Monoclonal immunoglobulin deposition disease: light chain and light and heavy chain deposition diseases and their relation to light chain amyloidosis. Clinical features, immunopathology, and molecular analysis

Monoclonal immunoglobulin deposition occurs in tissues as Congo Red binding fibrils in light chain amyloidosis, as less structured deposits in light chain deposition disease, and as similar but distinct deposits in light and heavy chain deposition disease. The nonamyloid forms were found in 13 patients who had evidence of plasmacytic dyscrasia by the immunohistochemical detection of immunoglobulin light chains of kappa or lambda class (with or without staining for a single heavy chain isotype) and by the absence of amyloid P component in tissue sections that did not show the birefringence characteristic of amyloid after Congo Red staining. All but two of the patients presented with proteinuria with or without azotemia. Clinical syndromes involving other organ systems were less common but occasionally severe. Four patients had overt multiple myeloma. Three others had hypercalcemia and mild bone marrow plasmacytosis but no lytic lesions. Analyses of immunoglobulin synthesis in bone marrow cells from seven patients showed excess light chains in all and incomplete light chains or heavy chain fragments in six, regardless of whether an intact monoclonal protein or related subunit was in the serum or urine. The fibrillar (amyloidotic) and nonfibrillar forms of monoclonal immunoglobulin deposition occur either in overt multiple myeloma or in the course of less neoplastically aggressive plasmacytic dyscrasias. Bone marrow cells from patients with either type produce immunoglobulin fragments that are related to those deposited in the affected tissues.     

Amyloid in bone marrow smears of patients affected by multiple myeloma

Systemic AL amyloidosis is associated with nearly 15% of cases of multiple myeloma, but data on the frequency and significance of amyloid deposits in the bone marrow of patients affected by multiple myeloma without clinical signs of systemic amyloidosis are scanty. Bone marrow smears of 166 unselected patients affected by multiple myeloma (126 at diagnosis and 40 after treatment) were stained with Congo red and studied by transmission and birefringence microscopy. Both focal and diffuse storages were considered positive. Overall, 67 patients were positive and 99 were negative to Congo red and apple-green birefringence. In particular, 51 of the 126 patients studied at diagnosis and 16 of the 40 patients with advanced disease were positive. Seventeen patients were reassessed after a mean follow-up of 32 months (range: 6–91): disappearance of amyloid deposits was verified in three cases, all responsive to bortezomib-based regimens. The preliminary data available suggest that amyloid deposition in the marrow of myeloma patients is frequent, as it can be traced in nearly 40% of cases. We failed to find correlations between bone marrow amyloid deposits and immunoglobulin type, disease stage, plasma cells percentage, hemoglobin, calcium, creatinine, albumin, or β₂microglobulin. Significantly higher incidence of moderate/severe peripheral neuropathy was found in patients with marrow amyloid exposed to potentially neurotoxic antineoplastic agents. Further studies and prolonged follow-up are needed to validate our findings and to define possible prognostic aspects.     

Patterns of pulmonary involvement in systemic amyloidosis.

The clinical and histopathologic features of pulmonary amyloidosis were reviewed in 22 patients with systemic amyloidosis who came to autopsy. Eleven of 12 patients (92 percent) with primary amyloidosis had prominent interalveolar amyloid deposits. Symptoms attributable to these deposits were found in four cases (33 percent), while severe lung involvement was the apparent cause of death in one. Extensive deposition was noted in all three cases of amyloidosis associated with multiple myeloma or Waldenstrom's macroglobulinemia. Five of seven patients (71 percent) with secondary amyloidosis showed histologic lung involvement, which was perivascular or tracheobronchial in location, but not associated with symptoms. Histologic lung involvement is frequent in all forms of amyloidosis and lung tissue obtained from any patient with unexplained interstitial or reticular-alveolar pulmonary disease should be stained with Congo-red and viewed for green birefringence under polarizing microscopy for the presence of amyloid.     

