Light chain deposition disease restricted to the brain: The first case report

A 35-year-old white male with symptoms of paranoid schizophrenia was treated by psychiatrists for 13 years. During the final year, he developed severe dysphagia, reduced strength of the upper extremity muscles, and cognitive dysfunction. The patient died in his sleep. The only pathology found in coronal brain sections was ill-defined periventricular foci with prominent, firm vessels. Microscopy revealed abundant, hematoxylin and eosin-eosinophilic, periodic acid-Schiff-positive, thioflavin T-positive, and Congo red-negative deposits in the vessel walls, with hypoxic encephalopathy in the affected regions. Immunohistochemistry showed lambda light chains as the main component of the deposits. Ultrastructural analysis showed amorphous electron dense material in the vessel walls. Perivascular B-cell proliferation was present in the vicinity of affected areas. Polymerase chain reaction was applied for the assessment of B-cell clonality, revealing monoclonal rearrangement of the heavy chain Ig gene. Neither in the kidney nor in any other organ were deposits detected. This is the first case report of light chain deposition disease restricted to the brain.     

Immunohistochemical study of immunoglobulin light chain amyloidosis with antibodies to the immunoglobulin light chain variable region

To detect immunoglobulin (Ig) light chain amyloidosis (AL amyloidosis) in formalin-fixed, paraffin-embedded tissue sections by immunohistochemistry, polyclonal antibodies were generated against synthetic peptides corresponding to amino acids 1-19 of the Ig lambda light chain V lambda VI subgroup (anti-V lambda VI (1-19)) and the Ig kappa light chain Vkappa I subgroup (anti-Vkappa I (1-19)). Anti-V lambda VI (1-19) antibody reacted with amyloid deposits in 21 of 22 Alambda amyloidosis cases, and anti-Vkappa I (1-19) antibody reacted with amyloid deposits in 10 of 11 Akappa amyloidosis cases. Immunoreactivity varied in intensity by case and within specimens. Surprisingly, amyloid deposits were positive for anti-V kappa I (1-19) staining in one case of Alambda amyloidosis. Analysis of anti-V lambda VI (1-19) and anti-Vkappa I (1-19) antibody reactivity by ELISA showed some cross-reactivity with peptides other than antigen peptides. The antibodies were not reactive in all cases of AL amyloidosis examined but may be useful, together with anti-Ig constant region antibodies, for immunohistochemical diagnosis of AL amyloidosis.     

Localized amyloidosis of the urinary bladder, clinically masquerading as bladder cancer

Amyloidosis is characterized by extracellular deposition of a proteinaceous, hyaline material. Localized deposition of amyloid in individual organs is uncommon. It can occur in the absence of systemic involvement. Herein, we describe two cases of localized amyloidosis of the urinary bladder, which clinically, radiologically, and on cystoscopy masqueraded as bladder cancer. A diagnosis of amyloidosis in both these cases was ascertained on biopsy, supplemented with special stains.     

Localized amyloidosis of urinary bladder: a diagnostic dilemma

Amyloidosis is a heterogeneous group of disorders affecting a single-or multiple-organ system and presents as generalized or localized disease. Both generalized amyloidosis and localized amyloidosis can be primary or secondary. Localized amyloidosis affects organs like urinary bladder, lung, larynx, skin, tongue and the region around the eye, producing detectable nodular masses which are clinically suspected as malignancy. We present six cases of localized urinary bladder amyloidosis that were clinically and cystoscopically suspected as bladder tumor or cystitis, which occurred over a period of last 10 years. Histology in all cases revealed diagnosis of primary amyloidosis. None of them had any stigmata of secondary disease. The cases were treated by simple transurethral resection of bladder. Two out of the six cases recurred after 3 to 5 years of initial presentation and were asymptomatic thereafter. Amyloidosis of the bladder is a rare condition which often mimics bladder neoplasm clinically and cystoscopically and histological examination is a must for definite diagnosis and proper management.     

