Primary Systemic Amyloidosis Associated With Multiple Myeloma: A Case Report and Review of the Literature

The evaluation suggested AL amyloidosis and indicated a malignant course with skin, cardiac, and gastrointestinal tract involvement. The patient was started on systemic dexamethasone sodium phosphate at a dosage of 40 mg intravenously daily for 4 days on and 4 days off. A percutaneous endoscopic gastrostomy tube was placed, and the patient was transferred to a smaller community hospital for nutritional rehabilitation prior to starting thalidomide or melphalan therapy. Unfortunately, the patient developed an ileus, continued to experience malnutrition, and was transferred to the palliative care service for pain management. She died approximately 2 weeks later, less than one month after diagnosis. 

Comment
Despite the separate classifications of systemic and localized, the different clinical types of amyloidosis look almost identical ultrastructurally. Under the electron microscope, straight, nonbranching, nonanastomosing, irregularly spaced fibrils measuring 7.5 to 10.0 nm in diameter and of indefinite length characterize all forms of amyloidosis.9 Additionally, all forms of amyloidosis share the same serum amyloid P (SAP) component and ground substance. SAP is an elastase inhibitor and normal constituent of the microfibrillar sheath of elastic fibers; however, as a component of amyloid, SAP is pathological, likely functioning with the β-pleated sheet structure to protect amyloid from phagocytosis and degradation. It is the third component—protein-derived amyloid fibers (AA [amyloid A], AK [altered keratin protein component], AL)—that varies according to deposition subtype. The type of fibril deposit and the clinical presentation are guidelines to classify various types of amyloidosis (Table 2).2,9 Three major types of amyloid fibril precursor proteins have been identified: tissue amyloid derived from light chain protein fragments, or AL; a nonimmuoglobulin acute phase reactant, known as serum AA; and AK. In the heredofamilial forms of familial amyloidotic polyneuropathy (FAP) I, II, III, and IV, other proteins (eg, transthyretin, apolipoprotein A-I, gelsolin) are modified into β-pleated sheets and deposited as amyloid.2 In addition to the type of protein deposited, amyloidosis is defined as either systemic or localized (Table 3) and varies greatly in terms of prognosis, with cutaneous confinement being more benign.

AL amyloidosis occurs without plasma cell dyscrasia in the minority of cases.10 In one study of 494 cases of primary systemic amyloidosis, only 13% of cases were associated with multiple myeloma; other monoclonal gammopathies were associated, specifically monoclonal gammopathy of undetermined significance and smoldering myeloma in 15% and 3% of cases, respectively.10 Sources historically estimated that an average of 15% of patients with multiple myeloma developed amyloidosis.11,12 As more sensitive diagnostic techniques become available, it is apparent that AL amyloidosis occurs more frequently with plasma cell dyscrasia than previously thought. Immunoelectrophoresis and/or immunofixation, more sensitive techniques than serum protein electrophoresis, show a serum M-protein spike in 72% (n=430) of cases as well as a urine M-protein spike in 73% (n=429) of cases; combined, of patients who had both urine and serum immunoelectrophoresis and/or immunofixation at the time of AL diagnosis, an M-protein spike was present in 89% of patients (n=408).10 Of the remaining 11% of patients (n=43) with urine and serum negative for M protein, 20 of 43 patients had bone marrow biopsy results demonstrate a monoclonal plasma cell proliferation or positive immunohistochemical stains.10 Waxy purpuric mucocutaneous lesions along with carpal tunnel syndrome and macroglossia—all secondary to AL amyloid tissue deposits—may serve as an early marker of plasma cell dyscrasia in general.9 Systemic—Systemic amyloidosis is divided into 3 subtypes, with amyloid fibril precursor proteins specific to each type: primary systemic amyloidosis (AL), secondary systemic amyloidosis (AA), and heredofamilial amyloidosis (eg, transthyretin, AA, β2-microglobulin, apolipoprotein A-I, gelsolin).9 Systemic amyloidosis has a poor prognosis, with a median survival of 13 to 43 months for primary systemic amyloidosis. Negative prognostic indicators for primary systemic amyloidosis include congestive heart failure, increased septal thickness, urinary light chains, hepatomegaly, and major weight loss (Table 4).10 Secondary systemic amyloidosis is the result of a chronic inflammatory process caused by a myriad of underlying systemic diseases, with the most common causes varying by country. In the United States and Western Europe, rheumatoid arthritis and chronic inflammatory bowel disease, predominantly Crohn disease, are the most common causes of secondary systemic amyloidosis. In contrast, tuberculosis and leprosy predominate in third-world countries.13 Amyloidosis is notable for deposition throughout the body of a modified acute phase reactant (AA), with no organ system spared; prognosis varies depending on the ability to effectively treat the underlying disease. The disease course often is irreversible because of the protection from phagocytosis offered by the β-pleated sheet configuration and elastase inhibitor properties of SAP.2

