Crystal-storing Histiocytosis Research Articles

Pulmonary crystal‐storing histiocytosis diagnosed by computed tomography‐guided fine‐needle aspiration

Crystal-storing histiocytosis (CSH) is a rare process most often occurring in conjunction with an underlying hematopoietic neoplasm, usually multiple myeloma or low-grade B-cell lymphoma. We report the first case of pulmonary CSH diagnosed by fine-needle aspiration biopsy. A patient with a history of urothelial carcinoma developed a lung nodule, which was evaluated by fine-needle aspiration biopsy. Cytologic examination revealed macrophages with abundant cytoplasmic crystals diagnostic of CSH. Based on this cytologic interpretation, additional clinical laboratory evaluation was pursued and revealed a previously unknown monoclonal serum protein. CSH must be differentiated from other non-neoplastic and neoplastic lesions and when diagnosed, should trigger a search for an underlying lymphoproliferative disorder.

Crystal-Storing Histiocytosis and Crystalline Keratopathy Caused by Monoclonal Gammopathy of Undetermined Significance

The purpose of this study was to report the occurrence of crystalline keratopathy and of orbital infiltrative disease resulting from crystal-storing histiocytosis (CSH) in a patient with monoclonal gammopathy of undetermined significance. The authors conducted a review of a medical record and immunohistopathologic studies. A 66-year-old man presented with a 3-year history of unilateral progressive ptosis, proptosis, and external ophthalmoplegia. Magnetic resonance imaging showed orbital fat expansion and extraocular muscle thickening with gadolinium enhancement. The patient also had bilateral crystalline keratopathy and had undergone penetrating keratoplasty in one eye. The urine and serum showed elevated levels of immunoglobulin, but the bone marrow aspirate was normal. The systemic evaluation was consistent with monoclonal gammopathy of undetermined significance. An orbital fat biopsy revealed histiocytes engorged with lambda light chain crystals. The corneal stroma also showed positive immunostaining for lambda light chains. The patient was diagnosed with orbital CSH and with lambda light chain crystalline keratopathy. CSH is characterized by the accumulation of reactive histiocytes filled with immunoglobulin crystals in various tissues and is frequently associated with systemic hyperglobulinemic states. For unknown reasons, in this patient, a systemic immunologic disorder led to lambda light chain abnormalities with histiocyte infiltration of the orbit and corneal deposition. Although CSH is rare, it should be part of the differential diagnosis of orbital infiltrative disease with or without crystalline keratopathy.

Renal crystal storing histiocytosis in a patient with multiple myeloma

Renal crystal storing histiocytosis in a patient with multiple myeloma

Crystal-storing histiocytosis associated with only one of two consecutive, but genetically unrelated B-cell lymphomas

A localized crystal-storing histiocytosis (CSH) making the underlying marginal zone lymphoma (MZL) hardly discernible microscopically is described. Image analysis of the hyper electron dense crystals localized light microscopically in swollen histiocytic cells exhibited a major equatorial periodicity of 6.6 nm. Rarely, crystals of this type were detected within plasma cells, but were always surrounded by smooth membrane in contrast to Russell bodies. IgM/lambda restriction and VH3-21*02, DH4-17*01, JH4*02 gene usage were detected behind the lesion. Within 26 months, a genetically unrelated lymphoma of CD5–CD20–CD23-positive phenotype with a different VH1-24*01, DH2-21*02, JH2*01 heavy chain rearrangement, but with the same light chain gene usage, was identified without CSH. This might indicate that the unique condition responsible for the crystal formation is likely to rely on the sequence of the first clonally rearranged heavy chain exhibiting much higher CDRIII pI value (6.0) than the average.

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 λ, but not κ, light chain as well as serum amyloid P in all amyloidomas. λ-Light-chain immunostaining was noted in amyloid (n=5), although demonstrable monotypic lymphoplasmacytic cells were seen in only one case. Conversely, in PDNOS κ, but not λ, 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 κ-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.

