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NEOPLASIA
From the Pathologisches Institut and the Medizinische
Klinik-Klinikum Innenstadt der Ludwig-Maximilians-Universität
München, Germany; Max-Delbrück-Centrum für Molekulare
Medizin, and the Max-Planck-Institut für Infektionsbiologie,
Protein Analyse Einheit, Berlin, Germany.
Crystal-storing histiocytosis (CSH) is a rare event in disorders
associated with monoclonal gammopathy. The intracellular crystal
formation is almost always accompanied by the expression of Crystal-storing histiocytosis (CSH) is an uncommon
phenomenon in disorders associated with the expression of monoclonal
immunoglobulins (multiple myeloma [MM], monoclonal gammopathy of
undetermined significance [MGUS], lymphoplasmacytic lymphoma [LPL],
extramedullary plasmacytoma).1-34 It is presumed to be an
intralysosomal accumulation of secreted paraproteins or
immunoglobulins, which aggregate in crystals. Given their rarity, the
appearance of crystal-laden macrophages in the bone marrow often
presents diagnostic difficulties because those cells may mimic Gaucher
cells or so-called pseudo-Gaucher cells in chronic myelogenous
leukemia.7,19,21,27 CSH in extramedullary sites has been
mistaken for adult rhabdomyoma,4,10 fibrosclerosis,2 Weber-Christian disease,5 or
other types of histiocytosis.35
Although CSH shows a variety of appearances, sometimes obscuring
the underlying disorder, immunoglobulins of light-chain type Proteome studies provide the possibility of analyzing the protein
pattern of several thousand proteins simultaneously to identify biologically important proteins, to characterize their modifications, and to describe their functions. High-resolution 2-dimensional electrophoresis and mass spectrometry are prerequisites for such proteome studies.
We present a case of generalized CSH associated with IgA Case report
Histopathology
Biopsy tissue of liver, peritoneum, and skin as well as specimens obtained at the time of autopsy were fixed in 4% neutral-buffered formalin, routinely processed, and embedded in paraffin. Sections were stained with hematoxylin-eosin (H-E), Giemsa, PAS, Congo red, Elastica-van Gieson trichrome, and Perls reaction for iron. Immunohistochemistry For immunohistochemical analysis acrylate and paraffin sections were used. Immunolabeling was done according to the alkaline phosphatase-antialkaline phosphatase (APAAP) and avidin-biotin peroxidase complex (ABC) techniques, following methods previously described.36 The primary antibodies, pretreatment procedures, and antibody dilutions used in this study are listed in Table 1.
Electron microscopy For ultrastructural analysis, fragments of the primarily formalin-fixed and paraffin-embedded biopsy samples were cut off the paraffin blocks and re-embedded in epoxy resin. Ultrathin sections were placed on uncoated grids, contrasted with uranyl acetate and lead citrate, and observed on a Philips 420 electron microscope (Philips, Einthoven, The Netherlands).Protein analysis To further characterize the stored proteins we performed 2-dimensional polyacrylamide gel electrophoresis (2-DE) supplemented by immunoblotting and mass spectrometry (MS) on tissue samples from the patient. Stored urine or serum samples from the patient and fresh or frozen tissue from the kidneys were not available for these protein analyses.2-DE. Soluble and membrane-bound proteins were extracted from the patient's liver tissue samples as from normal liver tissue (4 samples of age-related male donors) and were separated by high-resolution 2-DE according to Klose37-39 using the Iso-Dalt system. In brief, isoelectric focusing (IEF) was performed with 4% carrier ampholytes, the second dimension was run on gels (16 × 16 × 0.15 cm) with a 10% to 16% polyacrylamide gradient as described earlier.40-42 Then 400 µg protein (Lowry protein assay kit, Sigma-Aldrich, Deisenhofen, Germany) was separated for Coomassie brilliant blue-stained gels (CBB R-250, Merck, Darmstadt, Germany); 100µg protein was used for silver staining.43 Immunoblotting.
