CASE 2

Diagnosis: Amyloidosis L associated to multiple myeloma

A 42-year-old woman without known allergies or toxic habits presented with a history of carpal tunnel syndrome surgery in both hands 4 years previously. She was taking no medication on a regular basis. The patient was referred by her dentist due to the presence of multiple small, asymptomatic tumor lesions distributed over the entire oral mucosa. Intraoral examination revealed the presence of small irregular nodules of fibrous consistency, located in the upper and lower lip mucosa, cheek mucosa and tongue. There were no mucosal color changes. No adenopathies or general symptoms were noted. An orthopantomographic study was requested, together with a blood test and biopsy. Orthopantomography and the blood test findings (including complete blood count, hemostasia, biochemistry and total proteins) proved normal. The biopsy in turn revealed masses of amorphous material in the connective tissue that stained with Congo Red and generated green birefringence under polarized light. Amyloidosis was diagnosed. With this histological diagnosis, the patient was evaluated for the presence of deposits in other organs or tissues, and for discarding a possible underlying multiple myeloma or other pathological process. A radiographic bone scan was requested (skull, ribs, shoulders, hips and spine), together with maxillofacial, spinal and pelvic MRI, echo-doppler cardiological evaluation, specific laboratory tests, and a bone marrow aspirate. The bone scan and maxillofacial MRI showed no significant alterations. MRI of the pelvis and spine showed important signal alterations in the gluteal, abductor and iliac psoas muscles, with the identification of various deposits of variable size. There were no osteolytic lesions. The echocardiographic findings were within normal limits (ejection fraction 65%), as a result of which myocardial lesions were discarded. The blood test findings showed a rise in neutrophil count (66%), a reduction in lymphocytes (22%), an increase in mast cells (10%), slightly diminished total proteins (6.4 g/dl), slightly elevated serum TSH (4.44 IU/ml) and diminished folic acid (3.4 ng/ml). Alterations in lymphocyte populations were also observed, with a rise in CD4+ and CD8+ cell count and an increase in CD4/CD8 ratio (2.7). The gammaglobulin levels were slightly diminished (11.8%, 0.8 g/dl), with IgG 603 mg/dl, IgA 42.3 mg/dl and IgM 37 mg/dl. β-2 microglobulin concentration was 1.2 mg/l. The blood kappa and lambda light chain values were 486 mg/dl and 243 mg/dl, respectively. The bone marrow aspirate informed of moderate nucleus-cytoplasm maturation asynchronism of the red cell series, and plasmatic cellularity predominantly represented by cells of mature appearance but with atypical features: anisocytosis, nuclear constrictions, binuclearity and the presence of cytoplasmic vacuoles. Marrow plasmacytosis was 38%. The immunophenotypic study proved positive for CD56+ plasma cells, and negative for CD19, with intracytoplasmic clonal kappa chains suggestive of a myelomatous origin of the latter. In situ hybridization proved negative for IgH rearrangement and 13q14 deletion.

Amyloidosis L associated to multiple myeloma was diagnosed.

Chemotherapy was proposed, plus rescue intensification with peripheral hematopoietic progenitor cell transplantation.

Diagnosis: Lingual amyloidosis as first manifestation of multiple myeloma.

Multiple myeloma is a malignant disease characterized by the clonal proliferation of plasma cells generally within the bone marrow. These cells produce immunoglobulins or fragments of the latter, that generate certain forms of amyloidosis upon accumulating within the tissues (1).

Amyloidosis is the result of the extracellular accumulation of amyloid fibrillar proteins, of which 25 have been identified in humans to date, along with 8 variants in animals (2). The disease is classified according to the type of depositing protein involved in each case. The most important variants are the following: amyloidosis L (primary amyloidosis and associated to multiple myeloma) with the accumulation of light Ig chains; amyloidosis A (related to inflammation, infection or neoplastic processes) with the accumulation of serum amyloid protein; genetically determined amyloidosis, the paradigm of which is familial amyloidotic polyneuropathy with the accumulation of transtiretin; and amyloidosis due to ß-2-microglobulin related with patients subjected to hemodialysis (3).

