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 Table of Contents  
CASE REPORT
Year : 2017  |  Volume : 4  |  Issue : 2  |  Page : 117-121

Primary systemic amyloidosis presenting as macroglossia


1 Department of Biochemistry and Laboratory, Yashoda Hospital, Hyderabad, Telangana, India
2 Department of Pathology, Yashoda Hospital, Hyderabad, Telangana, India
3 Department of Medical Oncology, Yashoda Hospital, Hyderabad, Telangana, India
4 Department of Medical Publications, Yashoda Hospital, Hyderabad, Telangana, India

Date of Web Publication25-Jul-2017

Correspondence Address:
Karishma Rosann Pereira
Yashoda Hospitals, Nalgonda X Roads, Malakpet, Hyderabad - 500 036, Telangana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sjos.SJOralSci_5_17

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  Abstract 

Primary amyloidosis is a group of monoclonal plasma cell disorders, characterized by extracellular deposition of immunoglobulin light chain fibrils in multiple organs leading to progressive multiorgan dysfunction. We report a 61-year-old female patient with an enlarged tongue, difficulty in speech, gradually changing quality of voice, and loss of weight. Diagnosis of amyloidosis and systemic nature confirmed by tongue biopsy and anterior abdominal fat biopsy using Hematoxylin and Eosin staining and Congo red staining. Urine examination positive for Bence–Jones proteins. Bone marrow aspiration cytology, bone marrow aspirate flow cytometry immunophenotyping, serum immunofixation electrophoresis, and urine immunoelectrophoresis revealed plasmacytosis, clonal plasma cell population, marked increased in lambda light chain in serum and urine, respectively. Based on these observations, a definitive diagnosis of primary systemic amyloidosis associated with plasma cell dyscrasia was made. He was treated with intravenous (IV) bortezomib and IV dexamethasone. A battery of tests is necessary to differentiate localized amyloidosis from its systemic forms for diagnosis, treatment and to assess treatment outcome.

Keywords: Congo red stain, immunoelectrophoresis, plasma cell dyscrasia, primary systemic amyloidosis


How to cite this article:
Aluri A, Momin M, Ingle A, Reddy G V, Pereira KR. Primary systemic amyloidosis presenting as macroglossia. Saudi J Oral Sci 2017;4:117-21

How to cite this URL:
Aluri A, Momin M, Ingle A, Reddy G V, Pereira KR. Primary systemic amyloidosis presenting as macroglossia. Saudi J Oral Sci [serial online] 2017 [cited 2021 Apr 22];4:117-21. Available from: https://www.saudijos.org/text.asp?2017/4/2/117/211566


  Introduction Top


Amyloidosis is the term applied to a group of diseases characterized by extracellular deposition of fibrillar proteinaceous substance called amyloid having common morphological appearance, staining properties, and physical structure but with variable biochemical composition.

Primary (amyloid light-chain [AL] type) amyloidosis is the most common form of systemic amyloidosis seen in elderly.[1] Primary systemic amyloidosis (AL amyloidosis) is a rare disease with an age-adjusted incidence of 5.1–12.8 per million person-years. It is a plasma cell dyscrasia of unknown etiology with the production of monoclonal chains. Immunoglobulin light chains or fragments of light chains produced by these plasma cell clones form extracellular amyloid fibrils which are deposited in the organs. Most frequently organ involved are heart, smooth, and skeletal muscle, and other soft tissues (tongue), kidney, liver, and spleen.[2]

Once a diagnosis of AL is suspected, a monoclonal protein in the serum and the urine should be sought and a tissue biopsy with special stain such as Congo-red and bone marrow aspiration cytology and immunophenotyping performed. Screening for a monoclonal protein is done by serum immunoglobulin free light chain measurement and immunofixation (IF) studies of the serum and urine.[3] Typing the amyloid is imperative since treatment strategies are different depending on the source of precursor protein. Here, we report one such case of primary systemic amyloidosis from our tertiary care center one who initially presented as enlarged tongue.


