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Crystal storing histiocytosis: A disorder occurring in plasmacytic tumors expressing immunoglobulin kappa light chain
Crystal.Storing Histiocytosis: A Disorder Occurring in Plasmacytic Tumors Expressing Immunoglobulin Kappa Light Chain DAN JONES, MD, PHD, VINAY K, BHATIA, MBBS, MRCP, THOMAS KRAUSZ, MD, AND GERALDINE S, PINKUS, MD Intracellular immunoglobulin crystal formation within plasma cells is an uncommon finding in multiple myeloma and other lyanphoplasmacytie tumors. We present 12 cases of plasmacytic tumors with prominent crystal formation, including myeloma (5 cases), lymphoplasmacytic lymphoma (6 cases), and a nonneoplastic plasma cell proliferation. In all cases, crystal formation was associated with the proliferation of variable numbers of histiocytes containing similar inclusions. These cases showed a variety of appearances, sometimes obscuring the underlying plasma cell tumor and raising the differential diagnosis of a storage disorder, hemophagocytosis, or a mesenchymal lesion. In cases of lymphoplasmacytlc lymphoma, patients typically presented with marked paraproteinemia and symptoms of hyperviscosity. Crystal-storing hlstiocytosis was not associated with other immtmoglobulin deposition disorders, including amyloidosis, Mott cell tumors, or kappa-light chain deposition. In our cases and those previously reported, we found an overwhelming association of
crystal-storing histiocytosis (CSH) with tumors expressing inununoglobulin kappa fight chain with no consistent association with a particular heavy chain. These results suggest that CSH results from the ingestion of crystals produced by plasma cell tumors that either overproduce kappa light chain or express a structurally aberrant molecule. CSH persists in the marrow and other sites throughout the course of the disease and in our series was not highly associated with development of the adult Fanconi syndrome or rapid clinical deterioration. Hu~ PATROL30:1441-1448. Copyright © 1999 by W.B. Saunders Company Key words: multiple myeloma, plasma cell granuloma, storage disease, lymphoplasmacyfc lymphoma. Abbreviations: LCD, fight chain deposition disease; MGUS, monoclonal gammopathies of undetermined significance; CSH, crystalstoring histiocytosis; Ig, immunoglohulin; LPL, lymphoplasmacytic lymphoma.
In multiple myeloma, there are several distinct clinical syndromes involving deposition of excess immunoglobulin. These include myeloma nephrosis (precipitation o f excess light chains within renal tubules), amyloidosis (localized or systemic deposition of predominantly lambda light chain fibrillary material), and light chain deposition disease (LCD--extramedullary and glomerular deposition of non-fibrillary kappa light chains). 1,2 Deposition of immunoglobulin can contribute to progressive organ damage, particularly renal failure, in these patients. The rarest immunoglobulin deposition disorders in plasmacytic tumors are related to the property of some abnormal immunoglobulins to u n d e r g o crystallization intracellularly and extracellularly. Cryocrystalglobulinemia is an extremely unusual, often fatal, complication of plasma cell dyscrasia characterized by the intravascular formation of large immunoglobulin crystals. These are typically cryoprecipitible immunoglobulins and lead to vessel thrombosis with resultant skin ulceration and end-organ ischemic damage. 3 A related entity t e r m e d "crystal-storing histiocytosis" is the proliferation in the bone marrow and at extramedullary sites of Gaucher-like histiocytes that contain numerous immu-
noglobulin crystals. Deposition of similar crystals also can occur in other cell types, particularly in the kidney and cornea. 4,5 Deposition of immunoglobulin crystals within renal glomerular podocytes and proximal tubular epithelium is highly associated with the developm e n t of the adult Fanconi syndrome, a rapidly progressive dysfunction of proximal tubules associated with glycosuria, aminoaciduria, and hypophosphatemia. 6,7 Deposition within the c o r n e a leads to crystalline keratinopathy, s We present 12 cases of plasmacytic tumors associated with crystal formation and storage histiocytosis, review the previously reported cases, and c o m m e n t on clinical features and possible pathogenic mechanisms.
From the Department of Pathology, UT-M.D. Anderson Cancer Center, Houston, TX; the Department of Pathology and the Division of Hematopathology, Brigham and Women's Hospital, Boston, MA; and the Departments of Histopathology and Medicine, Hammersmith Hospital, London, United Kingdom. Accepted for publication August 16, 1999. Address correspondence and reprint requests to Dan Jones, MD, PhD~ UT-M.D. Anderson Cancer Center, Department of Pathology, 1515 Holcombe Blvd, Houston, TX 77030. Copyright © 1999 by W.B. Saunders Company 0046-8177/99/3012-0012510.00/0
METHODS The histology flies of the Brigham and Women's Hospital from 1982 to 1999 were searched for cases of multiple myeloma, lymphoma, or plasmacytosis associated with inclusions within lymphoma or plasma cells. Cases were identified by text search of the microscopic description of all hematopathology reports for "inclusion," "crystal," or "deposition." Case 12 was previously reported. 9 An additional case (#7) was obtained from the consultation files of Hammersmith Hospital, London, England. Histology was reviewed to assess the percentage of the cellularity in the biopsy-containing plasma cell and histiocyte crystals. Cases were included if histologically identifiable crystal-laden histiocytes constituted at least 5% of the tumor infiltrate. For bone marrow biopsies, the percentage of marrow cellularity comprising histiocytes and plasma cells was quantified after immunohistochemistry. Immunoperoxidase studies were performed on Zenker's or formalin-fixed, paraffin-embedded tissue using antibodies directed against the histiocyte markers lysozyme and CD68 (KP1) and rabbit polyclonal antibodies against immunoglobu-
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lins mu, alpha, gamma, kappa, and lambda chains (all from DAKO, Carpinteria, CA). Cryostat immunostains were done on cases 6, 8, 11, and 12 using mouse monoclonal antibodies against heavy and light immunoglobulins (provided by Dr Lee Nadler, Dana Farber Cancer Institute, Boston, M.A). In situ hybridization for kappa and lambda light chain sequences was done on case 7 using commercially available probes. Tissue for ultrastructural analysis (cases 6 and 12) was fixed in Karnovsky's fixative, postfixed in osmium tetroxide, embedded in epoxy resin, and stained with uranyl acetate before examination. RESULTS
Clinical F e a t u r e s The 12 patients reported here include 7 men and 5 women with a mean age at diagnosis of 59 years (range, 35 to 77 years). They include 5 myeloma or m o n o d o n a l gammopathy of u n d e t e r m i n e d significance (MGUS) patients, who had presentations typical of myeloma including bone pain, elevated serum proteins, hypercalcemia, and anemia (Table 1). One case of acute renal failure was noted at presentation. Four myeloma patients with follow-up biopsies showed persistence of crystal-storing histiocytosis (CSH) after chemotherapy or bone marrow transplantation. A full autopsy done on 1 patient (case 3) showed extensive myelomatous involvement of marrow with presence of crystal-containing histiocytes in skull and lymph node but not in kidney or bowel (data not shown). Six patients with CSH in association with lymphoplasmacytic lymphoma were noted, 3 of whom presented with splenomegaly, 2 with symptoms of hypervisTABLE 1. Case
A/S
cosity and 1 with renal failure. Four patients had marked immunoglobulin (Ig) G or IgM serum paraproteinemia (range, 3 to 4.5 g / d L ) , which remained high throughout the course of disease. Serum electrophoresis showed biclonal or triclonal gamma globulin Mspikes in 4 patients, which were confirmed to include kappa light chain by immunofixation or immunoelectrophoresis in 3 patients. Marrow disease (including CSH) and paraproteinemia persisted despite multiple rounds of chemotherapy in the 4 patients with long-term follow-up. One patient recently presented with a large cell transformation of an underlying lymphoplasmacytic lymphoma, with CSH present in both lymph node and marrow biopsies. Case 11 is that of a 36-year-old woman with a long-standing history of autoimmune abnormalities, including a diagnosis of childhood lupus. She developed abdominal discomfort and had gastric biopsies that showed crystal4aden histiocytes. The patient received only localized radiation therapy to the stomach but within months developed blurry vision attributable to a hyperviscosity syndrome with marked hypergammaglobulinemia containing both a monoclonal and polyclonal c o m p o n e n t . Extensive radiological workup showed a small retrosternal thymic lymphoma. Despite resection, radiation therapy, and chemotherapy, the patient had persistent disease, with plasmaphoresis used to control symptoms of hyperviscosity. The remaining patient was a M-year-old woman who was noted to have a solitary lung mass on routine chest radiograph, which showed a plasma cell granuloma on resection. The patient was noted to have a
Crystal-Storing Histiocytosis: Summary of Clinical and Pathological Features
Presenting Symptom(s)
Dx
Ig Type (IHC)
Paraprotein (g/dL)
Sites of Deposition
Clinical Course
1. 2. 3.
48/M Paraproteinemia 53/M Bone pain, anemia 50/M Bone pain
MM MM MM
IgAK IgAK IgGK
S = 4.5/IgAK S S = 0.2
BM BM BM, skull, LN
4.
77/F
MM
K only
S
BM
Recur S/P BMT Lost to follow-up BMT DOD at 10 mos Recur S/P CTX
MGUS IgAK
S = 1.0/IgAK
BM
Recur S/P BMT
LPL
IgMK
S = 0.04/biclonal U = 2.0/biclonal
BM, spleen (3860g) DOD at 8 mos
Nausea/hyponatremia LPL Renal failure Hy-percalcemia systemic amyloid Hyerviscosity LPL
IgMK
S = 4.0/triclonal LN IgM - > GK, two K U = K S = 3.6/IgMK BM +/-biclonal K Nd BM, LN S = 4.5/biclonal LN, BM spleen
5. 6.
