Crystal-storing Histiocytosis Research Articles

Monoclonal immunoglobulin crystalline nephropathies

Monoclonal immunoglobulin (MIg) crystalline nephropathies are rare lesions resulting from precipitation of MIgs in the kidney as crystalline inclusions. They can be categorized into lesions with predominant intracellular crystals (light chain [LC] proximal tubulopathy, LC crystal-storing histiocytosis, LC crystalline podocytopathy] and lesions with predominant extracellular crystals (crystalglobulin-induced nephropathy, crystalline variant of LC cast nephropathy). The majority of these lesions are associated with low tumor burden lymphoproliferative disorders, with the exception of crystalline variant of LC cast nephropathy. Extra-renal involvement (eg, skin, cornea) is frequent. Kidney biopsy is the cornerstone for diagnosis, which often requires electron microscopy and antigen retrieval. A thorough hematologic workup and evaluation of extra-renal involvement is mandatory for management. Treatment of these lesions is with clone-directed therapy, with the goal of achieving hematologic very good partial response or complete response which preserve or improve kidney function. In vitro and in vivo studies, animal models, and novel sequencing techniques have been invaluable tools to understand the pathogenesis of LC proximal tubulopathy, and can be utilized to increase our limited knowledge of the pathogenesis of the other MIg crystalline nephropathies. This review will provide an update on the pathology, renal and hematologic characteristics, extra-renal manifestations, prognosis, treatment, and pathogenesis of MIg crystalline nephropathies.

Renal crystal-storing histiocytosis successfully treated with bortezomib-based regimen

Renal crystal-storing histiocytosis successfully treated with bortezomib-based regimen

A novel approach to diagnosing crystal-storing histiocytosis: utility of scanning electron microscopy for formalin-fixed paraffin-embedded tissue specimens.

Crystal-storing histiocytosis (CSH) is a rare disorder that shows infiltration of histiocytes with an aberrant cytoplasmic accumulation of crystalline structures and is often accompanied by lymphoproliferative-plasma cell disorders (LP-PCD) as background diseases. The diagnosis of CSH requires identification of crystalline structures that accumulate in the infiltrating histiocytes, which may be challenging by optical microscopy alone. In this case report, we describe an atypical course of systemic CSH with multifocal fibrosclerosis of an unknown background disease that was diagnosed by ultrastructural observation, including transmission electron microscopy (TEM) and scanning electron microscopy (SEM), in pathological autopsy. In addition, crystalline structures were successfully identified by scanning electron microscopic observations using formalin-fixed and paraffin-embedded (FFPE) tissue from biopsy specimens taken before death. Since CSH was identified by SEM in a tiny biopsy specimen, observation of histiocytic infiltrative lesions by SEM using FFPE tissue may lead to early detection of and initiation of treatment for CSH.

CPC13 Cutaneous crystal storing histiocytosis

Abstract A 43-year-old woman presented with a 3-year history of a gradually enlarging lesion on the right upper chest. Her comorbidities included ankylosing spondylitis and recurrent anterior uveitis, and she was taking no regular medications. She had no systemic symptoms. She was initially seen by the breast team, who organized an ultrasound that showed chronic inflammation, and a biopsy that showed granulomatous chronic inflammatory tissue. Topical treatment with fucidin was unsuccessful, and she was referred to dermatology. On examination, she had a 3.5 × 4 cm pink subcutaneous nodule on the right upper anterior chest. There was no lymphadenopathy or organomegaly. Investigations revealed low IgA (0.71 g L−1), raised IgM (4.30 g L−1) and mild thrombocytopenia (141 × 109 cells L−1). Full blood count; urea and electrolytes; liver function tests; IgG; lactate dehydrogenase; thyroid stimulating hormone; serum angiotensin-converting enzyme; autoimmune serology, including antinuclear antigen; Borrelia serology; tuberculosis QuantiFERON; ferritin; erythrocyte sedimentation rate; serum protein electrophoresis and urine Bence Jones protein were normal or negative. Chest X-ray and computed tomography of the thorax, abdomen and pelvis did not reveal any evidence of underlying malignancy. Repeat skin biopsy showed a superficial and deep dermal histiocytic infiltrate. At high power, numerous needle-like eosinophilic crystals were seen within the histiocytes. There was a periadnexal and perifollicular infiltrate of lymphocytes and plasma cells. Light chain staining showed that the plasma cells were lambda light chain restricted and were IgM positive and IgG negative. The features were of a crystal-storing histiocytosis. Cutaneous crystal-storing histiocytosis is a rare condition, with only six reported cases. The pathophysiology involves the accumulation of crystalline material within the cytoplasm of histiocytes. It is strongly associated with an underlying haematological malignancy, including multiple myeloma, lymphoplasmacytic lymphoma and monoclonal gammopathy of undetermined significance (Li JJ, Henderson C. Cutaneous crystal storing histiocytosis: a report of two cases. J Cutan Pathol 2015; 42:136–43). In our case, a bone marrow biopsy was not performed given the lack of systemic symptoms, no significant serum paraprotein and normal imaging. The patient is currently being managed with topical clobetasol propionate 0.05% ointment and is under annual haematology surveillance with serum electrophoresis and immunoglobulins.