  Case Report Top


A 61-year-old female patient was presented to Surgery Department, Yashoda Hospitals, Malakpet, Hyderabad, with chief complaints of gradually progressive diffuse enlargement of the tongue for 6 months. On examination, she appeared to be in good general health, but his speech had been slurred ostensibly, due to tongue swelling. On clinical examination, the patient was found to be edentulous, with tongue grossly enlarged. No ulcerations or nodules were seen over the tongue surface. The patient is not a known case of hypertension, diabetes mellitus, or ischemic heart disease. Systemic examination was unremarkable.

An incisional biopsy was performed on the both lateral border and ventral aspect of the tongue and abdominal fat. Histopathological examination of Hematoxylin and Eosin (H and E)-stained sections revealed extracellular deposition of amorphous, eosinophilic hyaline-like material in the submucosal connective tissue, which appeared to be amyloid. To confirm the presence of amyloid, a special staining with Congo red was performed, which showed peach, red color on light microscopy, and apple green birefringence on polarized light microscopy. To rule out a systemic involvement, we performed a series of investigations[Figure 1].
Figure 1: Macroglossia and ventral, lateral aspect of tongue biopsy, and abdominal fat biopsy showing amorphous, eosinophilic hyaline-like material (blue color arrows)

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At the initial examination, laboratory results were as follows: red blood cells, 2.30 millions/mm 3 (4–5.5 millions/mm 3), hemoglobin10.5 g/dl (12–15 g/dl), white blood cells 7300/mm 3 (4000–11,000/mm 3), platelets, 5.94 lakhs/mm 3 (1.5–4.5 lakhs/mm 3), erythrocyte sedimentation rate 24 mm/h (10–20 mm/h). Coagulation study was normal. Biochemical examination revealed total serum protein 6.2 (6.3–8.5 g/dl), albumin 3.7 (3.5–5.1 g/dl), globulin 2.5 (2.3– 3.5 g/dl), A/G ratio 1.4. Total bilirubin 0.8 (0.2–1.3 mg/dl), alkaline phosphatase 69 (38–126 U/L), SGOT 28 (14–60U/L), and SGPT 26 (9–69U/L) were normal. Electrolytes, sodium 138 (137–145 mmol/L, potassium 4.7 (4.0–5.1 mmol/L) and chlorides 102 (98–107 mmol/L), random plasma glucose 102 mg/dl, serum creatinine 0.6 mg/dl (0.8–1.5 mg/dl), blood urea 22 mg/dl (19–43 mg/dl) were normal. Serum calcium, magnesium, and LDH were normal.

Chest X-ray shows normal study. Skull X-ray shows no lytic lesions. Ultrasonography abdomen was normal. Electrocardiogram and echocardiography were normal.

Urine examination revealed proteinuria and urine test for Bence–Jones protein by heat method was positive. Bone marrow aspiration cytology shows plasmacytosis constitute (25%) of marrow nucleated cells. Plasma cells are predominantly mature with few immature forms seen. At places, focal sheets of plasma cells seen. Flow cytometry immunophenotyping on bone marrow aspirate shows CD38 positive cells (plasma cells) are positive for CD56 (strong) and are negative for CD19 (negative). CD45 is moderate and heterogenous, suggestive of plasma cell dyscrasia[Figure 2] and [Figure 3].
Figure 2: Bone marrow aspirate cytosmear (Giemsa stain, ×40) with mature plasma cells (thin red arrow) and Leishman stain, ×100 smear with immature plasma cells (thick arrow)

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Figure 3: Forward and side scattergram of flow cytometry immunophenotyping

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Serum protein electrophoresis (SPE) revealed thin discrete band in the gamma globulin region. However, serum IF show marked incresed in seum lambda light chain and increased in beta 2 microglobulin. In view of the thin discrete band in the gamma globulin region in SPE and marked increased in isolated lambda light chain suggestive of light chain disease (LCD) and urine IF study suggested.


  Immunofixation, Serum Method: Chemiluminescence, Solid Phase Two-Site Top


Chemiluminescent immunometric assay



Urine (24 h) protein electrophoresis shows marked increased in total protein and monoclonal spike (5.2 gm%) in gamma region. Urine (24 h) IF results in increased in free lambda light chain. Bence–Jones present in urine by IF study.

