Crystal-storing histiocytosis as a cause of symptomatic cardiac mass: histologic, immunohistochemical, and electron microscopic findings.
Abstract: * Crystal-storing histiocytosis is a rare disorder that is typically associated with low-grade B-cell lymphomas and monoclonal gammopathy. We present a 64-year-old man with a prior history of weakness and weight loss and hematologic evaluation that had revealed immunoglobulin G [kappa] monoclonal light chains in the serum and negative bone marrow biopsy. He presented with supraventricular tachyarrhythmia and a right atrial mass seen on echocardiogram and excised surgically. Histologically, the tumor was composed of sheets of macrophages infiltrating the atrial myocardium. The histiocytes were filled with multiple needleshaped, periodic acid-Schiff-negative crystals. These cells and associated plasma cells failed to show clonal light chain restriction by in situ hybridization or immunohistochemistry, and there was no area of lymphoma in the tumor. Ultrastructural examination showed numerous sticklike, trapezoidal, or polygonal dense crystals in the cytoplasm of histiocytes corroborating the diagnosis of crystalstoring histiocytosis. Although rare, crystal-storing histiocytosis should be included in the differential diagnosis of heart masses in patients with hematologic conditions associated with monoclonal gammopathy.

(Arch Pathol Lab Med. 2009;133:1861-1864)
Article Type: Case study
Subject: Histology (Analysis)
Histiocytosis (Risk factors)
Histiocytosis (Diagnosis)
Histiocytosis (Case studies)
Immunohistochemistry (Usage)
Immunohistochemistry (Analysis)
Electron microscopy (Usage)
Authors: Sailey, Charles J.
Alexiev, Borislav A.
Gammie, James S.
Pinell-Salles, Paula
Stafford, J. Lawrence
Burke, Allen
Pub Date: 11/01/2009
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 College of American Pathologists ISSN: 1543-2165
Issue: Date: Nov, 2009 Source Volume: 133 Source Issue: 11
Accession Number: 230152097
Full Text: Crystal-storing histiocytosis (CSH) is a rare manifestation associated with disorders that express monoclonal immunoglobulins, such as multiple myeloma, monoclonal gammopathy of undetermined significance, and lymphoid disorders such as lymphoplasmacytic lymphoma. (1-7) Histiocytic phagocytosis of excessive light chains produced by neoplastic low-grade lymphoplasmacytoid cells has been identified in bone marrow, lungs, lymph nodes, thymus, spleen, and a variety of other locations. (1-7) The monoclonal light chains are typically [kappa] isotype, with no specific heavy chain association. (1,4)


In November 2007 a 64-year-old man was referred to the University of Maryland Medical Center (Baltimore), Division of Cardiology, for an evaluation of recurrent atrial arrhythmias and an intracardiac mass. The patient had a 5-year history of occasional fluttering in his chest that lasted for 1 to 2 seconds then spontaneously abated. He denied any central nervous system symptoms until August 2007 when he experienced a prolonged episode of dizziness that was not associated with palpitations. He was eventually hospitalized for atrial flutter with rates of approximately 200 beats per minute. The patient reported that his heart rate was well controlled with medications (metoprolol and digoxin) for a period posthospitalization. Transesophageal echocardiography and magnetic resonance imaging scan revealed a ball-shaped mass on the superior aspect of the right atrium with a thickened interatrial septum. Minimal details regarding the mass lesion were available from the reports of imaging done in the referring institution. Between August and his November referral he had multiple breakthrough episodes of arrhythmias. A biopsy of the atrial mass in November showed acute inflammation and fibrosis.

The patient's history is also remarkable for a monoclonal gammopathy diagnosed in April 2007, with follow-up immunofixation electrophoresis in September 2007 showing an immunoglobulin (Ig) G [kappa] monoclonal protein comprising 16.8% of the total protein, equivalent to 1294 mg/dL. Results of a urine protein electrophoresis and a subsequent trephine bone marrow biopsy were unremarkable.

In December 2007 the patient was admitted to the department of surgery for atrial mass excision. Laboratory findings at that time were white blood cells, 9.4 X [10.sup.3]/ [micro]L; hemoglobin, 14.7 g/dL; hematocrit, 44.2%; red blood cells, 4.75 X [10.sup.6]/[micro]L; and platelets, 452 X [10.sup.3]/[micro]L. A sternotomy was performed, the mass was identified in the right atrial myocardium just above the entry of the inferior vena cava, and debulking was performed. The tumor was received in multiple fragments by the department of pathology.

On postoperative day 1, the patient was extubated but remained on pressor support. On postoperative day 3, he was weaned off pressor support and was transferred to the cardiac surgery telemetry unit. On postoperative day 4, the patient was started on low-dose p-blocker with good response. On postoperative day 5, the patient was discharged home. Postoperative electrocardiogram showed no significant abnormalities. There is currently no follow-up information.







