Amyloid deposition in primary pulmonary marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue

A rare association between primary pulmonary marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), and pulmonary immunoglobulin light chain (AL) amyloidosis is described in a 65-year-old woman suffering from rheumatoid arthritis (RA). All four nodules in the resected upper lobe of the lung had a similar histological appearance. They were composed of small-medium-sized atypical lymphocytes. Centrocyte-like cells had lymphoepithelial lesions. Immunohistochemically, the tumor cells clonally expressed B-cell markers, and demonstrated clonal rearrangement of the immunoglobulin heavy chain gene on polymerase chain reaction. Based on these findings the diagnosis of primary pulmonary MALT lymphoma was made. In addition, uniform eosinophilic material deposition was identified randomly within the tumor. It was Congophilic and exhibited apple-green birefringence on polarizing microscopy, and remained unaffected by potassium permanganate digestion. Deposited material was immunoreactive to lambda light chain. It was concluded that this material was AL amyloid in primary pulmonary MALT lymphoma. Plasma cells with mRNA of lambda chain was found infiltrated along the border of amyloid deposition. Finally, it is speculated that primary pulmonary MALT lymphoma developing in an autoimmune setting, RA in the present case, is associated with overproduction and abnormal clearance of immunoglobulin by the tumor cells, resulting in AL amyloidosis within the tumor.     

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue with amyloid deposition: a clinicopathologic case series

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma is a mature B-cell neoplasm that typically follows an indolent clinical course. Amyloid deposition associated with MALT lymphoma is uncommon. We describe the clinical and pathologic features of 20 cases of MALT lymphoma and associated amyloid deposition across diverse primary sites. Frozen section immunofluorescence performed on 4 cases suggests that these deposits are a localized form of AL amyloid. Clinical follow-up was available for 15 patients. Amyloid deposits distant from the initial site occurred in 5 cases, always at sites also involved by the underlying lymphoma. No definitive evidence of systemic amyloidosis affecting the heart, kidneys, or liver was present in any patient. Given the generally indolent clinical behavior of MALT lymphomas with associated amyloid, we do not recommend extensive follow-up testing for systemic amyloidosis or more aggressive therapy than would be indicated for other MALT lymphomas of similar clinical stage.     

Amyloid localized to tenosynovium at carpal tunnel release. Natural history of 124 cases

One hundred fifty-two patients with amyloid in the tenosynovium who had carpal tunnel release were identified. Twenty-eight patients were excluded because of systemic amyloidosis: primary systemic amyloidosis (AL) in 24, secondary amyloidosis (AA) in 3, and familial amyloidosis (AF) in 1. The remaining 124 patients (82%) had carpal tunnel syndrome with local deposition of amyloid and no evidence of systemic amyloidosis. Median survival of the 124 patients from diagnosis of amyloidosis was 12 years. Only two patients had systemic amyloidosis develop--9 and 10 years after recognition of tenosynovial amyloid. Of particular interest were 12 patients who had an M-protein in the serum or urine. None of the 12 patients have had evidence of systemic amyloidosis or multiple myeloma during the median follow-up of 14 years. The authors conclude that amyloid may be localized to the tenosynovium and that systemic amyloidosis rarely develops during long-term follow-up.     

Bone marrow findings correlate with clinical outcome in systemic AL amyloidosis patients

AIMS: Bone marrow sampling is a key investigation in the work-up of amyloid light chain (AL) amyloidosis, but the relationship between bone marrow findings and the varied phenotype and clinical outcome of AL amyloidosis is unclear. The aim was to determine if bone marrow pathological parameters at diagnosis were related to clinical behaviour in AL amyloidosis patients. METHODS AND RESULTS: Bone marrow findings, clinical features and outcome of 80 patients referred with a diagnosis of systemic AL amyloidosis were evaluated; six patients were subsequently excluded due to re-categorization as other forms of amyloidosis. At latest follow-up (median 66 months), 11 of the 18 patients with no identifiable bone marrow neoplastic cells (61%) versus only seven of the 56 patients with neoplastic plasma cells or non-Hodgkin's lymphoma (13%) were alive (P = 0.0046). However, neither the quantity of the neoplastic cells nor the serum light chain levels were correlated with amyloid burden or patient survival. CONCLUSIONS: Identification of a neoplastic population in the bone marrow of AL amyloidosis patients by histology and immunohistochemistry correlates with poor outcome; however, the neoplastic cell burden is not prognostically significant, suggesting that additional factors are important in determining disease behaviour in AL amyloidosis.     