Anemia Renal failure 66/M Bone pain Hypercalcemia 66/M Splenomegaly Cold agglutinin
7.
68/F
8.
53/F
9. 10. 11. 12.
70/M Splenomegaly 70/M Abdominal pain Splenomegaly 35/F Gastric pain Hyperviscosity 54/F
Incidental
IgMK
LPL LPL
IgMK IgMX
CSH
IgA > IgG, S = 4.7/IgG)t K> X Polyclonal IgA IgGX polyclonal Nd
LPL PCG
Stomach, Thymus, BM Lung
Persistent S/P CTX (cyclophosphamide) PersistentS/P CTX (2-CDA, CVP, Rx) Transformed to LCL at 24 mos CTX (C-MOP, ara-C) DOD at 4 mos Polyclonal CSH Persistent S/P CTX (Chlor/Flud) Surgery only Recurred at 10 yr
Abbreviations: MM, multiple myeloma; LPL, lymphoplasmacytic lymphoma; PCG, plasma cell granuloma; S, serum M-spike; U, urine M-spike; BM, bone marrow; LN, lymph node; (a)BMT, (autologous) bone marrow transplant; DOD, died of disease; LCL, large cell lymphoma; CTX, chemotherapy; Chlor, chlorambucil; Flud, fludarabine; ND, not done; CVP, cyclophosphamide/vincristine/prednisone; Rx, Rituxan (anti-CD20 antibody).
CRYSTAL-STORINGHISTIOCYTOSIS(Joneset al) recurrent nodule in the same lung 10 years later, which had an identical histological appearance. Elevated total serum protein was not noted (serum electrophoresis not done). Forty-eight months late1; the patient shows no evidence of disease recurrence.
Histological, Ultrastructural and Immunophenotypic Features Prominent crystalloid inclusions were identified within plasma cells in all 5 cases of multiple myeloma/ MGUS, 6 cases of lymphoplasmacytic lymphoma (LPL), and the reactive plasmacytic lesion from the lung. Variable numbers of histiocytes containing similar crystalloid inclusions were seen. In 1 myeloma case, the crystal-containing histiocytes were present in such great numbers, diffusely infiltrating the marrow space, that the diagnosis of a hemophagocytic syndrome (Fig 1A) was suggested by the referring institution. The other 4 cases of myeloma showed multiple foci of numerous crystal-laden histiocytes that had the appearance of loose granulomas/aggregates. Immunohistochemical stains showed monotypic kappa immunoglobulin light chain staining of the plasma cells in all 5 cases (Fig 1C and not shown). Three cases were reactive for IgA, one for IgM, and 1 had no detectable heavy chain expression. CD68-positlve histiocytes generally showed only weak monotypic staining for immunoglobulin, possibly because of the inaccessibility of crystalline deposits to staining reagents. Two patients with lymphoplasmacytic lymphoma presented with replacement of the marrow space by crystal-containing plasma cells and histiocytes resembling those of a metabolic storage disorder such as Gaucher's disease (Fig 1D/E). However, in contrast to the faint cytoplasmic striations typical of Gaucher storage-type histiocytes (Fig 1F), the periodic acid-Schifffaint/negative immunoglobulin inclusions had either a chunky, angular appearance or a needle4ike refractile quality on aspirate smears. In the bone marrow of 3 other cases, crystal-containing histiocytes were admixed within neoplastic lymphoplasmacytic aggregates (not shown). In lymph node biopsies from 3 lymphomas, numerous crystal-laden histiocytes formed confluent sheets suggestive of nodal replacement by a systemic histiocytosis or infectious process (Fig 1G). Immunostaining showed monotypic IgM within tumor cells in 5 cases, with kappa light chain in 4, and lambda in 1 (Fig 1J). CD68- or lysozyme-positive histiocytes typically showed weak monotypic staining for immunoglobulins (Fig 1I). The findings in case 11, in which an autoimmune disorder and recurrent crystal-storing histiocytosis of the stomach preceded the diagnosis of a thymic lymphoma, were complex. In multiple gastric biopsies, sheets of histiocytes with needle-like crystals were present in the lamina propria with only a mild infiltrate of polyclonal plasma cells, mostly IgA/kappa (Fig 1K and data not shown). Crystals in the histiocytes showed predominant staining for kappa light chain. Subsequently, the patient's thymic lymphoma showed a monoclonal lambda IgG staining pattern, matching the pa-
tient's large serum paraprotein. Crystals were relatively sparse in the thymic tumor. Subsequent marrow infiltrates showed lymphoplasmacytic aggregates with a lambda light-chain predominance as well as crystalladen histiocytes. It thus is not clear whether the crystals in the stomach biopsy were derived from the monoclonal IgG lambda or the elevated polyclonal immunoglobulin. We also noted 1 case of a recurrent plasma cell lesion of the lung that showed an extensive infiltrate of epithelioid and spindle-shaped CD68-positive histiocytes filled with numerous needle-shaped immunoglobulin inclusions (Fig 1I). Crystals expanded the lung interstitium and extended into the alveolar spaces and were surrounded by foci of lymphoplasmacytic inflammation. In both the original tumor and the recurrence, we have previously shown polytypic reactivity for heavy and light chain immunoglobulin and absence of a heavy chain gene rearrangement by polymerase chain reaction analysis. 9 Electron microscopy in this case showed numerous rhomboidal and needle-shaped crystals present in both the cytoplasm of plasma cells and adjacent histiocytic-appearing mononuclear cells. Within plasma cells, crystals with a linear arrangement and faint fibrillarity were often present within dilated rough endoplasmic reticulum (Fig 2A). Some cells showed dilation of endoplasmic reticulum by amorphous material, and others showed an association of forming crystals with cylindrical inclusions (Fig 2B). Histiocytes, in this case and in case 6, typically showed only the angulated crystals (data not shown). In our review of cases for this study, we also noted 5 bone marrow biopsies with rare crystals present in less than 5% of plasma cells. Interestingly, 2 of these cases represented transient plasmacytic proliferations occurring in patients after bone marrow transplantation for chronic myelogenous leukemia. One case also showed a cluster of crystal-storing histiocytes (data not shown). Subsequent biopsies in both of these patients did not show persistent plasmacytosis or serum paraproteinemia. We also reviewed biopsy specimens of plasmacytic tumors that showed prominent Mott cells (2 LPLs), globular cytoplasmic inclusions (5 myeloma, 2 LPLs), or extracellular deposition of kappa light chain (9 myeloma) in the kidney or bone marrow. Proliferations of histiocytes were not seen in any of these cases. Tumors that showed prominent amyloid deposition (5 amyloidomas, 4 myeloma, 2 LPLs) often showed fibrosis and multinucleated giant cells surrounding areas of extracellular protein deposition without a generalized and diffuse histiocytic proliferation (data not shown).
Comparison With Previously Reported Cases We compared our immunophenotypic and ultrastructural findings with previously reported cases of tumors with immunoglobulin crystal formation (Table 2). In crystal-containing tumors classified by the authors as chronic lymphocytic leukemia, there was a striking predominance of lambda light chain expression (and IgM as expected). Crystals in these cases were large and
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FIGURE 1. Crystal-storing histiocytosis. (A-C) Case 4. Crystal-storing histiocytosis of the bone marrow in multiple myeloma resembling erythrophagocytosis. Marrow shows a diffuse infiltrate of histiocytes stuffed with eosinophilic inclusions (H&E stain), which have a globular appearance at high power (Giemsa stain). Immunostains demonstrated strong monotypic staining for immunoglobulin kappa light chain in plasma ceils and weak reactivity in histiocyte crystals. (D/E) Case 6. Lymphoplasmacytic lymphoma with crystalline inclusions in the bone marrow resembling a storage disease. Trephine biopsy shows numerous histiocytes and plasma cells filled with angular crystalline inclusions that have a globular or geometric appearance on Wright-Giemsa-stained aspirate. (F) in contrast, storage histiocytes from a patient with Gaucher's disease show cytoplasmic striations, (G) Case 7. Lymphoplasmacytic lymphoma with sheets of crystal-laden histiocytes replacing large areas of the lymph node (H&E). (H) In situ hybridization shows positivity for kappa light chain sequences in lymphoplasmacytic tumor ceils. (I) CD68 immunostain highiights crystal-containing histiocytes. (J) Case 10. Crystal-containing histiocytes in a lymphoplasmacytic lymphoma expressing monotypic Lambda light chain (Giemsa). (K) Case 11. Crystal-storing histiocytosis. Numerous crystal-storing histiocytes filling lamina propria surrounded by scant lymphoplasmacytic infiltrate (H&E), (L) Case 12. Plasma cell granuloma of the lung. Sheets of spindle-shaped histiocytes fining alveolar spaces surrounded by a polyclonal lymphoplasmacytic infiltrate (H&E).