Crystal storing histiocytosis: a rare presentation of plasma cell myeloma

Crystal storing histiocytosis (CSH) is a very rare association with plasma cell dyscrasias. It is presumed to be an intra-lysosomal accumulation of the secreted paraprotein aggregated into crystals and is associated with presence of variable numbers of histiocyte-like cells with phagocytosed crystalline inclusions in the bone marrow and other extramedullary sites Herein we report a case of multiple myeloma associated with CSH with a rapidly downhill clinical course. There was diagnostic confusion at the outset with a histiocytic disorder which was clarified with the use of Immunohistiochemistry along with serum protein electrophoresis and immunofixation.

Multi‐organ involvement with crystal‐storing histiocytosis

A 65-year-old man underwent a renal transplant for what was thought to be interstitial nephritis. His graft did not function as well as expected and he underwent renal biopsies to investigate this. These demonstrated an extensive infiltrate by crystal-containing macrophages throughout the grafted kidney. The crystal shapes varied but there were many rhomboid and spindle forms, seen most clearly on electron microscopy (top). A bone marrow trephine biopsy performed at this time demonstrated an extensive infiltrate of histiocytes packed with immunoglobulin crystals (bottom). A review of his diagnostic renal biopsy from 2 years previously confirmed the presence of these crystals. This rare phenomenon, crystal-storing histiocytosis, can be associated with myeloma but examination of urine, serum and bone marrow did not detect any monoclonality at that time. However a serum free-light chain assay subsequently performed did show a kappa excess, confirming plasma cell clonality.

CORRESPONDENCE: Reader Submitted Cases of the Month Edited by Dr Ronald L. Hamilton OCTOBER 2007 CASE 1: 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.

Histiocytic lesions and proliferations in the lung

Pulmonary lesions encountered by the pathologist in which histiocytes are the dominant finding histologically are reviewed. Lesions discussed include neoplasms of histiocytes and nonneoplastic processes. The nonneoplastic processes are divided into those that present as nodular histiocytic proliferations in the lung, those that present as diffuse proliferations of histiocytes in the lung, and those with a mixed pattern. Entities discussed include pulmonary Langerhans' cell histiocytosis, pneumonoconioses, infections, diffuse panbronchiolitis, crystal storing histiocytosis, respiratory bronchiolitis, alveolar hemorrhage, eosinophilic pneumonia, obstructive pneumonia, exogenous lipoid pneumonia, some drug reactions, and some metabolic/storage diseases. Entities of uncertain histogenesis, including Rosai-Dorfman disease and Erdheim-Chester disease, are also discussed. Qualitative features of the histiocytes are addressed, including the presence of foreign dust, hemosiderin, foamy change, and histiocytes showing features of Langerhans' cells.

Localized gastric crystal‐storing histiocytosis

Localized gastric crystal‐storing histiocytosis

Crystal-storing Histiocytosis due to Massive Accumulation of Charcot-Leyden Crystals: A Unique Association Producing Colonic Polyposis in a 78-year-old Woman With Eosinophilic Colitis

Crystal-storing histiocytosis is a rare diagnosis that to date has only been associated with 2 conditions: intracytoplasmic accumulation of crystallized immunoglobulins in patients with lymphoproliferative disorders or plasma cell dyscrasias, and histiocytic accumulations of phagocytosed clofazimine, a drug used to treat lepromatous leprosy. We describe a 78-year-old woman with a past medical history of dermatologic mastocytosis and peripheral eosinophilia who presented with diarrhea and weight loss, and was found at colonoscopy to have polyposis limited to the right and transverse colon. She eventually underwent subtotal colectomy to remove the segment of polyposis. At gross examination, the colonic mucosa contained numerous polyps ranging from 1 to 7 mm which on histologic evaluation proved to represent mucosal and submucosal collections of histiocytes whose cytoplasm was distended by numerous brightly eosinophilic crystals. An intense eosinophilic infiltrate surrounded the histiocyte collections and also mildly involved the intervening colonic mucosa and superficial submucosa. Electron microscopy confirmed the presence of intracytoplasmic material identical to Charcot-Leyden crystals within histiocytes, representing the breakdown products of degranulated eosinophils. This is the first reported case of crystal-storing histiocytosis produced by massive accumulation of Charcot-Leyden crystals in eosinophilic colitis.

