A 70-year-old woman with acute renal failure. Crystal-storing histiocytosis

Crystal-storing histiocytosis (CSH) is a rare disorder characterized by accumulation of immunoglobulin light chain within histiocytes in one or more organ systems, typically in association with multiple myeloma or, less frequently, with other conditions such as lymphoplasmacytic lymphoma, the use of certain medications, or even polyclonal gammopathies. The reason why only a few patients with multiple myeloma develop CSH, while the majority do not, is unknown, but it may at least partially reflect a defect in intralysosomal degradation because simple light chain overproduction is not sufficient for the development of CSH. Interestingly, CSH is associated with improved survival in multiple myeloma patients, perhaps due to earlier detection and treatment of myeloma because of the symptoms associated with CSH.     

Tryptase-positive mast cells accompany lymphocytic as well as lymphoplasmacytic lymphoma infiltrates in bone marrow trephine biopsies

AIMS: To investigate the specificity of increased bone marrow mast cell numbers in lymphoplasmacytic lymphoma (LPL) and to evaluate the relationship between mast cell number and the immunoglobulin phenotype of neoplastic lymphoid cells. METHODS AND RESULTS: Retrospective study of bone marrow trephine biopsy specimens from patients with LPL, compared with selected cases representing chronic lymphocytic leukaemia (CLL) and multiple myeloma (MM) of known immunoglobulin light and heavy chain phenotype. Bone marrow mast cells were counted following immunohistochemical staining of sections for mast cell tryptase. We have confirmed previous observations that mast cell numbers are increased in bone marrow infiltrates of LPL. However, we found similarly high mast cell numbers in CLL. High mast cell numbers were associated with neoplastic lymphoid cells expressing an IgM kappa phenotype. Mast cell numbers were low in all cases of MM studied and in controls with no lymphoma present. We observed an apparent bias towards kappa light chain expression in our cases of LPL. CONCLUSIONS: Mast cell number should not be considered a reliable factor in the differential diagnosis of LPL and CLL when assessing bone marrow histology. Possible bias towards kappa light chain expression in LPL requires further study, as do the mechanism and functions of mast cell recruitment by neoplastic lymphoid cells.     

Negative images of crystalline immunoglobulin in crystal storing histiocytosis: A potential cytologic mimic of mycobacteria in smears

Two cases are described of crystal storing histiocytosis (CSH) associated with extranodal marginal zone lymphoma, presenting as lung and subcutaneous masses respectively. Fine-needle aspiration of subcutis and smears prepared from the resected lung masses showed negative images. Cytology slides of both cases were reviewed to identify cytomorphological features for the differential diagnosis between immunoglobulin crystals and mycobacteria. The crystals in CSH consist of straight and needle shaped rods with pointed or angular edges and are more variable in thickness than the uniformly thin mycobacteria. Mycobacteria show a haphazard distribution, whereas crystals are frequently present in parallel arrays. Small lymphoid or plasma cells are identified in the background of CSH, whereas a necrotic and inflammatory background is seen in mycobacteriosis. Additional samples for culture in the case of mycobacteriosis, or flow cytometry and molecular clonality testing in the case of CSH can provide critical data for a definitive diagnosis.     

Serum free light chain (FLC) measurement can aid capillary zone electrophoresis in detecting subtle FLC-producing M proteins

We hypothesized that using a free light chain (FLC) assay as an adjunct to capillary zone electrophoresis (CZE) could improve detection of lymphoplasmacytic processes. We prospectively studied 1,003 consecutive serum samples submitted for routine protein electrophoresis and/or immunofixation electrophoresis by CZE and FLC. Samples from patients previously characterized as having M proteins were excluded. Protein electrophoresis was read by a pathologist unaware of the FLC results. Sixteen cases revealed an abnormal free kappa/lambda ratio in which CZE did not demonstrate an M protein. Nine cases of B-lymphocyte or plasma cell proliferative processes were detected by an abnormal free kappa/lambda ratio in which CZE did not demonstrate an M protein. Cases with low free kappa/lambda ratios included 1 chronic lymphocytic leukemia (CLL), 1 IgM lambda with aplastic anemia, and 1 lambda light chain myeloma. Cases with high free kappa/lambda ratios included 2 CLL, 1 lymphocytosis (possibly early CLL), 1 kappa light chain myeloma, 1 atypical lymphoma with neuropathy, and 1 nonsecretory myeloma. Addition of the free kappa/lambda ratio to CZE increases the yield of lymphocyte and plasma cell proliferative processes detected by 56%.     

