Introduction
Amyloidosis refers to the extracellular aggregation of misfolded proteins causing
cellular and organ dysfunction. It is a rare disorder, with an incidence of 5 to 10
cases per million people per year. To date, a total of 36 types of amyloid proteins
(14 involved in systemic forms, 19 involved in localized forms, and 3 subtypes in
both the localized and systemic forms) have been described in humans (as well as 10
other types in other vertebrates).[1] The amyloid proteins are named using the prefix ‘A’ (for amyloid) followed by the
name of the protein forming the fibril. The most common forms of amyloidosis encountered
in the clinical practice are: AL (formed by the κ or λ light chain of immunoglobulin
G, and constituting 75% of the systemic amyloidosis cases); AA (formed by the accumulation
of the misfolded acute phase reactant ‘serum amyloid A’ protein, and constituting
5% of the systemic amyloidosis cases); ATTR (deposition of misfolded transthyretin,
either normal or mutated); and Aβ2M (pathological deposition of the β2 microglobulin protein in patients on prolonged renal dialysis).[2] Clinically, amyloidosis has been classified as follows:
-
Localized versus systemic;
-
Primary (plasma cell dyscrasia) versus secondary (chronic inflammatory conditions);
and
-
Hereditary (ATTR, familial Mediterranean fever) versus acquired (multiple myeloma).
From a practical perspective, the prognosis of the localized and systemic forms lies
on the two extreme ends of the spectrum, with localized amyloidosis being associated
with an excellent prognosis in terms of survival (which remains nearly the same as
that of the general population), and systemic dissemination resulting in a dismal
outcome of a mean survival of 5 to 15 months.[3]
[4]
Head and neck involvement, either in isolation or as a part of the systemic disease,
occurs in up to 20% of patients, and is associated with the AL type of amyloid deposition.[2]
[5] We describe our experience with seven patients presenting with head and neck amyloidosis
and emphasize on keeping a high index of suspicion for the diverse faces of this rare
entity. The various ways in which the disease may present are reviewed, and the management
issues are discussed.
Materials and Methods
A retrospective chart review of the patients presenting with amyloidosis localized
to the head and neck subsites was conducted after obtaining permission from the institutional
Ethics Committee (MICR- 991/2019 [Academic]). Patient identification was performed
by searching the records of the past six years in the electronic database of the Departments
of Pathology and Otorhinolaryngology and Head and Neck Surgery. The details of the
patient were tabulated to include the demographic data and disease-specific data,
that is, age, gender, presenting complaints, associated systemic comorbidities, local
examination findings, treatment, type of amyloid protein deposition on immunohistochemistry,
workup for underlying systemic illness, and systemic amyloidosis. For the workup for
underlying systemic illness and systemic amyloidosis, the patients were reviewed in
the Department of Internal Medicine, where a complete blood count, renal & liver function
tests, urine routine microscopy, biochemistry, chest X-ray, electrocardiogram, abdominal
ultrasonography and more specific tests, like the C3 (complement factor 3), anti-nuclear
antibody, antineutrophilic cytoplasmic antibodies, rheumatoid factor, Bence-Jones
proteinuria, and serum & urine electrophoresis, abdominal fat pad biopsy were done
to rule out systemic amyloidosis. For the follow-up, the last follow-up clinical records
were referred to, and the patients were contacted by phone and called for clinical
assessment as needed.
Results
A total of 7 patients presenting with head and neck amyloidosis were identified ([Table 1]) over a period of 6 years (from January 2013 to January 2019). Three patients had
laryngeal involvement (all three with supraglottic involvement), three had involvement
of the tongue (macroglossia or involvement of the base of the tongue), while one patient
had diffuse involvement of the nose and paranasal sinuses. The clinical picture of
laryngeal amyloidosis is depicted in [Fig. 1], while [Fig. 2] shows the non-contrast computed tomography (CT) scan findings of the patient with
sinonasal amyloidosis. This patient has been previously reported in another study[6] from our institute. The ratio of female to male patients was of 1.3:1. The age of
the patients ranged from 19 to 69 years, with a median of 62 years. The diagnosis
of every patient was confirmed by the biopsy of the lesion showing typical apple-green
birefringence under polarized light microscopy with Congo red stain ([Fig. 3]). The immunohistochemistry showed that the amyloid deposits were of the AL type
in all but one patient (this one patient presented with macroglossia and was found
to have the AA type of amyloid deposits). None of the patients were found to have
any causative active systemic illness (only one patient was positive for hepatitis
B surface antigen [HBsAg +ve] on serology, but there was no evidence of liver dysfunction
on the blood biochemistry or fibroscan). The abdominal fat pad biopsy to look for
systemic involvement was negative in all of the patients.