Amyloid-like pulmonary nodules, including localized light-chain deposition: clinicopathologic analysis of three cases

Amyloid-like pulmonary nodules have been described in patients with systemic light-chain deposition disease, but their significance in other clinical contexts is unknown. We examined biopsy specimens of amyloid-like pulmonary nodules from 3 women without systemic light-chain deposition disease. Patient 1 (aged 62 years) had multiple pulmonary nodules and underwent 2 separate lung biopsies, the first showing nodules composed of kappa light-chain deposits accompanied by low-grade lymphoplasmacytic lymphoma limited to the lung and the second, obtained after chemotherapy 9 months later, showing only residual nodules without persistent lymphoma. Patients 2 (aged 65 years) and 3 (aged 69 years) had asymptomatic solitary pulmonary nodules. In all cases, electron microscopic examination showed dense granular extracellular deposits without the fibrillary characteristics of amyloid. Amyloid-like nodules should be distinguished from nodular amyloidosis and, in some patients, might represent a localized form of light-chain deposition.     

Cytologic findings and differential diagnoses of primary thyroid MALT lymphoma with striking plasma cell differentiation and amyloid deposition

We report two cases of thyroid mucosa‐associated lymphoid tissue (MALT) lymphoma with associated amyloid protein deposition. While other primary thyroid neoplasms sush as medullary carcinoma and plasmacytoma with associated amyloid protein are known to occur and have been previously described by fine‐needle aspiration cytology (FNAC), to our knowledge, the current cases are the first of thyroid MALT lymphoma with amyloid deposition to be detailed in the cytopathology literature. Case 1 was a 73‐year‐old female with chronic thyroiditis. FNAC suspected MALT lymphoma. The amyloid material was not noticed, nevertheless it existed. Case 2 was a 71‐year‐old female with a nodule of the thyroid. Malignant lymphoma and medullary carcinoma were suspected by FNAC. The possibility of medullary carcinoma was excluded by a measurement of serum calcitonin and carcinoembryonic antigen. After follow‐up for two years, the nodule was diagnosed as MALT lymphoma associated with plasma cell differentiation and amyloidosis by the fourth FNAC. When we encounter small round cell tumors associated with amyloid in thyroid FNAC, we should consider not only medullary carcinoma but also MALT lymphoma. Diagn. Cytopathol. 2014;42:73–77. © 2013 Wiley Periodicals, Inc.     

Analysis of the TTR gene in the investigation of amyloidosis: A 25‐year single UK center experience

Transthyretin amyloidosis (ATTR) is caused by deposition of either wild‐type (ATTRwt) or variant (ATTRm) transthyretin. ATTRwt presents with restrictive cardiomyopathy, while ATTRm displays a range of organ involvement. This retrospective analysis includes all patients referred to a single UK center in the last 25 years for clinical and laboratory assessment of known or suspected amyloidosis who underwent TTR gene sequencing. A total of 4459 patients were included in this study; 37% had final diagnosis of ATTR amyloidosis; 27% light chain amyloidosis; 0.7% other types of amyloidosis; 21.3% had no amyloid and 14% had no data. TTR variants were found in 770 (17%) cases; the most prevalent were p.V142I, p.T80A, and p.V50M identified in 42, 25, and 16%, respectively. The median age at referral in each group was: 76 (range 47–93), 66 (40–81), and 45 years (21–86), respectively. Overall 42 rare or novel variants were identified. Forty‐two percent patients with ATTRm died at a median age of 73 years (33–89) with a median survival from diagnosis of 50 months. ATTRwt was the final diagnosis in 20% of patients undergoing genetic testing. Our findings of TTR variants in 17% of screened patients highlight the need for routine genetic testing in the evaluation of suspected ATTR amyloidosis.     