Automated colorimetric in situ hybridization (CISH) detection of immunoglobulin (Ig) light chain mRNA expression in plasma cell (PC) dyscrasias and non-Hodgkin lymphoma.

Immunohistochemistry (IHC) is frequently used to detect plasma cell (PC) or B cell monoclonality in histologic sections, but its interpretation is often confounded by background staining. We evaluated a new automated method for colorimetric in situ hybridization (CISH) detection of clonality in PC dyscrasias and small B cell lymphomas. Cases of PC dyscrasia included multiple myeloma (MM; 31 cases), plasmacytoma (seven cases), or amyloidosis (one case), while cases of lymphoma included small lymphocytic (three cases), marginal zone (four cases), lymphoplasmacytic (three cases), and mantle cell lymphomas (three cases). Tissue sections were stained for kappa and lambda light chains by IHC and for light chain mRNA by automated CISH using haptenated probes. Twenty-eight of 31 MM cases had detectable light chain restriction by IHC. Thirty of 31 MM cases demonstrated light chain restriction by CISH, including 2 cases with uninterpretable IHC and one case of nonsecretory myeloma, which was negative for light chains by IHC. Seven of 7 plasmacytoma cases had detectable light chain restriction by CISH, including one case of nonsecretory plasmacytoma in which IHC was noninformative. Automated CISH demonstrated monoclonality in 9 of 13 cases of B cell non-Hodgkin lymphoma and had a slightly higher sensitivity than IHC (6 of 13 cases), especially in cases of lymphoplasmacytic and marginal zone lymphoma. Overall, there were no discrepancies in light chain restriction results between IHC, CISH, or serum paraprotein analysis. Automated CISH is useful in detecting light chain expression in paraffin sections and appeared superior to IHC for light chain detection in PC dyscrasias and B cell non-Hodgkin lymphomas, predominantly due to lack of background staining.     

Biclonal light chain gammopathy in multiple myeloma--a case report]

A 74-year-old woman was admitted to our hospital in March 1998 for low-back pain. In 1990, she had a chemotherapy for diffuse mixed cell lymphoma. Biochemical and serologic assays revealed a total protein level of 9.7 g/dl and an IgG level of 4,530 mg/dl. Immunoelectrophoresis showed monoclonal IgG protein associated with two monoclonal kappa and lambda light chain components. Bone marrow examination showed proliferation of myeloma cells comprising up to 25% of all nucleated cells. Myeloma cells were immunohistochemically positive for IgG and kappa and lambda light chains. IgG contained equal amounts of IgG 1 and IgG 2 subtypes and the complementarity determining region 3 (CDR 3) of myeloma cells showed oligoclonality by polymerase chain reaction, suggesting the myeloma cells may have two components. The patient received melphalan and prednisone in combination, resulting in only a minor response. She eventually developed angioimmunoblastic T-cell lymphoma. Biclonal gammopathy associated with malignant lymphoma is rare in case of multiple myeloma and may provide some insight into the pathogenesis of plasma cell tumors.     

Clinical, biochemical, and pathological features in a patient with plasma cell dyscrasia and Fanconi syndrome

Multiple myeloma is associated with a wide array of renal diseases that include myeloma cast nephropathy, monoclonal immunoglobulin deposition disease, amyloidosis, cryoglobulinemia, tubular dysfunction, pyelonephritis, nephrocalcinosis, urate nephropathy, and infiltration by atypical plasma cells (or myeloma cells). Filtered immunoglobulin light chains may affect both the distal and, more frequently, the proximal tubule. Tubular abnormalities in patients with plasma cell dyscrasia may be more frequent than previously thought. A patient with a plasma cell dyscrasia is described, who presented with biochemical features consistent with Fanconi syndrome. Immunoelectron microscopy performed on the renal biopsy confirmed the presence of kappa light chain immunoglobulin in intracytoplasmic crystals in proximal tubular epithelial cells. This report is one of a few demonstrating the presence of light-chain immunoglobulin in intratubular crystals in a human renal biopsy obtained from a patient with a plasma cell dyscrasia and Fanconi syndrome.     