Crystal storing histiocytosis of the skin associated with multiple myeloma

Crystal storing histiocytosis (CSH) imitating rhabdomyoma is a very rare disease entity involving different tissues. The skin is involved in extremely rare cases. To describe the clinical and histopathological characteristics in a patient with unusually extensive skin involvement. A 62-year-old woman presented with a large red infiltrated verrucosus lesion on the anterior aspect of the chest and on the neck. The skin biopsy revealed histiocytes throughout the whole dermis containing thin crystalloid structures in the cytoplasm. Upon histopathological examination, crystal-storing histiocytosis was diagnosed and consequently a hematological examination revealed multiple myeloma IgG Kappa. Skin involvement by CSH proceeded the diagnosis of multiple myeloma by 4 years. Phagocytosis of crystals of immunoglobulins by histiocytes (crystals storing histiocytosis) is a rare symptom associated most often with lymphoproliferative disease. The clinical picture is not characteristic, in the histopathologic picture it is striking similarity to rhabdomyoma. The skin involvement by crystal storing histiocytosis can be the first symptom of malignant lymphoma that can proceed the hematological malignancy by years.

Crystal-storing histiocytosis associated with MALT lymphoma of the ocular adnexa: a case report with review of literature

We report a case of crystal-storing histiocytosis (CSH) associated with mucosa-associated lymphoid tissue (MALT) lymphoma of the ocular adnexa. The patient was an 81-year-old woman who presented with a 5-month history of a slowly enlarging tumor on her left lower eyelid. The tumor was 2 cm in the largest diameter, involving both inferior oblique and inferior rectus muscles. Histological examination revealed that the tumor was composed predominantly of sheets of spindle-shaped cells resembling striated muscle cells, and scattered aggregates of atypical lymphoid cells at the periphery of the tumor, showing prominent plasmacytoid differentiation. Immunohistochemical and ultrastructural analyses demonstrated that the spindle-shaped cells were CD68-positive histiocytes containing abundant rod-like and/or rectangular crystals in their cytoplasm, consistent with the diagnosis of CSH. The scattered aggregates of atypical lymphoid cells were diagnosed as MALT lymphoma based upon their immunophenotype, featuring diffusely positive staining for CD20, but negative for CD3, CD5, and CD10, and monotypic expression of IgM-kappa in cells with plasmacytoid differentiation. Although CSH is a well-recognized manifestation in lymphoproliferative disorders in the literature, CSH complicated by MALT lymphoma has only very rarely been reported. Given the rarity of this, difficulties in diagnosis may arise especially in cases where histiocytic proliferation overwhelms the underlying lymphoproliferative diseases.

Dangerous small B-cell clones

AbstractThe detection of a monoclonal immunoglobulin in serum or urine usually raises concerns about the size of the underlying B-cell-derived clone and possible systemic effects caused by its expansion. However, a small clone can synthesize a very toxic protein, producing devastating systemic damage and protean clinical presentations. The resulting “monoclonal component-related diseases,” although difficult to diagnose, may be progressive and even fatal. The monoclonal protein can aggregate and deposit systemically as occurs in light-chain amyloidosis, monoclonal immunoglobulin deposition disease, crystal-storing histiocytosis, and monoclonal cryoglobulinemia. Alternatively, some monoclonal proteins possess antibody activity toward autogenous antigens and cause chronic cold agglutinin disease, mixed cryoglobulinemia, and peripheral neuropathies. Other humoral mediators may contribute to neuropathy in variant disorders such as the POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome. The clone synthesizing the noxious monoclonal proteins is often small, and sensitive techniques may be required to detect these immunoglobulins. A delay in diagnosis can allow irreversible organ damage and dramatically shorten survival. Prompt recognition of suggestive signs and symptoms should trigger a thorough diagnostic approach to reach the correct diagnosis quickly, because this is the key to effective therapy. Although the treatment of these conditions is not optimal, significant advances have been made, improving the duration and quality of life.

