Case 4 -

Crystal-storing Histiocytosis and Associated Small B-cell Lymphoma with Plasmacytic Differentiation Alyssa M. Krasinskas University of Pittsburgh

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Bullet Points The presence of abundant, large, eosinophilic cells in the lamina propria of the stomach is unusual. Finding these cells in a nodule is even more unusual. The differential diagnosis for such cells is quite broad and includes reactive, infectious, immunologic, iatrogenic and neoplastic processes. Clinical Summary A 59 year-old female presented to our gastroenterologist from an outside institution with the history of a "gastric deformity/subepithelial tumor." The in-house endoscopy showed a single 8 mm nodule in the gastric fundus. It "had a yellow hue, central depression, and was firm when probed." By EUS, this lesion appeared to originate from within the muscularis propria. The lesion was biopsied and essentially removed with cold jumbo forceps. Case 4 - Figure 1 Very low power view of the mucosal biopsy. Case 4 - Figure 2 Low power magnification of the gastric mucosa showing a chronic gastritis and eosinophilic cells within the lamina propria. An immunostain for H. pylori was positive. Case 4 - Figure 3 Medium power view. Case 4 - Figure 4 Higher magnification. Case 4 - Figure 5 600x magnification (dry). The acid fast and PASD stains are negative. Case 4 - Figure 6 Another medium power view of the gastric mucosa. Case 4 - Figure 7 - Cytokeratin AE1/3 A cytokeratin stain (AE1/3). Case 4 - Figure 8 - S100 An S100 stain. Pathologic Findings At low power, a band-like infiltrate expands the upper half of the lamina propria of the oxyntic mucosa and lymphoid aggregates are present. At higher magnification, the lamina propria contains a lymphoplasmacytic inflammatory cell infiltrate and numerous eosinophilic cells. The eosinophilic cells are large with abundant cytoplasm. The nuclei are slightly larger than plasma cell nuclei and some are ovoid while others are angulated. At even higher magnification, the eosinophilic cytoplasm appears to contain coarse, refractile granules. Special stains were performed. An immunohistochemical stain for Helicobacter pylori was positive. Acid fast and PAS-D stains were negative. The eosinophilic cells were negative for cytokeratin, S-100, CD138 and immunoglobulin heavy chains; these cells were positive for CD68 and weakly expressed kappa light chain. The background lymphoplasmacytic infiltrate was also characterized by immunohistochemical stains. The lymphoid aggregates co-expressed CD20 and CD43 and showed kappa light chain restriction. The CD20 positive cells did not co-express CD5 or CD10. Diagnosis Crystal-storing histiocytosis and associated small B-cell lymphoma with plasmacytic differentiation. Discussion Crystal-storing histiocytosis (CSH) is a rare condition in which crystalline material accumulates within histiocytes. In classic CSH, the material that accumulates is crystalline immunoglobulin. Most of these cases are associated with underlying lymphoplasmacytic neoplasms that produce monoclonal light chains. As such, most cases involve the bone marrow and lymph nodes. However, CSH can involve other organs, such as the lung, thyroid, kidney and soft tissue. Rare cases of gastrointestinal involvement have been reported [1, 2], and in one case report, the disease presented as gastric polyps [3]. When CSH occurs outside the setting of a lymphoproliferative disorder, it tends to be associated with an underlying chronic inflammatory condition, such as rheumatoid arthritis or Helicobacter pylori infection; in these cases, the immunoglobulin crystals are polyclonal [3, 4]. Two variants of CSH have been described in which the crystalline material is not immunoglobulin: clofazimine-induced CSH [5] and Charcot-Leyden crystal-associated CSH [6]. The formation of immunoglobulin crystals in CSH is thought to be the result of overproduction of light chain protein. Kappa light chains have been identified in the vast majority of cases of CSH that are associated with a lymphoplasmacytic neoplasm. Ultrastructurally, the crystalline material within the histiocytes can appear either needle-like and fibrillary with regular periodicity or rhomboid with angulated borders. The crystals tend to be membrane bound, often within dilated endoplasmic reticulum. It is hypothesized that the crystals form as the result of specific immunoglobulin mutations that prevent proper joining with heavy chains [2]. The presence of large, abundant, eosinophilic cells in the lamina propria of the stomach can pose a diagnostic challenge. Based on the H&E findings in this gastric biopsy, the differential diagnosis includes Russell body gastritis, granular cell tumor, infections (including atypical mycobacteria, Whipple disease and histoplasmosis), clofazimine-induced histiocytosis and eosinophilic gastritis with Charcot-Leyden crystal-associated CSH. Differential Diagnosis The main differential diagnosis in this case is localized Russell body gastritis. In contrast to CSH, the eosinophilic cells in the lamina propria in cases of Russell body gastritis are typically plasma cells. The eosinophilic inclusions (Russell bodies) expand the cytoplasm of the plasma cells, they tend to be homogeneous with a smooth round contour, and they often indent and push the nucleus to the very periphery of the cell. Ultrastructurally, Russell bodies are round, smooth and membrane-bound (adjacent to the endoplasmic reticulum). Russell bodies are believed to represent either mutated or possibly normal heavy chain immunoglobulins that are unable to be secreted or degraded [7]. While Russell bodies can be associated with lymphoplasmacytic neoplasms, they can also be found in reactive plasma cells, such as in chronic gastritis. Rare Russell bodies are occasionally seen in routine cases of chronic gastritis. However, when numerous Russell bodies are seen, the term "Russell body gastritis" can be used [8]. Most, but not all, cases