Cutaneous symptoms are found in up to 40% of patients with primary systemic amyloidosis6 and characteristically occur as waxy, smooth, shiny, nontender, nonpruritic nodules or plaques.9 The papules frequently are distributed on flexural areas (eg, eyelids, axillae, umbilicus), the neck, central parts of the face, lips, tongue, and buccal mucosa, as well as on retroauricular, inguinal, and anogenital regions.9 Occasionally, plaques on the head and neck coalesce to produce leonine facies or even to occlude the external auditory meatus, resulting in deafness as a presentation.9,14 Other skin findings related to primary systemic amyloidosis are purpura and ecchymosis on the face and neck in 16% of patients, most notably found on the periorbital or perioral regions.5 The periorbital ecchymoses predominately affect the upper eyelids, which gives the disease the reputation as "black-eye syndrome."2 Pinch purpura can be induced by gentle skin stretching and is thought to be secondary to blood vessel amyloid infiltration, decreased vitamin K–dependent clotting factors, acquired factor X deficiency, and increased fibrinolysis and antithrombin activities.2 The "shoulder pad" sign refers to infiltration of periarticular tissues by AL amyloid and often is painful, with resultant decreased joint motility.2,14 Additionally, patients may exhibit patchy alopecia and nail plate atrophy secondary to amyloid infiltration of follicular and matrix structures, respectively.9 β2-microglobulin and AA amyloid fibril precursor proteins are involved in hereditary inflammatory syndromes associated with secondary systemic amyloidosis—familial Mediterranean fever (AA), Muckle-Wells syndrome (AA), and hemodialysis associated (β2-microglobulin).2 Familial Mediterranean fever and Muckle-Wells syndrome, which are recessive and autosomal-dominant disorders, respectively, are associated with fever and renal amyloidosis. Additionally, familial Mediterranean fever is associated with angioneurotic edema and erysipelaslike erythema, arthralgia, and peritonitis, whereas Muckle-Wells syndrome is associated with deafness and urticaria.9 FAP rarely has cutaneous manifestations and only has been described in the past 4 decades in pedigrees in Portugal, Japan, and Sweden, as well as in several collections of cases in North America.15 FAP also is known as familial nephropathic polyneuropathy, with several manifestations that result from deposition of transthyretin, apolipoprotein A-I, or gelsolin amyloid fibril precursor protein in neural tissue. Peripheral neuropathy is the most prominent manifestation, but cardiac disease and autonomic neuropathy also can occur.4 According to a study of 52 patients with FAP from North America, 43 patients (83%) had peripheral neuropathy and 17 patients (33%) had autonomic neuropathy compared with 5 patients (10%) with renal disease and 14 patients (27%) with cardiomyopathy. The median duration of survival for FAP is 5.8 years, with an approximately 40% mortality from congestive heart failure and cardiac arrhythmia.15 Hemodialysis-associated amyloidosis results from dialysis membranes (cellulose, cuprophane) failing to clear β2-microglobulin proteins from the blood.2 After an average of 8 to 9 years of dialysis, the deposits become evident in some patients, while other patients with similar deposits remain asymptomatic, prompting thought that the process also must involve a hereditary component.2,16 Symptomatic β2-microglobulin deposition most commonly occurs in articular structures and is associated with bilateral carpal tunnel syndrome.16 Skin manifestations are uncommon, with wrinkling of fingers and lichenoid truncal lesions present in some patients.2 Peritoneal dialysis and newer dialysis membranes with a β2-microglobulin absorbent column can filter β2-microglobulin more effectively than traditional dialysis, and their use can sometimes reverse symptoms of carpal tunnel syndrome and arthralgia related to amyloid deposition.17 Localized—Localized amyloidosis includes primary and secondary subtypes. Primary cutaneous amyloidosis is further divided into nodular, macular, and lichenoid