Monoclonal Light Chain Deposits Within the Stomach Manifesting as Immunotactoid Gastropathy

Immunotactoid deposits are defined by their ultrastructural appearance and are characterized by microtubular or cylindrical structures typically measuring greater than 30?nm in diameter. Although a rare entity, immunotactoid deposition most often manifests as immunotactoid glomerulopathy and is associated with underlying lymphoplasmacytic disorders. Corneal immunotactoid deposition known as immunotactoid keratopathy has also been reported in patients with paraproteinemia. Here, we describe the first reported case of immunotactoid deposition in the stomach. The deposits were composed solely of kappa immunoglobulin light chains without significant lambda light chain or immunoglobulin heavy chain components. The patient displayed no renal signs or symptoms, and additional thorough clinical examination failed to detect any evidence of a paraproteinemia or plasma cell dyscrasia. Thus, the gastric immunotactoid deposits in this case appear to be an isolated finding of light chain deposition, of which the significance and etiology are unclear.     

Clinical,Biochemical, and Pathological Features in a Patient with Plasma Cell Dyscrasia and Fanconi Syndrome

Multiple myeloma is associated with a wide array of renal diseases that include myeloma cast nephropathy, monoclonal immunoglobulin deposition disease, amyloidosis, cryoglobulinemia, tubular dysfunction, pyelonephritis, nephrocalcinosis, urate nephropathy, and infiltration by atypical plasma cells (or myeloma cells). Filtered immunoglobulin light chains may affect both the distal and, more frequently, the proximal tubule. Tubular abnormalities in patients with plasma cell dyscrasia may be more frequent than previously thought. A patient with a plasma cell dyscrasia is described, who presented with biochemical features consistent with Fanconi syndrome. Immunoelectron microscopy performed on the renal biopsy confirmed the presence of kappa light chain immunoglobulin in intracytoplasmic crystals in proximal tubular epithelial cells. This report is one of a few demonstrating the presence of light-chain immunoglobulin in intratubular crystals in a human renal biopsy obtained from a patient with a plasma cell dyscrasia and Fanconi syndrome.     

Patterns of glomerular injury in kidneys infiltrated by lymphoplasmacytic neoplasms

Glomerular injury may occur as a result of immune dysfunction in patients with remote lymphoplasmacytic neoplasms. Glomerular injury concurrent with direct infiltration of the kidney by lymphoplasmacytic neoplasms has been reported but is not extensively characterized. We identified 18 patients, all presenting with elevated serum creatinine and many with proteinuria, whose renal biopsies showed direct involvement of kidney by a variety of neoplasms, including chronic leukocytic leukemia/small lymphocytic lymphoma (n = 7), diffuse large B-cell lymphoma (n = 6), multiple myeloma (n = 4), or B-cell lymphoblastic lymphoma (n = 1). In 10 cases (55%), there was coexistent glomerular pathology: 5 of these cases, including glomerulonephritis with membranoproliferative glomerulonephritis-like pattern of injury (n = 4) and membranous nephropathy (n = 1), featured deposition of immune complexes; 2 demonstrated deposition of monoclonal immunoglobulin components: λ light chain amyloidosis (n = 1) and light chain deposition disease (n = 1); 2 showed minimal change disease; and, in 1 case, there was focal crescentic pauci-immune-type glomerulonephritis. In addition, 1 biopsy revealed diabetic nephropathy and 3 showed nonspecific ischemic changes. In the remaining 4 cases, there were no significant glomerular abnormalities. In 11 cases (61%), the diagnosis of lymphoproliferative disease was established following the kidney biopsy. Our study indicates that lymphoplasmacytic neoplasms may be first diagnosed in renal biopsies performed for evaluation of renal dysfunction with or without proteinuria. Concurrent glomerular injury may be a direct result of the lymphoplasmacytic disorder through a paraprotein deposition process resulting in amyloid or monoclonal immunoglobulin deposition disease, or may be caused indirectly through immune-mediated mechanisms, as in the cases of glomerulonephritis with membranoproliferative glomerulonephritis-like pattern of injury, membranous nephropathy, and possibly minimal change disease.     