The technique used for immunoblotting has been described earlier in
detail.44 After 2-DE separation of proteins (400 µg protein/sample), selected areas in the 2-DE gels were excised for
immunoblotting. The heavy chain region of IgA, IgD, IgM (~90-40 kDa,
pI ~5.0-7.0, gel area 7.5 × 6.5 cm) and IgG (~75-35 kDa, pI
~6.6-8.0, gel area 8.5 × 5cm) as well as light chain region of Protein identification. Peptide mass fingerprinting (PMF) by matrix-assisted laser desorption-ionization mass spectrometry (MALDI-MS) and nanoelectrospray ionization mass spectrometry (nano-ESI-MS/MS) were applied to identify distinct proteins. Conspicuous protein spots (~kDa/~pI) as compared to controls were cut out from the CBB-stained 2-DE gels of the liver tissue samples and analyzed; spot 25 (25/5.6) resulted from the soluble protein fraction, spots 23 (23/5.0), 22 (22/5.0), 20 (20/5.0) as well as 13-1, 13-2, and 13-3 (13/4.5, 4.7, and 5.1, respectively) from the membrane bound fraction. Tryptic in-gel digestion and PMF by MALDI-MS were performed according to Lamer and Jungblut.45 The mass spectra were obtained by a Voyager Elite MALDI-TOF mass spectrometer (Perseptive Biosystems, Framingham, MA). Proteins were identified by using the search program MS-Fit (http://falcon.ludwig.ucl.ac.uk/ucsfhtml3.2/msfit.com). The sequence database of the National Center for Biotechnology Information (NCBI) was reduced to the "human rodent" proteins. A mass tolerance of 0.1 Da and 2 incomplete cleavages were allowed. Sequence support was obtained by nano-ESI-MS/MS46 performed with a Q-Tof mass spectrometer (Micromass, Manchester, England). An additional in-gel digestion with endoproteinase Glu-C (Roche Diagnostics, Mannheim, Germany) was performed to obtain other peptides and potentially increase the sequence coverage. The peptides were fragmented in a collision cell. The resulting MS/MS spectra allowed us to determine parts of the peptide sequence or the whole sequence. The sequence tag method47 was used to search the proteins in the NCBI protein database. Similarly, a search was additionally performed at the SWISS-PROT database at the European Bioinformatics Institute (EMBL) with the program FASTA 348 and at the BLAST server of the NCBI.
Histopathology Bone marrow biopsies performed 7 and 5 months before the patient died revealed an increasing accumulation of histiocytes stuffed with needlelike crystalline material in a proportion of 30% and 50% of the total cell volume, respectively (Figure 1A). Additionally erythrophagocytosis was observed in these cells. Plasma cells without significant nuclear atypia were rarely admixed in the groups of crystal-laden histiocytes and hematopoietic cells (Figure 1B). Cytoplasmic inclusions were observed only occasionally in plasma cells, which were slightly increased in the second biopsy but comprised even less than one tenth of the cellularity of the bone marrow. The hematopoiesis was at least slightly repressed except for a minimal elevation of eosinophilic granulopoiesis.
In the liver biopsy performed 5 months before the patient died, swollen Kupffer cells containing crystalline inclusions that obstructed the sinusoidal spaces were evident predominantly in central areas (Figure 1J-K). Some laden histiocytes were also observed in the portal areas. Crystal-storing histiocytes were detected as well in the connective tissue of the peritoneum, cutis, and subcutis. The crystalline inclusions stained pinkish red with H-E, reddish brown with Elastica-van Gieson, and dark blue with Giemsa in the acrylate sections but only weakly in paraffin sections. They reacted faintly positive with Perls reaction for iron. PAS and Congo red failed to stain. Immunohistochemistry The crystal-storing histiocytes in all localizations examined reacted positively with the anti-CD68 antibody KP1. Antibodies against CD20 (L26), CD79a (MB1), CD3, and myeloperoxidase gave negative reactions in these cells. Immunohistochemically, the majority of the crystal-storing histiocytes were positive for IgA and IgG heavy chains as well as and  light chains (Figure 1C-F). However, IgM and IgD
were not detected in the histiocytes. The exact assignment of
immunoglobulin expression in the only rarely admixed plasma cells was
not possible.
Electron microscopy Electron microscopy showed crystalline inclusions in the macrophages of the bone marrow, liver, and skin. The electron-dense crystalline inclusions varied in dimension and structure. Rectangular and rhomboid shapes predominated. Similar inclusions were also detected occasionally in plasma cells of the bone marrow and in some hepatocytes (Figure 2A-B). No periodic organization of the substructure was observed.
Autopsy findings Autopsy of the cachectic patient (164 cm, 56 kg) revealed a tremendous number of large histiocytes storing excess amounts of irregularly outlined crystals diffusely spread in the bone marrow. Most of the histiocytes were immunohistochemically positive for IgA, IgM, and IgG heavy chains as well as and light chains. Among the
crystal-storing histiocytes, plasma cells were seen interspersed. In
contrast to the bone marrow biopsies done 7 and 5 months before, the
number had increased up to a portion of 10% to 15%. Consistent with
MM the cells were at least partly arranged in groups up to 20 cells.