Fig. 1
(A) Microlaryngoscopic view showing the mucosa-covered bulge involving bilateral true
vocal cords (*). (B) Excision of the lesion using CO2 laser in the process. (Patient-1)
Fig. 2 Non-contrast computed tomography (CT) scan of the paranasal sinuses: (A) coronal and (B) axial views showing bulky soft-tissue density involving the bilateral nasal cavity,
the middle meatus and the anterior ethmoid region, causing expansion of the nasal
cavity with lateral displacement of the lateral nasal wall. The ‘fluffy’ bony changes,
most pronounced in the inferior turbinate bone, can be appreciated (arrows). (Patient-7)
Fig. 3
(A; B) Light microscopic view showing homogenous extracellular eosinophilic amorphous subepithelial
and perivascular deposition of amyloid ([A] hematoxylin and eosin stain; [B] Congo
red stain, non-polarized; original magnification: 100x). (C) Polarized microscopy showing apple-green birefringence with Congo red corresponding
to areas of amyloid deposition. (Original magnification: 100x.)
Table 1
Clinical and demographic details of the patients diagnosed with head and neck amyloidosis
|
SN
|
Age (years)/ Gender
|
Site
|
Chief complaints
|
Examination findings
|
Systemic involvement
|
Treatment
|
Co-morbidities
|
Amyloid protein type
|
Follow-up
|
|
1
|
62/F
|
Larynx
|
Change in voice × 1 year, MLS 10 years back for similar symptoms
|
Nodular growth over left false vocal cord and ventricle, reaching up to the anterior
commissure
|
No
|
MLS excision using CO2 laser
|
DM
|
AL
|
7 months, no recurrence
|
|
2
|
66/M
|
Larynx
|
Change in voice × 10 months
|
Broad based indurated lesion over the left false vocal cord
|
No
|
MLS excision using CO2 laser
|
HBsAg +ve
|
AL
|
18 months, no recurrence
|
|
3
|
29/F
|
Larynx
|
Change in voice × 18 months
|
Broad-based nodular lesion involving both the false vocal cord and ventricle with
polypoidal changes involving the anterior commissure area
|
No
|
MLS excision using CO2 laser
|
−
|
AL
|
3 months, no recurrence
|
|
4
|
69/F
|
Oropharynx
|
Pain in right ear and foreign body sensation in the throat × 1 year
|
Firm mass involving the base of the tongue
|
No
|
CO2 laser excision
|
HTN, DM
|
AL
|
18 months, no recurrence
|
|
5
|
52/M
|
Oral cavity and oropharynx
|
Gradual progressive dysphagia × 2 years
|
Macroglossia
|
No
|
Surgical treatment refused by the patient
|
HTN
|
AA
|
Expired after 1.5 years following the diagnosis (suspected cardiac involvement; documents
not available)
|
|
6
|
62/F
|
Oral cavity and oropharynx
|
Dysphagia × 1 year
|
Macroglossia
|
No
|
Surgical treatment refused by the patient in view of the mild symptoms
|
DM
|
AL
|
7 years, stable disease
|
|
7a
|
19/M
|
Nasal cavity and paranasal sinuses
|
Nasal blockage
|
1) broadened nasal dorsum with telecanthus; 2) grossly edematous mucosa with polypoidal
changes on the right septum, the turbinates, and both sides of the nasal wall
|
No
|
FESS and microdebrider-assisted turbinoplasty
|
−
|
AL
|
4 years, symptom recurrence after 6 months of surgery, further surgery refused by
the patient after ruling out systemic disease
|
Abbreviations: +ve, positive; AL, amyloidosis formed by the κ or λ light chain of
the immunoglobulin G; AA, amyloidosis formed by the accumulation of the misfolded
acute phase reactant ‘serum amyloid A’ protein; DM, diabetes mellitus; F, female;
FESS, functional endoscopic sinus surgery; HBsAg, hepatitis B surface antigen; HTN,
hypertension; M, male; MLS, microlaryngeal surgery; NA, not available; SN, serial
number.
Note: a Patient previously reported in another study6 from our institute.
Surgical treatment was undertaken with curative intent in five patients, and four
of them (in whom disease excision was performed with CO2 laser for supraglottic involvement or that of the base of the tongue) were free of
disease at the last follow-up. The patient with sinonasal amyloidosis experienced
recurrence after six months of surgery, but refused any further surgical intervention.
A total of two patients (presenting with mild dysphagia and found to have macroglossia)
refused surgical intervention in view of the mild symptomatology. One of them, despite
being negative for systemic amyloidosis, died of a cardiac cause 18 months after the
diagnosis. We could not discern whether the mortality was a result of the systemic
amyloidosis or of an independent event.
