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Crystal-storing histiocytosis complicating primary pulmonary marginal zone lymphoma of mucosa-associated lymphoid tissue.

Crystal-storing histiocytosis (CSH) is an uncommon histopathologic finding that poses diagnostic challenges for the unwary when encountered in surgical pathology specimens. It can affect a wide range of anatomic locations, including not only lung and pleura but also various sites in the head and neck, kidney, bone marrow, lymph nodes, skin, and gastrointestinal tract. (1) In most patients CSH is a manifestation of an underlying lymphoproliferative disorder. In this case report we highlight the histologic features common in lung biopsies that are helpful in identifying CSH and distinguishing it from other entities characterized by sheets of similarly enlarged macrophages. We also review the literature to more clearly articulate the significance of this rare but important finding.

REPORT OF A CASE

An asymptomatic 54-year-old woman was discovered to have a solitary lung nodule on a computed tomography scan of her chest performed for unknown reasons. A right upper and middle bilobectomy was performed. On gross examination a centrally located 1.9-cm nodule with a white cut surface was present in the right middle lobe immediately adjacent to a stapled bronchial margin.

At low magnification, sections showed an unencapsulated mass that was well delineated from the uninvolved lung parenchyma (Figure 1, A). The center of the lesion was composed of solid sheets of large polygonal cells (Figure 1, B) that obscured the underlying lung architecture. Foci of coagulative necrosis were present, resulting in a vaguely granulomatous appearance (Figure 1, B). At the periphery the large cells infiltrated and expanded contiguous alveolar septa, interlobular septa, and bronchovascular bundles (Figure 1, C). At high magnification, the cytologically bland mononuclear cells were characterized by abundant eosinophilic cytoplasm demonstrating somewhat refractile and striated inclusions (Figure 1, D). No mitoses were identified. Nodular aggregates of monocytoid lymphocyte without secondary germinal centers were scattered throughout the lesion. Compressed bronchioles were surrounded by lymphocytes and plasma cells with occasional Russell bodies.

Immunohistochemical stains were performed on formalin-fixed, paraffin-embedded tissue using antibodies directing against CD 68, CD3, CD20, CD138, and [kappa] and [lambda] light chains. In situ hybridization using probes for [kappa] and [lambda] light chains was also performed. The nodular lymphoid aggregates were composed predominantly of CD20-positive B lymphocytes (Figure 2, A) with only rare CD3positive T lymphocytes (Figure 2, B) and CD138-positive plasma cells (Figure 2, C). The crystal-laden cells showed strong and diffuse immunoreactivity with CD68 (Figure 2, D), confirming their histiocytic origin. The intracytoplasmic crystal inclusions were weakly immunoreactive for k (Figure 2, E) and negative for [lambda] light chain (Figure 2, F). In situ hybridization demonstrated monotypic k light-chain expression (Figure 2, G) without [lambda] light-chain expression (Figure 2, H) in peribronchiolar plasma cells. These results supported the diagnosis of CSH complicating mucosaassociated lymphoid tissue (MALT) lymphoma.

COMMENT

Crystal-storing histiocytosis refers to deposition of crystalline immunoglobulin inclusions within the cytoplasm of histiocytes. (1-6) Nearly all patients have underlying neoplasms of plasma cells or B lymphocytes, although occasional patients have no identifiable clonal lymphoplasmacytic disorder. (7,8) In a review of 80 patients with CSH by Dogan et al, (1) 90% had underlying lymphoproliferative or plasma cell disorders. The most common underlying lymphoproliferative or plasma cell disorders included multiple myeloma (32%), lymphoplasmacytic lymphoma (24%), paraproteinemia/monoclonal gammopathy of undetermined significance (21%), and B-cell lymphomas (15%). (1) In patients with generalized disease the most commonly affected sites are the bone marrow (97%), liver (47%), lymph nodes (44%), spleen (44%), and kidney (38%). Numerous extranodal sites may be affected, but the lung is an uncommon site of involvement and is seen in only about 10% of patients with generalized disease. (1,2,9-16) More than half of reported CSH patients have localized disease, and in these patients lung and pleura is second only to head and neck as a common site of presentation, accounting for 11 (24%) of 46 patients summarized by Dogan et al. (1)

