estimated approximately at 1:60,000  or less (1:87,410)
. The gold standard for diagnosis is the development of
bilateral or unilateral vestibular schwannomas accompa-
nied by hearing loss, tinnitus, and/or imbalance. Other
Fig. 1 Nodular lesion on the dorsum surface of the tongue, covered
by normal mucosa
Fig. 2 Multiple cranial meningiomas and schwannoma of the ear
Fig. 3 Fibrillar depositions positive for Congo-Red stain as observed
by light microscopy (magnification 9100)
Head and Neck Pathol (2011) 5:302–305303
important tumor features are schwannomas of cranial,
spinal and peripheral nerves, intracranial and intraspinal
meningiomas, ependymomas and gliomas [15, 16].
In our case, the laboratory, imaging and clinical exam-
ination revealed a single, localized lesion in the middle of
the tongue dorsal surface without any signs of systemic
amyloidosis. In fact, based on the patient’s medical history
of Neurofibromatosis type II (NF2), the nodular lesion was
clinically suspicious for a ‘‘neurogenic’’ tumor. Cases of
neurofibromas have been described in oral mucosa in NF-1
 and perineuriomas in patients with NF2-gene abnor-
malities , but so far nothing is known of oral mani-
festations as part of NF2 disorder, except for a case of a
nodular lesion of the tongue but without histological con-
firmation, as described by Barsley and Cottone  in
As aforementioned, our patient’s genetic analysis
revealed ring-shape chromosome 22 or even its loss
(mosaicism) and according to Ruggieri and Huson  this
phenomenon may explain the development of ipsilateral
(left ear) but not bilateral vestibular schwannomas. Note-
worthy, imaging and/or histological investigation of the
excised lesion revealed multiple intracranial meningiomas,
including an optic nerve meningioma (right) leading to
unilateral blindness as well as multiple meningiomas in the
thoracic spine. Instead, our patient had not cutaneous
nodules resembling neurofibromas of NF-1.
Not only neurofibroma or schwannoma, but also other
entities such as fibroma, granular cell tumor, lipoma, lei-
omyoma, thyroglossal duct cyst, salivary gland neoplasm
and median rhomboid glossitis were also included in the
clinical differential diagnosis. On microscopic examination
of the excised lesion, detection of eosinophilic amorphous
material positive for Congo-Red in association with the
clinical and laboratory analysis confirmed the diagnosis of
localized amyloidosis without systemic involvement.
Amyloidosis represents a rare heterogenous group of
conditions characterized by extracellular proteinaceous
depositions of amyloid which may cause organ abnormal-
ities [3, 8]. The mechanism, of amyloid formation, includes
amyloid (pro)precursor genes activation, under the influ-
ence of cytokines, clonal plasma cells, abnormal proteol-
ysis and the production of several precursor pools of
different amyloidogenic molecules, which in turn form
fibrils of amyloid after their enrichment with proteogly-
cans, glycosaminoglycans, inorganic ions and serum
amyloid P [3, 21, 22].
The incidence of amyloidosis is approximately 5-12
patients per million per year [23, 24], with a peak age in
50 years and male to female ratio 2:1, without racial bias.
Disease severity ranges from asymptomatic to severe, life-
threatening [4, 7, 25]. Beyond the initial symptoms like
fatigue and weight loss, organs such as heart , kidney
, gastrointestinal, liver, spleen  and nervous system
(central and peripheral)  may involved with severe
Prognosis depends on the severity of the disease at the
time of diagnosis and the rate of amyloid accumulation.
Median survival, after diagnosis of AL amyloidosis is
1–2 years, whereas 10-year survival rate is seen only in less
than 5% of patients. The poor prognosis is associated with
of any possible underlying plasma-cell disease (i.e. multiple
myeloma). In contrast, the prognosis of localized amyloi-
dosis is much better, but as in our case a careful follow-up is
needed for the possible demonstration of a latent hemato-
logical disorder or organ involvement, in the future .
Oral manifestations of amyloidosis are quite uncommon,
and may be presented early in the course of the disease as
mucosal papules, nodules or ulcers, macroglossia, pete-
chiae/ecchymoses or even hemorrhagic bullae .
Although the tongue is the most common oral site [6, 10,
30–32], cases of amyloid deposition in the palate [11, 33,
34], maxillary vestibule , gingival  and floor of the
mouth  have been mentioned as well. Rarely, minor or
major salivary glands infiltration and related hypofuction-
xerostomia can be seen [37–39]. Noteworthy, oral
involvement is extremely rare as the localized solitary
manifestation of amyloidosis, but when present the tongue
is primarily affected [6, 8–12].
In summary, this case report describes the existence of
localized amyloidosis in a patient with NF-2. Although a
familial ‘‘neuro’’-related type of amyloidosis with periph-
eral neuropathy caused by ATTR amyloid accumulations
has been described, so far nothing is known of an associ-
ation between Amyloidosis and Neurofibromatosis. Thus,
the synchronouspresenceof thesetwo distinctive
Fig. 4 The amyloid depositions presented as apple green birefrin-
gence, under polarized light (magnification 9100)
304Head and Neck Pathol (2011) 5:302–305
pathological entities in our patient at this time suggests a Download full-text
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