Discussion
The amyloid fibrils are linear, non-branching, tubular proteins, 7.5–10 nm in diameter,
formed by misfolding of normal body proteins, arranged in an antiparallel crossed
β-pleated sheet ultrastructure on X-ray crystallography (instead of the normally observed
α-helical structure). The fibrils autoaggregate in association with other components
(glycosaminoglycans [GAGs], apolipoprotein-E and serum amyloid P [SAP]) in a ratio
of roughly 9:1, and, being insoluble, get deposited in the extracellular/interstitial
compartment, forming homogenous, eosinophilic, amorphous precipitates that exhibit
the pathognomonic ‘apple-green birefringence’ with Congo red stain under polarized
light microscopy.[4]
Localized amyloidosis constitutes ∼ 9% of all the cases of amyloidosis. The AL is
the type of amyloid protein commonly deposited in these patients. The pathogenesis
of localized amyloid deposition is not fully understood, but there is some evidence
indicating that it may be the result of a localized collection of plasma cells producing
light chains (speculated to be a burnt-out plasmacytoma) in a disordered fashion.
These plasma cell deposits are not observed in systemic AL amyloidosis, in which the
circulating free light chains produced from the bone marrow plasma cells (in the setting
of plasma cell dyscrasia) are deposited in distant body sites. Giant cells of the
foreign-body type are also often observed in the vicinity of the localized amyloid
deposits, and are thought to be involved in the pathogenesis by modification of the
light chains produced locally by the plasma cells.[5]
[7]
In the head and neck area, the larynx and the tongue are the most common sites affected.
Laryngeal involvement has been estimated to occur in 9% to 15% of all cases of amyloidosis,
and amyloidosis constitutes between 0.2% and 1.2% of all benign tumors involving the
larynx.[8] The most common pattern of laryngeal involvement is in the form of submucosal nodular
deposits in false vocal cords/ventricles, followed by the aryepiglottic fold, and
the subglottic and true vocal cord involvement. Systemic involvement with laryngeal
amyloidosis is unusual, and the need for a systemic workup in the setting of clinically-isolated
laryngeal amyloidosis is debated in the literature. There are opinions for and against
performing systemic investigations to search for the underlying etiology and systemic
dissemination of the amyloidosis, with no consensus.[8]
[9]
[10]
[11]
[12] In our cohort of patients, the largest proportion was constituted by the laryngeal
patients, followed by those with oral tongue involvement.
The most common presentation with tongue involvement is macroglossia (it occurs exclusively
in the AL type); however, focal involvement of the tongue and other oral subsites
has been reported.[2]
[13] Unlike isolated laryngeal disease, amyloidosis presenting with macroglossia needs
to be thoroughly evaluated to rule out the common association with plasma cell dyscrasia/multiple
myeloma and systemic amyloidosis. One of our patients was harboring the AA type of
amyloidosis, while none of the patients were positive for systemic disease.
The differentials are site and morphology specific, and, for the usual sites of involvement,
that is, the larynx and the tongue, they are listed in [Table 2]. Amyloidosis involving other head and neck subsites is rarer. In one case report,[14] the amyloidosis involved the nasopharynx, the sinonasal compartment, the oropharynx
(pharyngeal wall, tonsils, base of the tongue) and the hypopharynx. Some of the peculiarities
associated with nasal amyloidosis can offer the clue to the diagnosis. The fluffy
appearance of the surrounding sinonasal bone (probably representing the osteoblastic
activity in response to the submucosally-deposited amyloid) and unusually extensive
and early synechiae formation postsurgery should alert the clinician to the underlying
amyloidosis.[15]
[16] Our patient with sinonasal amyloidosis had extensive synechiae formation intraoperatively
along with the polypoidal changes, and the CT scan showed the fluffy appearance of
the surrounding sinonasal bone consistent with amyloidosis. Localized amyloidosis
generally does not affect life expectancy, while, with systemic amyloidosis, the prognosis
is grave, with a mean survival of 5 to 15 months (it is worse with multiple myeloma
than with the idiopathic cases).[17]
Table 2
Differential diagnosis of laryngeal and lingual amyloidosis
|
Serial number
|
Laryngeal amyloidosis
|
Tongue amyloidosis (localized)
|
Tongue amyloidosis (macroglossia)
|
|
1
|
Malignancies (like squamous cell carcinoma, chondrosarcoma, salivary gland tumors,
metastasis from the medullary thyroid carcinoma)
|
Benign tumors (like granular cell tumors, minor salivary gland tumors, neurogenic
tumors, fibroma, lipoma)
|
Endocrine abnormalities (like acromegaly and hypothyroidism)
|
|
2
|
Laryngeal nodule/polyp
|
Malignancy
|
Mycobacterial infection
|
|
3
|
Benign tumors (like schwannoma, chondroma, granular cell tumors)
|
Fungal infection
|
Lymphangioma
|
|
4
|
Chronic indolent fungal infection
|
Mycobacterial infection
|
Lymphoma
|
|
5
|
Mycobacterial infection or syphilitic gumma
|
Syphilitic gumma
|
Neurofibromatosis
|
|
6
|
Laryngeal sarcoidosis
|
Sarcoidosis
|
Beckwith–Wiedemann Syndrome
|