Development of diagnostic antibodies against immunoglobulin heavy chain variable region for heavy chain amyloidosis (AH amyloidosis)

It is difficult to diagnose immunoglobulin heavy chain amyloidosis (AH amyloidosis) without proteomic analysis due to no useful diagnostic antibodies. The aim of this study was to develop diagnostic antibodies available to immunohistochemistry and immunoblotting. Two rabbit anti-heavy chain variable region antibodies were generated and evaluated in immunohistochemical studies performed on 11 AH amyloidosis patients and 64 patients with other systemic amyloidoses. Additionally, immunoblotting was performed using extracted amyloid protein from one patient and serum samples from two patients with AH amyloidosis. Immunohistochemical analysis generated a positive outcome in 10 of 11 AH amyloidosis patients (sensitivity 90.9%). While positive staining was also observed in 9 of 64 non-AH amyloidosis patients (specificity 85.9%), substitution of the blocking agent reversed the positive reactivity in 5 of 9 patients. Amyloid protein band was clearly detected via immunoblotting analysis, and protein bands with similar molecular weights of amyloid protein were observed in serum samples from patients with AH amyloidosis. The two antibodies may represent a powerful diagnostic tool for AH amyloidosis. In addition, our data revealed the existence of amyloidogenic variable region fragments in the serum of patients, suggesting their potential as diagnostic markers for AH amyloidosis.     

Light chain deposition disease derived from the kappa I light chain subgroup. Biochemical characterization.

The authors biochemically analyzed the nonamyloidotic light chain deposits, the first studied in this way, from a patient with systemic kappa light chain deposition disease (LCDD). The light chain deposits from myocardium were extracted in 6 M guanidine-HCl under reducing conditions, partially purified by column chromatography, and analyzed by immunoblotting and amino-terminal sequencing. The extracted material contained four main bands reactive with anti-kappa antibody: intact kappa light chain (MW, 28 kd), under reducing conditions, and 3 fragments (MW, 20, 16, and 15 kd). As revealed by the aminoterminal sequencing performed on three of the four bands, the intact light chain molecule and two fragments belong to the kappa I subgroup. Thus, similar to light chain amyloid (AL), the deposits in LCDD are derived from both intact light chain and fragments. Unlike in AL, amyloid P component was not detected in the deposits of this patient or those examined previously. The differences demonstrated thus far between AL and LCDD are the lack of fibrils and amyloid P component in LCDD, suggesting that local tissue factors may be responsible for different processing of the light chain deposits in LCDD.     

Association light chain deposition disease (LCDD) and amyloidosis. One case

Up to now, light chain deposition disease (L.C.D.D.) and amyloidosis have been shown to occur in different individuals. A case of association is described in a 76 year old man with terminal renal failure and normal size kidneys. Percutaneous renal biopsy showed glomerular and peritubular fixation of labeled antikappa light chain serum. Stains for amyloidosis were positive in small vessels. Kappa free chains were found in both serum and urine and the bone marrow showed predominantly kappa-containing plasma cells. By electron microscopy both electron-dense granular deposits and amyloid like fibrils were found in the wall of arterioles and small arteries.     

Light chain deposition disease of the kidney. Morphological aspects in 24 patients

Renal biopsies and autopsy specimens of 23 patients with light chain deposition disease (LCDD) and one with only heavy chain deposits, were studied by light (LM) and electron microscopy (EM) as well as immunohistology (IH). Thirteen patients had multiple myeloma; 1 had lymphoma, and 1 chronic myeloid leukaemia with polycythaemia vera. In nine patients, no lymphoproliferative disease was identified. The LM lesions most suggestive of LCDD, nodular glomerulosclerosis (NS) and thickening and wrinkling of the tubular basement membranes (TBM), were present in only ten and 13 patients, respectively. In five of seven specimens without NS or TBM thickening by LM, EM was negative, indicating a limited value of EM in confirming the diagnosis. Renal amyloidosis was not identified, but in one patient amyloid in the heart and tongue was seen at autopsy. One patient had both granular and extensive glomerular non-amyloid fibrillary deposits. In two patients myeloma casts were identified. Twenty-one patients showed renal LC immune reactivity, 1 had both alpha heavy and lambda LC, 1 had only detectable gamma heavy chain. One biopsy was negative by IH, but had characteristic electron dense deposits. In six patients with immune reactivity to LC, no electron dense deposits could be identified by EM. This study emphasizes the spectrum of renal changes by LM and EM in LCDD, the frequent lack of consistency between deposits detected by IH and EM and the difficulty in coming to a definite diagnosis without LM, EM and IH. The results of this study and examination of the literature indicates that extensive morphological changes are more often present in kappa than in lambda LCDD.     

Light and electron microscopic demonstration of extracellular immunoglobulin deposition in renal tissue.