Although small and monomorphic plasma cells predominated, some
cells were enlarged and showed vesicular inclusions in their cytoplasm.
Electron microscopy revealed crystalline inclusions in these cells
identical to those observed in the histiocytes (Figure 2C).
Immunohistochemistry confirmed the plasma cell nature of these cells
(Figure 1G) and the expression of IgA heavy chains as well as light
chains (Figure 1H-I). Compared to the histiocytes, plasma cells stained
only faintly positive. A conspicuous increase of plasma cells was also
found in the spleen, which showed a lymphatic depletion of the white
pulpa. The spleen was enlarged (300 g) and the liver was approximately
normal size (1450 g). CSH involved the reticuloendothelial system of
bone marrow, liver, spleen, and lymph nodes as well as macrophages of
the peritoneum, pericardium, pleura, skin, retroperitoneum, and several
parenchymatous organs (lungs, myocardium, kidneys, adrenals, testes,
mucosa of the gastrointestinal tract). CSH in the retroperitoneum was
accompanied by fibrosis with sparsely intermingled lymphocytes. Lymph
nodes showed lymphatic depletion in addition to the accumulation of
crystal-storing histiocytes. Segmental sclerosis of occasional
glomeruli was present in the kidneys in association with slight focal
interstitial fibrosis and tubular atrophy most likely due to a moderate
atherosclerosis. Hyaline protein casts were seen in different portions
of the tubules without crystallike inclusions in tubular epithelial
cells or the characteristic pathologic features of myeloma kidneys.
Light microscopy revealed bronchopneumonia in the upper lobe of the right lung with septicopyemic spread in the myocardium and the right adrenal gland with detection of fungal hyphae corresponding to aspergillus in the myocardium. There were serous effusions in each pleural (200 mL each) and peritoneal (5000 mL) cavity. Additionally, a cavernous hemangioma was present in the left lobe of the liver (5 cm in diameter) and a pulmonary hamartoma was seen in the middle lobe of the right lung (2 cm in diameter). Protein analysis Use of 2-DE in combination with immunoblotting revealed the storage of great quantities of heavy chains of type
and light chains of type, each in a monoclonal pattern in
accordance with the criteria of Tissot and Spertini.49 The
remaining immunoglobulins were detected only in normal amounts showing
a polyclonal pattern each.
The 2-DE patterns of the soluble and membrane-bound protein fraction of
the patient's liver tissue are shown in Figure
3. IgA heavy chain was visible in a
monoclonal pattern in the 2-DE gel of the soluble fraction (Figure 3A).
In contrast to polyclonal heavy chains, monoclonal heavy chains are
detectable as sets of well-resolved spots characterized by charge
microheterogeneity.49 This result was confirmed by
immunoblotting where a set of well-defined red spots corresponded to
charge microheterogeneity of monoclonal IgA (Figure
4A). Great amounts of
The membrane-bound protein fraction of the liver showed additional
protein spots in the 2-DE gels. These proteins were distributed over a
region from 23 kDa to about 13 kDa/pI 4.5 to 5.1 as shown in Figure 3B.
Immunoblotting with antibodies directed against Nano-ESI-MS/MS was performed on spot 25 for sequence support to confirm
the PMF data and to identify the nonmatching peaks. The results of this
microsequencing that covered about 67% of the complete
The peaks 1579.76 Da, 1749.98 Da, and 1860.98 Da (Table 2) were
prominent in all spots under investigation, thus suggesting that spots
23, 22, 20, as well as 13-1, 13-2, and 13-3 represent Provided that the membrane-bound protein fraction reflects
especially the proteolytically resistant intralysosomal-stored immunoglobulins or their fragments, Figure 3B indicates that the amount
of stored
We present a case of generalized CSH associated with a monoclonal
IgA To date about 60 cases of CSH have been reported in the
literature. Predominantly they were found in association with MM
and LPL.1-35,54-56 Some (22 cases) have been
detected primarily in extramedullary sites, associated with plasma cell
granuloma, LPL, mucosa-associated lymphoid tissue (MALT)
lymphoma, large-cell lymphoma, and extramedullary plasmocytoma.1,3-7,9,10,16,19,20,24,25,28,31,35,55 However, the involvement of the bone marrow has been described in
the majority of the cases. The association with crystalline storage in
cells of the reticuloendothelial system at other sites has been
reported in 21 cases so far (Table 4).
