Transthyretin Amyloid Goiter in a Renal Allograft Recipient

Amyloid deposition in the follicular, perifollicular blood vessels, and thyroid stroma can occur in systemic forms of amyloidosis, although diffuse enlargement of the thyroid is generally not present. Marked, widespread enlargement of the thyroid gland with amyloid deposits or amyloid goiter is a rare condition reported in association with primary and secondary amyloidosis but has not been described in association with transthyretin amyloid deposition. Senile transthyretin amyloidosis is primarily associated with amyloid deposits in the heart, while the familial forms of amyloidosis due to transthyretin gene mutations are associated with deposits of amyloid in multiple tissues, classically giving rise to polyneuropathy. In this report, we describe the findings of parathyroid and lymph node amyloid deposits and amyloid goiter with transthyretin reactivity in a recipient of a kidney allograft, reportedly for renal amyloidosis, initially assumed clinically to be due to inflammatory bowel disease-related secondary amyloid deposition. This case underscores the importance of routine immunohistochemical classification of amyloid deposits for accurate diagnosis and to guide clinical management decisions.     

Amyloid goiter: the first evidence in secondary amyloidosis. Report of five cases and review of literature

Amyloid deposition in secondary amyloidosis frequently involves thyroid gland, but rarely is responsible of a goiter. Amyloid goiter in secondary amyloidosis is characterized by deposition of amyloid A protein (AA) in the gland, associated to atrophic follicles. We identified cases of amyloid goiter in the files of our department in the period from 1985 to 1998. Five cases of amyloid goiter with ingravescent symptomatology, characterized by dyspnea, dysphagia and hoarseness were selected. In four cases of five we observed predisposing conditions as, for example, tuberculosis, Crohn's disease, or rheumatoid arthritis. In all cases the symptoms relative to thyroid enlargement preceded or, anyway, predominated over other clinical evidence of systemic amyloidosis. In one case a symptomatology of systemic amyloidosis was not evident. We would like to underline that in all cases the immunoreactivity for amyloid A in the amorphous material present in the gland permitted the diagnosis of secondary amyloidosis even in the absence of systemic symptoms.     

The pattern of amyloid deposition in the lung

A review of routine histopathological samples and autopsies examined at the Department of Pathology, University of Malaya revealed 15 cases of amyloidosis of the lung. Two were localized depositions limited to the lung while in the remainder, lung involvement was part of the picture of systemic amyloidosis. Both cases of localized amyloidosis presented with symptomatic lung/bronchial masses and a clinical diagnosis of tumour. Histology revealed "amyloidomas" associated with heavy plasma cell and lymphocytic infiltration and the presence of multinucleated giant cells. In both cases, the amyloid deposits were immunopositive for lambda light chains and negative for kappa chains and AA protein. One was a known systemic lupus erythematosus patient with polyclonal hypergammaglobulinaemia. The other patient was found to have plasma cell dyscrasia with monoclonal IgG lambda gammopathy. Both patients did not develop systemic amyloidosis. In contrast, lung involvement in systemic AA amyloidosis was not obvious clinically or macroscopically but was histologically evident in 75% of cases subjected to autopsy. Amyloid was detected mainly in the walls of arterioles and small vessels, and along the alveolar septa. It was less frequently detected in the pleura, along the basement membrane of the bronchial epithelium and around bronchial glands. In one case of systemic AL amyloidosis associated with multiple myeloma, an "amyloidoma" occurred in the subpleural region reminiscent of localized amyloidosis. These cases pose questions on (1) whether localized "tumour-like" amyloidosis is a forme fruste of systemic AL amyloidosis and (2) the differing pattern of tissue deposition of different chemical types of amyloid fibrils, with the suggestion that light chain amyloid has a greater tendency to nodular deposition than AA amyloid.     

Clinicopathological importance of deposits of amyloid in the femoral head.

The pattern of amyloid deposits in the femoral head is described in four cases, two of which had deposits of amyloid related to age and two of which had generalised systemic amyloidosis (one of primary amyloidosis, one of multiple myeloma). The deposition of amyloid in the articular cartilage of the femoral head was similar in all four cases. Heavy deposits of synovial amyloid were identified in the case with primary amyloidosis and in one of the cases with amyloidosis related to age. Both cases of generalised systemic amyloidosis showed abundant deposits of amyloid in the bone marrow. Amyloid was not present in the bone marrow of either case with amyloidosis related to age. The importance of these findings is discussed in relation to the pathogenesis of the arthropathy syndrome of a rheumatoid type described in cases of primary amyloidosis and multiple myeloma.     