In the absence of good evidence (understandable in light of the rare occurrence of
the disease), systemic symptomatology, the clinical pattern of involvement along with
institutional policies continue to influence the decision-making regarding the systemic
workup. The latter aims to locate the cause/source of the amyloid protein formation
and to rule out systemic amyloidosis. In addition to the routine blood workup with
complete blood count and renal & liver function tests, urine routine microscopy and
biochemistry, chest X-ray, electrocardiogram, abdominal ultrasonography, and more
specific tests, like the mantoux test, erythrocyte sedimentation rate, C3, antinuclear
antibody, antineutrophilic cytoplasmic antibodies, rheumatoid factors, Bence-Jones
proteinuria, serum or urine electrophoresis, as well as bone marrow biopsy should
be ordered. Systemic amyloidosis may be identified by using imaging (iodine [123I] SAP scintigraphy, non-invasive and fairly accurate, but used seldom in view of
the limited availability) or tissue diagnosis with abdominal fat pad needle aspiration/biopsy
(sensitivity ∼ 80%) or rectal biopsy (sensitivity ∼ 75%) as a surrogate for the detection
of deeper organ involvement (since performing a biopsy directly from the vital organs
may be riskier).[2]
[8]
[12]
[16] We used abdominal fat pad biopsy in our patients to assess the systemic involvement
in view of the easy availability, acceptable sensitivity and patient compliance with
the procedure.
Differentiation of the type of amyloid protein (amyloid typing) can be performed with
immunohistochemistry (IHC), immunofluorescence (IF) of formalin-fixed paraffin-embedded
(FFPE) tissue or laser microdissection followed by liquid chromatography with mass
spectrometry (LMD-LC-MS). The latter is the gold standard of proteomics-based amyloid
typing.[18] The availability of these specialized investigations, however, is not universal.
The management of localized head and neck amyloidosis is symptom-directed. When there
is no suspicion of systemic involvement or the systemic disease has been ruled out
with appropriate tests, the treatment can include watchful waiting in patients with
asymptomatic disease or conservative resection for symptomatic relief. In view of
the presence of fragile capillaries because of amyloid infiltration, resection of
the lesion with simultaneous hemostasis, with the laser, for example, may be the most
suitable strategy wherever possible and accessible.[19] Keeping in mind the slow and prolonged disease progression, conservative resection
with a yearly follow-up extended for up to 10 years is advised. All of our patients
were offered surgical treatment. In four of our patients (three with laryngeal amyloidosis
and one with base of the tongue amyloidosis), complete excision could be performed,
and they did not develop recurrence during subsequent the follow-up. Conservative
debulking was performed in one of the patients with macroglossia, and the patient
had a stable disease at the seven-year follow-up, while another macroglossia patient
refused surgery. The sinonasal amyloidosis patient underwent palliative debridement
in view of the diffuse sinonasal involvement, and did in fact develop recurrence,
but opted for the routine follow-up after receiving an explanation about the nature
of the disease.
Local or systemic chemotherapy (including steroids) play no role in the control of
localized amyloidosis. Radiotherapy has been used sparingly, in cases not amenable
to surgery, or in cases of patients refusing surgery for localized amyloidosis. The
results with radiotherapy have been equivocal, with some benefits in terms of control
of the progression of the local disease. However, the optimal dose of radiotherapy
remains poorly defined, with dosages from 20 Gy to 40 Gy being used for cases of tracheobronchial
amyloidosis.[20]
[21]
[22] Sinonasal and nasopharyngeal amyloidosis are considered unsuitable for treatment
with radiation in view of the close proximity to the surrounding vital structures.
Oral and oropharyngeal amyloidosis are usually accessible to surgical debulking when
needed, since radiotherapy is not usually contemplated in these patients.
Our study suffers from the limitations of any retrospective study and a limited patient
population. The follow-up for some of the patients was limited to a few months, which
is too short to comment on the recurrence rate. However, given the rarity of the isolated
amyloidosis limited to the head and neck subsites, it is barely practical to involve
patients prospectively or to carry out randomization. The current study focuses on
the clinical profile of the patients with isolated amyloidosis in the ENT domain,
and reinforces the fact that the otorhinolaryngologists and head & neck surgeons must
be cognizant of the implications of localized versus systemic amyloidosis.
Conclusion
The present study describes our experience with seven patients with amyloidosis isolated
to the head and neck subsites. The localized form of this disease has an excellent
prognosis in terms of survival. The workup for systemic amyloidosis should be offered
to every patient with localized head and neck amyloidosis. In cases of truly localized
disease, when needed, surgical excision is the treatment of choice, with prolonged
follow-up to watch for disease recurrence.