A 72-year-old woman with right frontal extra-axial mass

We present a case of plasma cell predominant lymphoplasmacyte-rich meningioma with numerous crystalline inclusions. A 72-year-old woman presented with 1-year history of memory disturbance and an MRI revealing a right frontal extra-axial mass. Histology showed a benign meningioma with multifocal accumulation of numerous large cells with abundant eosinophilic cytoplasm, filled with lamellar inclusions and bipyramidal crystals. In addition, some classic plasma cells, mastocytes and lymphocytes were also detected. The crystal-containing cells were positive by CD79a and PGM1 and expressed polyclonal light chains, with kappa predominance. Electron microscopy showed crystals with needle or rectangular shape in plasma cells. Plasma cell inclusions have been reported occasionally in reactive inflammatory lesions but more frequently in plasma cell tumors and lymphoplasmacytic lymphoma, maybe associated with crystal-storing histiocytosis. Although plasma cell predominant lymphoplasmacyte-rich meningioma is not uncommon, to our knowledge, similar crystalline inclusions in plasma cells have not been reported previously in meningioma.     

Biclonal light chain gammopathy with aberrant CD33 expression in secondary plasma cell leukemia

Plasma cell leukemia is a rare neoplastic proliferation of circulating plasma cells. Clonal proliferations of plasma cells, such as in plasma cell leukemia or plasma cell myeloma, are typically characterized by production of a monoclonal heavy and/or light chain immunoglobulin. We present a case of a secondary plasma cell leukemia arising from plasma cell myeloma with dual expression of lambda and kappa light chains along with aberrant expression of CD33, CD20, and dim CD56. This case emphasizes the importance of recognizing aberrant immunophenotypes in plasma cell leukemias and represents the first reported case of biclonal light chain expression in a secondary plasma cell leukemia.     

Massive crystal-storing histiocytosis associated with low-grade malignant B-cell lymphoma of MALT-Type of the parotid gland

Massive crystal deposition is unusual in lymphoproliferative disorders. In this report, a mucosa-associated lymphoid tissue (MALT) low-grade B-cell lymphoma of the parotid gland containing large numbers of crystal-storing histiocytes is described. The patient, an 81-yr-old female, presented with a history of long-standing left parotid gland enlargement. FNA cytology of the tumor showed a lymphoplasmacytic infiltrate and sheets of large benign histiocytes with abundant eosinophilic intracytoplasmic inclusions. Paraffin-section immunohistochemistry performed on the cell block demonstrated that the histiocytic cells were immunoreactive for the KP-1 (CD-68) antibody and monotypic for cytoplasmic IGM and L-light chain. The cytological diagnosis was consistent with a low-grade B-cell lymphoma with plasmacytic differentiation associated with crystal-storing histiocytosis. A periparotid lymph node was biopsied and showed involvement by a monocytoid B-cell lymphoma with plasmacytic differentiation and crystal-storing histiocytosis in the pericapsular region. Diagn. Cytopathol. 17:148–152, 1997. © 1997 Wiley-Liss, Inc.     

Generalized crystal-storing histiocytosis as a presentation of multiple myeloma: a case with a possible pro-aggregation defect in the immunoglobulin heavy chain

Crystal-storing histiocytosis (CSH) with massive accumulation of particulate immunoglobulins is a rare phenomenon accompanying B-cell dyscrasias. In the reported case (M51), the disease presented as systemic CSH and later was proved to be a frank multiple myeloma. The aggregates of crystal-laden histiocytes were demonstrated in the bone marrow, lungs, kidney, and liver. Additionally, the crystalline immunoglobulin particles were identified in renal stromal cells and in hepatocytes. The patient developed lung adenocarcinoma and died 12 months after the presentation, shortly after the lobectomy. In this paper, we report the results of morphological (including electron microscopy), immunohistochemical, and biochemical analysis. The tendency for aggregation of the IgG kappa monoclonal protein was due to the abnormal physicochemical properties of its heavy chain. Massive accumulation of crystal-storing histiocytes surpassed the myeloma tumor burden and markedly contributed to the severity of the disease.     