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.     

Splenic amyloidosis: correlations between chemical types of amyloid protein and morphological features

Sixty-one autopsy cases of splenic amyloidosis were reviewed to assess the relationship between the morphological patterns and chemical types of amyloid protein. On the basis of immunohistochemical reactions of amyloid protein, the cases were classified into 34 cases of AA and 27 of AL amyloidosis. Amyloid deposition in the spleen was divided into three major sites: the red pulp, the white pulp, and blood vessels. Red pulp involvement by amyloid was noted in 52% of the AL cases but in none of the AA cases. White pulp amyloid deposition was found in 70% of the AL and 35% of the AA cases. This difference was statistically significant (P less than 0.001). On the other hand, vascular deposition of amyloid was invariably noted in all cases with AA or AL amyloidosis, affecting the AA cases rather severely. These results strongly suggest that the widely held concept of deposition of amyloid as predominantly vascular in AL amyloidosis and parenchymal in AA amyloidosis requires revision. Our findings indicate that parenchymal, especially the red pulp, involvement is a consistent feature of AL amyloidosis, whereas vascular involvement is a finding common to both types of systemic amyloidosis.     

Classification of amyloid deposits in diagnostic cardiac specimens by immunofluorescence

BackgroundAt least 12 distinct forms of amyloidosis are known to involve the heart or great vessels. Patient treatment regimens require proper subtyping of amyloid deposits in small diagnostic cardiac specimens. A growing lack of confidence in immunohistochemical staining for subtyping amyloid has arisen primarily as a result of studies utilizing immunoperoxidase staining of formalin-fixed paraffin-embedded tissue. Immunofluorescence staining on fresh frozen tissue is generally considered superior to immunoperoxidase staining for subtyping amyloid; however, this technique has not previously been reported in a series of cardiac specimens.MethodsAmyloid deposits were subtyped in 17 cardiac specimens and 23 renal specimens using an immunofluorescence panel.ResultsAmyloid deposits were successfully subtyped as AL, AH, or AA amyloid by immunofluorescence in 82% of cardiac specimens and 87% of renal specimens. In all cases, the amyloid classification was in good agreement with available clinical and laboratory assessments. A cross-study analysis of 163 cases of AL amyloidosis reveals probable systemic misdiagnosis of cardiac AL amyloidosis by the immunoperoxidase technique, but not by the immunofluorescence technique.ConclusionsAmyloid deposits can be reliably subtyped in small diagnostic cardiac specimens using immunofluorescence. The practical aspects of implementing an immunofluorescence approach are compared with those of other approaches for subtyping amyloid in the clinical setting.     

Histopathological diagnosis of amyloidosis

For the diagnosis of amyloidosis, histological evidence of amyloid deposition is essential. Histologically, an amyloid deposit is stained orange red with Congo red and shows green birefringence under polarized light. When amyloidosis is clinically suspected, endoscopic biopsy of the stomach, duodenum or colon, or aspiration biopsy of abdominal fat is usually performed. If clinicians suspect amyloidosis, they should advise pathologists. Identification of the chemical type of amyloid is necessary with respect to treatment and prognosis. Immunohistochemical examination of amyloid in formalin-fixed, paraffin-embedded sections is simple to perform in most pathological laboratories. In Japan, almost all cases of systemic amyloidosis are classified as AL, AA, ATTR or Abeta2M amyloidosis, so the use of anti-immunoglobulin light chain, anti-amyloid A, anti-transthyretin and anti-beta2 microglobulin antibody is recommended for the classification of systemic amyloidosis. Formic acid pretreatment, which is often used for immunohistochemical detection of amyloidosis, is useful and easy for antigen retrieval. Amyloid deposits of AL amyloidosis are sometimes not immunostained well with commercial anti-immunoglobulin light chain antibody. Previously, we generated polyclonal antibodies against synthetic peptides corresponding to positions 118-134 of immunoglobulin lambda light chain and positions 116-133 of immunoglobulin kappa light chain. These antibodies are very useful for detecting AL amyloidosis because they react with amyloid deposits on formalin-fixed, paraffin-embedded specimens in almost all AL amyloidosis cases. Exact diagnosis and typing of amyloidosis are necessary for therapy.     