Gross examination of the mass revealed multiple fragments of pink and tan soft tissue that was received as 3 separate specimens that measured 1.5 X 1.4 X 0.3 cm, 1.1 X 0.6 X 0.4 cm, and 4.3 X 3.9 X 1.1 cm in loose aggregate, respectively.


The resected tissues were fixed in 10% buffered formalin and embedded in paraffin. Subsequently, the tissue blocks were sectioned at 5 [micro]. The following routine and special stains were performed: hematoxylin-eosin, periodic acid-Schiff (with and without diastase pretreatment), Congo red, von Kossa (for calcium), and Kinyoun acid-fast bacilli stain.


Immunohistochemical staining was performed using Ventana Enhanced DAB Detection Kit and Biotin-StreptAvidin amplified methodology (Ventana, Tucson, Arizona) and commercially available prediluted monoclonal antibodies against the following antigens: CD3, CD20, CD68, CD138, S100, IgA, IgM, IgG, [kappa] light chain, k light chain, desmin, and myogenin (all Ventana).

In Situ Hybridization for Detection of [kappa] and [lambda] Light Chains

In situ hybridization staining was performed using an in situ hybridization iVIEV Blue Detection Kit and [kappa] and [lambda] light chain probe reagents with affinity to [kappa] and [lambda] light chain immunoglobulin messenger RNA (Ventana).

Electron Microscopy

Representative tissue samples (1-mm cubes) were fixed in 4F1G (4 parts 10% formalin, 1 part glutaraldehyde) for 4 hours, dehydrated in graded alcohols, and embedded in epoxy resin (Polysciences Inc, Warrington, Pennsylvania). The sections were stained with uranyl acetate (Polysciences) and lead citrate (Polysciences) and examined on a JEM 1200 transmission electron microscope (JEOL USA Inc, Peabody, Massachusetts).


Histologic sections of the mass stained with hematoxylin-eosin showed a predominant large histiocytic cell population, associated with plasma cells and rare lymphocytes, infiltrating the interstitium and replacing the cardiomyocytes (Figure 1). Scattered nodular or irregularshaped lymphoid aggregates without well-defined germinal centers were also present. At higher magnification, the cytoplasm of the histiocytes contained numerous needle-shaped, eosinophilic, periodic acid-Schiff-negative crystals (Figure 2). Mitoses and atypical plasma cells were not identified. Stains for acid-fast bacilli, calcium, and amyloid were all negative. The residual cardiomyocytes showed extensive degenerative changes. Mild interstitial fibrosis was also seen.

Immunohistochemical study revealed a polyclonal weak immunoreactivity for IgG, IgA, and [kappa] and [lambda] light chains in the cytoplasm of [CD68.sup.+] histiocytes (Figure 3, A and B). Focal weak immunoreactivity for IgM was also noted. A similar immunostaining pattern was seen in [CD138.sup.+] plasma cells. However, the staining was stronger in plasma cells than in histiocytes. Lymphocytes were strongly immunoreactive for CD3, consistent with a predominant T-cell phenotype; scattered [CD20.sup.+] B cells were also seen. Cardiomyocytes stained strongly positive for desmin and myogenin. S100 was negative.

In situ hybridization showed a polyclonal cell pattern of high mRNA levels for the immunoglobulin [kappa] and [lambda] light chain-constant regions in plasma cells. Histiocytes were negative with both antibodies (Figure 4, A and B).

Ultrastructural examination showed numerous sticklike, trapezoidal, or polygonal osmiophilic crystals and lysosomes in the cytoplasm of histiocytes (Figure 5). Plasma cells were notable for an eccentric nucleus with classic chromatin pattern, a well-developed endoplasmic reticulum, and numerous ribosomes. No crystals were seen in the cytoplasm of plasma cells.


Crystal-storing histiocytosis is a rare disorder occurring in patients with lymphoproliferative diseases, predominantly multiple myeloma and low-grade B-cell lymphoma. (1-7) Our case occurred in a male patient with monoclonal gammopathy (IgG kappa). To the best of our knowledge, this is the first report of cardiac CSH. Most patients with CSH have a serum paraprotein composed of [kappa] light chain, but the heavy chains can be varied. (4)

In agreement with previous reports of CSH, (1-7) the histiocytes in the current case contained numerous needleshaped eosinophilic crystals in the cytoplasm. Moreover, they showed a weak positive polyclonal IgG, IgA, IgM, and [kappa] and [lambda] light-chain pattern by immunohistochemistry. Plasma cells stained strongly for IgM, IgA, and [kappa] and [lambda] light chains. By in situ hybridization, we detected high levels of mRNA for the immunoglobulin k and k light chain-constant regions (polyclonal pattern) only in plasma cells, whereas histiocytes were negative. In this context, it is generally believed that the only source of immunoglobulin is mature B lymphocytes/plasma cells. The lack of strong staining for the crystals with [kappa] and [lambda[ chain antibodies by immunohistochemistry, the presumed component of the inclusions, is difficult to explain. Previous reports of CSH have also demonstrated negative stain for [kappa] or [lambda] in histiocytes. (1,4) Ionescu et al, (5) however, reported that the crystals stained mildly positive for both [kappa] and [lambda] light chains. It is likely that the crystalline structure of the light chains renders them nonimmunoreactive by surface alteration of antigenic epitopes. The underlying mechanism for crystal formation in CSH is not well understood, but proposed theories include the overproduction of [kappa] light chains by plasma cells, an aberrant light chain molecule due to amino acid substitutions in the region of the protein involving hydrophobic interactions, altered interchain disulfide bonds, and the production of protease-resistant peptides. (4,8) Crystal-storing histiocytosis is typically a systemic process found initially at bone marrow biopsy, although there are reports of discrete nodules as a primary presentation as well as crystal-storing histiocytes being present in low-grade B-cell lymphomas and plasmacytomas. (7,9)