Evaluation of systemic amyloidosis by scintigraphy with 123I-labeled serum amyloid P component

BACKGROUND. In systemic amyloidosis the distribution and progression of disease have been difficult to monitor, because they can be demonstrated only by biopsy. Serum amyloid P component (SAP) is a normal circulating plasma protein that is deposited on amyloid fibrils because of its specific binding affinity for them. We investigated whether labeled SAP could be used to locate amyloid deposits. METHODS. Purified human SAP labeled with iodine-123 was given intravenously to 50 patients with biopsy-proved systemic amyloidosis--25 with the AL (primary) type and 25 with the AA (secondary) type--and to 26 control patients with disease and 10 healthy subjects. Whole-body images and regional views were obtained after 24 hours and read in a blinded fashion. RESULTS. In the patients with amyloidosis the 123I-SAP was localized rapidly and specifically in amyloid deposits. The scintigraphic images obtained were characteristic and appeared to identify the extent of amyloid deposition in all 50 patients. There was no uptake of the 123I-SAP by the control patients and the healthy subjects. In all patients with AA amyloidosis the spleen was affected, whereas the scans showed uptake in the heart, skin, carpal region, and bone marrow only in patients with the AL type. Positive images were seen in six patients in whom biopsies had been negative or unsuccessful; in all six, amyloid was subsequently found on biopsy or at autopsy. Progressive amyloid deposition was observed in 9 of 11 patients studied serially. CONCLUSIONS. Scintigraphy after the injection of 123I-SAP can be used for diagnosing, locating, and monitoring the extent of systemic amyloidosis.     

Deposition of amyloid proteins in the epicardial coronary arteries of 58 patients with primary systemic amyloidosis.

INTRODUCTION: We sought to determine the distribution and the effect of amyloid on epicardial coronary arteries in patients with primary cardiac amyloidosis. METHODS: We reviewed pathologic specimens taken after autopsy or cardiac transplantation from 58 patients with primary cardiac amyloidosis. Patients were seen from 1981 to 2000. Multiple sections of epicardial coronary arteries (left anterior descending artery, left circumflex artery, and right coronary artery) were examined to determine the degree of amyloid deposition in the intima, media, adventitia, and vasa vasorum (vasa vasorum are nutrient arteries for the coronary arteries themselves). RESULTS: In 56 of 58 patients (97%), amyloid was present in epicardial coronary arteries. Amyloid was identified in all artery layers (intima, media, and adventitia), and more patients had amyloid in the adventitia. However, amyloid did not cause intraluminal obstruction of epicardial coronary arteries in any patient. The vasa vasorum had considerable deposits and, in many patients, were obstructed by amyloid. Patients with obstruction of the vasa vasorum were significantly more likely to have obstructive intramural coronary amyloidosis than patients without vasa vasorum obstruction (P=.002). CONCLUSIONS: The epicardial coronary arteries of patients with primary cardiac amyloidosis had extensive amyloid deposition. This deposition, however, did not lead to obstruction of epicardial coronary arteries and therefore did not contribute to ischemic syndromes observed in these patients. Obstruction of the vasa vasorum was associated with obstructive intramural coronary amyloidosis.     

Marginal zone B-cell lymphoma of MALT in small intestine associated with amyloidosis: a rare association

A 62-yr-old man presented with a 5-yr history of intermittent abdominal distention and pain. These symptoms persisted for several months and subsided without treatment. A diagnosis of suspected small bowel lymphoma was made based on plain radiograph and computerized tomogram findings, and he was referred to our institution for further evaluation. Segmental resection of the small intestine was performed and the diagnosis of marginal zone B-cell lymphoma associated with amyloidosis was made. This is the first case of marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) in the small intestine associated with amyloidosis in Korea.     

Light chain amyloidosis of the urinary bladder. A site restricted deposition of an externally produced immunoglobulin