Because of the rarity of the disease, the accumulation of
crystal-storing histiocytes in the bone marrow often presents
diagnostic difficulties. Sometimes the number of histiocytes in the
bone marrow is so increased in proportion to the clonal plasma cells
that the diagnosis of a storage disorder like Gaucher disease is
initially considered, as in a bone marrow smear in our case. Because
the crystal-storing macrophages may adopt the appearance of Gaucher
cells, they have been referred to as pseudo-Gaucher
cells.13,27 However, at least the ultrastructure of the
crystalline inclusions distinguishes these cells from
glucocerebroside-storing real Gaucher cells as well as from the
so-called pseudo-Gaucher cells that are sometimes observed in chronic
myeloid leukemia57 and thalassemia.58 Therefore Schaefer7 proposed the term
"pseudo-pseudo-Gaucher cells" (PPGCs) as a specific designation for
this particular type of macrophage. The real Gaucher cells exhibit
tubular structures in the electron microscope with a unique
substructure of 10 or 12 fibrils that spiral in a right-handed screw
sense along the length of the tubule.59 Pseudo-Gaucher
cells in chronic myeloid leukemia discriminate from these by a
microfibrillar ultrastructure.57 In contrast, macrophages
in CSH present with many often membrane-bound electron-dense rhomboid,
hexagonal, or more needlelike crystal profiles in the cytoplasm, as in
our patient.7 At higher magnification these crystals often
show a periodical hexagonal crystal lattice with a center-to-center
distance of about 75 Å.7 In some cases the clonal myeloma
or lymphoma cells also contain similar protein crystals.7
This finding contributes to the view that the stored proteins represent
crystallized immunoglobulins.
In our case electron microscopy revealed crystal storage in the macrophages at different sites, just as described in the literature but without periodic organization of the crystalline substructure. Whether this is due to the composition of the stored proteins or the amino acid sequence of the immunoglobulins is unclear. Crystalline inclusions were also detected in hepatocytes as reported by Kjeldsberg et al23 in a case of MM associated with generalized CSH. Crystalline plasma cell inclusions were already occasionally seen in the initial bone marrow biopsy and at the time of autopsy when plasma cells were increased in number and fulfilled the diagnostic criteria of MM. The phenomenon that the number of PPGCs may exceed by far the number of plasma cells has also been described by others.1,22 Therefore, the cell proliferation might not fulfill the criteria of MM at the time of initial presentation. The association of MGUS with CSH has been described twice in the literature.1,22 However regarding the rapid clinical course of the disorder in our patient and in others,22 it seems debatable if the diagnosis of MGUS in association with CSH reflects the prognosis sufficiently. Immunohistochemistry of the stored material revealed conflicting
results. In the cases of CSH reported in the literature, the stored
protein in PPGCs remained either unstained5,7-10,12,16,18 or exhibited only a weak reaction mainly restricted to the surfaces of
the crystals.1,13,35 This failure to stain has been
attributed to the coverage of the epitopes in the crystal structure and
the degradation by limited lysosomal proteolysis. The storage of
immunoglobulins other than the paraprotein has been reported only 3 times.1,6,19 The pathogenesis for this phenomenon as well
as for the crystal storage in the histiocytes has not been clarified
yet. Interestingly, every published case of CSH with MM and nearly all
cases of LPL with known paraprotein type have been reported to produce
monoclonal immunoglobulins of light-chain type A possible mechanism of crystal formation may be overproduction. This is supported by the observation that focal CSH occurs also in combination with polyclonal immunoglobulin expression such as plasma cell granuloma or posttransplantation plasmacytosis.1 But some of the patients reported in the literature have minimal or no serum or urine paraprotein levels, respectively, and the number of clonal plasma cells in the bone marrow might be low as in our case.1,4,10,12,19,22,54,55 Thus, more likely than overproduction is that the stored paraproteins have sequence abnormalities at specific sites that promote crystallization or adversely affect intralysosomal degradation or both. To date there are only limited data on sequence analyses from However, there have not been any publications on the exact nature of
the stored immunoglobulins in CSH. To the best of our knowledge this is
the first report using 2-DE and protein identification of tissue
samples of a patient with CSH. The stored proteins were characterized
especially with regard to the observed unusual immunostaining pattern.