Extracellular immunoglobulin (IgG) deposits were shown by both light and electron microscopy in renal biopsy material using immunogold labelling. After fixation of tissue in 4% paraformaldehyde and embedding in Lowicryl K4M, semithin sections were cut and stained using the immunogold silver stain. The sections were then viewed and areas of interest were noted; ultrathin sections were cut from the same block of tissue, then stained using immunogold. Good localisation was achieved at both optical and ultrastructural levels allowing direct correlation to be made in the same area of tissue.     

Immunogold quantitation of immunoglobulin light chains in renal amyloidosis and kappa light chain nephropathy.

By quantitative immunoelectron microscopy using protein A-gold, the authors compared the content and distribution of immunoglobulin light chain (LC) antigens in glomeruli from 11 cases of renal amyloidosis with that in two cases of kappa LC glomerulopathy and two cases of diabetic glomerulosclerosis. In a supplementary study and using a similar immunogold technique, the authors identified amyloid A in deparaffinized renal tissue from three of the 11 cases of renal amyloidosis. Each patient had similar clinical manifestations (chronic renal failure with proteinuria) and similar glomerular morphology (thickened glomerular basement membranes and nodular expansion of the mesangium). In 12 cases (10 amyloid, 2 kappa LC), immunoelectron microscopy localized LC antigens over the glomerular deposits and allowed indirect tissue quantitation of each LC antigen to the various cellular and interstitial compartments. In 6 of the 11 cases of renal amyloidosis, the amyloid labeled only for lambda, and in one, only for kappa. In one patient with Waldenström''s macroglobulinemia, who had a biclonal gammopathy, both LC were identified in the amyloid. In two cases, both of whom had a history of chronic suppurative lung disease, both LC antigens as well as amyloid A were localized to the amyloid fibrils. In only one case, in which glomerular amyloid labeled for amyloid A, the amyloid did not label for either LC. Whereas lambda LC-derived fibrils often appeared as spicules in the glomerular subepithelial space, other amyloid deposits usually accumulated in the subendothelial zone and did not form spicules. The epimembranous location of spicules suggested that the amyloid precursor protein transformed into amyloid fibrils after filtration into the urinary space. Presence of epimembranous spicules may explain the more severe proteinuric renal failure and the more rapid progression to glomerulosclerosis described in primary amyloidosis.     

Useful polyclonal antibodies against synthetic peptides corresponding to immunoglobulin light chain constant region for immunohistochemical detection of immunoglobulin light chain amyloidosis

For the immunohistochemical detection of immunoglobulin (Ig) light chain amyloidosis on formalin-fixed, paraffin-embedded tissue sections, we prepared polyclonal antibodies against synthetic peptides corresponding to positions 118-134 of Ig lambda light chain and positions 116-133 of Ig kappa light chain. Nineteen cases of systemic Ig lambda light chain amyloidosis (Alambda amyloidosis), 10 cases of systemic Ig kappa light chain amyloidosis (Akappa amyloidosis), one case of immunohistochemically unclassified systemic amyloidosis and five cases of localized Alambda amyloidosis were tested with these antibodies. Anti-lambda (118-134) antiserum and the affinity-purified antibody both reacted with 18 of the 19 cases of systemic Alambda amyloidosis and all cases of localized Alambda amyloidosis, although the immunoexpression was somewhat variable in intensity in different areas within the same specimen in both systemic and localized amyloidosis. The signal intensities in plasma cells and serum reacted for anti-lambda (118-134) antiserum were weaker than signals obtained with commercially available anti-Ig lambda light chain antibodies. Anti-kappa (116-133) antiserum and the affinity-purified antibody reacted with nine of the 10 cases of systemic Akappa amyloidosis. We conclude that these antibodies against synthetic peptides corresponding to the Ig light chain constant region are useful for the classification of amyloidosis on formalin-fixed, paraffin-embedded tissue sections.     

Pathology of dysproteinemia: light chain amyloidosis, non-amyloid immunoglobulin deposition disease, cryoglobulinemia syndromes, and macroglobulinemia of Waldenstr?m