AIMS:To identify the amyloid protein in a patient with amyloidosis localised to the urinary bladder, and to see whether subtyping of the protein by sequence analysis increases the understanding of the selection of the urinary bladder as the site of amyloid deposition. METHODS:A patient with gross haematuria and a congophilic mass in his urinary bladder was evaluated further. Characterisation of the amyloid protein was performed using conventional histological and immunohistochemical methods. Determination of the N-terminal amino acid sequence of the amyloid protein was performed using protein sequencers. RESULTS:The patient's history, physical examination, and laboratory evaluation excluded the involvement of other organs, justifying a diagnosis of amyloidosis localised to the urinary bladder. Histological and immunological studies showed that the amyloid protein deposited in the urinary bladder of the patient was probably of the amyloid light chain type. No plasma cells or lymphocytes were seen in sections of the urinary bladder and lower ureter adjacent to the amyloid deposits. Molecular analysis showed the sequence NFMLTQPHSISGSPG, which assigned the amyloid protein to either the Vlambda(I) or the Vlambda(VI) immunoglobulin (Ig) light chain families. CONCLUSIONS:The findings suggest that the amyloid protein in this patient originated outside the urinary bladder. The heterogeneity of the Ig proteins in known cases of amyloidosis of the lower urinary tract suggests that the amino acid residues, which determine the Vlambda subtyping, have no major role in restricting the deposited protein to the urinary bladder.     

Peripheral T-cell lymphoma mimicking marginal zone B-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) may assume a variety of histologic and cytologic appearances. We describe eight cases of PTCL morphologically simulating marginal zone B-cell lymphoma. We reviewed PTCL cases diagnosed in our institution between 1990 and 2000 and selected eight cases for study based on the following criteria: small-cell morphology with abundant, clear cytoplasm and either marginal zone involvement by the neoplastic infiltrate in lymph node biopsies or lymphoepithelial lesions in extranodal biopsies. Histologic features and ancillary studies were reviewed. Patients included six women and two men with a median age of 53 years (range, 35 to 74 years). Six patients were diagnosed with primary nodal PTCL, and two presented with primary extranodal disease. The original diagnosis was PTCL in only four cases; three cases were diagnosed as atypical lymphoid infiltrate, and one case as benign lymphoepithelial lesion. Lymph node biopsies revealed partial effacement of the architecture with residual follicles surrounded by the neoplastic small cells. Extranodal sites included hard palate, tongue, tonsil, and submandibular glands; all but one case demonstrated lymphoepithelial lesions. Monoclonality was demonstrated in six of eight cases (rearrangement of T-cell receptor gene), and three of eight had an aberrant T-cell population by flow cytometry. The differential diagnosis of atypical lymphoid infiltrates with morphologic features of marginal zone B-cell lymphoma should include PTCL. This uncommon morphological mimicry should be recognized, because PTCL is an aggressive disease regardless of morphology and should be treated accordingly.     

The role of fibronectin in the development of experimental amyloidosis. Evidence of immunohistochemical codistribution and binding property with serum amyloid protein A.

Azocasein-induced amyloid A (AA) amyloidosis in CBA/K1Jms mice was investigated to elucidate a preference of serum amyloid A (SAA) deposition in the spleen. By indirect immunofluorescence using anti-SAA/AA antibodies the initial deposition of SAA/AA was recognized in the marginal zone of spleen at 20 days after azocasein injection. Indirect immunofluorescence using anti-fibronectin antibodies also showed meshwork positivity in the corresponding area more intensely than that in controls. Immunoelectron microscopy using anti-SAA/AA revealed the presence of positively stained flocculent materials on cell surfaces of macrophages in the marginal area in addition to amyloid fibril. The tissue fibronectin rapidly increased in the spleen and maintained 10 times more than that of controls until the 20th day. Binding assay of SAA on frozen sections revealed the presence of SAA-binding substances in the perifollicular area. Affinity chromatographic assay showed fibronectin have a binding capacity to SAA1 and SAA2. By binding assay on the microtiter plate, SAA had more affinity to fibronectin than those of heparan sulfate, collagen type I, or serum amyloid P component. These results indicate that fibronectin plays an important role in the development of amyloidosis by working as a linking protein between SAA and the cell surface of macrophages.     