Ten patients with pulmonary CSH previously described in the English language peer-reviewed literature presented in the sixth to seventh decades of life, with a mean age of 61.8 years (see Table). (4,7,9-12,14-17) All presented with either solitary (7) or multiple (3) lung masses or nodules. An underlying lymphoproliferative or plasma cell disorder was documented in 7 patients. (4,9-12,16,17) Three patients had no apparent lymphoproliferative disease. One patient had a longstanding history of rheumatoid arthritis, (14) and another was status posttreatment of tuberculosis with a persistent solitary lung nodule. Three previously reported patients with pulmonary CSH were similar to our own in that they had associated primary pulmonary extranodal marginal zone B-cell lymphoma of MALT type. (11,12,17) Only a single death was recorded in the 5 patients for whom follow-up was reported, and that occurred in the postoperative period in a patient with multiple myeloma who underwent lobectomy for primary pulmonary adenocarcinoma and was incidentally discovered to have CSH intimately associated with his carcinoma. (4)

Primary pulmonary involvement by malignant lymphoma is rare, and concomitant CSH even more so. In a review of 1464 cases of lymphomas primarily involving extranodal sites by Freeman et al, (18) pulmonary lymphomas comprised only 3.6% of the cases. Marginal zone lymphomas of MALT type are the most common form of primary pulmonary lymphoma; nonetheless, pulmonary MALT lymphomas are rare and comprise less than 1% of all lymphomas. (19) Light chains elaborated by neoplastic plasma cells in pulmonary MALT lymphomas occasionally contribute to unusual histologic features that may further complicate diagnosis of these already uncommon tumors. Tumor-related light chains can result in not only CSH but also deposits of amyloid and nonamyloid light chain. Amyloid deposits comprising monotypic immunoglobulin light chain have been described in several studies of primary pulmonary MALT lymphomas. (20-22) In a retrospective review of 41 patients with primary pulmonary MALT lymphomas by Kurtin et al, (19) 3 (7.3%) demonstrated localized amyloid deposits that were randomly distributed in the pulmonary parenchyma or within blood vessel walls and surrounded by a foreign body-type giant cell reaction. The amyloid deposits were composed of immunoglobulin light chains of the same types expressed by the neoplastic cells in all 3 cases. Nodular deposits of nonamyloid light chain also are occasionally seen in MALT lymphomas presenting as lung nodules. (23) It is unknown how mechanisms that result in deposits of amyloid and nonamyloid light chain in MALT lymphomas differ from the pathogenesis of light-chain phagocytosis by histiocytes resulting in CSH.

Crystal-storing histiocytosis in the context of systemic lymphoproliferative disease is typically associated with a poor prognosis, regardless of the type of neoplasm.3 The prognosis of CSH with localized lymphoproliferative diseases is highly variable, depending to a large extent on the underlying condition. In general, the prognosis of localized extranodal pulmonary marginal zone lymphoma of MALT type is excellent, and some studies suggest no difference in survival of MALT lymphoma patients compared with ageand sex-matched control patient populations. (24) Two previously reported patients with CSH complicating primary pulmonary MALT lymphoma followed an indolent, nonprogressive clinical course. (11,12)

The histologic features of CSH are distinctive and comprise sheets of cytologically bland mononuclear cells containing refractile, eosinophilic, crystalline, cytoplasmic inclusions. When CSH occurs focally as a secondary finding in plasmacytic or lymphoplasmacytic neoplasm, similar crystalline deposits are often present in neoplastic plasmacytic cells. More commonly the crystalline-containing histiocytes of CSH partially or completely obscure the presence of an associated or underlying lymphoplasmacytic disorder. It is in these cases that the diagnosis may be especially difficult. Recognition hinges on identification of the characteristic attributes of the cytoplasmic inclusions. Immunostains can be helpful in showing a histiocytic phenotype (ie, CD68 positive) as well as staining for immunoglobulin light chains. Most cases are [kappa] light-chain restricted, although examples of [lambda] light chain have also been described. (2,25) The associated heavy chain is variable. (2) Occasional examples have been described without clonal light-chain restriction or evidence of any underlying lymphoplasmacytic neoplasm. (7,14,15) Ultrastructural studies demonstrate electron-dense, membrane-bound, rhomboid, and needle-shaped intracytoplasmic crystals. (3,5,8,10-12)

