Amyloidosis of the breast

We report on three cases of amyloidosis of the breast, two of which coincided with breast cancer. Patient no. 1, a 60-year-old woman, presented with two mass lesions measuring 2 cm in diameter, one in each breast. Histologically, a tubulo-lobular carcinoma was found in the left breast accompanied by vascular, interstitial, and periductal amyloid deposits; the lesion in the right breast consisted of amyloid deposits only. Patient no. 2, an 86-year-old woman, presented with an ulcerated breast tumor measuring 5 cm in diameter on the left side. A poorly differentiated invasive ductal carcinoma was found in the mastectomy specimen, and it coincided with interstitial and vascular amyloid deposits. In both patients, tumor cells had invaded the amyloid deposits. Patient no. 3, a 73-year-old woman, presented with a mass measuring 5 x 3 x 3 cm in her left breast. Fibrocystic changes, as well as interstitial and periductal amyloid deposits, were found histologically. In each case electron microscopy showed rigid, non-branching fibrils of indefinite length and measuring 10-12 nm in diameter; these were consistent with amyloid fibrils. Clinical data, immunohistochemistry, and/or amino acid sequencing of the fibril proteins extracted from formalin-fixed and paraffin-embedded tissue specimens provided evidence that the amyloid deposits were of immunoglobulin light chain origin in all three cases. A review of the literature revealed that kappa-light chain has been described more frequently than lambda-light chain in the breast and that there are no specific clinical or radiological symptoms of amyloidosis affecting the breast; a diagnosis can be achieved only by histology.     

Elastosis in breast carcinoma: I. Immunohistochemical characterization of elastic fibres

Elastosis associated with invasive ductal and lobular carcinomas of the breast was examined by tinctorial and immunohistochemical staining methods, enzyme digestion, and electron microscopy. The elastotic material exhibited the tinctorial staining properties of elastic fibres, and the ultrastructural appearances were those of elastic fibres although there was a higher proportion of microfibrils than in normal mature elastic fibres. The elastosis was immunostained by antisera to human fetal elastin, lysozyme and amyloid P component, as in other sites where elastic fibres are found. These findings indicate that immunohistochemically intact elastic fibres are present in the elastosis of breast cancer. They also demonstrate that lysozyme and amyloid P component are co-distributed with elastic fibres in elastosis of breast carcinoma, as distinct components with different susceptibilities to enzyme digestion. The cellular origin of elastosis in breast carcinoma remains uncertain.     

Localized primary amyloid tumor associated with osseous metaplasia presenting as bilateral breast masses: Cytologic and radiologic features

This report details the cytologic features of primary localized amyloid tumor of the breast presenting as bilateral breast masses in a 72-yr-old woman. Clinically and radiographically, the masses simulated metastatic or multifocal carcinoma. Fine-needle aspiration revealed irregular globules of acellular amorphous material and numerous multinucleated giant cells resembling granulomatous inflammation. Histology confirmed amyloid tumors with a foreign-body giant cell reaction in response to amyloid and foci of osseous metaplasia. Subsequent clinical workup included a serum electrophoresis and immunofixation which showed a small IgG k monoclonal protein. Urine immunofixation was negative for Bence Jones protein. Bone marrow examination revealed no evidence of a plasma cell dyscrasia. To date the patient has not developed clinical or laboratory evidence of systemic amyloidosis or multiple myeloma. Amyloidosis involving the breast and specifically localized primary amyloid tumors of the breast are rare and infrequently reported entities. To our knowledge, osseous metaplasia within isolated primary amyloid tumors of the breast has not been reported. We present this unusual case to illustrate the intratumoral calcification patterns mimicking carcinoma and to characterize the cytologic features. Emphasis is placed on the inclusion of amyloidosis in the differential diagnosis of breast masses.     

Primary amyloid tumour of the breast: a case report

A case of primary amyloid tumour of the breast is reported with a brief review of the literature. The tumour was mammographically suspicious of carcinoma. Fine needle aspiration cytology yielded clumps of amorphous material surrounded by giant cells and lymphocytes. Subsequent histology showed nodular amyloid associated with osseous metaplasia and giant cell reaction. There are 13 cases of amyloid tumour of the breast reported in the literature and in four of these fine needle aspiration had been undertaken.     