Primary local orbital amyloidosis: biochemical identification of the immunoglobulin light chain kappaIII subtype in a small formalin fixed, paraffin wax embedded tissue sample

BACKGROUND: Amyloidosis refers to a heterogeneous group of disorders associated with the deposition of chemically distinct amyloid fibril proteins. Precise determination of chemical amyloid type has diagnostic, therapeutic, and prognostic relevance. Although immunohistochemical techniques are used routinely to determine the amyloid type, the results can be negative or inconclusive, so that biochemical characterisation is often required. The development and application of new biochemical microtechniques suitable for examination of extremely small tissue samples is essential for precise identification of the deposited amyloid proteins. AIMS: To investigate biochemically the amyloid proteins present in a formalin fixed paraffin wax embedded orbital tissue from a patient with localised orbital amyloidosis in whom immunohistochemistry was not helpful in the determination of amyloid type. METHODS: Extraction of amyloid proteins from fixed tissue and their identification was carried out by a recently developed microtechnique. An extremely small tissue sample was dewaxed and extracted with formic acid. The extracted material was analysed using electrophoresis, western blotting, and amino acid sequencing.RESULTS: Biochemical examination of the extracted proteins showed the presence of immunoglobulin (Ig) derived amyloid proteins, which were composed of the N-terminal fragments of the Ig light chain kappaIII subtype (AL-kappaIII) (16, 8, and 3 kDa). CONCLUSIONS: This is the first chemically proved AL case reported in association with primary localised orbital amyloidosis. The biochemical microtechnique used was useful in achieving a precise diagnosis of amyloid disease, in a case where the results of routine immunohistochemical examination of amyloid were inconclusive.     

Beta 2-microglobulin amyloidosis in hemodialysis patients. An autopsy study of intervertebral disks and posterior longitudinal ligaments

Ninety-five autopsy cases of chronic renal failure, which had or had not been treated by hemodialysis, were examined histologically and immunohistochemically for evidence of amyloid deposition in the intervertebral disks and posterior longitudinal ligaments of the spine. beta 2-Microglobulin (beta 2M) amyloid was not present in non-dialyzed patients with chronic renal failure. In cases showing beta 2M amyloid deposition, the shortest term of hemodialysis was 2 years and 5 months. The incidence of beta 2M amyloidosis tended to increase as the dialysis period was prolonged. An inverse correlation was present between dialysis period and age in 22 cases showing beta 2M amyloid deposition (correlation coefficient: -0.43, p less than 0.05), and beta 2M amyloidosis tended to occur earlier in elderly patients than in younger patients. This suggests that elderly patients are more susceptible to beta 2M amyloidosis. beta 2M amyloid was absent in all of 8 cases of systemic lupus erythematosus which were treated by dialysis for periods ranging from 2 days to 12 years. In these patients, beta 2M amyloidosis may have been prevented by steroids, which had been administered for long periods in all cases. Another amyloid of unknown composition was also frequently present in the intervertebral disks and posterior longitudinal ligaments not only in patients with chronic renal failure but also control patients without chronic renal failure. This amyloid was immunohistologically negative for beta 2M, amyloid A protein, light chain kappa or lambda, prealbumin, and apolipoprotein A-II.     

Amyloid localized to tenosynovium at carpal tunnel release. Immunohistochemical identification of amyloid type.

Thirty-five patients seen at the Mayo Clinic from 1968 to 1977 who had carpal tunnel syndrome and local deposition of amyloid without evidence of systemic amyloidosis were identified. The unlabeled immunoperoxidase method was used with antisera against purified amyloid proteins of the AA, A kappa, A lambda, AF/ASC1 (prealbumin) (transthyretin), and AB (beta 2-microglobulin) types. In 33 of the 35 patients, amyloid stained with antisera to transthyretin; in the remaining 2 patients, the amyloid did not stain with any antisera. Nine of the 35 patients had a monoclonal protein in the serum, and 2 had a monoclonal light chain in the urine. Systemic amyloidosis or multiple myeloma did not develop in any of these 11 patients. During follow-up, systemic amyloidosis developed in only 2 of the 35 patients: 1 had senile systemic amyloidosis and 1 had tissue that was inadequate for immunohistochemical staining. Amyloid localized to the tenosynovium consists of transthyretin, and systemic amyloidosis rarely develops.     

Pulmonary vascular amyloid causing pulmonary hypertension: Report of a case and review of literature

Although amyloid may deposit in the lungs, it is rare for pulmonary vascular involvement to cause appreciable luminal obstruction. To our knowledge, only three well-documented cases of pulmonary hypertension caused by amyloidosis have been reported. We describe pulmonary hypertension in a 54-year-old woman with primary (amyloid light chain; AL) amyloidosis. Although myocardial deposition of amyloid had produced restrictive hemodynamics, the diffuse and severely obstructive nature of pulmonary vascular involvement was considered to be of greater importance in the production of pulmonary hypertension in this patient. Amyloid-associated pulmonary hypertension may be associated with an insidious clinical presentation and contribute to morbidity and mortality.     