Generalized crystal-storing histiocytosis with noncirrhotic portal hypertension: an autopsy case report.

Crystal-storing histiocytosis (CSH) is a rare disease associated with the accumulation of histiocytes containing crystalline matter within their cytoplasm. Herein, we present the case of a female patient who was diagnosed with Tolosa-Hunt syndrome at 45years of age and idiopathic retroperitoneal fibrosis when she was 48years. She developed portal hypertension (PH), but did not present with cirrhosis; as such, the cause of PH was not identified. Her PH gradually worsened when she was 54years, and at the age of 60years, she died from an acute subdural hematoma. Autopsy revealed retroperitoneal fibrosis with severe fibrosis extending around the hepatic veins and into the porta hepatis. Histologically, the retroperitoneal tissue showed a dense infiltrate of eosinophilic histiocytes with crystal structures in the cytoplasm, which was pathologically diagnosed as CSH. Nodular regenerative hyperplasia was observed in the liver parenchyma, whereas cirrhosis was not. In the present case, CSH caused fibrosis, which was believed to be the cause of PH. In addition, we considered that nodular regenerative hyperplasia caused by the altered hepatic blood flow due to treatment of gastric varices contributed to worsening PH. Hence, CSH should be considered as an underlying disease in noncirrhotic portal hypertension.

Combined crystal-storing histiocytosis, light chain proximal tubulopathy, and light chain crystalline podocytopathy in a patient with multiple myeloma: a case report and literature review

Background Crystal-storing histiocytosis (CSH), light chain proximal tubulopathy (LCPT), and light chain crystalline podocytopathy (LCCP) are rare complications of multiple myeloma (MM) or monoclonal gammopathy of renal significance, and their diagnoses are challenging. Case presentation In this case, a 69-year-old Chinese woman presented with suspicious Fanconi syndrome with renal insufficiency. Immunofixation electrophoresis of both serum and urine revealed elevated immunoglobulin G kappa (IgGkappa) and kappa light chain. Bone marrow aspirate revealed 15% plasma cells with considerable cytoplasmic granular inclusions and needle-shaped crystals. Renal biopsy confirmed the final pathologic diagnosis of kappa-restricted CSH, combined LCPT and LCCP by immunoelectron microscopy. A number of special casts were present which could easily be misdiagnosed as light chain cast nephropathy. Immunofluorescence on frozen tissue presented false negative for kappa light chain, as ultimately proven by paraffin-embedded tissue after pronase digestion. MM and CSH were diagnosed, and two cycles of chemotherapy were given. The patient subsequently refused further chemotherapy, and her renal function remained relatively stable during a 2.5-year follow-up period. Conclusions In conclusion, we report a rare case of generalized kappa-restricted CSH involving bone marrow and kidney, combined with LCPT and LCCP, provide a comprehensive summary of renal CSH, and propose a new nomenclature of monoclonal immunoglobulin-induced crystalline nephrology. The presentation of monoclonal immunoglobulin and Fanconi syndrome should suggest the presence of monoclonal immunoglobulin-induced crystalline nephrology. Use of paraffin-embedded tissue after pronase digestion and immunoelectron microscopy is beneficial to improve the sensitivity of diagnosis.