The use of 2-DE in combination with immunoblotting of the extracted
proteins demonstrated an accumulation of monoclonal immunoglobulins of
type IgA Protein identification by MS of conspicuous protein spots confirmed the
storage of tremendous amounts of The microsequencing with MS has not yielded the complete sequence of
the stored DNA and cDNA sequencing were not included in our investigations because neoplastic plasma cells were only rarely admixed in the bone marrow biopsies, not sufficient for the extraction of DNA or mRNA in adequate purity and quantity for sequence analysis. Thus, the role of the relative contribution of germ line versus somatic mutations in the pathogenesis of this disease remains to be elucidated. The additional deposition of polyclonal immunoglobulins in our case might have been caused by the accumulation of the proteolytically resistant paraprotein that impaired the intralysosomal degradation of the remaining proteins especially for stereologic reasons. It seems unlikely that the storage of crystalline immunoglobulins is caused by an enzyme defect itself because the enzymes involved in the degradation of immunoglobulins are rather nonspecific and are not restricted to the cleavage of them. Finally, some questions concerning the pathogenesis of CSH remain
open: (1) While roughly one half of the cases with CSH occur localized
at the site of lymphoplasmacellular proliferation, the other half
develops a generalized accumulation of crystalline proteins in the
reticuloendothelial system. The generalized distribution is often
associated with a rapid, fatal clinical course, as in our patient.
Therefore, it seems to be critical to find adequate therapeutic
strategies especially for these patients. The application of
plasmapheresis has been reported only in one case in the literature so
far, used to control symptoms of hyperviscosity.1
Nevertheless many myeloma patients with CSH have reported survivals of
5 to 15 years after diagnosis, which is longer than the median survival for MM alone.76 (2) With regard to the discussion of
possible mechanisms that might cause CSH, the hypothesis of the
expression of abnormal paraproteins by neoplastic plasma cells that are
at least partly resistant to enzymatic degradation seems to be the most
probable right now. But it is unclear whether resistance comes from
crystal formation, high intrinsic stability, or fortuitous loss of
proteolytic sites. Consequently, there is a need to obtain complete
sequence data so that recombinant forms can be produced for laboratory
studies. Sufficient serum, Bence Jones protein, or tissue samples
from CSH patients should be obtained to support such studies. (3) The
observation of localized CSH in individual cases of extramedullary
polyclonal nonneoplastic plasma cell proliferations in the
literature1 is not explained by the above-mentioned pathogenic suggestion.35 One might speculate that the
accumulation of crystalline proteins is here, in fact, the result of
overproduction. But this has not been proven yet. (4) Although
crystallizable In summary, we report a case that represents a very rare association of
MGUS with generalized CSH. The case presented here and the review of
the previous literature strongly suggest that the generalized form of
CSH is highly associated with a poor prognosis, whereas localized forms
of CSH have a more favorable clinical course. Although
immunohistochemistry showed a polyclonal storage pattern of
immunoglobulins, 2-DE revealed the prevalence of a monoclonal IgA Because collection of protein samples for sequence analysis has not been a standard procedure in CSH patients so far, we recommend the storage and analysis of serum, urine, and tissue samples from such patients to accumulate sequence data systematically.
We are grateful to Dr S. Liebmann, S. Madsen-Unverfärth, H. Muthmann, S. Schäfer, and A. Sendelhofert for skillful technical assistance. We thank Priv-Doz Dr R. Gruber for his excellent support and keen observation in the interpretation of the immunobiologic serum and urine data.
Submitted July 5, 2001; accepted April 25, 2002.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Annette Lebeau, Pathologisches Institut der Ludwig-Maximilians-Universität, Thalkirchner Str. 36, 80337 München, Germany; e-mail: a.lebeau{at}lrz.uni-muenchen.de.
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  P. Shenjere, A. Roy, B. Eyden, and S. S Banerjee Pseudo-Gaucher Cells in Multiple Myeloma International Journal of Surgical Pathology, April 1, 2008; 16(2): 176 - 179. [Abstract] [PDF]
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A Wei and S Juneja Bone marrow immunohistology of plasma cell neoplasms J. Clin. Pathol., June 1, 2003; 56(6): 406 - 411. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
I variability subgroup. We identified some unusual amino acid
substitutions including Leu59, usually important for
hydrophobic interactions within a protein, at a position where it has
never been previously described in plasma cell disorders. In
conclusion, we present the first case of CSH with molecular
identification of the stored 
Leu), 70 (Asp
organ distribution and modulation in vitro.
Eur J Biochem.
1997;247:792-800