forms. Secondary cutaneous amyloidosis often is an incidental finding on biopsy of multiple benign and malignant skin tumors, or is associated with psoralen plus UVA therapy.2 In both primary cutaneous macular and lichenoid amyloidosis, as well as in secondary cutaneous amyloidosis, the derived amyloid fibers are from keratin protein (AK) and are released following injury to keratinocytes. The lichenoid and macular forms demonstrate features of epidermal damage—necrotic keratinocytes, pigment incontinence, and focal hemorrhage.4 AK presence within the skin can be evaluated with keratin immunoperoxidase stains and direct immunofluorescence staining of immunoglobulin M, which is passively absorbed by AK deposits.2 The degenerated keratin AK amyloid deposits in lichenoid and macular amyloidosis consist of amorphous deposits explained by 2 current theories—Hashimoto fibrillar body theory18 and Yanagihara secretion theory.19 The former theory explains that necrotic epidermal cells are transformed by dermal macrophages and fibroblasts into AK amyloid,18 whereas the latter theory postulates that disrupted basal cells secrete AK amyloid.19 Lichenoid amyloidosis occurs more commonly among the Chinese population, and macular amyloidosis is more common among Hispanic, Asian, and Middle Eastern populations.2,4 Multiple endocrine neoplasia 2, or Sipple syndrome, is an autosomal dominant RET oncogene mutation classically associated with medullary thyroid carcinoma, parathyroid hyperplasia, pheochromocytoma, and both primary cutaneous macular and lichenoid amyloidosis. Pruritus presenting in infancy should include multiple endocrine neoplasia 2 in the differential in terms of its syndromic association with primary cutaneous lichenoid amyloidosis, which can present shortly after birth in this population.4 Macular and lichenoid amyloidosis can coexist in the same individual and thus are regarded by some authors as one pathological process; however, lichenoid amyloidosis may be distinguished from macular amyloidosis histologically by hyperkeratosis, acanthosis, and larger deposits of AK amyloid fibril protein. Small hyperkeratotic papules and sometimes larger infiltrated plaques characterize lichenoid amyloidosis, which affects shins bilaterally with rare involvement of the thighs, forearms, and upper back.2,9 In contrast, primary cutaneous macular amyloidosis typically involves the interscapular upper back, shows salt-and-pepper pigmentation, and displays a rippled appearance when small papules coalesce.5 The absence of perivascular amyloid in the primary cutaneous macular and primary cutaneous lichenoid forms of amyloidosis largely rules out systemic disease, in which perivascular invasion is characteristic.4 Primary cutaneous nodular amyloidosis is unique among the cutaneous amyloidosis subgroup in that its amyloid fibrils are derived from AL, which is the same amyloid present in primary systemic amyloidosis. One study questioned the neoplastic origin of primary cutaneous nodular amyloidosis, citing that the fibril protein studied was polyclonal and could have been secondary to a reactive process.20 However, histologically, numerous plasma cells suggest localized plasmocytomas are present at the periphery of diffuse amyloid deposits at all levels within the dermis and subcutis.2,4 Nodules typically are singular, located preferentially in acral areas, and can be bullous with an atrophic overlying epidermis.4 Fewer than 50 cases of primary cutaneous nodular amyloidosis have been reported in the medical literature.3

Conclusion
The systemic pattern of amyloid involvement in the present case, as well as the underlying diagnosis of multiple myeloma, is consistent with AL amyloidosis secondary to multiple myeloma. Even though the M protein often found in multiple myeloma is the κ light chain, this patient's M protein was λ light chain, which is consistent with two thirds of patients with AL amyloidosis but is inconsistent with multiple myeloma.10 Our patient presented with weight loss, fatigue, and weakness, which are notably the most frequent initial symptoms in AL amyloidosis.5 Of note