Pulmonary crystal-storing histiocytosis and extranodal marginal zone B-cell lymphoma associated with a fibroleiomyomatous hamartoma

Crystal-storing histiocytosis (CSH) is a rare disorder occurring in patients with lymphoproliferative diseases, predominantly in cases of multiple myeloma and low-grade B-cell lymphoma. To the best of our knowledge, only three cases of pulmonary CSH have been reported in the English literature and one of them was associated with a low-grade B-cell lymphoma (immunocytoma). We document a case of a 59-year-old man with bilateral lung masses in which a right middle lobe pulmonary lobectomy specimen showed CSH associated with an extranodal marginal-zone B-cell lymphoma. A single nodule showing features of fibroleiomyomatous hamartoma was present in a wedge biopsy specimen from the left lung. Two nodules within the right middle lobe were composed of sheets of histiocytic cells with abundant eosinophilic cytoplasm resembling striated muscle cells. In addition, there were nodular aggregates and a more diffuse infiltrate of small slightly atypical centrocyte-like lymphocytes, as well as bronchial lymphoepithelial lesions. Immunohistochemistry performed on paraffin-embedded sections demonstrated that the histiocytic cells were immunoreactive with the KP-1 (CD68) antibody while the lymphocytic infiltrate was CD20 positive, co-expressed for CD43, and was negative for CD3, CD5, and CD10. Genotypic analysis demonstrated the presence of an immunoglobulin heavy-chain gene rearrangement, indicating the presence of a monoclonal B-cell population. These features were consistent with pulmonary CSH associated with extranodal marginal-zone lymphoma of baltoma type.     

Cyto-histologic correlation of crystal-storing histiocytosis: Rare presentation in breast,predating diagnosis of B-cell lymphoma by two years

Crystal-storing histiocytosis (CSH) is a rare disorder characterized by the accumulation of crystalized immunoglobulins within the cytoplasm of histiocytes. It is often associated with an underlying lymphoproliferative or plasma cell disorder. Most patients with CSH are asymptomatic in regard to the disease and are incidentally discovered. Herein we present cyto-histologic correlation of a rare example of CSH presenting with a two-year interval between original diagnosis of CSH and confirmation of a low-grade B-cell lymphoma.     

Immunoglobulin derived depositions in the nervous system: novel mass spectrometry application for protein characterization in formalin-fixed tissues

Proteinaceous deposits are occasionally encountered in surgically obtained biopsies of the nervous system. Some of these are amyloidomas, although the precise nature of other cases remains uncertain. We studied 13 cases of proteinaceous aggregates in clinical specimens of the nervous system. Proteins contained within laser microdissected areas of interest were identified from tryptic peptide sequences by liquid chromatography-electrospray tandem mass spectrometry (LC-MS/MS). Immunohistochemical studies for immunoglobulin heavy and light chains and amyloidogenic proteins were performed in all cases. Histologically, the cases were classified into three groups: 'proteinaceous deposit not otherwise specified' (PDNOS) (n=6), amyloidoma (n=5), or 'intracellular crystals' (n=2). LC-MS/MS demonstrated the presence of lambda, but not kappa, light chain as well as serum amyloid P in all amyloidomas. lambda-Light-chain immunostaining was noted in amyloid (n=5), although demonstrable monotypic lymphoplasmacytic cells were seen in only one case. Conversely, in PDNOS kappa, but not lambda, was evident in five cases, both light chains being present in a single case. In three cases of PDNOS, a low-grade B-cell lymphoma consistent with marginal zone lymphoma was present in the brain specimen (n=2) or spleen (n=1). Lastly, in the 'intracellular crystals' group, the crystals were present within CD68+ macrophages in one case wherein kappa-light chain was found by LC-MS/MS only; the pathology was consistent with crystal-storing histiocytosis. In the second case, the crystals contained immunoglobulin G within CD138+ plasma cells. Our results show that proteinaceous deposits in the nervous system contain immunoglobulin components and LC-MS/MS accurately identifies the content of these deposits in clinical biopsy specimens. LC-MS/MS represents a novel application for characterization of these deposits and is of diagnostic utility in addition to standard immunohistochemical analyses.     