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FIGURE2. Ultrastructure of crystalloid inclusions, Case 12. (A) Angulated crystals with fine fibrillarity noted within the dilated rough endoplasmic reticulum of a plasma cell. (B) Geometrically shaped crystals were noted in association with cylindrical membranebound inclusions.
few in numbeI, with a rectangular or polygonal shape (Table 2). In n o n e of these cases was crystal-storing histiocytosis reported. Cases of cryocrystalglobulinemia were also not associated with CSH and showed no consistent association with any immunoglobulin type. In contrast, crystal-containing tumors with plasmacytic differentiation (multiple myeloma, MGUS, LPL, and plasmacytoma) showed a striking p r e d o m i n a n c e of kappa light chain expression, especially in those cases associated with CSH. Besides our cases, only 3 lambdaexpressing tumors have been r e p o r t e d that show the sheet-like proliferation of crystaMaden histiocytes characteristic of CSH. 1°'12 This is in contrast to the more than 60 cases that express kappa light chain. Indeed, cases of lymphom a with lambda-containing crystal formation t e n d e d to show large intracellular/extracellular rhomboidal crystals that were not present in adjacent histiocytes. ~°,13,14 Thus, there is a highly significant association of CSH with kappa light chain expression. DISCUSSION
We present 12 cases of plasmacytic tumors with p r o m i n e n t crystal formation, including 5 myelomas, 6 lymphoplasmacytic lymphomas, and 1 apparently nonneoplastic plasma cell proliferation. In all cases, crystal TABLE 2,
formation was associated with proliferation of histiocytes containing similar crystals. Crystal-storing histiocytosis was not f o u n d in association with other immunoglobulin deposition disorders, including Mott cell myeloma/lymphoma, LCD, and amyloidosis. These cases are similar to previously published case reports and provide additional evidence that immunoglobulin crystal formation by plasma cells is frequently (perhaps invariably) associated with proliferations of crystalladen histiocytes. Given their rarity, the appearance of crystal-storing histiocytes often presents diagnostic difficulties. In several cases of myeloma, the degree of histiocytosis in the marrow was so increased in p r o p o r t i o n to the plasma cell c o m p o n e n t that the diagnoses of a storage disorder or hemophagocytic syndrome were initially considered. Several reports have emphasized that because o f their ample fibrillary cytoplasm, crystal-storing histiocytes can be misidentified, especially if the plasma cells c o m p o n e n t is not readily appreciated. ~5 Cases presenting in the marrow most often resemble storage disorders such as Gaucher's disease. However, on aspirate smears, the coarse, crystalloid nature of the inclusions can be distinguished from the fine fibrillarity seen in Gaucher cells.16 Crystal-storing histiocytes seen in extramedullary sites may be mistaken for rhabdomyoma
Summary of Previously Characterized Tumors With Crystalloid Immunoglobulin Inclusions
Tumor Type CLL and CLLVariants Lymphoplasmacytic Lymphoma Myeloma/Plasmacytoma MGUS Cryocrystalglobulinemia
Ig Type
Associated CSH
CrystalAppearance
References
K;2, k; 23 IgM; 22 IgG; 3, IgA; 3 K:8, k: 5, c/k: 1 IgM10, IgG/M: 1 IgG; 2, IgA; 1 K:37, k: 9 IgG; 30, IgA; 9 IgM; 2, IgD; 1 K:5, X; 1 IgG; 5, IgM: 1 K:4, k: 4 IgG; 5, IgD; 1
None reported
Large, rhomboidal Few per cell
24, 30-34,36, 37
K:8, K/k: 1 k: 2
K/k: Needle-shaped
4, 11, 12, 17, 32, 38-43
~: 35 k: 1
K:Needle-shaped k: Large extracellular (with giant cells)
3, 5, 8, 10, 13, 14, 16, 25, 27, 28, 44-78 79-83
None reported
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cells, 4 fibrosclerosis, 17 or other types of histiocytosis. 12,1s Identifying similar crystalloid inclusions in the surrounding plasma cells is the key to diagnosis. T h e mechanism of formation of plasma cell crystals is not known. The cases presented here, and our extensive review of the previous literature, strongly support a primary role for kappa light chain in crystals that p r o d u c e CSH. Although CSH can occur in plasmacytic tumors expressing any or n o n e of the heavy chains, nearly every case r e p o r t e d expresses kappa light chain (Table 2). Only a single case of heavy-chain-only CSH has been seen, suggesting a role for light chain multimerization in crystal formation. 19 Crystal-forming tumors that show deposition of crystals in renal or corneal epithelium are also nearly completely associated with kappa light chain expression, supporting the close association of CSH to these entities (Table 2). Ultrastrucrural evidence presented here and elsewhere also clearly demonstrates that crystal formation occurs within the plasma cells in the endoplasmic reticulum before excretion, likely making immunoglobulin aggregates difficult to degrade or excrete. We also noted the association of tubular structures within the same saccules as forming crystals, suggesting that these arrays may be a substrate for crystallization. A possible mechanism of crystal formation may be overproduction of kappa light chain. Indeed, 4 of the patients in our study demonstrated free kappa chain by immunofixation/immunoelectrophoresis. It has b e e n previously demonstrated that intraperitoneal injection of free kappa light chain from a myeloma patient can result in a Fanconi-like syndrome in mice, with the formation in the kidney of intracellular crystals identical to those in CSH. O u r 2 cases and 1 from Bosman et al is indicate that CSH also can occur in cases of polyclonal immunoglobulin activation, supporting overproduction as a mechanism of crystal formation. O f interest in this regard was our finding of occasional plasma cell crystals and focal CSH in several patients with posttransplantation plasmacytosis, because transplant patients are known to have transient dysregulation and overproduction of immunoglobulin. 2°,~1In our review, however, other types of immunoglobulin inclusions (eg, Mort cell globular inclusions) were not associated with CSH, and some of the patients in our series had minimal serum or urine paraprotein levels, emphasizing that immunoglobulin overproduction is unlikely to be the sole cause of CSH. It is likely that many cases of CSH arise from tumors with specific immunoglobulin mutations. Earlier studies o f the structure of mutant crystallizable immunoglobulins showed heavy chain hinge region deletions in some cases. An aberrant crystallizable immunoglobulin also has been r e p o r t e d that does not form appropriate disulfide bridges. I° More recent studies of 4 immunoglobulin molecules isolated from patients with the adult Fanconi syndrome have shown consistent use of the same variable region of the kappa chain as well as variable region amino acid substitutions similar to those seen in kappa-amyloidogenic molecules. 22 This supports a model whereby crystallization of immunoglobu-
lin is related to sequence variations in immunoglobulin that prevent p r o p e r interaction of heavy and light chains. Unlike amyloidogenic lambda light chain, kappa light chains may not dimerize, so the exact structure of these immunoglobulin aggregates remains to be determinedY s It is possible that an abnormal kappa chain may be less efficiently secreted or improperly glycosylated and thereby b e c o m e trapped within the secretory machinery, allowing time for the multimerization to occur. 2,24 The reason for persistence of crystals within histiocytes is also unknown. Given that crystals deposit at remote sites such as corneal epithelium, it is likely that larger crystals reform within phagocytic cells after ingestion of smaller crystallizable immunoglobulin aggregates circulating in the bloodstream. ~5 Reports of CSH at autopsy show widespread deposition of crystals within cells from numerous sites in addition to kidney, cornea, and histiocytes. 5,1s,15,26-28 Electron microscopic studies have shown a morphological spectrum in histiocyte crystals from poorly f o r m e d fibriUary inclusions to well-formed geometric structures as well as intermediary forms present in the lysosomes. 8 A separate study showed that 4 cases of kappa light chains from Fanconi syndrome patients (unlike those producing cast nephropathy) were resistant to proteolytic cleavage in vitro, suggesting that crystal accumulation in the lysosomes may result from resistance to degradation. 29 The few cases o f CSH resulting from tumors expressing lambda light chain (our case 9 and references 10-12) show that lambda light chain can form crystals, although the inclusions often appear larger and more globular as c o m p a r e d with kappa-producing cases. They appear similar to those occasionally seen in lambdaexpressing small lymphocytic lymphoma, which have fewer, large, rhomboidal crystals with a well-formed lattice structure and secrete little if any immunoglobulin. 24,s°s4 Crystal-storing histiocytosis is not a feature of these cases. Thus, the type of immunoglobulin light chain molecule, as well as the a m o u n t o f i m m u n o g l o b u lin produced, determines the degree o f crystal formation and resultant histiocytosis observed. Although crystallizable kappa light chains are present in nearly all cases of renal failure due to adult Fanconi syndrome, 6 the cases r e p o r t e d here and many others in the literature emphasize that this is an uncomm o n complication of patients with CSH. Indeed, many myeloma patients with CSH have r e p o r t e d survivals of 5 to 15 years after diagnosis, which is longer than the median survival for this tumor, s5 Patients with CSH also commonly present at an early stage with low paraprotein levels, hypogammaglobulinemia, and minimal plasma cell infiltrates. It is likely that the symptoms of immunoglobulin crystallization (eg, organomegaly, or visual problems secondary to keratinopathy) lead to diagnosis at earlier stages of disease than would otherwise occur. In the absence of renal failure, crystalstoring histiocytosis is not necessarily associated with a p o o r clinical prognosis.
Acknowledgment. The authors thank Dr A.G. Gibson of Kent and Canterbury Hospital, Canterbury, UK, for contribu-
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CRYSTAL-STORING HISTIOCYTOSIS(Jones et ol) tion of case material, Dr Carl O ' H a r a for preliminary studies, Myson Smeedy for e x p e r t technical assistance, and Drs R. Schlossman and H. H o c k (Dana Farber Cancer Center, Boston, MA) for providing clinical information.