Crystal-Storing Histiocytosis: The Iceberg of More Serious Conditions.

Crystal-storing histiocytosis is a rare condition that is histologically characterized by intracellular cytoplasmic crystalline inclusions. It usually presents monoclonal immunoglobulins that deposit within histiocytes, which accumulate and affect different organs of the human body and are commonly associated with lymphoproliferative conditions, especially those with plasmacytic differentiation. The prognosis of this condition is variable and related to the underlying clinical disease. In this review article, we aim to describe and discuss the clinical and pathological characteristics of crystal-storing histiocytosis based on the available literature and to provide a thorough differential diagnosis.

Crystal-Storing Histiocytosis in a Patient with Nodal Marginal Zone Lymphoma

We present a case of a 72-year-old male diagnosed with concurrent crystal-storing histiocytosis and nodal marginal zone lymphoma with plasmacytic differentiation following a finding of new axillary lymphadenopathy during active surveillance for an early stage lung cancer.

Dural Marginal Zone Lymphoma With Extensive Crystal Storing Histiocytosis: Spotting the Zebra Among the Horses.

Dural Marginal Zone Lymphoma With Extensive Crystal Storing Histiocytosis: Spotting the Zebra Among the Horses.

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.

Monoclonal Gammopathy-Related Kidney Diseases.

Monoclonal gammopathies occur secondary to a broad range of clonal B lymphocyte or plasma cell disorders, producing either whole or truncated monoclonal immunoglobulins. The kidneys are often affected by these monoclonal proteins, and, although not mutually exclusive, can involve the glomeruli, tubules, interstitium, and vasculature. The nephrotoxic potential of these monoclonal proteins is dependent on a variety of physicochemical characteristics that are responsible for the diverse clinicopathologic manifestations, including glomerular diseases with organized deposits, glomerular diseases with granular deposits, and other lesions, such as C3 glomerulopathy and thrombotic microangiopathy with unique pathophysiologic features. The diseases that involve primarily the tubulointerstitial and vascular compartments are light chain cast nephropathy, light chain proximal tubulopathy, crystal-storing histiocytosis, and crystalglobulin-induced nephropathy with distinct acute and chronic clinicopathologic features. The diagnosis of a monoclonal gammopathy-related kidney disease is established by identification of an underlying active or more commonly, low-grade hematologic malignancy, serologic evidence of a monoclonal gammopathy when detectable, and most importantly, monoclonal protein-induced pathologic lesions seen in a kidney biopsy, confirming the association with the monoclonal protein. Establishing a diagnosis may be challenging at times, particularly in the absence of an overt hematologic malignancy, with or without monoclonal gammopathy, such as proliferative glomerulonephritis with monoclonal immunoglobulin deposits. Overall, the treatment is directed against the underlying hematologic disorder and the potential source of the monoclonal protein.

Surgical resection of pulmonary crystal-storing histiocytosis with Sjögren's syndrome: A case report

Introduction and importanceCrystal-storing histiocytosis (CSH) is a rare clinical entity characterized by an abnormal increase in the number of histiocytes with massive accumulation of crystallized immunoglobulins. Yano et al. reported only one case of gastric CSH associated with Sjögren's syndrome. In this report, we present a case of pulmonary CSH with Sjögren's syndrome, and discuss the relevant literature.Case presentationA 64-year-old woman who had never smoked presented with cough 2 years earlier. Chest CT showed that the nodule in the right lower lobe had slowly enlarged to 12 × 10 mm. We suspected primary lung cancer and performed video-assisted thoracoscopic right S6 segmentectomy. Histopathological evaluation of the resected specimen revealed crystal-storing histiocytosis. As of 6 months postoperatively, no recurrence has been identified.Clinical discussionEighteen cases of pulmonary CSH have been described in the English language peer-reviewed literature, including our case. In this case, the patient had a history of Sjögren's syndrome, but no lymphoproliferative or plasma cell disorder (LP-PCD). Therapy for all patients without LP-PCD was excisional resection of the lung. Treatment and prognosis of patients with CSH varied according to the defined pathology. Jones et al. reported the case of 54-year-old woman without LP-PCD who presented with a solitary asymptomatic focus of CSH in the lung and initially underwent lesion resection, but showed recurrence 10 years later.ConclusionPulmonary CSH is one differential diagnosis for pulmonary nodule enlargement in patients with autoimmune disease. Surgical resection appears to represent an effective therapeutic option for localized CSH, but long-term follow-up remains necessary.

