Amyloidosis with oral involvement. Case report F. C. Loh, AM, BDS, MDS, MSc* N. Ravindranathan, MB BS, FDS, FRCS, Ed? J. F. Yeo, AM, BDS, MSc, MDS*

Key words: Amyloidosis, case report, medical conditions, oral involvement.

Abstract A patient with chronic renal failure was investigated after complaining of oral discomfort which was found to be due to macroglossia and generalized involve- ment of the oral soft tissues by amyloidosis. A search for multiple myeloma proved to be positive. She also had a previous history of Carpal-tunnel syndrome. Despite an initial good response to treatment with phenylalanine nitrogen mustard (melphalan hydrochloride), she finally succumbed to end-stage renal failure.

(Received for publication February 1988. Accepted August 1989.)

Introduction Amyloidosis is a metabolic disease of connective

tissue in which an amorphous substance is deposited in the wall of small blood vessels in close proximity to the collagen fibres. The term was coined by Schleiden in 1838 to describe a normal amylaceous constituent of plants. It can be classi- fied as primary and secondary. While primary amyloidosis arises idiopathically or as a complica- tion of multiple myeloma, secondary amyloidosis is associated with disease processes of a chronic infective or inflammatory nature.'

As oral manifestations have been reported in 39 per cent of patients,* this case which showed some unusual oral features is described.

*Department of Oral Surgery, National University of Singapore. tFormerly with Department of Oral Surgery, National Univer- sity of Singapore. Now in general practice.

Classification The most recent classification of amyloidosis is

based on the biochemistry of the amyloid fibrils. There are two main groups. In one group (primary amyloidosis), the fibrils consist of mainly amyloid light chains (AL chains) and the other group consists mainly of amyloid A or AA fibril proteins (secondary amyloidosis). There are several other types of fibrils, for example, AS, Af,, Af, and so on, but they are of minor importance. The clinical classification of amyloidosis put forward at the Third International Symposium on Amyloidosis is shown in Table l .3

Path o 1 o gy Primary amyloidosis can be diagnosed only when

no predisposing condition exists. It usually involves tissues such as the skin, mucous membrane, heart, tongue, nerves and gastro-intestinal tract. The amyloid material is deposited in the tunica adven- titia of small blood vessels in close proximity to the collagen fibres. Primary amyloidosis is commoner in males and shows the highest incidence in the sixth decade. Secondary amyloidosis usually affects parenchymatous organs such as the liver, spleen, kidney and adrenals. Secondary amyloidosis is more common than primary amyloidosis.

Amyloidosis is also very frequently seen in multiple myeloma. Amyloid infiltration into small joints can mimic rheumatoid arthritis. Amyloid is also seen in certain odontogenic tumours (calcifying odontogenic tumour). Vicken4 postulated in 1965 that, in this neoplasm, amyloid deposition precedes calcification.

Biochemistry Amyloid is a substance that appears to be

homogenous and amorphous under the light micro- scope. It stains pink with haematoxylin and eosin.

14 Australian Dental Journal 1990;35(1):14-8.

Table 1. Classification amyloidosis' Classification Amyloid typet Major protein component$

1 . Primary amyloidosis: no evidence of preceding or co-existing disease

2. Secondary amyloidosis: co-existence of other conditions such as

3. Localized amyloid: involvement of a single organ without evidence of

4. Familial amyloidosis AF

except multiple myeloma AL k-V,

generalized involvement AL IPV,

Protein A rheumatoid arthritis or chronic infection AA

Prealbumin Prealbumin Prealbumin Protein A

Portuguese AFP Japanese AFt Swedish AF, Familial Mediterranean fever AA

5. Senile amyloid AS Senile cardiac amyloid AS, Prealbumin Isolated atrial amyloid IAA Brain AS,

=Third International Symposium on Amyloidosis. tAL = amyloid light chain, may be x or A; AA = amyloid, protein A. $IgVL =variable portion of immunoglobulin.

Table 2. Syndromes associated with AL chains

Syndromes Per cent association of raised AL chains

Nephrotic syndrome Congestive heart failure Orthostatic hypotension Carpal-tunnel syndrome Peripheral neuropathy

32 23 14 24 17

~

*Compiled by Creipp PR' from a retrospective Mayo Clinic study.'