REFERENCES 1. Cohen AH, Border WA: Myeloma kidney: An immunomorphogenetic study of renal biopsies. Lab Invest 42:248-256, 1980 2. Preud'Homme JL, Morel-Maroger L, Broeut JC: Synthesis of abnormal immunoglobulins in lymphoplasmacytic disorders with visceral light chain deposition. AmJ Med 69:703-710, 1980 3. Kalderon AE, Bognaars HA, Diamond I, et al: Ultrastructure of myeloma cells in a case with crystalcryoglobulinemia. Cancer 39:1475-1481, 1977 4. ILapadia SB, Enzinger FM, Heffner DK, et al: Crystal-storing histiocytosis associated with lymphoplasmacytic neoplasms: Report of three cases mimicking adult rhabdomyoma. AmJ Surg Pathol 17:461467, 1993 5. Yamamoto T, Hishida A, Honda N, et al: Crystal-storing histiocytes and crystalline tissue deposition in multiple myeloma. Arch Pathol Lab Med 115:351-354, 1991 6. MaldonadoJE, VelosaJA, Kyle RA, et al: Fanconi syndrome in adults. AmJ Med 58:354-361, 1975 7. Engle RI, WMlis LA: Multiple myeloma and the adult Fanconi syndrome. AmJ Med 22:5-12, 1957 8. StirlingJ'W, Henderson DW, Rozenbilds MA, et al: Crystalloidal paraprotein deposits in the cornea: An ultrastructural study of two new cases with tubular crystalloids that contain IgG kappa light chains and IgG gamma heavy chains. Ultrastruct Patho121:337-344, 1997 9. Jones D, Renshaw A: Recurrent crystal-storing histiocytosis of the lung. Arch Pathol Lab Med 120:978-980, 1996 10. Green ED, Morrison LK, Love PE, et al: A structurally aberrant immunoglobulin paraprotein in a patient with multiple myeloma and corneal crystal deposits. AmJ Med 88:304-11, 1990 11. Llobet M, Castro P, Barcelo C, et al: Massive crystal-storing histiocytosis associated with low-grade malignant B-cell lyanphoma of MALT-type of the parotid gland. Diagn Cytopathol 17:148-152, 1997 12. Harada M, Shimada M, Fukayama M, et al: Crystal-storing histiocytosis associated with lymphoplasmacytic lymphoma mimicking Webel~Christian disease: Immunohist0chemical, ultrastructural, and gene-rearrangement studies. HuM PAXI-IOL27:84-87, 1996 13. Hirota S, Miyamoto M, Kasugai T, et al: Crystalline fightchain deposition and amyloidosis in the thyToid gland and kidneys of a patient with myeloma. Arch Pathol Lab Med 114:429-431, 1990 14. Schvartz H, Bonhomme P, Caulet S, et al: Bone marrow lambda-type light chain crystalline structures associated with multiple myeloma. Virchows Arch A Pathol Anat Histopathol 407:449-456, 1985 15. Terashima K, Takahashi K, Kojima M, et al: Kappa-type light chain crystal storage histiocytosis. Acta Path Jap 28:111-138, 1978 16. Scullin DC Jr, Shelburne JD, Cohen HJ: Pseudo-Gaucher cells in multiple myeloma. AmJ Med 67:347-352, 1979 17. GarciaJF, SanchezE, LloretE, etal: Crystal-storinghistiocytosis and immunocytoma associated with multifocal fibrosclerosis. Histopathology 33:459-464, 1998 18. Bosman C, Camassei FD, Boldrini R, et al: Solitary crystalstoring histiocytosis of the tongue in a patient with rheumatoid arthritis and polyclonal hypergammaglobulinemia. Arch Pathol Lab Med 122:920-924, 1998 19. Veloso FT, Saliero JV, Olviera AO, et al: Atypical plasma ceils in alpha-chain disease. Cancer 52:79-82, 1983 20. Mitus AJ, Stein R, Rappeport JM, et al: Monoclonal and oligoclonal gammopathy after bone marrow transplantation. Blood 74:2764-2768, 1989 21. Kagan JM, Champlin RE, Saxon A: B cell dysfunction following human bone marrow transplantation: Functional-phenotypic dissociation in the early post-transplant period. Blood 74:777785, 1989 22. Khamlichi AA, Rocca A, Touchard G, et al: Role of light chain variable region in myeloma with light chain deposition disease: Evidence from an experimental model. Blood 86:3655-3659, 1995
23. Stevens FJ, Solomon A, Schiffer M: BenceJones proteins: A powerful tool for the fundamental study of protein chemistry and pathophysiology. Biochemistry 30:6803-6805, 1991 24. Roberts GH, Gordon J, Smith JL, et al: Biosynthesis and characterisation of IgM-lambda in a case of chronic lymphocytic leukemia with intracellular immunoglobulin inclusions. J Clin Pathol 32:271-279, 1979 25. Hashimoto N, Kurihara K, Sakai H: Extramedullary plasmacytoma with crystal inclusions arising from the palatal tonsil. J Oral Pathol 12:309-318, 1983 26. Agress H, Smith MG: Purpura hemorrhagica associated with widespread deposits of crystalline material: Reticuloendotheliosis. Arch Pathol 29:553-560, 1940 27. Ito S, Goshima K, Niinimi M, et al: Electron microscopic studies of the crystalline inclusions in the myeloma cells and kidneys of c~-BenceJones protein type myeloma. Acta HaematJap 33:598-617, 1970 28. Chejfec G, Natarelli J, Gould VE: "Myeloma lung": A previously unreported complication of multiple myeloma. HuM PATHOL 14:558-561, 1983 29. Leboulleux M, Lelongt B, Mougenot B, et al: Protease resistance and binding of Ig light chains in myeloma-associated tubulopathies. Kidney Int 48:72-79, 1995 30. Ralfldaer E, Hou-Jensen K, Geilser C, et al: Cytoplasmic inclusions in lymphocytes of chronic lymphocytic leukaemia. Virchows Arch 395:227-236, 1982 31. Cawley JC, Smith J, Goldstone AH, et al: IgA and IgM cytoplasmic inclusions in a series of cases of chronic lymphocytic leukaemia. Clin Exp Immunol 23:78-82, 1976 32. Feremans WW, Neve P, Caudron M: IgM lambda cytoplasmic crystals in three cases of immunocytoma: A clinical, cytochemical, and ultrastructural study.J Clin Pathol 31:250-258, 1978 33. Hurez D, Flandrin G, Preud'homme JL, et al: Unreleased intracellular monoclonal macroglobulin in chronic lymphocytic leukaemia. Clin Exp lmmunol 10:223-234, 1972 34. Peters O, Thielemans C, Steenssens L, et al: Intracellular inclusion bodies in 14 patients with B cell lymphoproliferative disorders.J Clin Pathol 37:45-50, 1984 35. Pasqualetti P, Festuccia V, Collacciani A, et al: The natural history of monoclonal gammopathy of undetermined significance. Acta Haematol 97:174-179, 1997 36. Ricci A Jr, Monahan RA, Paradise C, et al: Unusual inclusions in plasmacytoid cells: Their occurrence in a patient with Waldenstrom's macroglobulinemia. Arch Pathol Lab Med 106:452-457, 1982 37. Clark C, Rydell RE, Kaplan ME: Frequent association oflgM lambda with crystalline inclusions in chronic lymphatic leukemic lymphocytes. N Engl J Med 289:113-117, 1973 38. Prasad MJ, Charney DA, Sarlin J, Keller SM: Pulmonary immunocytoma with massive crystal storing histiocytosis. Am J Surg Pathol 22:1148-1153, 1998 39. Fend E Gabl C, Hittmair A, et al: Gastric malt lymphoma with crystalline immunoglobulin inclusions and secondary immunoblastic lymphoma in a cervical lymph node. Pathol Res Pract 191:1053-1058, 1995 40. Mennemeyer R, Hammar SE Cathey WJ: Malignant lymphoma with intracytoplasmic IgM crystalline inclusions. N EnglJ Med 291:960-963, 1974 41. Friedman MT, Molho L, Valderrama E, et al: Crystal-storing histiocytosis associated with a lymphoplasmacytic neoplasm mimicking adult rhabdomyoma. Arch Pathol Lab Med 120:1133-1136, 1996 42. Kaufmann O, Hansen A, Deicke P, et al: Subcutaneous crystal-storing histiocytosis associated with lymphoplasmacytic lymphoma (immunocytoma). Pathol Res Pract 192:1148-51, 1996 43. Padmalatha C, Warner TF, Hafez GR: Pseudo-Gaucher cell in IgMK plasmacytoid lymphoma. AmJ Surg Pathol 5 (5) :501-5, 1981 44. Hailemariam S, Engeler DS, Koller TL, et al: [Unusual crystalline inclusions in plasmacytoma ceils of the testis in primary medullary plasmacytoma]. Pathologe 17:455-8, 1996 45. Chan KW, Ho FC, Chan MK: Adult Fanconi syndrome in kappa light chain myeloma. Arch Pathol Lab Med 111:139-142, 1987 46. Graham RC, Bernier GM: The bone marrow in multiple myeloma: Correlation of plasma cell ultrastructure and clinical state. Medicine 54:225-243, 1975