Primary localized amyloid tumor of the breast with osseous metaplasia

A case of primary localized amyloid tumor of the breast is described. It Is an extremely rare condition and has not been seen in literature in Japan. A 76-year-old woman visited a hospital because of a painless, hard mass of the right breast. A relatively well demarcated, calcified mass was excised under clinical diagnosis of fibroadenoma. Histologically, massive eoslnophilic amorphous material was deposited in breast stroma. It was stained red-orange by Congo red and displayed apple-green birefringence under polarized light. The staining persisted after incubation with KMnO₄ and immunolabeling by immunoglobulin x-light chain antlserum, consistent with the amyloid of AL (Ax) type. Osseous metaplasia with bone marrow cavity, foreign body type giant cells in response to amyloid, and scattered plasma cell infiltration were also recognized. Osseous metaplasia in the breast amyloid tumor has been reported in only one case before. To date, the patient has not developed any clinical or laboratory evidence of systemic amyloidosis or multiple myeloma.     

Invasive breast carcinoma with granulomatous response and deposition of unusual amyloid.

AIMS: To report an unusual case of invasive breast ductal carcinoma associated with non-caseating epithelioid granuloma and unusual deposition of amyloid. METHODS: Formalin fixed, paraffin wax embedded tissue from breast and lymph nodes were stained with a variety of methods. Representative tissue fragments were sampled and fixed in 2.5% buffered glutaraldehyde, postfixed in 1% osmium tetroxide, dehydrated and embedded in Araldite. Thin sections were viewed under a Phillips 400T transmission electron microscope. RESULTS: Multinucleated giant Langhans' cells were found in the granulomatas tissue in both breast carcinoma and metastatic axillary lymph node carcinoma. Electron microscopic examination showed "tubular" amyloid deposition intermingled with invasive carcinoma and granuloma. "Tubular amyloid" was characterised by a mesh of non-branching curving fibrils with hollow profiles. These tended to be located in the cell membranes. CONCLUSION: The presence of an epithelioid granulomatous reaction and deposition of "tubular" amyloid in an invasive breast carcinoma could be related to an abnormal immunological response.     

Biochemical effect of liver transplantation in two Swedish patients with familial amyloidotic polyneuropathy (FAP-met30)

Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant inherited disorder characterized by progressive peripheral and autonomic neuropathy, associated with neural and systemic amyloid deposits. The amyloid fibrils contain a variant transthyretin (TTR) molecule (TTR met30), over 90% of which is produced in the liver. After liver transplantation in two patients with severe symptomatic FAP, only normal TTR was detectable in circulation. The two patients are being monitored at regular intervals, and, although in one patient there was no evidence of reduction in the quantity of amyloid present at 6 months, there had been no further progression of the neuropathy.     

MEDIAN RHOMBOID GLOSSITIS ASSOCIATED WITH AMYLOID DEPOSITION

There are some controversies over the pathogenesis and clinical features of median rhomboid glossitis. A case of median rhomboid glossitis associated with amyloid deposition was presented. Clinically there was no organ involved in amyloid other than the tongue. It was suspected that median rhomboid glossitis occurred first and that amyloid was induced later.     

Comparisons of the texture of amyloid,collagen and alzheimer cells

Summary This investigation was performed in order to determine textural similarities and differences between variable amyloid types. Alzheimer fibrils and collagen were also compared with these structures. For this reason we used tissue specimens of secondary amyloid (so-called perireticular amyloid), primary amyloid (so-called pericollagen amyloid), senile plaques, Alzheimer cells and collagen of tendons, scars, atherosclerotic aortes, rheumatic synovial membranes and of a dura mater cerebri, and examined these fibre types by polarization optical-histochemical methods.The findings allowed the conclusion that the texture of primary and secondary amyloid is not the same, because of differences in the fibrillar texture and probably of a distinctive interfibrillar substance in each case. Senile plaques seem to be a further variant of amyloid; some behaved as primary, and some as secondary amyloid. Alzheimer fibrils showed structural resemblance on senile plaques, although they contain no amyloid fibrils. The staining features of collagen clearly revealed that there is no structural relationship with amyloid, and therefore a direct transformation of collagen to amyloid and vice versa must be refuted. The collagen fibre types showed a variable texture because of their different mucopolysaccharide content. An important result is the changed hyaluronic acid metabolism of the rheumatic collagen fibres reported by other investigators.     