Congo red stained section produces a green birefrin- gence under polarized light. Electron microscopy has revealed amyloid as consisting of linear non- branching fibrils about 10 nm wide that are vari- able in length with hollow cores. The arrangement of the amyloid fibrils into a cross$ sheet formation contributes to the optical pleated features of amyloid and produces the typical staining features. Amyloid fibrils are insoluble.

In AL amyloidosis, amyloid is said to involve the heart, tongue gastrointestinal tract, skin and nerves. In AA amyloidosis, amyloid is said to involve the liver, spleen and kidney. The protein fibrils of approximately 10 nm diameter lie in sheets with polypeptide chains perpendicular to the axis of the fibrils. The configuration contributes to the now accepted p pleated structure of amyloid as proposed by Earnes and Glenner.5 This structure contributes to the insoluble nature of the fibrils which are also resistant to proteolytic digestion. All amyloid deposits also contain a glycoprotein called amyloid P component. Glenner" proposed that partial proteolysis of abnormal protein precursors, poly- merize into p pleated fibril sheets. Glenner and associates' also demonstrated that amyloid fibrils

in a patient with amyloidosis were virtually iden- tical to the variable portion of a monoclonal light chain. Thus the monoclonal light chain or a vari- able portion constitutes the typical fibril of AL. Light chains of the Lambda class are more often associated with amyloidosis than the Kappa light chains. It is not known whether the light chain components of the amyloid are synthesized de novo or whether they represent degradation of the entire light chain.

In AA amyloidosis (secondary type), the major component of the amyloid fibril is protein A which consists of 76 amino acids and is not related to any known immunoglobulins.

Signs and symptoms in the oral cavity The tongue is a commonly affected organ in

amyloidosis.* It is usually enlarged and firm and eventually loses mobility. Dental indentations are common due to moulding pressure against the teeth. There may also be associated enlargement of submandibular structures. Pain is not usually a common feature. Petechiae, papules or plaques may occur on the face, neck and mucous membrane.

Diagnosis The detection of a monoclonal protein in the

serum or urine helps to distinguish the primary amyloidosis (AL type) from the secondary (AA type). Electrophoresis and immunoelectrophoresis can detect monoclonal protein in about 90 per cent of patients. It is important to realize the associa- tion between patients who present with the syndromes listed in Table 2 and their association with raised AL chains.P

Australian Dental Journal 1990:35:1 15

Fig. 1.-Intra-oral view of the patient showing enlarged tongue which was nodular and indented.

Fig. 2.-Multiple small nodules on the rnucosal aspect of the lower lip which resembled sago seeds in appearance.

Symptomatically involved tissue such as the tongue, or uninvolved tissue, for example, from the rectum Or bone marrow should be chosen for biopsy and subjected to electron microscopic examination, this being the most specific diagnostic method.

comfort for three months. Her tongue had become progressively swollen and sore. She also gave a history of a lumpy sensation in the inner aspect of her lower lip. She gave no history of a similar episode.

Case report A 55 year old Indian woman was referred by her

physician on 4 January 1987 for investigation of oral discomfort. At the time of referral, she was an in- patient undergoing investigation of chronic renal failure. She gave a history of increasing lethargy,

Her medical history revealed that she had had rheumatoid arthritis for five years, decompression of left Carpal-tunnel syndrome in 1984, and frac- tured right neck of a femur in August 1986. She denied taking any drugs except methoxynapthpropi- onic acid for rheumatoid arthritis. She reported no

loss of apetite, worsening backache, and oral dis- history of drug allergy.

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Fig. 3. -Photomicrograph showing infiltration of the underlying connective tissue by homogeneous eosinophilic glassy material which stained orange with Congo red test ( x 100). Fig. 4. -Photomicrograph demonstrating the vivid birefringence of the amyloid deposits

in a Congo red-stained section viewed under polarized light ( x 100).

Investigation and results upper lips and both cheeks were very nodular, The patient was pale and dyspnoeic and confined resembling sago seeds (Fig. 2). She had no cervical

to a wheelchair. On examination ofthe oral cavity, lymphadenopathy, and was partially edentulous. the tongue was seen to be enlarged, nodular and General examination revealed limitations of indented (Fig. 1). The inner aspect of the lower and movement of the lumbar spine in flexion and exten-

Australian Dental Journal 1990;35:1. 17

sion. The cardiovascular system and respiratory system were essentially normal.