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47. Henderson DW, StirlingJW, LipsettJ, et al: Paraproteinemic crystaUoidal keratopathy: An ultrastructural study of two cases, including immunoelectron microscopy. Ultrastruct Pathol 17:643-668, 1993 48. Orfila C, Lepert JC, Modesm A, et al: Fanconi's syndrome, kapp a light-chain myeloma, non-amyloid fibrils and cytoplasmic crystals in r~nal tubular epithelium. Am J Nephrol 11:345-349, 1991 49. Pillay GS, Jacobs P: Crystalline cytoplasmic inclusions in myeloma. Arch Pathol Lab Med 118:1169-1170, 1994 50. Raman SB, Van Slyck EJ: Nature of intracytoplasmic crystalline inclusions in myeloma ceils (morphologic, cytochemical, ultrastructural, and immunofluorescent studies). AmJ C!in Patho180:224228, 1983 51. Truong LD, Mawad J, Cagle P, et al: Cytoplasmic crystals in multiple myeloma-associated Fanconi's syndrome: A morphological study including immunoelectron microscopy. Arch Pathol Lab Med 113:781-785, 1989 52. Stavem P, Forre O: The same type of crystalline inclusions in T-lymphocytes as in plasma cells and B-lymphocytes in multiple myeloma: A pathological clone originating from a common lymphocyte stem cell? ScandJ Haemato126:265-271, 1981 53. Pinkerton RH, Robertson DM: Corneal and conjunctival changes in dysproteinemia. Opthalmology 8:357-364, 1969 54. Klintworth GK, Bredehoeft SJ, ReedJW: Analysis of corneal crystalline deposits in multiple myeloma. Am J Ophthalmol 86:303313, 1978 55. Gabriel L, Escribano L, Perales J, et al: Multiple myeloma with crystalline inclusions in most hematopoietic cells. AmJ Hematol 18:405411, 1985 56. Barr CC, Gelender H, Font RL: Corneal crystalline deposits associated with dysproteinemia: Report of two cases and review of the literature. Arch Ophthalmo198:884-889, 1980 57. Hoisen H, Ringvold A, Kildahl-Andersen O: Corneal crystalline deposits in multiple myeloma: A case report. Acta Ophthalmol (Copenh) 61:493-500, 1983 58. Steuhl KP, Knorr M, Rohrbach JM, et al: Paraproteinemic corneal deposits in plasma cell myeloma. AmJ Ophthalmol 111:312318, 1991 59. Towheed TE, Ferrari R, Corbett WE, et al: Multiple myeloma presenting as a manubrial mass with intracytoplasmic crystal accumulation within macrophages. AmJ Hematol 48:66-67, 1995 (letter) 60. Tsuchikawa K, Yokomichi H, Satoh I, et al: A study of intracytoplasmic inclusions in myeloma cells from two patients with multiple myeloma. TohokuJ Exp Med 153:11-20, 1987 61. Takahashi K, Naito M, Takatsuki K, et al: Multiple myeloma, IgA kappa type accompanying crystal-storing histiocytosis and amyloidosis. Acta PatholJpn 37:141-154, 1987 62. Schillinger F, Hopfner C, Montagnac R, et al: [IgG kappa myeloma with Fanconi's syndrome and crystalline inclusions. Immunohistochemical and ultrastructural study]. Presse Med 22:675-679, 1993 63. Perry HD, Donnenfeld ED, Font RL: Intraepithelial corneal immunoglobulin crystals in IgG-kappa multiple myeloma. Cornea 12:448-450, 1993 64. Matsumoto K, Shikuwa S, Kawase Y, et al: Gastric plasmacytoma with rod-shaped intracytoplasmic inclusions. Acta Pathol Jpn 38:815-821, 1988 65. Levine SB, Bernstein LD: Crystalline inclusions in multiple myeloma.JAMA 254:1985, 1985 66. Kobayashi Y, Miyake T, Funakoshi N, et al: Gastric plasmacytoma with cylindrical crystalline inclusions. Gastro Japonica 22:81-87, 1987 67. Kornstein MJ, deBlois GG, Williams ME: Unusual biclonal plasma cell dyscrasia with crystaUike inclusions producing colonic
tumors (plasma cell polyposis) and terminating in T-cell lymphoma. Arch Pathol Lab Med 116:168-172, 1992 68. Kim YG, Yang KH, Gang SJ, et al: Solitary myeloma with massive extracellular crystalline structures: A case report. J Korean Med Sci 6:165-171, !991 69. Kawamura H, Seo T, Watanabe I, et al: [A case of corneal crystalline deposits associated with multiple myeloma]. Nippon Ganka Gakkai Zasshi 92:1473-1478, 1988 70. Jennette JC, Wilkman AS, Benson JD: IgD myeloma with intracytoplasmic crystalline inclusions. A m J Clin Pathol 75:231-235, 1981 71. Jenkins RE, Calonje E, Fawcett H, et al: Cutaneous crystalline deposits in myeloma. Arch Dermatol 130:484-488, 1994 72. Ishido T, Mori N: Primary gastric plasmacytoma: A morphological and immunohistochemical study of five cases. Am J Gastroentero187:875-878, 1992 73. Grossniklaus HE, Stulting RD, L'Hernanlt N: Corneal and conjunctival crystals in paraproteinemia. HUM PATHOL21:1181-1183, 1990 74. Ferrer-Roca O: Primary gastric plasmacytoma with massive intracytoplasmic crystalline inclusion. Cancer 50:755-759, 1982 75. E1-Naggar AK, Ordonez NG, Batsakis JG: Parotid gland plasmacytoma with crystalline deposits. Oral Surg Oral Med Oral Pathol 71:206-208, 1991 76. Carstens PH, Woo D: Crystalline glomerular inclusions in multiple myeloma. AmJ Kidney Dis 14:56-60, 1989 77. Azzaz B, Dewar A, Corrin B: An unusual pulmonary plasmacytoma. Histopathology 21:285-287, 1992 78. Auran JD, Donn A, Hyman GA: Multiple myeloma presenting as vortex crystalline keratopathy and complicated by endocapsular hematoma. Cornea 11:584-585, 1992 79. Nakamine H, Nshihara T, Saito K, et al: Needle-shaped inclusions in plasma cells in a patients with hypogammaglobulinemia. AmJ Clin Pathol 78:549-555, 1982 80. Ormerod LD, Collin HB, Dohlman CH, et al: Paraproteinemic crystalline keratopathy. Ophthalmology 95:202-212, 1988 81. Matsuyama N, Joh K, Yamaguchi Y, et al: Crystalline inclusions in the glomerular podocytes in a patient with benign monoclonal gammopathy and focal segmental glomerulosclerosis. Am J Kidney Dis 23:859-865, 1994 82. Eiferman RA, Rodrigues MM: Unusual superficial stromal corneal deposits in IgGk monoclonal gammopathy. Arch Ophthalmol 98:78-81, 1980 83. Cherry PMH, Kraft S, McGowan H, et al: Corneal and conjunctival deposits in monoclonal gammopathy. CanJ Ophthalmol 18:142-149, 1983 84. Dornan TL, Blundell JW, Morgan AG, et al: Widespread crystallisation of paraprotein in myelomatosis. Q J Med 57:659-667, 1985 85. Dotten DA, Pruzanski W, Olin J, et al: Cryocrystalglobulinemia. Can Med AssocJ 114:909-912, 1976 86. Schoengen A, Schreiner T, Anselstetter V, et al: Cryocrystalglobulinemia: pH-dependent precipitation ofa monoclonal IgG-kappaimmunoglobulin. Blut 58:255-260, 1989 87. Ball NJ, Wickert W, Marx LH, et al: Crystalglobulinemia syndrome: A manifestation of multiple myeloma. Cancer 71:12311234, 1993 88. Stone GC, Wall BA, Oppliger IR, et al: A vasculopathy with deposition of lambda light chain crystals. Ann Intern Med 110:275278, 1989
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crystal-storing histiocytosis (CSH) with tumors expressing inununoglobulin kappa fight chain with no consistent association with a particular heavy chain. These results suggest that CSH results from the ingestion of crystals produced by plasma cell tumors that either overproduce kappa light chain or express a structurally aberrant molecule. CSH persists in the marrow and other sites throughout the course of the disease and in our series was not highly associated with development of the adult Fanconi syndrome or rapid clinical deterioration. Hu~ PATROL30:1441-1448. Copyright © 1999 by W.B. Saunders Company Key words: multiple myeloma, plasma cell granuloma, storage disease, lymphoplasmacyfc lymphoma. Abbreviations: LCD, fight chain deposition disease; MGUS, monoclonal gammopathies of undetermined significance; CSH, crystalstoring histiocytosis; Ig, immunoglohulin; LPL, lymphoplasmacytic lymphoma.
In multiple myeloma, there are several distinct clinical syndromes involving deposition of excess immunoglobulin. These include myeloma nephrosis (precipitation o f excess light chains within renal tubules), amyloidosis (localized or systemic deposition of predominantly lambda light chain fibrillary material), and light chain deposition disease (LCD--extramedullary and glomerular deposition of non-fibrillary kappa light chains). 1,2 Deposition of immunoglobulin can contribute to progressive organ damage, particularly renal failure, in these patients. The rarest immunoglobulin deposition disorders in plasmacytic tumors are related to the property of some abnormal immunoglobulins to u n d e r g o crystallization intracellularly and extracellularly. Cryocrystalglobulinemia is an extremely unusual, often fatal, complication of plasma cell dyscrasia characterized by the intravascular formation of large immunoglobulin crystals. These are typically cryoprecipitible immunoglobulins and lead to vessel thrombosis with resultant skin ulceration and end-organ ischemic damage. 3 A related entity t e r m e d "crystal-storing histiocytosis" is the proliferation in the bone marrow and at extramedullary sites of Gaucher-like histiocytes that contain numerous immu-
noglobulin crystals. Deposition of similar crystals also can occur in other cell types, particularly in the kidney and cornea. 4,5 Deposition of immunoglobulin crystals within renal glomerular podocytes and proximal tubular epithelium is highly associated with the developm e n t of the adult Fanconi syndrome, a rapidly progressive dysfunction of proximal tubules associated with glycosuria, aminoaciduria, and hypophosphatemia. 6,7 Deposition within the c o r n e a leads to crystalline keratinopathy, s We present 12 cases of plasmacytic tumors associated with crystal formation and storage histiocytosis, review the previously reported cases, and c o m m e n t on clinical features and possible pathogenic mechanisms.