IgD myeloma with amyloid arthropathy

A case of Immunoglobulin D (IgD) myeloma with amyloid arthropathy is described. The patient presented with bilateral symmetrical enlargement of multiple joints with subcutaneous nodules; the clinical picture suggested the diagnosis of rheumatoid arthritis. At necropsy, however, the joint swelling and nodules were proved to be amyloid deposition.     

Type and distribution of pulmonary parenchymal and vascular amyloid: Correlation with cardiac amyloidosis

The spectrum of amyloidosis was studied in 223 patients examined at autopsy at The Johns Hopkins Hospital since 1889. Of these patients, pulmonary involvement with amyloid was found in 68 patients including 31 with senile cardiac amyloidosis, 23 with primary amyloidosis, eight with myeloma associated amyloidosis, two with familial amyloidosis with polyneuropathy, three with isolated nodular pulmonary parenchymal amyloidosis and only one patient with secondary amyloidosis. The degree of pulmonary involvement ranged from either focal parenchymal or vascular amyloid to severe diffuse parenchymal and vascular amyloid. In general, cardiac amyloid involvement tended to parallel the pulmonary involvement and usually was more severe. Correlations between pulmonary amyloidosis and cardiac amyloidosis were statistically significant. Patients with primary amyloidosis, senile cardiac amyloidosis, myeloma associated amyloidosis, nodular pulmonary amyloidosis and familial amyloidosis with polyneuropathy had potassium permanganate-resistant amyloid. These findings suggest that the amyloid in these types of amyloidosis, in which pulmonary involvement is frequent, is a protein of either immunoglobulin origin or of a similar structure.     

Asymptomatic immunoglobulin light chain amyloidosis (AL) at the time of diagnostic bone marrow biopsy in newly diagnosed patients with multiple myeloma and smoldering myeloma. A series of 144 cases and a review of the literature

The rate of asymptomatic amyloidosis (AL) among patients with newly diagnosed multiple myeloma (MM) or smoldering multiple myeloma (SMM) is unknown. We evaluated number and clinical significance of asymptomatic AL in consecutive MM and SMM patients, not having recognition of symptomatic AL at the time of their diagnostic bone marrow biopsy. Bone marrow biopsies were stained with Congo red and considered diagnostic for AL in case of positive Congo red staining with apple-green birefringence. Biopsies from 144 patients were evaluated: 77 had a diagnosis of MM and 67 of SMM. The median age was 59 (range 26?C84) years; the median follow-up was 76?months (range 0?C216). Immunoglobulin isotypes were 96/144 (67%), IgG; 23/144 (16%), IgA; 12/144 (8%), light chain only; 1/77 (1%), IgD; and biclonal or indeterminate, 12/144 (8%). Fifty-eight percent (84/144) were ?? restricted. The presence of amyloid was found in two cases (1%, 95% CI ?0.6 to 3.2), one in MM, and one in SMM group, and none had or developed signs or symptoms suggestive of organ involvement by amyloid. Among the 142 other patients without amyloid deposition in their index bone marrow, one (0.7%, 95% CI ?0.6 to 2.0) developed symptomatic AL after 119?months.     

A case of multiple myeloma with heart failure improved remarkably by chemotherapy alone

A rare case is reported, in which heart failure in a patient with multiple myeloma without amyloidosis was improved following chemotherapy for the myeloma. The patient, a 50 year-old man, came to our hospital for examination because of anemia and hematuria. He was diagnosed as having an IgG kappa type of myeloma with the relatively rare complication of renal cancer. A chest X-ray revealed cardiomegaly and pulmonary congestion. An echocardiogram revealed an enlarged left ventricle with decreased wall motion. No cardiac amyloid deposits were detected upon endomyocardial biopsy. Chemotherapy for the myeloma which was carried out before the operation for renal cancer was not only effective for control of the myeloma, but also decreased the pulmonary congestion and improved the heart function. It is suggested that the lowering of heart function in this patient was not due to amyloid infiltration as is relatively frequent in heart failure but was due to increased blood viscosity due to the multiple myeloma.     