Immunohistochemical and immunochemical study of amyloid in liver affected by systemic Alambda amyloidosis with antibodies against three different regions of immunoglobulin lambda light chain

The purpose of the present paper was to investigate the heterogeneous nature of amyloid deposits in the liver, by immunohistochemical and immunochemical examination of liver samples from cases of immunoglobulin lambda light chain amyloidosis (Alambda amyloidosis) with antibodies generated against the peptides corresponding to the three different regions of the lambda light chain. Amyloid deposits in the hepatic artery tended to react better with anti-lambda(118-134) than with anti-lambda(159-175). Amyloid deposits in the space of Disse tended to react weakly or partially with anti-lambda(118-134) but well with anti-lambda(159-175). Amyloid deposits in the portal vein reacted relatively well with both antibodies. By western blotting of water-extracted amyloid in which amyloid deposits were not stained with anti-lambda(118-134) immunohistochemically, the three antibodies detected 27 kDa bands consistent with the full-length Ig lambda chain and some smaller bands. These findings indicate that amyloid deposits may not be homogeneous in the liver of AL amyloidosis, and that molecular heterogeneity of amyloid fibril protein or a difference in the mode of deposition results in the histopathological heterogeneity of AL amyloid deposits even within a single patient.     

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.     

Senile amyloid deposition

Amyloid deposition in the aged was studied in a wide selection of tissues from 194 necropsies of subjects aged over 65 years, there being no clinical manifestation of amyloidosis. We employed conventional Congo red staining with the aid of a polarising filter for the identification of amyloid. We analysed the deposits histochemically for tryptophan content and reaction to oxidation using the potassium permanganate method in 26 subjects aged over 85 years. Both the frequency of amyloid deposition and the number of organs involved tended to increase with advancing age, and both increased after the ninth decade with little sex difference. Amyloid deposition preferentially occurred in the aorta, heart, lung, prostate and pancreas among the organs examined. Visceral involvement tended to be confined to the vasculature except in the prostate and pancreas. In cases associated with predisposing conditions considered to evoke secondary amyloidosis such as tuberculosis, multiple myeloma, and rheumatoid arthritis more amyloid was found but the distribution of the deposits was similar by organ and intravisceral site to that of cases unassociated with predisposing disorders. In both groups of cases amyloid was found to contain tryptophan, indicative of immunoamyloid and, with a few exceptions, to be resistant to oxidation by potassium permanganate indicating an immunoglobulin AL component. It can be concluded that senile amyloid should be classified as a form of so-called primary amyloidosis because of its widespread distribution, its occurrence independent of predisposing disorders and its chemical composition. Subclinical chronic inflammation of the respiratory, gastrointestinal and urogenital tracts may provide the necessary prolonged immunological stimulus to lead to amyloid deposition in ageing tissues.     

Immunofluorescence study of "non-idiopathic" renal amyloidosis

The authors report the results of immunofluorescence (IF) studies of 17 cases of "non-idiopathic" renal biopsy-proven amyloidosis and 18 cases of various nephropathies and normal kidneys (as controls), investigated by IF by simultaneous use of antisera against routine IgG, IgM, IgA, C3, C4, Clq, beta-lipoprotein, albumin, and fibrinogen. Antisera against kappa and lambda light chains and amyloid A and amyloid P components were also used. Six of the 17 cases of amyloidosis were associated with immunocyte dyscrasia, and 11 were cases of reactive systemic amyloidosis associated with chronic infections or inflammatory and neoplastic disorders. In amyloidosis, IF deposits appeared for all antisera as homogeneous staining of mesangial nodules, and, more rarely, there was staining along the glomerular basement membranes. Overall immunoglobulins and C3 were present in 11 cases (64 per cent). Kappa and lambda light chains were demonstrated in 14 (82 per cent) and 12 (70 per cent) cases, respectively. In immunocyte dyscrasia associated with amyloidosis, immunoglobulin and light-chain deposits corresponding to a paraprotein abnormality were demonstrated in glomeruli and in tubular casts. Amyloid P component was always present in glomeruli with a bright and characteristic fluorescence, and it was frequently observed in arterioles. Amyloid A component was observed in six cases of reactive systemic amyloidosis but also in one case of immunocyte dyscrasia with amyloidosis. In view of the diversity of amyloid fibril types and their chemical nature, IF studies confirm the presence of different constituents but do not warrant any conclusion concerning the pathogenesis of this disease.     