From the Department of Pathology, UT-M.D. Anderson Cancer Center, Houston, TX; the Department of Pathology and the Division of Hematopathology, Brigham and Women's Hospital, Boston, MA; and the Departments of Histopathology and Medicine, Hammersmith Hospital, London, United Kingdom. Accepted for publication August 16, 1999. Address correspondence and reprint requests to Dan Jones, MD, PhD~ UT-M.D. Anderson Cancer Center, Department of Pathology, 1515 Holcombe Blvd, Houston, TX 77030. Copyright © 1999 by W.B. Saunders Company 0046-8177/99/3012-0012510.00/0
METHODS The histology flies of the Brigham and Women's Hospital from 1982 to 1999 were searched for cases of multiple myeloma, lymphoma, or plasmacytosis associated with inclusions within lymphoma or plasma cells. Cases were identified by text search of the microscopic description of all hematopathology reports for "inclusion," "crystal," or "deposition." Case 12 was previously reported. 9 An additional case (#7) was obtained from the consultation files of Hammersmith Hospital, London, England. Histology was reviewed to assess the percentage of the cellularity in the biopsy-containing plasma cell and histiocyte crystals. Cases were included if histologically identifiable crystal-laden histiocytes constituted at least 5% of the tumor infiltrate. For bone marrow biopsies, the percentage of marrow cellularity comprising histiocytes and plasma cells was quantified after immunohistochemistry. Immunoperoxidase studies were performed on Zenker's or formalin-fixed, paraffin-embedded tissue using antibodies directed against the histiocyte markers lysozyme and CD68 (KP1) and rabbit polyclonal antibodies against immunoglobu-
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lins mu, alpha, gamma, kappa, and lambda chains (all from DAKO, Carpinteria, CA). Cryostat immunostains were done on cases 6, 8, 11, and 12 using mouse monoclonal antibodies against heavy and light immunoglobulins (provided by Dr Lee Nadler, Dana Farber Cancer Institute, Boston, M.A). In situ hybridization for kappa and lambda light chain sequences was done on case 7 using commercially available probes. Tissue for ultrastructural analysis (cases 6 and 12) was fixed in Karnovsky's fixative, postfixed in osmium tetroxide, embedded in epoxy resin, and stained with uranyl acetate before examination. RESULTS
Clinical F e a t u r e s The 12 patients reported here include 7 men and 5 women with a mean age at diagnosis of 59 years (range, 35 to 77 years). They include 5 myeloma or m o n o d o n a l gammopathy of u n d e t e r m i n e d significance (MGUS) patients, who had presentations typical of myeloma including bone pain, elevated serum proteins, hypercalcemia, and anemia (Table 1). One case of acute renal failure was noted at presentation. Four myeloma patients with follow-up biopsies showed persistence of crystal-storing histiocytosis (CSH) after chemotherapy or bone marrow transplantation. A full autopsy done on 1 patient (case 3) showed extensive myelomatous involvement of marrow with presence of crystal-containing histiocytes in skull and lymph node but not in kidney or bowel (data not shown). Six patients with CSH in association with lymphoplasmacytic lymphoma were noted, 3 of whom presented with splenomegaly, 2 with symptoms of hypervisTABLE 1. Case
A/S
cosity and 1 with renal failure. Four patients had marked immunoglobulin (Ig) G or IgM serum paraproteinemia (range, 3 to 4.5 g / d L ) , which remained high throughout the course of disease. Serum electrophoresis showed biclonal or triclonal gamma globulin Mspikes in 4 patients, which were confirmed to include kappa light chain by immunofixation or immunoelectrophoresis in 3 patients. Marrow disease (including CSH) and paraproteinemia persisted despite multiple rounds of chemotherapy in the 4 patients with long-term follow-up. One patient recently presented with a large cell transformation of an underlying lymphoplasmacytic lymphoma, with CSH present in both lymph node and marrow biopsies. Case 11 is that of a 36-year-old woman with a long-standing history of autoimmune abnormalities, including a diagnosis of childhood lupus. She developed abdominal discomfort and had gastric biopsies that showed crystal4aden histiocytes. The patient received only localized radiation therapy to the stomach but within months developed blurry vision attributable to a hyperviscosity syndrome with marked hypergammaglobulinemia containing both a monoclonal and polyclonal c o m p o n e n t . Extensive radiological workup showed a small retrosternal thymic lymphoma. Despite resection, radiation therapy, and chemotherapy, the patient had persistent disease, with plasmaphoresis used to control symptoms of hyperviscosity. The remaining patient was a M-year-old woman who was noted to have a solitary lung mass on routine chest radiograph, which showed a plasma cell granuloma on resection. The patient was noted to have a
Crystal-Storing Histiocytosis: Summary of Clinical and Pathological Features
Presenting Symptom(s)
Dx
Ig Type (IHC)
Paraprotein (g/dL)
Sites of Deposition
Clinical Course
1. 2. 3.
48/M Paraproteinemia 53/M Bone pain, anemia 50/M Bone pain
MM MM MM
IgAK IgAK IgGK
S = 4.5/IgAK S S = 0.2
BM BM BM, skull, LN
4.
77/F
MM
K only
S
BM
Recur S/P BMT Lost to follow-up BMT DOD at 10 mos Recur S/P CTX
MGUS IgAK
S = 1.0/IgAK
BM
Recur S/P BMT
LPL
IgMK
S = 0.04/biclonal U = 2.0/biclonal
BM, spleen (3860g) DOD at 8 mos
Nausea/hyponatremia LPL Renal failure Hy-percalcemia systemic amyloid Hyerviscosity LPL
IgMK
S = 4.0/triclonal LN IgM - > GK, two K U = K S = 3.6/IgMK BM +/-biclonal K Nd BM, LN S = 4.5/biclonal LN, BM spleen
5. 6.
Anemia Renal failure 66/M Bone pain Hypercalcemia 66/M Splenomegaly Cold agglutinin
7.
68/F
8.
53/F
9. 10. 11. 12.
70/M Splenomegaly 70/M Abdominal pain Splenomegaly 35/F Gastric pain Hyperviscosity 54/F
Incidental
IgMK
LPL LPL
IgMK IgMX
CSH
IgA > IgG, S = 4.7/IgG)t K> X Polyclonal IgA IgGX polyclonal Nd
LPL PCG
Stomach, Thymus, BM Lung
Persistent S/P CTX (cyclophosphamide) PersistentS/P CTX (2-CDA, CVP, Rx) Transformed to LCL at 24 mos CTX (C-MOP, ara-C) DOD at 4 mos Polyclonal CSH Persistent S/P CTX (Chlor/Flud) Surgery only Recurred at 10 yr
Abbreviations: MM, multiple myeloma; LPL, lymphoplasmacytic lymphoma; PCG, plasma cell granuloma; S, serum M-spike; U, urine M-spike; BM, bone marrow; LN, lymph node; (a)BMT, (autologous) bone marrow transplant; DOD, died of disease; LCL, large cell lymphoma; CTX, chemotherapy; Chlor, chlorambucil; Flud, fludarabine; ND, not done; CVP, cyclophosphamide/vincristine/prednisone; Rx, Rituxan (anti-CD20 antibody).
CRYSTAL-STORINGHISTIOCYTOSIS(Joneset al) recurrent nodule in the same lung 10 years later, which had an identical histological appearance. Elevated total serum protein was not noted (serum electrophoresis not done). Forty-eight months late1; the patient shows no evidence of disease recurrence.