Urine (24 h) protein electrophoresis/immunofixation/free light chain assay

Based on these battery of investigations, a diagnosis of primary systemic amyloidosis with mild normocytic normochromic anemia was made. Patient treated with high-dose melphalan followed by autologous peripheral blood stem cell transplantation (SCT) planned.


  Discussion Top


Amyloidosis is divided clinicopathologically into two major categories. (1) Systemic (generalized) amyloidosis and (2) localized amyloidosis. Systemic amyloidosis can be classified as follows: (1) Primary systemic amyloidosis, usually with no evidence of preceding or coexisting disease, plasma cell dyscrasia or paraproteinemia, amyloid is derived from monoclonal immunoglobulin light chain and is called as AL amyloid; (2) amyloidosis associated with multiple myeloma; or (3) secondary systemic amyloidosis with evidence of coexisting previous chronic inflammatory or infectious conditions.[1],[4]

Amyloidosis of the oral cavity is uncommon. The tongue is the most frequent site, followed by the floor of the mouth, buccal mucosa, soft palate, gingiva, hard palate, and lower lip region. It can also affect pharynx, orbital sinuses, larynx, and salivary glands.[5]

Amyloid results from an abnormal folding of proteins which are not recyclable or biodegradable and cannot be broken down easily. Therefore, the body finds it difficult to remove these proteins. This leads to the formation of oligomers and fibrils that are deposited in tissues and organs.[1]



Symptoms vary greatly from patient to patient and between the different types of amyloidosis. Symptoms are often vague, mimicking other medical conditions. The most common symptoms are fatigue, unexplained weight loss, swelling of the ankles and legs due to fluid accumulation (edema), shortness of breath, loss of appetite, an enlarged tongue (macroglossia), unexplained bruising around the eyes, numbness, or tingling in the hands and feet (peripheral neuropathy).[6]

Clinically, for generalized macroglossia, besides amyloidosis, one should consider tuberculosis, lymphangioma, hypothyroidism, acromegaly, granular cell tumors, lingual infarction caused by giant cell arteritis, idiopathic muscular hypertrophy, and Beckwith–Wiedemann syndrome under differential diagnosis.[7] All these pathologies were ruled out after the biopsy was done, which furnished the final diagnosis as confirmed amyloidosis. Abdominal fat biopsy, had a 94% success rate, shows positivity if systemic amyloidosis is involved.

All amyloid deposits share the following physical characteristics, which include (a) appearance of amorphous, eosinophilic deposits under light microscope after H and E staining (b) a bright, apple green birefringence under polarized light after staining with Congo red.[8]

In our case, tongue biopsy specimen led us to the diagnosis of amyloidosis, and analysis of abdominal fat aspirate led us to the diagnosis of systemic amyloidosis. After we established the diagnosis of systemic amyloidosis, in our case, we then tried to determine whether it was primary or secondary. It is very essential to rule out systemic forms of amyloidosis since the etiology, treatment, and outcome of both vary. This can be done by carrying out extensive biochemical investigations, which include serum and urine IF, to detect Bence–Jones proteins and by doing a bone marrow examination for plasma cell dyscrasia.[9]

Although an important part of the workup, serum, and 24-h urine protein electrophoresis alone are insufficient as screening tools. Among patients with AL amyloidosis, the sensitivity of SPE for detecting a monoclonal protein is only 66%, whereas the sensitivity of serum IF is 74%, and serum immunoglobulin free light chain assay is 88%. The sensitivity for detecting a monoclonal protein further increases to 94% if one combines all three serum tests and rises to 98% if urine IF is added.[3] The sensitivity of a biopsy of a symptomatic organ is higher than that of the more accessible tissues, i.e., more than 95% for symptomatic tissue, 75%–80% for fat, and 50%–65% for bone marrow.[10] In primary systemic and myeloma-associated amyloidosis, the fibrils are composed of “protein AL,” commonly λ class with low-molecular-weight and of lower isoelectric point.[11] The laboratory features of LCD are different from classical myeloma and hence present considerable challenge to diagnosis.[5] The serum total protein is normal to low. Hypogammaglobulinemia is commonly encountered as opposed to hypergammaglobulinemia seen in classical multiple myeloma. This is because of the fact that only light chains are produced which because of their low molecular weight is easily filtered out by the kidneys. A total of 100% of the patients shows evidence of Bence–Jones protein. Many patients do not have a serum M (monoclonal) component on electrophoresis as most light chains are quickly filtered by the kidneys. Urine electrophoresis therefore becomes an important test in such cases. Urine immunofixation electrophoresis reveals the type of monoclonal component present in case it is not detected by serum. The usual picture in the disease population reveals kappa:lambda ratio of 2:1. This distinction is important because lambda LCD has a three times worse prognosis than kappa LCD.[6]