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.     

Distribution of cerebral amyloid deposition and its relevance to clinical phenotype in Lewy body dementia

Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are clinically distinguished based only on the duration of parkinsonism prior to dementia. It is known that there is considerable pathological overlap between these two conditions, but the pathological difference between them remains unknown. We evaluated Alzheimer-type pathology in 30 brains of patients with Lewy body dementia using standardized methods based on those of the Brain-Net Europe (BNE) Consortium. Only 2 of 13 PDD cases (15%) showed Aβ-immunoreactive pathology in the midbrain (amyloid phase IV). In contrast, 12 of 17 DLB cases (71%) exhibited midbrain involvement. Four of the DLB cases (24%) but none of the PDD cases exhibited Aβ-immunoreactive pathology in the cerebellum (amyloid phase V). The ratio of cases with subtentorial involvement of amyloid deposition was significantly higher in DLB than in PDD. The median of amyloid phases was significantly greater in DLB than in PDD, but there was no difference in neurofibrillary tangle (NFT) Braak stages or in Lewy body scores. When patients were classified according to whether dementia or parkinsonism had occurred first, the rate of dementia having occurred first was significantly greater in amyloid phase IV and V than in phase 0–I, with phase III in the middle, though there was no significant difference in median NFT Braak stage or mean Lewy body score associated with amyloid phase. These results suggest that amyloid deposition may contribute to the timing of the onset of dementia relative to that of parkinsonism in Lewy body dementia.     

Amyloid tumor: a clinical and cytomorphologic study

We describe the cytologic findings and clinical presentation of three unusual cases of amyloid tumor. Two of our patients had low-grade lymphoid malignancies and the third insulin-dependent diabetes mellitus. In no cases was amyloid suspected as the cause of mass lesion. Two of our cases presented with superficial soft tissue mass and the third with right breast masses and bilateral axillary lymph node enlargement. Air-dried slides from all aspirated cases were stained with Diff-Quik for specimen adequacy evaluation. The remaining fixed slides were stained with Papanicolaou stain. Amyloid appeared as dark-blue to purple clumps of acellular material on Diff-Quik stain, accompanied with chronic inflammatory cell infiltrates and multinucleated giant cells, simulating granulomatous inflammation. Papanicolaou stain demonstrated cyanophilic to orangophilic acellular material. Amyloid was suspected and subsequently confirmed by Congo red stain.     

The use of formic acid to embellish amyloid plaque detection in Alzheimer's disease tissues misguides key observations

We compared our heat pretreatment method to the widely used formic acid pretreatment technique to immunohistochemically detect amyloid in control and Alzheimer's disease brain tissues. Both methods detected amyloid in plaques, neurons, ependymal cells, circulating monocytes, vascular smooth muscle and endothelial cells. Although there were no observable differences in the intensity of the amyloid labeling in these cell types using both pretreatment methods, there were considerable differences in the intensity of amyloid immunolabeling in the plaques. The formic acid produced much more intense amyloid labeling in the plaques than the heat method. With the heat method, the intensity of the amyloid labeling in the plaques was similar to that detected in nearby neurons suggesting a neuronal origin of plaques. Conversely, the intensity of the amyloid in nearby neurons and plaques was drastically different using the formic acid suggesting unique origins of amyloid. The obvious benefits of formic acid for increasing the sensitivity of amyloid plaque immunolabeling may artifactually emphasize plaques over amyloid-containing cells during analyses.     

Amyloid in pituitary adenomas

71 surgically removed pituitary adenomas with amyloid deposits were studied by light microscopical and immunohistological means. In none of the adenomas was there a predominance of amyloid deposits. There were no correlations between the extent or pattern of the deposits with either age, immunohistological hormone content or localization. Our results do not support either of the theories about the origin of amyloid--whether mesenchymal or produced by adenoma cells--in pituitary adenomas.     