The incidence of amyloidosis is estimated to be 8 patients/million inhabitants/year, with a mean patient age at presentation in the primary form and associated to myeloma of 65 years (42 in our patient) – the male/female ratio being 2:1 (3,4).

The clinical manifestations depend on the anatomical distribution and amount of protein deposited. The symptoms tend to be nonspecific (fatigue, edema, weight loss), and the common clinical syndromes associated with the disease include nephrotic syndrome, myocardiopathy, hepatomegalia and peripheral neuropathy (5).

Amyloidosis often affects the oral cavity; indeed, manifestation at this level is frequently the first expression of the disease, and can be considered a marker of plasma cell dyscrasia (1,6-8). In our patient the presence of tongue nodules led to the diagnosis of amyloidosis and, posteriorly, multiple myeloma. These are yellowish and painless nodules that can also develop on the internal lip surface (as in our case) and in the cheek mucosa. The nodules are of firmer consistency than in other areas of the tongue and mucosas.

Macroglossia is observed in 10% of cases of amyloidosis L, and may interfere with speech and swallowing. In amyloidosis associated to multiple myeloma, the prevalence of macroglossia varies from 26-83% (7). In other forms of amyloidosis involvement of the tongue is not as common – affecting about 8% of patients dialyzed for over 20 years. In these cases the fibrillar protein deposited is ß-2-microglobulin (9,10).

Other lingual manifestations include papules, nodules, plaques and even verrucose masses on the lateral margins of the tongue (8,11). In the rest of orofacial regions the disorder may manifest as inflammation and bleeding of the gingiva if the gums are affected; dysgeusia; amyloid infiltration of the submaxillary glands (12); xerostomia; neck adenopathies; or even temporomandibular joint alterations (13). A biopsy is essential for the diagnosis of amyloidosis. Although the abdominal subcutaneous fat and rectal mucosa are the suggested biopsy sites, the technique causes patient discomfort. Oral tissue biopsies are therefore proposed as a valid alternative. The gums are adequate for biopsy, though recently a punch biopsy of the cheek mucosa has been shown to afford superior diagnostic performance with less patient discomfort (14).

The amyloid material stains with Congo Red, with green birefringence when examined under polarized light. Identification of the specific type of amyloid material is established by immunofixation. This procedure is able to detect 90% of patients with monoclonal light chains. In 75% of the remaining cases, Ig free light chain nephelometry is seen to be altered (5).

The systemic treatment of the disease comprises autologous hematopoietic precursor cell transplantation. In cases where this is not possible, dexamethasone and melphalan are indicated – though improved results are being obtained with pulses of dexamethasone and maintenance treatment with dexamethasone and interferon (15).

When macroglossia interferes with speech or swallowing, a reductive glossectomy in any of its variants is indicated, though the lesions may relapse to their previous state or even worsen (16).

References

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12.-Mateo-Arias J, Molina-Marínez M, Borrego A, Mayorga F. Afectación de la glándula submaxilar en paciente con amiloidosis. Med Oral 2003; 8 :66-70.

13.-Sumi Y, Hayashi H, Hattori M, Ueda M. Dialisis-related amyloidosis of the temporomandibular joint. Int J oral Maxillofac Surg 2005, 34 :696-8.

14.-Stoopler E, Sollecito T, Chen S. Amyloid deposition in the oral cavity: a retrospective study and review of literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003; 95 :674-80.

15.-Palladini G, Perfetti V, Obici L, Caccialanza R, Semino A, Adami F, et al. Association of melphalan and high-dose dexametasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood 2004;103 :2936:8.

16.-Mardinguer O, Rotenberg G, Chaushu S, Taicher S. Surgical management of macroglossia due to primary amyloidosis. Int J Oral Maxillofac Surg. 1999; 28 :129-31.