Amyloid arthropathy resembling seronegative rheumatoid arthritis in a patient with IgD-kappa multiple myeloma

A 67-year-old woman suffered from symmetrical polyarthralgia and multiple joint swelling simulating rheumatoid arthritis (RA). Laboratory examination showed negative results for rheumatoid factor, decreased levels of IgG, IgA, and IgM, and an increased level of IgD. Immunoelectrophoresis in her serum and urine revealed an IgD-kappa monoclonal component and Bence Jones protein (kappa), respectively. A bone marrow biopsy showed an excess of atypical plasma cells. A synovial biopsy revealed amyloid deposition composed of IgD-kappa. She was diagnosed with amyloid arthropathy (AmyA) secondary to IgD-kappa multiple myeloma. It is important to pay attention to AmyA due to multiple myeloma in patients with seronegative RA.     

Light-heavy chain deposition disease progressing to multiple myeloma

Light chain deposition disease (LCDD) and light and heavy chain deposition disease (LHCDD) are rare clinical entities that have been associated with multiple myeloma, with monoclonal gammopathy of unknown significance (MGUS), or without any detectable protein abnormality. Renal failure is common, the diagnosis is difficult and prolonged survival is rare. The first patient with LHCDD and MGUS who progressed to multiple myeloma after 11 years is presented. A rising level of monoclonal IgA immunoglobulin, bone marrow plasmacytosis, and the presence of multiple bone marrow lesions on magnetic resonance imaging provided the first evidence of disease evolution. When management of serious complications permits a long survival, some patients with LCDD or LHCDD will develop multiple myeloma.     

Multiple myeloma accompanying splenic amyloidosis and overwhelming pneumococcemia

We present the case of an 84-year-old woman with multiple myeloma who developed overwhelming pneumococcemia. Significant pathologic findings of amyloidosis were confirmed in the spleen, adrenal glands, kidneys, liver and bone marrow on autopsy. In particular, the spleen was almost replaced by diffuse linear deposition of amyloid, and residual lymphoid tissue was scant. There is a well-established association between asplenia and a predisposition to fulmination, frequently with fatal bacterial infection. In this case, functional hyposplenism as a result of amyloid replacement of the spleen led to overwhelming pneumococcemia. Functional hyposplenism due to amyloidosis predisposes patients to septicemia. As bacterial infections are a common complication in patients with multiple myeloma, it is important to know whether they have accompanying splenic amyloidosis. If there are findings of hyposplenism, it may be necessary to establish strategies to prevent fatal infection. Thought needs to be given to providing detailed education, and prophylactic or stand-by antibiotics for such patients.     

Obstructive jaundice from hepatic amyloidosis in a patient with multiple myeloma

A patient with multiple myeloma is described who developed severe intrahepatic cholestasis secondary to hepatic deposition of amyloid. This is the first reported case of this complication's developing in a patient with multiple myeloma.     

Renal failure and multiple myeloma: pathogenesis and treatment of renal failure and management of underlying myeloma.

Renal impairment is a common complication of multiple myeloma occuring in 50% of patients at some stage in their disease. Pathogenesis is multifactorial. Nephrotoxic manifestations of monoclonal immunoglobulin overexpression include the 'myeloma kidney', light chain deposition disease, AL amyloid, plasma cell infiltration and glomerulonephritis. Other factors, such as hypercalcaemia, hyperuricaemia, infection, hyperviscocity and nephrotoxic drugs can precipitate or exacerbate acute and chronic renal failure. Aggressive treatment has dramatically improved outcome in patients who present with acute or acute-on-chronic renal failure. Dialysis has become an accepted treatment acutely and in end stage renal disease due to myeloma. Conventional therapy with melphalan and prednisolone is still advocated for elderly patients. However, renal failure is not a contraindication to aggressive cytoreduction, stem cell collection, double hemibody radiotherapy and autologous transplantation in those otherwise fit to tolerate these procedures. Prognosis is primarily determined by the response of the myeloma clone to chemotherapy. Outcome in chemosensitive patients approaches that of patients with equivalent disease stage without renal dysfunction.     