Multiple oral biopsies were carried out and the histological diagnosis was amyloidosis (Fig. 3, 4).

The results of her haematological, biochemical and special investigations are as given below.

The patient’s ESR was markedly raised at 101 in the first hour. The urea was found to be raised at 15 mmol/L and creatinine at 199 mmol/L. All other haematological and biochemical indices were within normal limits. The creatinine clearance was reduced to 14.46 mLlmin (normal 75-135 mllmin). The urinary protein was 10.30 g/day (normal 0.00- 0.30 glday). Serum and urinary electrophoresis revealed as a predominant feature, monoclonal bands (Kappa light chains). Thus a provisional diag- nosis of light chain myeloma was diagnosed. The IgG was markedly raised. Other immunoglobulins were also raised.

The bone marrow biopsy revealed 38 per cent of plasma cells, and the bone marrow aspirate confirmed the diagnosis of multiple myeloma.

The skeletal survey showed no skull lesions. The cervical spine radiographs showed degenerative changes compatible with osteoarthritis. The lumbar spine radiographs were essentially normal.

Treatment and progression Treatment was commenced with melphalan

hydrochloride. Initially the patient made good progress, but her condition deteriorated rapidly within six week of commencing active treatment. She died of end-stage renal failure.

Discussion Amyloidosis is considered by many to be a rare

disease. Alexanian, Fraschini and Smithlo reviewed the diagnosis of 30 cases in a 15 year span. Diagnos- is of amyloidosis demands proof through a biopsy.

In this case report, the most unusual feature was generalized deposition of amyloid in the oral cavity. In a series of 229 patients reviewed by Kyle and Creipp,2 approximately 39 per cent had macro- glossia and 24 per cent had Carpal-tunnel syndrome. In this case, the patient’s left carpal tunnel had been decompressed in 1985, but she still had persistent symptoms.

Smith and Speculandll reported a case where a patient initially presented with a non-healing ulcer in the lower left quadrant and nine months later presented with a swelling of the tongue and left submandibular salivary gland which was found on biopsy to be involved with amyloidosis. Babajews12reported a case of an occult multiple myeloma associated with amyloidosis of the tongue.

Amyloidosis is a disease of interest to the dental surgeon as it is a multisystem disease and oral struc-

tures are affected. Treatment considerations for AL amyloidosis include melphalan hydrochloride, pred- nisolone and colchicinum. The median survival period of amyloidosis after diagnosis ranges from six months to two and a half years. It may be concluded in the case under review that amyloidosis must be suspected in case of gradual enlargement of the tongue in adults, espe- cially if the general medical history reveals some serious condition elsewhere in the body.

Acknowledgements The authors would like to record their gratitude

to Emeritus Professor K. Shanmugaratnam, Department of Pathology, National University of Singapore, for having kindly provided us with the materials for the photomicrographs; and to Dr Peter Egyedi (former Professor of Oral and Maxillo-facial Surgery, University of Utrecht, Holland), Senior Teaching Fellow, National University of Singapore. We would also like to thank Miss Linda Lee and Mr B. Joseph for their assistance in the prepara- tion of the manuscript.

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Earnes ED, Glenner GG. X-ray diffraction studies of amyloid filaments. J Histochem Cytochem 1986;16:673-7. Glenner GG. Amyloid deposits and amyloidosis. N Engl J Med 1980;302:1283-92. Glenner GG, Terry WD, Isersky G. Amyloidosis: its nature and pathogenesis. Semin Hematol 1973; 10:65-81. Keith D. Oral features of primary amyloidosis. Br J Oral Surg 1972;lO: 107-15. Greipp PR. Amyloidosis (AL) an approach to early diag- nosis. Arch Intern Med 1984;144:2145-6. Alexanian R, Fraschini G, Smith L. Amyloidosis in multiple myeloma or without apparent cause. Arch Int Med

Smith A, Speculand B. Amyloidosis with oral involvement. Br J Oral Maxillofac Surg 1985;23:435-44. Babajews A. Occult multiple myeloma associated with amyloid of the tongue. Br J Oral Maxillofac Surg

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Address for correspondence/reprints: Department of Oral Surgery,

Faculty of Dentistry, National University of Singapore, C/o National University Hospital,

5 Lower Kent Ridge Road, Singapore 05 1 1.

18 Australian Dental Journal 1990;35:1.