A putative role for cathepsin K in degradation of AA and AL amyloidosis

The aims of this study were to investigate the role of cathepsin K in the pathology of amyloidosis by demonstrating its presence in multinucleated giant cells (MGCs) adjacent to amyloid deposits, and determining its ability to degrade amyloid fibril proteins in vitro. The study was performed using autopsy and biopsy specimens from patients with AA or AL amyloidosis. In six (55%) patients with AA amyloidosis and seven (58%) patients with AL amyloidosis, variable numbers of CD68-immunoreactive MGCs were found adjacent to amyloid deposits. In each case strong cytoplasmic immunostaining for cathepsin K was found in MGCs; immunostaining of amyloid deposits was present in five (45%) patients with AA amyloidosis and three (25%) patients with AL amyloidosis. In vitro degradation experiments showed that recombinant cathepsin K completely degraded AA amyloid fibril proteins at pH 5.5 as shown by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting. Less effective degradation took place at pH 7.4 and there was no degradation in the presence of a general cysteine protease inhibitor (E64) or in the absence of cathepsin K. This is the first study to show that cathepsin K is expressed in MGCs adjacent to amyloid deposits and to demonstrate its ability to degrade amyloid fibril proteins.     

Myocardial ischemia due to vascular systemic amyloidosis: a quantitative analysis of autopsy findings on stenosis of the intramural coronary arteries

A case is reported of a 65 year old man who suffered myocardial ischemia resulting from extensive stenosis of the intramural coronary arteries secondary to systemic vascular involvement by primary amyloidosis. In the myocardium, there were multiple fibrotic foci scattered mainly in the subendocardial region of the ventricle. Intramural coronary arteries were stenotic or occlusive due to amyloid-induced luminal narrowing, but there was no significant stenosis of the epicardial coronary arteries. Quantitative analysis of amyloid deposits in the intramural coronary arteries demonstrated that occlusive arteries were predominant in the surrounding area of myocardial fibrosis, and the extent of coronary stenosis by amyloid deposition was significantly more severe than in hearts of the five control patients who had coronary amyloidosis without myocardial fibrosis. These results indicate that myocardial fibrosis originates from coronary ischemia due to vascular amyloid deposition. This is the first time that the relationship between myocardial lesions and coronary amyloid deposition has been elucidated using histopathologic quantitative analysis.     

Amyloid deposits in surgically removed articular and periarticular tissue

In tissue from 13 of 30 patients subjected to meniscectomy, amyloid degeneration was found to varying extent along the surface of the meniscus. Tissue from 30 synovectomies, 30 bursectomies and 30 ganglia showed amyloid deposits in four, six and eight cases, respectively. Amyloid was found significantly more frequently in older patients, but there was no sex difference and no relation to duration of the symptoms or to other histological changes in the tissue. Micro-deposits of amyloid in joint tissue and tissue neighbouring joints are a frequent finding, especially in elderly persons, but the clinical significance of this finding is not clear.     

Distribution pattern of matrix metalloproteinases 1, 2, 3, and 9, tissue inhibitors of matrix metalloproteinases 1 and 2, and α2-macroglobulin in cases of generalized AA- and AL amyloidosis

Matrix metalloproteinases (MMPs) degrade basement membranes and connective tissue and play an essential role in the homeostasis of the extracellular matrix which is disrupted by the deposition of amyloid. This immunohistochemical study investigated the distribution pattern of matrix metalloproteinases (MMP-1, -2, -3, and -9) and their inhibitors [alpha 2-macroglobulin (alpha 2-M), tissue inhibitors of MMPs (TIMP)-1, and TIMP-2] in human AA- and AL amyloid deposits. Specimens of liver, kidney, and spleen from 22 autopsy cases were investigated. Nine patients had suffered from generalized AA amyloidosis, eight from generalized AL amyloidosis, and five from rheumatoid arthritis or tuberculosis with no histological evidence of amyloid. In all amyloidotic and non-amyloidotic patients, each protease and protease inhibitor was detected in almost every organ investigated. In the amyloidotic cases, there was no indication that a specific protease or protease inhibitor was absent or expressed, but a difference was observed in their spatial distribution patterns. The most noticeable difference was found in immunostaining of amyloid. Only MMP-1, -2, and -3, and alpha 2-M were present in AA amyloid deposits, and only TIMP-1 and TIMP-2 were found in deposits of AL amyloid. This is the first study to show that MMP-1, -2, and -3 are present in AA amyloid deposits. They may be involved in tissue remodeling or in proteolysis of the precursor and fibril proteins.