Histological, Ultrastructural and Immunophenotypic Features Prominent crystalloid inclusions were identified within plasma cells in all 5 cases of multiple myeloma/ MGUS, 6 cases of lymphoplasmacytic lymphoma (LPL), and the reactive plasmacytic lesion from the lung. Variable numbers of histiocytes containing similar crystalloid inclusions were seen. In 1 myeloma case, the crystal-containing histiocytes were present in such great numbers, diffusely infiltrating the marrow space, that the diagnosis of a hemophagocytic syndrome (Fig 1A) was suggested by the referring institution. The other 4 cases of myeloma showed multiple foci of numerous crystal-laden histiocytes that had the appearance of loose granulomas/aggregates. Immunohistochemical stains showed monotypic kappa immunoglobulin light chain staining of the plasma cells in all 5 cases (Fig 1C and not shown). Three cases were reactive for IgA, one for IgM, and 1 had no detectable heavy chain expression. CD68-positlve histiocytes generally showed only weak monotypic staining for immunoglobulin, possibly because of the inaccessibility of crystalline deposits to staining reagents. Two patients with lymphoplasmacytic lymphoma presented with replacement of the marrow space by crystal-containing plasma cells and histiocytes resembling those of a metabolic storage disorder such as Gaucher's disease (Fig 1D/E). However, in contrast to the faint cytoplasmic striations typical of Gaucher storage-type histiocytes (Fig 1F), the periodic acid-Schifffaint/negative immunoglobulin inclusions had either a chunky, angular appearance or a needle4ike refractile quality on aspirate smears. In the bone marrow of 3 other cases, crystal-containing histiocytes were admixed within neoplastic lymphoplasmacytic aggregates (not shown). In lymph node biopsies from 3 lymphomas, numerous crystal-laden histiocytes formed confluent sheets suggestive of nodal replacement by a systemic histiocytosis or infectious process (Fig 1G). Immunostaining showed monotypic IgM within tumor cells in 5 cases, with kappa light chain in 4, and lambda in 1 (Fig 1J). CD68- or lysozyme-positive histiocytes typically showed weak monotypic staining for immunoglobulins (Fig 1I). The findings in case 11, in which an autoimmune disorder and recurrent crystal-storing histiocytosis of the stomach preceded the diagnosis of a thymic lymphoma, were complex. In multiple gastric biopsies, sheets of histiocytes with needle-like crystals were present in the lamina propria with only a mild infiltrate of polyclonal plasma cells, mostly IgA/kappa (Fig 1K and data not shown). Crystals in the histiocytes showed predominant staining for kappa light chain. Subsequently, the patient's thymic lymphoma showed a monoclonal lambda IgG staining pattern, matching the pa-
tient's large serum paraprotein. Crystals were relatively sparse in the thymic tumor. Subsequent marrow infiltrates showed lymphoplasmacytic aggregates with a lambda light-chain predominance as well as crystalladen histiocytes. It thus is not clear whether the crystals in the stomach biopsy were derived from the monoclonal IgG lambda or the elevated polyclonal immunoglobulin. We also noted 1 case of a recurrent plasma cell lesion of the lung that showed an extensive infiltrate of epithelioid and spindle-shaped CD68-positive histiocytes filled with numerous needle-shaped immunoglobulin inclusions (Fig 1I). Crystals expanded the lung interstitium and extended into the alveolar spaces and were surrounded by foci of lymphoplasmacytic inflammation. In both the original tumor and the recurrence, we have previously shown polytypic reactivity for heavy and light chain immunoglobulin and absence of a heavy chain gene rearrangement by polymerase chain reaction analysis. 9 Electron microscopy in this case showed numerous rhomboidal and needle-shaped crystals present in both the cytoplasm of plasma cells and adjacent histiocytic-appearing mononuclear cells. Within plasma cells, crystals with a linear arrangement and faint fibrillarity were often present within dilated rough endoplasmic reticulum (Fig 2A). Some cells showed dilation of endoplasmic reticulum by amorphous material, and others showed an association of forming crystals with cylindrical inclusions (Fig 2B). Histiocytes, in this case and in case 6, typically showed only the angulated crystals (data not shown). In our review of cases for this study, we also noted 5 bone marrow biopsies with rare crystals present in less than 5% of plasma cells. Interestingly, 2 of these cases represented transient plasmacytic proliferations occurring in patients after bone marrow transplantation for chronic myelogenous leukemia. One case also showed a cluster of crystal-storing histiocytes (data not shown). Subsequent biopsies in both of these patients did not show persistent plasmacytosis or serum paraproteinemia. We also reviewed biopsy specimens of plasmacytic tumors that showed prominent Mott cells (2 LPLs), globular cytoplasmic inclusions (5 myeloma, 2 LPLs), or extracellular deposition of kappa light chain (9 myeloma) in the kidney or bone marrow. Proliferations of histiocytes were not seen in any of these cases. Tumors that showed prominent amyloid deposition (5 amyloidomas, 4 myeloma, 2 LPLs) often showed fibrosis and multinucleated giant cells surrounding areas of extracellular protein deposition without a generalized and diffuse histiocytic proliferation (data not shown).
Comparison With Previously Reported Cases We compared our immunophenotypic and ultrastructural findings with previously reported cases of tumors with immunoglobulin crystal formation (Table 2). In crystal-containing tumors classified by the authors as chronic lymphocytic leukemia, there was a striking predominance of lambda light chain expression (and IgM as expected). Crystals in these cases were large and
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FIGURE 1. Crystal-storing histiocytosis. (A-C) Case 4. Crystal-storing histiocytosis of the bone marrow in multiple myeloma resembling erythrophagocytosis. Marrow shows a diffuse infiltrate of histiocytes stuffed with eosinophilic inclusions (H&E stain), which have a globular appearance at high power (Giemsa stain). Immunostains demonstrated strong monotypic staining for immunoglobulin kappa light chain in plasma ceils and weak reactivity in histiocyte crystals. (D/E) Case 6. Lymphoplasmacytic lymphoma with crystalline inclusions in the bone marrow resembling a storage disease. Trephine biopsy shows numerous histiocytes and plasma cells filled with angular crystalline inclusions that have a globular or geometric appearance on Wright-Giemsa-stained aspirate. (F) in contrast, storage histiocytes from a patient with Gaucher's disease show cytoplasmic striations, (G) Case 7. Lymphoplasmacytic lymphoma with sheets of crystal-laden histiocytes replacing large areas of the lymph node (H&E). (H) In situ hybridization shows positivity for kappa light chain sequences in lymphoplasmacytic tumor ceils. (I) CD68 immunostain highiights crystal-containing histiocytes. (J) Case 10. Crystal-containing histiocytes in a lymphoplasmacytic lymphoma expressing monotypic Lambda light chain (Giemsa). (K) Case 11. Crystal-storing histiocytosis. Numerous crystal-storing histiocytes filling lamina propria surrounded by scant lymphoplasmacytic infiltrate (H&E), (L) Case 12. Plasma cell granuloma of the lung. Sheets of spindle-shaped histiocytes fining alveolar spaces surrounded by a polyclonal lymphoplasmacytic infiltrate (H&E).
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FIGURE2. Ultrastructure of crystalloid inclusions, Case 12. (A) Angulated crystals with fine fibrillarity noted within the dilated rough endoplasmic reticulum of a plasma cell. (B) Geometrically shaped crystals were noted in association with cylindrical membranebound inclusions.
few in numbeI, with a rectangular or polygonal shape (Table 2). In n o n e of these cases was crystal-storing histiocytosis reported. Cases of cryocrystalglobulinemia were also not associated with CSH and showed no consistent association with any immunoglobulin type. In contrast, crystal-containing tumors with plasmacytic differentiation (multiple myeloma, MGUS, LPL, and plasmacytoma) showed a striking p r e d o m i n a n c e of kappa light chain expression, especially in those cases associated with CSH. Besides our cases, only 3 lambdaexpressing tumors have been r e p o r t e d that show the sheet-like proliferation of crystaMaden histiocytes characteristic of CSH. 1°'12 This is in contrast to the more than 60 cases that express kappa light chain. Indeed, cases of lymphom a with lambda-containing crystal formation t e n d e d to show large intracellular/extracellular rhomboidal crystals that were not present in adjacent histiocytes. ~°,13,14 Thus, there is a highly significant association of CSH with kappa light chain expression. DISCUSSION
We present 12 cases of plasmacytic tumors with p r o m i n e n t crystal formation, including 5 myelomas, 6 lymphoplasmacytic lymphomas, and 1 apparently nonneoplastic plasma cell proliferation. In all cases, crystal TABLE 2,
formation was associated with proliferation of histiocytes containing similar crystals. Crystal-storing histiocytosis was not f o u n d in association with other immunoglobulin deposition disorders, including Mott cell myeloma/lymphoma, LCD, and amyloidosis. These cases are similar to previously published case reports and provide additional evidence that immunoglobulin crystal formation by plasma cells is frequently (perhaps invariably) associated with proliferations of crystalladen histiocytes. Given their rarity, the appearance of crystal-storing histiocytes often presents diagnostic difficulties. In several cases of myeloma, the degree of histiocytosis in the marrow was so increased in p r o p o r t i o n to the plasma cell c o m p o n e n t that the diagnoses of a storage disorder or hemophagocytic syndrome were initially considered. Several reports have emphasized that because o f their ample fibrillary cytoplasm, crystal-storing histiocytes can be misidentified, especially if the plasma cells c o m p o n e n t is not readily appreciated. ~5 Cases presenting in the marrow most often resemble storage disorders such as Gaucher's disease. However, on aspirate smears, the coarse, crystalloid nature of the inclusions can be distinguished from the fine fibrillarity seen in Gaucher cells.16 Crystal-storing histiocytes seen in extramedullary sites may be mistaken for rhabdomyoma
Summary of Previously Characterized Tumors With Crystalloid Immunoglobulin Inclusions
Tumor Type CLL and CLLVariants Lymphoplasmacytic Lymphoma Myeloma/Plasmacytoma MGUS Cryocrystalglobulinemia
Ig Type
Associated CSH
CrystalAppearance
References