Primary amyloidosis associated with multiple myeloma. Predictors of successful therapy

Of 34 patients with primary amyloidosis seen at the University of Arizona between 1973 and 1984, 25 had amyloidosis in association with overt multiple myeloma. Response to treatment was evaluable in 16 of the 25 patients. Median survival in the seven patients (44 percent) with response to treatment was 28 months versus a median of seven and a half months for the nine patients without response (p less than 0.001). Although there were no absolute predictors of response, patients with response were much less likely to have cardiac amyloid (14 percent versus 78 percent, p = 0.02), but more likely to have unusually high serum beta 2-microglobulin (above 15 micrograms/dl in three of four with response versus in neither of two without response) and kappa subtype monoclonal protein (57 percent versus 33 percent). Renal amyloid and/or serum creatinine levels above 2 mg/dl in three of seven (43 percent) patients with response did not preclude a good outcome. It is concluded that a chemotherapy induction trial is worthwhile in primary amyloidosis associated with myeloma since a subset of patients can have prolonged survival (more than two years).     

Synthesis of abnormal immunoglobulins in lymphoplasmacytic disorders with visceral light chain deposition

Three patients presented with renal or more diffuse tissue deposits of a nonamyloid material reactive with anti-κ antibody by immunofluorescence. All patients had progressive renal failure with the nephrotic syndrome and extensive tubular basement membrane deposits. Glomerular lesions were conspicuous but heterogeneous. One patient also had hepatic deposits with peliosis at histopathologic examination. An underlying lymphoplasmacytic disorder was found in all patients: multiple myeloma in one, pleomorphic lymphoplasmacytic malignancy analogous to Waldenström's macroglobulinemia in one and bone marrow monoclonal plasmacytosis without overt myeloma in one. Biosynthesis experiments in two cases showed production of abnormal κ chains which were not detected in appreciable amounts in serum and urine. These light chains had an aberrant size (abnormally short or large), their apparent molecular weight was larger in secretion than in cytoplasmic extracts (suggesting their glycosylation) and they were secreted as polymers. These results suggest a causal relationship between production of abnormal light chains and tissue deposition.     

Bullous amyloidosis in a hemodialysis patient is myeloma-associated rather than hemodialysis-associated amyloidosis

We report a 78-year-old woman on hemodialysis who presented with refractory multiple pruritic vesicles and bullae on her trunk and extremities for 2 months. Histopathologic examination of skin biopsy specimen showed subepidermal bullae with many amyloid deposits in the papillary dermis. No evidence of systemic amyloidosis could be found on physical examination. While the initial clinical diagnosis was bullous pemphigoid, the histopathology and direct immunofluorescence result favored hemodialysis-associated amyloidosis. However, immunochemical study for β₂-microglobulin was negative. Further hematologic and immunologic work-up revealed the presence of multiple myeloma and that the deposit was AL amyloid. This is the first case of bullous amyloidosis in a hemodialysis patient and should remind dermatologists that bullous amyloidosis should be considered in addition to the usual presentation of porphyria cutanea tarda and pseudoporphyria for bullous dermatosis in the hemodialysis patient. We also suggest that hemodialysis-associated amyloidosis should not be taken for granted in the hemodialysis patient with cutaneous amyloidosis without systemic signs and symptoms. Further testing for other types of amyloid should be performed.     

Pulmonary hypertension as a dominant clinical picture in a case of amyloidosis and smoldering multiple myeloma

A 48-year-old male patient presented with dyspnea on exertion. Patient was found to have pulmonary hypertension. Myocardial biopsy showed amyloidosis and further work-up revealed Salmon-Durie stage 1A multiple myeloma. Patient had no other clinical manifestations of amyloidosis. It is possible that the pulmonary hypertension is caused by amyloid deposition into pulmonary arteries as the arterial amyloid deposition is common in AL amyloidosis. Treatment with sildenafil led to hemodynamic and symptomatic improvement.     