This review has dealt with four syndromes associated with dysproteinemia, and has emphasized studies of the tissue deposits and forms of tissue injury which occur in such patients. However, similar tissue deposits and tissue damage occasionally occur in the absence of a serum or urine paraprotein, in which case other clinical data are necessary to suggest the need for examination of tissue for Ig heavy and light chain determinants in order to provide a correct diagnosis of dysproteinemia. In such cases, one may speculate that there is a low rate of paraprotein production and secretion, in addition to tissue tropism. Some paraproteins are antibodies, in which case they may circulate and/or deposit as immune complexes, or bind to tissue antigens with immune complex formation in situ. Some paraproteins are also cryoproteins, and clues to this property can also be found in the tissue, particularly at the ultrastructural level. Thus, a wide spectrum of clinical manifestations of a B cell proliferative disorder may be associated with any of a variety of circulating paraproteins and a variety of forms of tissue deposit and injury. Consequently, the best understanding of an individual patient requires correlation of the clinical features of the disorder, the immunochemical characterization of the circulating and excreted paraproteins, and an immunohistochemical analysis of the tissue deposits and associated morphologic abnormalities. This should be correlated with histologic and immunohistologic assessment of bone marrow, looking for overt B cell neoplasia, the more difficult to define "lymphoproliferative disorders," or alterations in kappa to lambda plasma cell ratios which may correlate with the deposited material. Studies of the Ig synthesized by cultured bone marrow plasma cells, and biochemical analyses of the deposited material, have demonstrated structural abnormalities of paraproteins which may be responsible for their tissue deposition.     

A reinvestigation of the function of the mammalian urinary bladder.

The function of adult mammalian urinary bladder is evaluated in light of recent in vitro experiments. The discrepancy between in vivo and in vitro experimental results is examined and a possible solution proposed. Techniques for eliminating edge damage and measuring apical membrane surface area are described. A new chamber design for microelectrode studies is illustrated. The possibility of apical cell membrane damage caused by microelectrodes is critically examined and tested using the polyene antibiotic Nystatin. Using data from transepithelial and microelectrode experiments, a model for net Na+ transport across the bladder is proposed and then critically analyzed. The possible clinical implications of the in vitro experiments are briefly discussed.     

Tubulovillous adenoma of the urinary bladder.

We report a case of vesical tubulovillous adenoma that occurred in a background of protracted chronic cystitis with intestinal-type glandular metaplasia and extensive cellular atypia (dysplasia) in the flat mucosa. Flow cytometry analysis showed DNA aneuploidy in the adenoma. Increased expression of the tumor suppresser gene, p53, and also of cellular proliferation markers (proliferating cell nuclear antigen and MIB-1) were detected in the villous adenoma and in the dysplastic regions of the flat metaplastic mucosa. These findings provide insight into the biology of intestinal metaplasia and also lend support to the theory of the chronic irritation-metaplasia-dysplasia-carcinoma sequence.     

Proliferative glomerulonephritis with discrete deposition of monoclonal immunoglobulin γ1 CH2 heavy chain and κ light chain: A new variant of monoclonal immunoglobulin deposition disease

A 45‐year‐old man presented with moderate proteinuria and hematuria. A renal biopsy showed mesangial/endocapillary proliferative glomerulonephritis, linear deposition of monoclonal immunoglobulin γ1 C_H2 heavy chain along glomerular and tubular basement membranes (GBMs and TBMs), granular deposition of κ light chain within the mesangial area, and continuous linear deposits of finely granular electron‐dense materials along GBMs and TBMs. Dual immunostaining showed essentially discrete glomerular localization of γ1 C_H2 heavy chain and κ light chain. Monoclonal protein was not detected in urine and serum. A bone marrow aspiration showed no abnormalities. Steroid therapy led to the improvement of proteinuria and hematuria. We would classify this case as a new variant of monoclonal immunoglobulin deposition disease, light chain/heavy chain deposition disease. In contrast with light and heavy chain deposition disease, the remarkable characteristics of this variant are separate deposition of monoclonal heavy chain and light chain, deposition of largely deleted γ heavy chain lacking the C_H1 domain, and good response to steroid therapy.     

A case report of inflammatory pseudosarcoma of the urinary bladder.

A case of inflammatory pseudosarcoma of the urinary bladder in a 35-year-old Japanese male is presented. This benign lesion can easily be mistaken for spindle cell sarcoma since it consists of rhabdomyoblast-like elongated strap cells showing infiltrative growth, and whether it is benign or malignant is difficult to determine by microscopic examination. In this case, spindle cell proliferation extended among bundles of the superficial muscle layer. However, no abnormal mitoses, severe nuclear atypia or cellular pleomorphism could be seen, thus indicating inflammatory pseudosarcoma. Although the lesion was not completely resected, no recurrent disease has been clinically observed for two years following transurethral resection. Urologists and surgical pathologists must be able to detect this lesion in order to avoid unnecessary surgical procedures.