Immunoglobulin-Storing Histiocytosis: A Case Based Systemic Review.

Crystal-storing histiocytosis (CSH) is a rare event in disorders associated with monoclonal gammopathy and is mostly associated with the accumulation of immunoglobulins (Igs) in the cytoplasm of histiocytes. In this article, we present a case of a 75-year-old female with IgG kappa monoclonal gammopathy of undetermined significance (MGUS) and signs of a non-crystallized version of immunoglobulin-storing histiocytosis (IgSH) in a vertebra corpus. Furthermore, we performed a literature review based on all cases of storing histiocytosis identified by literature search between 1987 and 2020 and identified 140 cases in total. The median age at diagnosis was 60 years (range 18–91), with an equal sex distribution (51% men). The majority of the patients had an underlying neoplastic B-cell disorder, most often multiple myeloma (MM), MGUS, or lymphoplasmacytic lymphoma (LPL). The main affected organ systems or tissue sites were bone (n = 52), followed by head and neck (n = 31), kidney (n = 23), lung (n = 20), and gastrointestinal (GI)-tract (n = 18). IgG was the main immunoglobulin class involved, and most cases were associated with kappa light chain expression. We conclude that IgSH is a rare disease entity but should be considered with unusual findings in several organ systems associated with monoclonal gammopathy, especially with kappa light chain expression.

POS-499 CLINICAL AND PATHOLOGY SPECTRUM OF NON-AMYLOID MONOCLONAL GAMMOPATHY OF RENAL SIGNIFICANCE – ONE CENTER EXPERIENCE

In 2012, the International Kidney and Monoclonal Gammopathy Research Group (IKMG) introduced the term monoclonal gammopathy of renal significance (MGRS) to highlight causal relationship between gammopathy and monoclonal immunoglobulin (MIg)-mediated renal damage in cases, which do not meet criteria for B-cell malignancies. MGRS spectrum included various patterns with organized and non-organized paraprotein deposition: light chain proximal tubulopathy (LCPT), crystal-storing histiocytosis, MIg related amyloidosis, monoclonal fibrillary glomerulonephritis (GN), immunotactiod GN, type I cryoglobulinemic glomerulonephritis (cryo-GN), MIg deposition disease (MIDD), proliferative GN with MIg deposits (PGNMID), and C3-glomerulonephritis (C3-GN). According to the IKMG 2019 Consensus report, MGRS in addition to the above listed variants now merges type II cryo-GN, (cryo)-crystalglobulin GN, thrombotic microangiopathy associated with monoclonal gammopathy, monotypic membranous nephropathy (MN), monotypic anti-glomerular basement (anti-GBM) GN, smoldering myeloma (SM), smoldering Waldenström’s macroglobulinemia (SWM), and low-grade B-cell non-Hodgkin lymphoma (B-cell NHL) associated with renal lesions. Cast-nephropathy (CN) regarded as myeloma-defining event, and as such - does not belong to the MGRS, even though it is not exclusive to multiple myeloma. Same, intracapillary MIgM deposits, traditionally attributed to overt Waldenström’s macroglobulinemia, not included into MGRS list For this retrospective study, we evaluated 87 cases matching the updated MGRS criteria and followed in our unit in 2002-2020. The main data collected were clinical diagnosis, proteinuria, eGFR (CKD-EPI equation), need for dialysis at the time of kidney biopsy, and pathology pattern. Pathology evaluation of kidney tissue per protocol included light microscopy and immune staining; with the electron microscopy additionally performed 9% of cases. MGRS diagnosis based on evaluation of kidney pathology findings, serum and urine immunochemistry, and bone marrow biopsy. For this particular study, we evaluated non-amyloid variants of MGRS and non-amyloid patterns presenting in combination with MIg amyloidosis, and excluded from further analysis cases of “pure” MIg related amyloidosis. Study group included 29 patents - 9 males and 20 females of mean age 64 [53; 82] years; 8 patients were ultimately diagnosed with SM, 6 - with SWM, 2- with low-grade B-cell NHL, the rest 13 had no underlying hematological disease. At the time of kidney biopsy nephrotic syndrome presented in 16 (55%) of cases; 6 patients had CKD stage G2, 4 - stage G3a, 5 - stage G3b, 10 - stage G4, and 4 - stage 5, two of the latter required dialysis at the time of biopsy. Pathology patterns shown in the Table 1 Patterns with the organized MIg deposits presented mostly in SM cases, whereas non-organized deposits, mainly MIDD, dominated in patients without underlying hematological condition and in cases of SWM. The combination of organized and non-organized MIg deposits found rarely - both in SM and in cases without underlying hematological condition. Amyloidosis was combined with other patterns in 4 cases. Single cases of C3-GN alone and in combination with LCPT revealed only in SM and SWM. Importantly, we found 3 cases of SM with CN and 2 cases of SWM with intracapillary deposits MIgM, which complement the MGRS spectrum