CD138 (syndecan-1), a plasma cell marker immunohistochemical profile in hematopoietic and nonhematopoietic neoplasms

We evaluated the immunohistochemical profile and specificity of CD138 reactivity in 238 specimens from hematopoietic and nonhematopoietic neoplasms. In 91 bone marrow biopsies, CD138 reactivity was observed for nonneoplastic plasma cells, neoplastic plasma cells in multiple myeloma cases (43/43), and the plasmacytic component in lymphoplasmacytic lymphoma cases (4/4). Stromal reactivity was noted in 7 multiple myeloma cases. Of 9 bone marrow specimens involved by metastatic carcinoma, tumor cells were CD138+ in 5 cases; stromal reactivity was noted in 7 cases. Studies of 76 nodal and extranodal lymphomas (B-cell, 49; T-cell, 8; Hodgkin lymphoma, 19), 1 Langerhans cell histiocytosis, and 14 nonneoplastic lymph nodes revealed CD138 reactivity only for nonneoplastic plasma cells, the neoplastic cells of 2 large B-cell lymphomas (immunoblastic type, plasmacytoid features), and the clonal plasmacytic component of 3 of 3 extranodal and 1 nodal marginal zone lymphoma. Evaluation of 56 epithelial and nonepithelial tumors revealed CD138 positivity for neoplastic cells of carcinomas of various types (30/33), frequently with associated stromal reactivity, and for neoplasms of mesenchymal, melanocytic, and other tumor types (12/23). Within the hematopoietic system, CD138 is an excellent marker of plasmacytic differentiation. Based on its broad staining profile, CD138 reactivity for neoplastic cells is not a definitive marker for plasmacytic derivation, unless a hematolymphoid origin has been established.     

Renal manifestations of plasma cell dyscrasias: an appraisal from the patients' bedside to the research laboratory

One of the most prominent features of plasma cell dyscrasias is the frequent occurrence of renal dysfunction. Renal insufficiency is a common finding with elevated serum creatinine in more than 50% of patients with multiple myeloma at the time of diagnosis. Renal failure is the second most common cause of death in myeloma surpassed only by infections. The reasons for renal failure are multifactorial and early accurate diagnosis of the renal alterations may significantly impact morbidity and survival. Renal failure may result from selective glomerular, tubular interstitial, or vascular pathology or from a combination of pathologic events. The disorders associated with plasma cell dyscrasias include those characterized by monoclonal light chain deposition, encompassing AL-amyloidosis, in addition to the less well-characterized entities, such as heavy chain deposition disease and heavy chain amyloidosis. Therefore, it is more accurate to refer to them as monoclonal immunoglobulin deposition diseases. Staining of renal biopsy specimens for kappa and lambda light chains using immunofluorescence techniques and more sophisticated advanced diagnostic techniques such as immunoelectron microscopy permit detailed characterization of the various renal pathologic manifestations. Renal biopsies can identify monoclonal immunoglobulin deposition, and nephrologists have an opportunity to detect an underlying plasma cell dyscrasia early in its clinical course before overt hematologic alterations become manifest and irreversible renal damage has occurred. The overall spectrum of clinical and pathologic manifestations of monoclonal immunoglobulin deposition renal diseases has expanded considerably in recent years. Recent developments in the research arena promise new therapeutic interventions aimed at avoiding or ameliorating renal damage and even promoting reversal of some of the pathologic alterations. Currently, the 5-year survival rate in myeloma is 29% in white patients and 30% in African-American patients, a rather modest improvement from 24% in the 1970s. Bone marrow ablation followed by transplantation is available as an alternative mode of therapy that may be extraordinarily helpful in a subset of patients with early myeloma.