Dysproteinemia-related nephropathy associated with crystal-storing histiocytosis

CASE PRESENTATION A 41-year-old white man presented with a 6-month history of worsening neck pain accompanied by 20Ib weight loss. He was initially referred to an orthopedic surgeon and work-up including magnetic resonance imaging revealed shoulder bursitis for which he received a steroid injection. However, neck pain continued and laboratory tests revealed anemia and renal insufficiency, leading to his referral to an internist. The patient had no significant past medical history or family history of renal disease and he was not taking any medications. Physical examination revealed temporal wasting but was otherwise unremarkable. Laboratory investigations revealed the following: blood urea nitrogen 32 mg/dl (normal 7-25 mg/dl), serum creatinine 4.2 mg/dl (normal 0.5-1.4 mg/dl), serum calcium 9.8 mg/dl (normal 8.5-10.4 mg/dl), phosphorous 4.3 mg/dl (normal 2.5-4.5 mg/dl), sodium 143mmol/l (normal 135-146 mmol/l), potassium 3.6mmol/l (normal 3.5-5.3 mmol/l), chloride 109 mmol/l (normal 98-110 mmol/l), bicarbonate 17 mmol/l (normal 21-33 mmol/l), glucose 95 (normal 65-139 mg/dl), lactate dehydrogenase 505 (normal 105-333 IU/I), white blood cell count 9800/μl, hemoglobin 9.7 g/dl, hematocrit 28.3%, and platelet count 316000/μl. Erythrocyte sedimentation rate was markedly elevated (>100mm/h). Total serum protein was 8.8 g/dl (normal 6.0-8.3 g/dl), serum albumin was 4.2 g/dl (normal 3.5-4.9 g/dl), and β2-microglobulin was elevated (10.7 mg/l, normal < 1.85 mg/l). Quantitative serum immunoglobulins (Ig) revealed elevated IgD (842 mg/dl, normal 0-14 mg/dl) and decreased levels of IgG (450 mg/dl, normal 694-1618 mg/dl), IgA (32 mg/dl, normal 81-463 mg/dl), and IgM (9.9 mg/dl, normal 48-271 mg/ dl). Serum protein electrophoresis revealed a monoclonal spike (0.82 g/dl) with IgD kappa (κ) specificity, elevated free K light chains (81 200 mg/l, normal range 3.3-19.4 mg/l), and normal level of lambda (λ) light chains (10.6 mg/l, normal range 5.7-26.3 mg/l). Urinalysis revealed 100mg/dl glucose; these findings, together with the normal serum glucose, normal serum phosphate, and low serum bicarbonate levels, suggested partial Fanconi's syndrome. Urinalysis also revealed 1 + protein; however, 24-h urine collection contained 20.2 g protein of which 13.975 g (69.2%) consisted of free K light chains. Bone marrow examination revealed diffuse infiltration by IgD K-positive plasma cells, accounting for 50% of overall cellularity, consistent with multiple myeloma. Based on the finding of significant urinary light chain excretion, the patient's multiple myeloma was stage III-B. A skeletal survey revealed no bony lesions, and magnetic resonance imaging of the axial skeleton revealed marrow abnormalities consistent with myeloma but no osseous lesions. Given the new onset of renal insufficiency and partial Fanconi's syndrome with massive urinary light chain excretion, a renal biopsy was performed to determine the pattern of dysproteinemia-related renal disease.