Crystal-storing histiocytosis in Bing-Neel syndrome

Crystal-storing histiocytosis in Bing-Neel syndrome

Monoclonal gammopathy of renal significance: Spectrum of diseases and approach to a case.

The occurrence of kidney diseases associated with a monoclonal gammopathy in the absence of symptomatic multiple myeloma is increasingly recognized. When the kidney is involved, the monoclonal etiology of these diseases results in clinical and laboratory features distinct from those of other disease, necessitating the nomenclature monoclonal gammopathy of renal significance (MGRS). The detection of these monoclonal diseases involving the kidney is important since they are poorly responsive to conventional immunosuppression and instead require clone-directed therapy. The new International Kidney and Monoclonal research group consensus definition of MGRS includes all proliferative conditions of B cells and/or plasma cells. Renal lesions due to monoclonal immunoglobulins are quite capable of progression with resulting end-stage renal disease development. Hence, these lesions require therapeutic intervention even if they do not satisfy myeloma criteria or the presence of any myeloma defining event. The spectrum of renal lesions that can be observed in a case of MGRS is wide and mirrors the list that may be seen in a case of any plasma cell neoplasm. This includes Ig light chain, heavy chain, and heavy and light chain amyloidosis; immunotactoid glomerulonephritis (GN); monoclonal immunoglobulin deposition disease including light chain, heavy chain, or heavy and light chain disease; light chain proximal tubulopathy; crystal-storing histiocytosis; proliferative GN with monoclonal immunoglobulin deposits; C3 glomerulopathy with monoclonal gammopathy and cast nephropathy. The initial approach after histological assessment is based on presence or absence of monoclonal immunoglobulin deposits. If monoclonality is evident, it is important to distinguish between conditions with deposition of intact immunoglobulin molecule or light chains only. The treatment of MGRS is directed at the underlying neoplastic B-cell or plasma cell clones.

Orbital Crystal-Storing Histiocytosis: A Clinicopathologic Study of 4 Cases

The authors report the clinicopathological features of crystal-storing histiocytosis (CSH) that involved the orbit and conjunctiva and review published cases of CSH. Cases of histologically proven CSH were identified from archives at the Institute of Ophthalmology, London, and a retrospective review of clinical details and pathology was performed for cases between 1997 and 2017. Four cases of CSH were identified: 1 might have arisen from an inflammatory reaction to a silicone retinal buckle and 3 others occurred with localized B-cell lymphomas. Two patients presented with a conjunctival mass, and 2 had an orbital mass causing proptosis and hypoglobus. One case was associated with amyloid deposition and another had an earlier diagnosis of IgG4-related disease. In the patient without underlying lymphoma, the condition settled with removal of the explant and orbital mass, and the 3 with lymphoma underwent orbital radiotherapy with cessation of disease progression. All patients retained good vision. Ocular CSH is rare, can present in several ways, and should prompt investigation for an underlying lymphoproliferative disorder.