The differential diagnosis of a cardiac mass with features similar to CSH includes genetic storage disorders, adult rhabdomyoma, Weber-Christian disease, Langerhans cell histiocytosis, Rosai-Dorfman disease, Erdheim-Chester disease, or cardiac inflammatory myofibroblastic tumor. In this context, CSH has morphologic similarities with Gaucher disease. (3) However, the needle-shaped crystalloid nature of the inclusions in CSH can be easily distinguished from the fibrillarity seen in Gaucher cells. Numerous histiocytes infiltrating the myocardium can be observed in Weber-Christian disease with systemic cytophagic histiocytosis. (10) In the latter, unlike CSH, the histiocytes often appear as regularly stuffed "bean bag cells" secondary to phagocytosis of erythrocytes and leukocytes. In the case presented here, considering the morphologic features, the lesion should also be differentiated from adult rhabdomyoma, which is composed of large cells with abundant eosinophilic or clear cytoplasm and scattered spider cells. (11) Typical cytoplasmic glycogen can be demonstrated on periodic acid-Schiff stain, whereas the muscle characteristics of the cells can be confirmed by strong positive reaction for desmin, muscle-specific actin, and myoglobin. In Langerhans cell histiocytosis, the neoplastic cells display linear nuclear grooves and consistently express S100 and CD1a, unlike the histiocytes in our case. On electron microscopy, Birbeck granules should theoretically be present in all cases in which adequate examination was carried out. (12) Unlike CSH, the histiocytes in Rosai-Dorfman disease express S100 and show emperipolesis with lymphocytes within the cytoplasm. (13) Last but not least, Erdheim-Chester disease and inflammatory myofibroblastic tumor can mimic CSH. In this context, Erdheim-Chester disease is a type II (non-Langerhans cell) histiocytosis with fibroxanthogranulomatous tissue infiltrates and nested sheets of histiocytes that stain positive for CD68 and variable with S100. (14) Unlike CSH, cardiac inflammatory myofibroblastic tumor has been shown to stain with ALK1 in a proportion of tumors. (15) In addition, histiocytes in both diseases do not contain needle-shaped crystals.

It has been stressed that the finding of CSH should raise the suspicion of low-grade B-cell lymphoma, especially marginal zone lymphoma. (7) In the current case report, the entire tumor was sampled to exclude the concomitant presence of lymphoma, but none was found, and most of the background lymphocytes were T cells. The prognosis of CSH is generally dependent on the underlying lymphoproliferative disease and is poor in patients with multiple myeloma and relatively favorable for patients with low-grade B-cell neoplasms. A rapid course resulting in multiorgan failure and shock has been reported. (4) A benign reactive variant, namely crystal-storing histiocytoma, without evidence of associated hematolymphoid disorder, has been described. (5) The prognosis of the current patient is unknown, as the underlying basis for the paraproteinemia is yet unclear. In this context, immunofixation electrophoresis demonstrated a monoclonal IgG [kappa] protein, whereas immunohistochemistry and in situ hybridization revealed a polyclonal pattern of light- and heavy-chain expression.

In summary, CSH is a rare disorder that may pose difficulty in pathologic diagnosis, especially when occurring in unusual locations such as the heart. Awareness of CSH is important because the histopathology may mimic other lymphoproliferative disorders, genetic storage diseases, or soft tissue neoplasms in their clinical presentation and morphologic appearance. The key feature suggestive of CSH is the presence of needle-shaped crystals in the cytoplasm of histiocytes by light and electron microscopy.


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Charles J. Sailey, MD; Borislav A. Alexiev, MD; James S. Gammie, MD; Paula Pinell-Salles, MD; J. Lawrence Stafford, MD; Allen Burke, MD

Accepted for publication December 2, 2008.

From the Departments of Pathology (Drs Sailey, Alexiev, and Burke), Surgery (Dr Gammie), and Cardiology (Drs Pinell-Salles and Stafford), University of Maryland Medical System, Baltimore.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Charles J. Sailey, MD, Department of Pathology, University of Maryland Medical Center, NBW69, 22 S Greene St, Baltimore, MD 21201 (e-mail:
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