Demonstration of amyloid A (AA) protein and amyloid P component (AP) in deposits of systemic amyloidosis associated with renal adenocarcinoma

The fibril protein in three cases of systemic amyloidosis associated with renal adenocarcinoma was identified as amyloid A protein (AA) using immunohistochemical staining techniques. Amyloid P component was also present in all deposits. In one case unfixed snap frozen tissues were studied directly whilst in the other two, which were investigated retrospectively, fixed paraffin sections were stained by immuno-fluorescence and immunoperoxidase methods after treatment with trypsin. Enzymatic digestion was necessary to restore reactivity with anti-AP but anti-AA reacted well without any such treatment. These findings establish that renal carcinoma, the carcinoma most frequently associated with systemic amyloidosis, causes the same type of secondary or reactive systemic amyloid as chronic infections and inflammatory disorders.     

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.     

Cerebrovascular involvement in systemic AA and AL amyloidosis: a clear haematogenic pattern

 Amyloid deposits in cerebral vessels are common in β-amyloid diseases (Alzheimer’s disease, congophilic amyloid angiopathy, Down’s syndrome and hereditary cerebral amyloidosis with haemorrhage of the Dutch type). We report of 20 autopsies on patients who had died with systemic amyloidosis of the AA, Aλ and Aκ types: the brains were examined for the occurrence of amyloid. Vascular amyloid was detected in choroid plexus (in 17 of 20 cases), infundibulum (5 of 8), area postrema (6 of 11), pineal body (3 of 7) and subfornical organ (2 of 3), but not in cortical and leptomeningeal vessels. Immunohistochemical classification of the cerebral amyloid and the systemic amyloid syndrome showed identity proving the same origin of both. The distribution is indicative of a haematogenic pattern of amyloid deposition in systemic amyloidosis and is different from that in Alzheimer’s, prion, ATTR and cystatin C diseases. It corresponds to areas of the brain with a ”leaky” blood–brain barrier. Additionally, all the cases with AA amyloidosis exhibited an Aβ coreactivity in choroid plexus vessels. In one exceptional case, Aβ reactivity of AA amyloid also occurred outside of the brain. Received: 2 November 1998 / Accepted: 25 January 1999     

Disease-associated prion protein is not detectable in human systemic amyloid deposits

Cerebral and cardiac amyloid deposits have been reported after scrapie infection in transgenic mice expressing variant prion protein (PrP(C)) lacking the glycophosphatidylinositol anchor. The amyloid fibril protein in the systemic amyloid deposits was not characterized, and there is no clinical or pathological association between prion diseases and systemic amyloidosis in humans. Nevertheless, in view of the potential clinical significance of these murine observations, we tested both human amyloidotic tissues and isolated amyloid fibrils for the presence of PrP(Sc), the prion protein conformation associated with transmissible spongiform encephalopathy (TSE). We also sequenced the complete prion protein gene, PRNP, in amyloidosis patients. No specific immunohistochemical staining for PrP(Sc) was obtained in the amyloidotic cardiac and other visceral tissues of patients with different types of systemic amyloidosis. No protease-resistant prion protein, PrP(res), was detectable by Western blotting of amyloid fibrils isolated from cardiac and other systemic amyloid deposits. Only the complete normal wild-type PRNP gene sequence was identified, including the usual distribution of codon 129 polymorphisms. These reassuringly negative results do not support the idea that there is any relationship of prions or TSE with human systemic amyloidosis, including cardiac amyloid deposition.     

Diagnosis and immunohistochemical classification of systemic amyloidoses

 Fourty-three cases of systemic amyloidosis were identified in an unselected autopsy series from our institute (6305 autopsies between 1979 and 1993) and classified immunohistochemically by means of a panel of antisera directed against five major amyloid fibril proteins. Amyloid A (AA) amyloidosis was the most common type, being found in 21 cases (48.8%). Transthyretin-derived (ATTR) amyloidosis was present in 11 cases (25.6%), and immunoglobulin light chain-derived (AL) amyloidosis in 10 cases (23.3%). A single case (2.3%) contained deposits of more than one type of systemic amyloid. AA amyoloidosis was associated with chronic inflammatory or infectious diseases (81%), malignant tumours (19%) or both (9.5%). Immunoglobulin light chain-derived amyloidoses were associated with myeloma (50%) or primary (idiopathic; 50%). In AA and AL amyloidosis the kidney was the organ most frequently involved. ATTR amyloid affecting mostly the heart and lungs presented as senile systemic amyloidosis. Systemic amyloidosis was the cause of death in 5 cases (12%) and caused symptoms in 17 cases (39%). Our results suggest that most cases can be classified by using a panel of sensitive and specific antibodies against five major amyloid fibril proteins. This technique may make amyloid type-specific therapy possible for AL amyloid patients who do not have evidence of an underlying plasma cell dyscrasia. Received: 9 December 1997 / Accepted: 2 February 1998     

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.