A colonic mass revealing a disseminated crystal storing histiocytosis secondary to indolent multiple myeloma: a case report with literature review

BackgroundCrystal storing histiocytosis is a rare disorder associated with monoclonal gammopathy. In this disease, monoclonal heavy and light chains accumulate in the lysosome of macrophages, leading to histiocytic reaction in different organs. It is secondary to the presence of a small B-cell clone, responsible for monoclonal immunoglobulin production. Histological diagnosis is a challenge and differential diagnoses include fibroblastic and histiocytic neoplasm. Clinical manifestations depend on the involved organs, rarely including peritoneum or digestive tract.Case presentationWe present a case of a 75-year-old with a medical history of colonic carcinoma. She presented with abdominal pain and inflammatory syndrome revealing a colonic mass. Hemicolectomy was performed. Initial diagnosis was fibroblastic tumour. The patient worsened, and diagnosis of a diffuse crystal storing histiocytosis was finally done. Haematological exploration found an indolent IgG-kappa multiple myeloma. The initial treatment with conventional chemotherapy did not permit an improvement of the patient condition. Immunotherapy with anti-CD38 monoclonal antibody (daratumumab) was proposed with a clinical and biological response.ConclusionThis case report emphasizes the histopathological challenge of histiocytic tumours which may involve digestive track. It focuses on the concept of monoclonal gammopathy of clinical significance, which can have a large spectrum of manifestations.

Gastric crystal-storing histiocytosis with concomitant mucosa-associated lymphoid tissue lymphoma.

Crystal-storing histiocytosis (CSH) is a rare entity that is characterized by intrahistiocytic accumulation of crystallized immunoglobulins. CSH is not a malignant process per se, but the majority of CSH cases are associated with underlying lymphoproliferative disorder. Although CSH can occur in a variety of organs, gastric CSH is very rare. We present a localized gastric CSH with concomitant mucosaassociated lymphoid tissue (MALT) lymphoma, manifesting as an ulcer bleeding in a 56-year-old man. Histologically, the biopsied gastric mucosa demonstrated expansion of the lamina propria by prominent collections of large eosinophilic mononuclear cells containing fibrillary crystalloid inclusions. Immunohistochemical studies revealed that the crystal-storing cells were histiocytes harboring kappa light chain-restricted immunoglobulin crystals. Within the lesion, atypical centrocyte-like cells forming lymphoepithelial lesions were seen, consistent with MALT lymphoma. Since this entity is rare and unfamiliar, difficulties in diagnosis may arise. Particularly, in this case, the lymphomatous area was obscured by florid CSH, making the diagnosis more challenging.

Localised pulmonary crystal-storing histiocytosis with underlying extranodal marginal zone lymphoma: A case report

Crystal-storing histiocytosis (CSH) is a rare entity, composed of a proliferation of non-neoplastic histiocytes with an accumulation of intracytoplasmic crystalline material. It is often associated with an underlying lymphoproliferative disorder, most often those that express monoclonal immunoglobulins, such as multiple myeloma and lymphoplasmacytic lymphoma. Here we report a case of localised pulmonary CSH in an asymptomatic 54-year-old man, found to have an incidental solid lesion in the right lung on computed tomography (CT). The lesion was composed of sheets of CD68 positive histiocytes that contained refractile eosinophilic crystalline inclusions, scattered lymphoid follicles of CD20 positive B lymphocytes, and occasional plasma cells. PCR for immunoglobulin heavy chain gene rearrangement confirmed the presence of a monoclonal population of B cells. These findings were supportive of a diagnosis of CSH with an underlying B cell/ plasma cell lymphoproliferative disorder, which was favoured to be an extranodal marginal zone lymphoma after clinical and radiological workup. Recognition of this rare entity is important as it may obscure an underlying lymphoproliferative disorder. A diagnosis of CSH should prompt careful exclusion of neoplasia, including clinical workup for systemic disease. In this case report we also discuss clinical features and diagnostic pitfalls.