of Russell body gastritis in the literature are associated with Helicobacter pylori infection. Russell body gastritis has also been reported to present as a tumor-like lesion [9], but due to the association of Russell bodies with lymphoproliferative disorders, an underlying lymphoma needs to be excluded in such cases. Granular cell tumors can arise anywhere in the gastrointestinal tract, with the esophagus and colorectum being the most common sites. In the stomach, the antrum is the most common location. Endoscopically, granular cell tumors can appear as yellow to white nodules or sessile lesions. Histologically, these tumors are composed of nests and sheets of polygonal to elongated cells with (as the name implies) granular cytoplasm, indistinct cell borders and small, oval nuclei. While these cells can mimic histiocytes, they are of neural origin and stain for S-100; they are also PAS-D positive. Whenever collections of histiocytes are seen within the lamina propria of the gastrointestinal tract, infectious etiologies should be excluded. Mycobacterium avium-intracellulare infection can result in expansion of the lamina propria by numerous enlarged macrophages; an acid fast stain will highlight the numerous intracellular organisms. Although often present in granulomatous inflammation, Histoplasma capsulatum can also be detected in scattered lamina propria macrophages of immunosuppressed individuals with disseminated disease; a sliver stain will highlight the small yeast forms. While Whipple disease tends to affect the small bowel, one would not want to miss a case just because only the stomach was biopsied. In addition to lamina propria macrophages, there may also be dilated lymphatics and foamy or lipid-laden macrophages. A PAS-D stain will highlight substance (the organisms) within the macrophages, but a confirmatory test, such as PCR or an immunostain for Tropheryma whippeli, should be performed. There are two forms of CSH that are not related to the accumulation of immunoglobulin. One is Clofazimine-induced CSH [5]. Clofazimine is used to treat leprosy and other mycobacterial infections. A side effect of this medication is gastrointestinal toxicity. Patients with Clofazimine-induced CSH can have lymphadenopathy and thickened bowel loops radiographically, resulting in mucosal biopsies to exclude malignancy. Clofazimine crystals can accumulate within lamina propria macrophages throughout the GI tract. In contrast to the immunoglobulin crystals described above, Clofazimine crystals appear clear both on routine H&E stain and by electron microscopy; interestingly, the crystals appear red on frozen sections. The macrophages are often admixed with plasma cells and eosinophils. Another form of CSH that is not associated with immunoglobulin aggregation is Charcot-Leyden crystal-associated CSH. The case that led to the description of this entity involved the colon [6]. The patient had eosinophilic colitis and associated polypoid lesions that resulted from the accumulation of large collections of macrophages and eosinophils within the deep lamina propria and superficial submucosa. The macrophages were filled with brightly eosinophilic needle-shaped crystals. Ultrastructurally, the crystals were identical to Charcot-Leyden crystals (electron dense needle-like and hexagonal crystals). Although this case involved the colon, it seems plausible that Charcot-Leyden crystal-associated CSH could also occur in the stomach in association with eosinophilic gastritis. Follow-up information The patient was treated for her H. pylori infection. Upon repeat EGD 3 months later, a scar but no nodule was seen in the fundus. The mucosa around the scar was biopsied and was involved by the B-cell lymphoma and CSH. She then received radiation therapy and an EGD was performed 9 months after the initial diagnosis; a small nodule and scar were seen in the fundus. The biopsy of the nodule showed chronic active gastritis and scattered lymphoid aggregates without histiocytes; there was no evidence of a clonal plasmacytic population. Repeat biopsies 1 year and 21 months after the original diagnosis were negative for lymphoma and histiocytes. References Lebeau A, Zeindl-Eberhart E, Müller EC, Müller-Höcker J, Jungblut PR, Emmerich B, Löhrs U. Generalized crystal-storing histiocytosis associated with monoclonal gammopathy: molecular analysis of a disorder with rapid clinical course and review of the literature. Blood. 2002;100(5):1817-27. Jones D, Bhatia VK, Krausz T, Pinkus GS. Crystal-storing histiocytosis: a disorder occurring in plasmacytic tumors expressing immunoglobulin kappa light chain. Hum Pathol 1999;30:1441–1448. Joo M, Kwak JE, Chang SH, Kim H, Chi JG, Moon YS, Kim KM. Localized gastric crystal-storing histiocytosis. Histopathology. 2007;51(1):116-9. Bosman C, Camassei FD, Boldrini R, et al. Solitary crystal-storing histiocytosis of the tongue in a patient with rheumatoid arthritis and polyclonal hypergammaglobulinemia. Arch Pathol Lab Med. 1998; 122:920–924. Sukpanichnant S, Hargrove NS, Kachintorn U, Manatsathit S, Chanchairujira T, Siritanaratkul N, Akaraviputh T, Thakerngpol K. Clofazimine-induced crystal-storing histiocytosis producing chronic abdominal pain in a leprosy patient. Am J Surg Pathol. 2000;24(1):129-35. Lewis JT, Candelora JN, Hogan RB, Briggs FR, Abraham SC. 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. Am J Surg Pathol. 2007; 31(3):481-5. Valetti C., Grossi, C.E., Milstein, C. and Sitia, R. Russell bodies: a general response of secretory cells to synthesis of a mutant immunoglobulin which can neither exit from, nor be degraded in, the endoplasmic reticulum. J. Cell Biol. 1991;115:983–994. Ensari A, Savas B, Okcu Heper A, Kuzu I, Idilman R. An unusual presentation of Helicobacter pylori infection: so-called "Russell body gastritis". Virchows Arch. 2005;446(4):463-6. Erbersdobler A, Petri S, Lock G. Russell body gastritis: an unusual, tumor-like lesion of the gastric mucosa. Arch Pathol Lab Med. 2004;128(8):915-7.