Histomorphometric analysis of intramyocardial vessels in primary and senile amyloidosis: epicardium versus endocardium.

BACKGROUND: The literature is unclear as to the frequency and degree of vascular involvement among the various types of cardiac amyloidosis, specifically the senile type. METHODS: We analyzed the intramyocardial vascular involvement, both qualitatively and quantitatively, in 18 patients with autopsy-proven cardiac amyloidosis [11 with primary amyloidosis (AL) and 7 with senile systemic amyloidosis (SSA)]. RESULTS: AL patients (10/11) showed focally transmural vascular involvement by amyloid with thickening of the wall and impingement on the lumens. In SSA patients (6/7), the amyloid deposition was concentrated largely in the adventitia and external media. Histomorphometric analysis revealed that all patients with AL, SSA, and heart failure without amyloidosis had greater luminal areas than normal controls. In addition, the median of the ratio of subendocardial to subepicardial vascular luminal areas was 0.59 in AL patients, 1.17 in SSA patients, 0.94 in heart failure without amyloidosis patients, and 0.89 in normal controls (P=.034). CONCLUSIONS: This study shows that the degree of vascular involvement and wall thickening with subsequent impingement on the lumen is much greater in AL than in SSA. All patients with heart failure, with and without amyloidosis, displayed greater luminal areas than normal controls. Moreover, a twofold dilatation of the vessels in the subepicardium compared to those in the subendocardium was noted only in patients with AL. This may be due to transmural vascular involvement by amyloid in these patients, which concomitantly decreases the transmural ventricular perfusion pressure, leading to compensatory expansion of the subepicardial vessels.     

Transmission of mouse senile amyloidosis

SUMMARY: In mouse senile amyloidosis, apolipoprotein A-II polymerizes into amyloid fibrils (AApoAII) and deposits systemically. Peripheral injection of AApoAII fibrils into young mice induces systemic amyloidosis (Higuchi et al, 1998). We isolated AApoAII amyloid fibrils from the livers of old R1.P1-Apoa2(c) mice and injected them with feeding needles into the stomachs of young R1.P1-Apoa2(c) mice for 5 consecutive days. After 2 months, all mice had AApoAII deposits in the lamina propria of the small intestine. Amyloid deposition extended to the tongue, stomach, heart, and liver at 3 and 4 months after feeding. AApoAII suspended in drinking water also induced amyloidosis. Amyloid deposition was induced in young mice reared in the same cage for 3 months with old mice who had severe amyloidosis. Detection of AApoAII in feces of old mice and induction of amyloidosis by the injection of an amyloid fraction of feces suggested the propagation of amyloidosis by eating feces. Here, we substantiate the transmissibility of AApoAII amyloidosis and present a possible pathogenesis of amyloidosis, ie, oral transmission of amyloid fibril conformation, where we assert that exogenous amyloid fibrils act as templates and change the conformation of endogenous amyloid protein to polymerize into amyloid fibrils.     

AA-type amyloidosis associated with non-Hodgkin's lymphoma: a case report

Amyloid-associated protein (AA)-type systemic amyloidosis has been referred to as secondary amyloidosis because it is secondary to an associated inflammatory condition. It is extremely rare in patients with non-Hodgkin's lymphoma (NHL). Here we report an autopsy case of follicular small cleaved cell lymphoma with focal large B-cell lymphoma transformation in association with systemic AA-type amyloidosis. Formalin-fixed, paraffin-embedded tissues from autopsy and the patient's previous surgical specimen were studied by Congo red stain; electron microscopy; and immunostaining with antibodies against AA protein, P component, and kappa and lambda light chains. There was a marked AA amyloid deposition in the glomeruli of both kidneys, the retroperitoneal lymphoma mass, the blood vessels, the adrenal glands, and the adipose tissues. The patient's previous surgical specimens were negative for amyloid. We propose that this patient's systemic AA-type amyloidosis developed along the course of his NHL.