Surgical reduction of tongue has been suggested in cases of amyloid macroglossia. In our case, surgery was not done due morbidity associated with the procedure and lack of consensus in literature regarding the benefits of surgery. Treatment aim is to reduce the precursor protein by decreasing the proliferation of plasma cells, by cytotoxic agents, immunosuppressants. Antineoplastic drugs can be used to slow down the renal impairment by inhibiting polymerization of amyloid fibrils.[12]


  Conclusion Top


Amyloid involvement of the tongue is almost always secondary to systemic disease. An extensive workup to differentiate systemic and localized amyloidosis required to treat underlying pathology and to prevent organ damage. Encouraging report reported with current therapies with antineoplastic agents and autologous peripheral blood SCT.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Mohan H. Immunopathology including amyloidosis. In: Mohan P, Mohan T, Mohan S, editors. Textbook of Pathology. 5th ed. New Delhi: Jaypee Brothers; 2005. p. 83-92.  Back to cited text no. 1
    
2.
Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Engl J Med 1997;337:898-909.  Back to cited text no. 2
    
3.
Katzmann JA, Kyle RA, Benson J, Larson DR, Snyder MR, Lust JA, et al. Screening panels for detection of monoclonal gammopathies. Clin Chem 2009;55:1517-22.  Back to cited text no. 3
    
4.
Baethge BA, Jacobson DR. Amyloidosis, Overview. Available from: http://www.emedicine.medscape.com/article/1093258-overview. [Last accessed on 2017 May 05].  Back to cited text no. 4
    
5.
Andreadis D, Poulopoulos A, Papadopoulos P, Epivatianos A. Localized tongue amyloidosis in a patient with neurofibromatosis type II. Head Neck Pathol 2011;5:302-5.  Back to cited text no. 5
    
6.
Robbins S, Cotran RS, Kumar V, Abbas AK. Pathologic Basis of Disease. 8th ed. South Asia Edition: Saunders; 2010. p. 258-64.  Back to cited text no. 6
    
7.
Topouzelis N, Iliopoulos C, Kolokitha OE. Macroglossia. Int Dent J 2011;61:63-9.  Back to cited text no. 7
    
8.
Speranza VD. Amyloid. Histologic Preparations: Common Problems and Their Solutions; 2009. p. 133-7. Available from: http://www.cap.org/apps/docs/cap_press/Amyloid.pdf. [Last accessed on 2017 May 05].  Back to cited text no. 8
    
9.
Rajkumar SV, Dispenzieri A, Kyle RA. Monoclonal gammopathy of undetermined significance, Waldenström macroglobulinemia, AL amyloidosis, and related plasma cell disorders: Diagnosis and treatment. Mayo Clin Proc 2006;81:693-703.  Back to cited text no. 9
    
10.
Kyle RA, Gertz MA. Primary systemic amyloidosis: Clinical and laboratory features in 474 cases. Semin Hematol 1995;32:45-59.  Back to cited text no. 10
    
11.
Gertz MA, Lacy MQ, Dispenzieri A. Amyloidosis: Recognition, confirmation, prognosis, and therapy. Mayo Clin Proc 1999;74:490-4.  Back to cited text no. 11
    
12.
Fahrner KS, Black CC, Gosselin BJ. Localized amyloidosis of the tongue: A review. Am J Otolaryngol 2004;25:186-9.  Back to cited text no. 12
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]



 

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Introduction
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