K;2, k; 23 IgM; 22 IgG; 3, IgA; 3 K:8, k: 5, c/k: 1 IgM10, IgG/M: 1 IgG; 2, IgA; 1 K:37, k: 9 IgG; 30, IgA; 9 IgM; 2, IgD; 1 K:5, X; 1 IgG; 5, IgM: 1 K:4, k: 4 IgG; 5, IgD; 1
None reported
Large, rhomboidal Few per cell
24, 30-34,36, 37
K:8, K/k: 1 k: 2
K/k: Needle-shaped
4, 11, 12, 17, 32, 38-43
~: 35 k: 1
K:Needle-shaped k: Large extracellular (with giant cells)
3, 5, 8, 10, 13, 14, 16, 25, 27, 28, 44-78 79-83
None reported
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cells, 4 fibrosclerosis, 17 or other types of histiocytosis. 12,1s Identifying similar crystalloid inclusions in the surrounding plasma cells is the key to diagnosis. T h e mechanism of formation of plasma cell crystals is not known. The cases presented here, and our extensive review of the previous literature, strongly support a primary role for kappa light chain in crystals that p r o d u c e CSH. Although CSH can occur in plasmacytic tumors expressing any or n o n e of the heavy chains, nearly every case r e p o r t e d expresses kappa light chain (Table 2). Only a single case of heavy-chain-only CSH has been seen, suggesting a role for light chain multimerization in crystal formation. 19 Crystal-forming tumors that show deposition of crystals in renal or corneal epithelium are also nearly completely associated with kappa light chain expression, supporting the close association of CSH to these entities (Table 2). Ultrastrucrural evidence presented here and elsewhere also clearly demonstrates that crystal formation occurs within the plasma cells in the endoplasmic reticulum before excretion, likely making immunoglobulin aggregates difficult to degrade or excrete. We also noted the association of tubular structures within the same saccules as forming crystals, suggesting that these arrays may be a substrate for crystallization. A possible mechanism of crystal formation may be overproduction of kappa light chain. Indeed, 4 of the patients in our study demonstrated free kappa chain by immunofixation/immunoelectrophoresis. It has b e e n previously demonstrated that intraperitoneal injection of free kappa light chain from a myeloma patient can result in a Fanconi-like syndrome in mice, with the formation in the kidney of intracellular crystals identical to those in CSH. O u r 2 cases and 1 from Bosman et al is indicate that CSH also can occur in cases of polyclonal immunoglobulin activation, supporting overproduction as a mechanism of crystal formation. O f interest in this regard was our finding of occasional plasma cell crystals and focal CSH in several patients with posttransplantation plasmacytosis, because transplant patients are known to have transient dysregulation and overproduction of immunoglobulin. 2°,~1In our review, however, other types of immunoglobulin inclusions (eg, Mort cell globular inclusions) were not associated with CSH, and some of the patients in our series had minimal serum or urine paraprotein levels, emphasizing that immunoglobulin overproduction is unlikely to be the sole cause of CSH. It is likely that many cases of CSH arise from tumors with specific immunoglobulin mutations. Earlier studies o f the structure of mutant crystallizable immunoglobulins showed heavy chain hinge region deletions in some cases. An aberrant crystallizable immunoglobulin also has been r e p o r t e d that does not form appropriate disulfide bridges. I° More recent studies of 4 immunoglobulin molecules isolated from patients with the adult Fanconi syndrome have shown consistent use of the same variable region of the kappa chain as well as variable region amino acid substitutions similar to those seen in kappa-amyloidogenic molecules. 22 This supports a model whereby crystallization of immunoglobu-
lin is related to sequence variations in immunoglobulin that prevent p r o p e r interaction of heavy and light chains. Unlike amyloidogenic lambda light chain, kappa light chains may not dimerize, so the exact structure of these immunoglobulin aggregates remains to be determinedY s It is possible that an abnormal kappa chain may be less efficiently secreted or improperly glycosylated and thereby b e c o m e trapped within the secretory machinery, allowing time for the multimerization to occur. 2,24 The reason for persistence of crystals within histiocytes is also unknown. Given that crystals deposit at remote sites such as corneal epithelium, it is likely that larger crystals reform within phagocytic cells after ingestion of smaller crystallizable immunoglobulin aggregates circulating in the bloodstream. ~5 Reports of CSH at autopsy show widespread deposition of crystals within cells from numerous sites in addition to kidney, cornea, and histiocytes. 5,1s,15,26-28 Electron microscopic studies have shown a morphological spectrum in histiocyte crystals from poorly f o r m e d fibriUary inclusions to well-formed geometric structures as well as intermediary forms present in the lysosomes. 8 A separate study showed that 4 cases of kappa light chains from Fanconi syndrome patients (unlike those producing cast nephropathy) were resistant to proteolytic cleavage in vitro, suggesting that crystal accumulation in the lysosomes may result from resistance to degradation. 29 The few cases o f CSH resulting from tumors expressing lambda light chain (our case 9 and references 10-12) show that lambda light chain can form crystals, although the inclusions often appear larger and more globular as c o m p a r e d with kappa-producing cases. They appear similar to those occasionally seen in lambdaexpressing small lymphocytic lymphoma, which have fewer, large, rhomboidal crystals with a well-formed lattice structure and secrete little if any immunoglobulin. 24,s°s4 Crystal-storing histiocytosis is not a feature of these cases. Thus, the type of immunoglobulin light chain molecule, as well as the a m o u n t o f i m m u n o g l o b u lin produced, determines the degree o f crystal formation and resultant histiocytosis observed. Although crystallizable kappa light chains are present in nearly all cases of renal failure due to adult Fanconi syndrome, 6 the cases r e p o r t e d here and many others in the literature emphasize that this is an uncomm o n complication of patients with CSH. Indeed, many myeloma patients with CSH have r e p o r t e d survivals of 5 to 15 years after diagnosis, which is longer than the median survival for this tumor, s5 Patients with CSH also commonly present at an early stage with low paraprotein levels, hypogammaglobulinemia, and minimal plasma cell infiltrates. It is likely that the symptoms of immunoglobulin crystallization (eg, organomegaly, or visual problems secondary to keratinopathy) lead to diagnosis at earlier stages of disease than would otherwise occur. In the absence of renal failure, crystalstoring histiocytosis is not necessarily associated with a p o o r clinical prognosis.
Acknowledgment. The authors thank Dr A.G. Gibson of Kent and Canterbury Hospital, Canterbury, UK, for contribu-
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CRYSTAL-STORING HISTIOCYTOSIS(Jones et ol) tion of case material, Dr Carl O ' H a r a for preliminary studies, Myson Smeedy for e x p e r t technical assistance, and Drs R. Schlossman and H. H o c k (Dana Farber Cancer Center, Boston, MA) for providing clinical information.
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47. Henderson DW, StirlingJW, LipsettJ, et al: Paraproteinemic crystaUoidal keratopathy: An ultrastructural study of two cases, including immunoelectron microscopy. Ultrastruct Pathol 17:643-668, 1993 48. Orfila C, Lepert JC, Modesm A, et al: Fanconi's syndrome, kapp a light-chain myeloma, non-amyloid fibrils and cytoplasmic crystals in r~nal tubular epithelium. Am J Nephrol 11:345-349, 1991 49. Pillay GS, Jacobs P: Crystalline cytoplasmic inclusions in myeloma. Arch Pathol Lab Med 118:1169-1170, 1994 50. Raman SB, Van Slyck EJ: Nature of intracytoplasmic crystalline inclusions in myeloma ceils (morphologic, cytochemical, ultrastructural, and immunofluorescent studies). AmJ C!in Patho180:224228, 1983 51. Truong LD, Mawad J, Cagle P, et al: Cytoplasmic crystals in multiple myeloma-associated Fanconi's syndrome: A morphological study including immunoelectron microscopy. Arch Pathol Lab Med 113:781-785, 1989 52. Stavem P, Forre O: The same type of crystalline inclusions in T-lymphocytes as in plasma cells and B-lymphocytes in multiple myeloma: A pathological clone originating from a common lymphocyte stem cell? ScandJ Haemato126:265-271, 1981 53. Pinkerton RH, Robertson DM: Corneal and conjunctival changes in dysproteinemia. Opthalmology 8:357-364, 1969 54. Klintworth GK, Bredehoeft SJ, ReedJW: Analysis of corneal crystalline deposits in multiple myeloma. Am J Ophthalmol 86:303313, 1978 55. Gabriel L, Escribano L, Perales J, et al: Multiple myeloma with crystalline inclusions in most hematopoietic cells. AmJ Hematol 18:405411, 1985 56. Barr CC, Gelender H, Font RL: Corneal crystalline deposits associated with dysproteinemia: Report of two cases and review of the literature. Arch Ophthalmo198:884-889, 1980 57. Hoisen H, Ringvold A, Kildahl-Andersen O: Corneal crystalline deposits in multiple myeloma: A case report. Acta Ophthalmol (Copenh) 61:493-500, 1983 58. Steuhl KP, Knorr M, Rohrbach JM, et al: Paraproteinemic corneal deposits in plasma cell myeloma. AmJ Ophthalmol 111:312318, 1991 59. Towheed TE, Ferrari R, Corbett WE, et al: Multiple myeloma presenting as a manubrial mass with intracytoplasmic crystal accumulation within macrophages. AmJ Hematol 48:66-67, 1995 (letter) 60. Tsuchikawa K, Yokomichi H, Satoh I, et al: A study of intracytoplasmic inclusions in myeloma cells from two patients with multiple myeloma. TohokuJ Exp Med 153:11-20, 1987 61. Takahashi K, Naito M, Takatsuki K, et al: Multiple myeloma, IgA kappa type accompanying crystal-storing histiocytosis and amyloidosis. Acta PatholJpn 37:141-154, 1987 62. Schillinger F, Hopfner C, Montagnac R, et al: [IgG kappa myeloma with Fanconi's syndrome and crystalline inclusions. Immunohistochemical and ultrastructural study]. Presse Med 22:675-679, 1993 63. Perry HD, Donnenfeld ED, Font RL: Intraepithelial corneal immunoglobulin crystals in IgG-kappa multiple myeloma. Cornea 12:448-450, 1993 64. Matsumoto K, Shikuwa S, Kawase Y, et al: Gastric plasmacytoma with rod-shaped intracytoplasmic inclusions. Acta Pathol Jpn 38:815-821, 1988 65. Levine SB, Bernstein LD: Crystalline inclusions in multiple myeloma.JAMA 254:1985, 1985 66. Kobayashi Y, Miyake T, Funakoshi N, et al: Gastric plasmacytoma with cylindrical crystalline inclusions. Gastro Japonica 22:81-87, 1987 67. Kornstein MJ, deBlois GG, Williams ME: Unusual biclonal plasma cell dyscrasia with crystaUike inclusions producing colonic
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