Monoclonal gammopathy of undetermined significance. Natural history in 241 cases

Two hundred forty-one patients with a monoclonal protein in the serum but initially no evidence of multiple myeloma, macroglobulinemia, amyloidosis or lymphoma were followed up for more than five years. At the conclusion of the studies the patients were classified as follows: Group 1, patients without significant increase in monoclonal protein, 57 per cent; group 2, patients with more than 50 per cent increase in monoclonal serum protein or development of monoclonal urine protein, 9 per cent; group 3, patients who died without five-year serum studies, 23 per cent; and group 4, patients in whom myeloma, macroglobulinemia or amyloidosis developed, 11 per cent. Initially, the hemoglobin level, size of serum monoclonal protein peak, number of plasma cells in the bone marrow and levels of normal immunoglobulins were not significantly different among the four groups. The median interval from recognition of the monoclonal protein to diagnosis of multiple myeloma was 64 months, of macroglobulinemia 103 months and of amyloidosis 92 months. A significant increase of the monoclonal protein or development of myeloma, macroglobulinemia or amyloidosis occurred in 18 per cent of the patients with monoclonal immunoglobulin G(IgG), in 28 per cent with immunoglobulin A (IgA) and in 25 per cent with immunoglobulin M (IgM). Retrospective analysis of age, sex, presence of organomegaly, hemoglobin level, size and type of serum monoclonal protein peak, presence of small amounts monoclonal light chain in the urine, serum albumin level, levels of uninvolved immunoglobulins, IgG subclass and level of plasma cells in the bone marrow did not show how to distinguish initially between stable benign disease and progressive disease. Therefore, periodic reexamination of patients with monoclonal gammopathy is essential.     

Bullous amyloidosis in a hemodialysis patient is myeloma-associated rather than hemodialysis-associated amyloidosis.

We report a 78-year-old woman on hemodialysis who presented with refractory multiple pruritic vesicles and bullae on her trunk and extremities for 2 months. Histopathologic examination of skin biopsy specimen showed subepidermal bullae with many amyloid deposits in the papillary dermis. No evidence of systemic amyloidosis could be found on physical examination. While the initial clinical diagnosis was bullous pemphigoid, the histopathology and direct immunofluorescence result favored hemodialysis-associated amyloidosis. However, immunochemical study for beta(2)-microglobulin was negative. Further hematologic and immunologic work-up revealed the presence of multiple myeloma and that the deposit was AL amyloid. This is the first case of bullous amyloidosis in a hemodialysis patient and should remind dermatologists that bullous amyloidosis should be considered in addition to the usual presentation of porphyria cutanea tarda and pseudoporphyria for bullous dermatosis in the hemodialysis patient. We also suggest that hemodialysis-associated amyloidosis should not be taken for granted in the hemodialysis patient with cutaneous amyloidosis without systemic signs and symptoms. Further testing for other types of amyloid should be performed.     

CASE REPORT: Light Chain Deposition Disease of the Liver Without Renal Involvement in a Patient with Multiple Myeloma Related to Liver Failure and Rapid Fatal Outcome

We describe a 36-year-old man with advanced multiple myeloma (Salmon and Durie stage III) who developed jaundice and severe cholestasis after a first cure with systemic chemotherapy of vincristine, doxorubicin, and oral dexamethasone (VAD). Serology for hepatitis A, B, and C and for CMV was negative. A liver ultrasound and CT scan showed mild hepatomegaly without evidence of extrahepatic or intrahepatic biliary tree dilatation. A percutaneous liver biopsy revealed perisinusoidal deposits of an abundant slightly eosinophilic, PAS-positive amorphous substance. Immunohistochemistry showed positivity for kappa-light chains and was negative for lambda-light chains, for IgA, IgG, IgM, and IgD immunoglobulins as well as for AA and AL proteins and for amyloid P component. A diagnosis of light chain deposition disease (LCDD) of the liver was made. The patient developed rapid deterioration of liver function, leading to a multisystem dysfunction and death. The occurrence of LCDD in multiple myeloma is close to 5% and myeloma is the underlying disease in two thirds of patients with LCDD. The kidneys are involved in almost all cases of LCDD and renal dysfunction usually reveals the disease. Only three patients with LCDD of the liver without overt renal involvement have been reported so far. This is the first observation of LCDD presenting with jaundice and severe cholestasis shortly after the diagnosis of high tumor mass myeloma, without overt renal involvement, leading rapidly to the patient's death.