Clinical and molecular characteristics of patients with non-amyloid light chain deposition disorders, and outcome following treatment with high-dose melphalan and autologous stem cell transplantation

Light chain deposition disease (LCDD) is caused by a clonal plasma cell disorder in which fragments of monoclonal immunoglobulin light chains form non-fibrillary deposits in various tissues resulting in organ dysfunction. Crystal storing histiocytosis (CSH) is another light chain deposition disorder in which monoclonal light chains form intracytoplasmic crystals. Both are uncommon diseases for which there is limited treatment experience. Between 2003 and 2005, five patients with LCDD and one with CSH were treated at Boston University Medical Center with high-dose melphalan and autologous peripheral blood stem cell transplantation (HDM/SCT). Five of the six patients had predominantly renal involvement, and one patient with LCDD had biopsy-proven deposits in the myocardium. Molecular characterization revealed that the pathologic light chains were kappa in four of the six patients, and sequence analysis revealed unusual germline donor genes and high rates of amino-acid substitutions. One light chain sequence encoded a new potential N-linked glycosylation site, and another showed evidence of antigen selection. All patients are alive and five of the six patients are in complete hematologic remission at a median follow-up of 12 months (range 4-29 months) after HDM/SCT. In our experience, HDM/SCT is a feasible and effective treatment approach for these disorders.

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.

A 70-Year-Old Woman With Acute Renal Failure

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.

Pulmonary Extranodal Marginal Zone Lymphoma With Massive Crystal Storing Histiocytosis

We present an incidentally discovered, unusual case of pulmonary bronchial mucosa-associated lymphoid tissue lymphoma associated with massive crystal storing histiocytosis in a 69-year-old woman. The neoplastic process was masked by large numbers of epithelioid and spindled histiocytes containing crystalline material. Histochemical stains showed intracytoplasmic crystals and immunoperoxidase staining confirmed the histiocytic nature of the swollen cells. Electron microscopy demonstrated the characteristic appearance of immunoglobulin crystals. Lymphoepithelial lesions were identified on immunohistochemical staining, compounding suspicions of an underlying lymphoid neoplasm. Molecular studies later revealed a monoclonal B-cell population. The patient had no systemic evidence of a paraproteinemia. Crystal storing histiocytosis is a rare phenomenon in which macrophages accumulate light chain or immunoglobulin crystalline inclusions. The disease may be systemic, or localized as in this case. It is usually associated with the excess production of a monoclonal immunoglobulin, although there have been many case reports without this feature. An overview of crystal storing histiocytosis is given.

High-Dose Melphalan and Autologous Stem Cell Transplantation in Unusual Non-Amyloid Light Chain Deposition Disorders.

Light chain deposition disease (LCDD) is caused by a clonal plasma cell disorder in which fragments of monoclonal immunoglobulin light chains, usually with a kappa genotype, are deposited in various tissues in a globular form resulting in organ dysfunction. Crystal-storing histiocytosis (CSH) is another light chain deposition disorder in which monoclonal light chains form intracytoplasmic crystalline deposits. Both LCDD and CSH are uncommon diseases, for which there is limited treatment experience. However, conventional anti-plasma cell chemotherapy with oral melphalan as is used in multiple myeloma has been tried in LCDD with little benefit. Between 1999–2005, five patients with LCDD and one patient with CSH have been treated at Boston University Medical Center with high-dose intravenous melphalan (IVM) followed by autologous peripheral blood stem cell transplantation (SCT). Patients have been treated with either 200mg/m2 of IVM (n=5) or 140 mg/m2 (n=1) depending on age and clinical status and subsequently have been assessed for hematologic responses and for improvements in organ function at 3, 6 and 12 months, and annually thereafter. The median age of patients at the time of treatment has been 45 years (range 34–51). Four patients with LCDD had kappa light chain deposition involving the kidneys and 1 of these patients had extrarenal involvement of the heart on electron microscopy of endomyocardial biopsy as well. One patient with LCDD had lambda deposition involving kidneys only. The patient with CSH had only renal involvement, with kappa light chain plasma cell dyscrasia. All except 1 patient had impaired renal function with creatinine clearance ranging from 21 – 64 ml/min. All treated patients are alive and well at a median follow up of 13.6 months (range 5–24 months). Median survival has not yet been reached. No treatment-related deaths were noted, and treatment-related toxicities were manageable and reversible. All evaluable patients (n=4) have achieved a hematologic complete response of the underlying plasma cell dyscrasia after IVM/SCT. In conclusion, this experience indicates that IVM/SCT is a safe, feasible, and effective modality for the treatment of these unusual light chain deposition disorders.