Rare conditions in which sheets of macrophages contain eosinophilic inclusions other than immunoglobulin light chain have also been called CSH, although in our view the term CSH may not be appropriate in these circumstances. Most of the rare conditions showing histologic overlap with CSH are not difficult to recognize with a relevant clinical history. Clofazimine, a drug used for treating leprosy, is a rare cause of crystalline deposits limited to histiocytes within the bowel wall and mesenteric lymph nodes that resembles CSH. (26) Sheets of CSH-like histiocytes resulting from accumulation of Charcot-Leyden crystals has been described in the gastrointestinal tract and skin of patients with hypereosinophic syndrome such as eosinophilic colitis and aggressive systemic mastocytosis. (27) Histiocytes containing deeply eosinophilic, needle-shaped crystals accumulated in the colonic mucosa and submucosa or subcutis, which were always associated with an intense infiltrate of eosinophils. A unique case of crystalline histiocytosis was described in a 23-year-old man with hereditary cystinosis whose bone marrow biopsy showed numerous macrophages containing cystine crystals that were birefringent with polarized light. (28)

To our knowledge, none of these conditions that might mimic CSH has been described in the lung.

Other conditions in the differential diagnosis of CSH include metabolic storage diseases, primarily Gaucher disease. (29) Accumulation of immunoglobulin light chains within histiocytes may mimic the appearance of Gaucher cells or of the so-called pseudo-Gaucher cells seen in chronic myelogenous leukemia. The histiocytic infiltrates associated with Gaucher disease are less tumefactive and instead diffusely infiltrate interlobular septa, bronchovascular bundles, and alveolar septa. The striated appearance in Gaucher disease is due to the deposition of glucocerebroside, not immunoglobulins; therefore, the pale-staining striated inclusions in Gaucher cells lack the refractile and tinctorial characteristics of those in CSH. Moreover, the Gaucher cell is usually strongly positive for iron as opposed to the histiocytes in CSH. In cases of doubt, assays for bglucocerebrosidase activity should be obtained to reach a definitive diagnosis of Gaucher disease. Patients with lung involvement due to Niemann-Pick disease show accumulation of mainly air space macrophages with finely vacuolated cytoplasm, again lacking the tumefactive and cytologic characteristics of CSH. (30)

Pulmonary malakoplakia is an uncommon manifestation of Rhodococcus equi infection seen almost exclusively in HIV-infected patients. (31) Malakoplakia is characterized by a distinctive and potentially tumefactive infiltrate of histiocytes with abundant granular pink cytoplasm (von Hansemann histiocytes) that resemble the histiocytes of CSH. The pathognomonic targetoid inclusions (Michaelis-Gutmann bodies), if present, can be very helpful in establishing the diagnosis. The histiocytes in malakoplakia lesions are also CD68 positive but lack immunoglobulins and may contain bacteria on Gram stain. The underlying immunosuppressive status is often a hint to the diagnosis of pulmonary malakoplakia.

Neoplasms comprising nodular aggregates of cytologically bland histiocytic-like cells with abundant eosinophilic cytoplasm are rare but may also enter the differential diagnosis of CSH. Granular cell tumors occur occasionally in the lungs and are composed of cytologically bland tumor cells with abundant eosinophic granular cytoplasm. (32) In contrast to the refractile and crystalline appearance of the cytoplasmic inclusions in CSH, the cytoplasm of granular cell tumor is more dense, homogeneous, and finely granular. Granular cell tumor is positive for S-100 protein and does not contain crystals or immunoglobulins. Some authors have highlighted the cytologic resemblance of CSH to the cells of adult rhabdomyoma, a tumor that has not yet been described in the lung and therefore is an unlikely diagnostic problem in pulmonary pathology. (33,34) Although CSH and adult rhabdomyoma are both composed of cells that contain eosinophic crystals and striations, they can be relatively easily separated on routine hematoxylin-eosinstained sections. The crystals in adult rhabdomyoma ("jackstraw" crystals) are usually more densely eosinophilic and represent cross-striated tropomyosin rather than immunoglobulins. The parallel arrays of crystals in CSH are typically more linear rather than crossed. Adult rhabdomyoma is invariably positive for muscle makers such as desmin and muscle-specific actin, and negative for immunoglobulins.

Recognizing CSH in an obscured background lymphoproliferative disease such as lymphoma is critical in that it triggers more careful search for underlying problems. Upon the diagnosis of CSH, an extensive clinical workup including radiologic studies, a bone marrow biopsy, and serum protein electrophoresis is usually followed to exclude systemic involvement of lymphoproliferative diseases.

Caption: Figure 1. A, At low magnification, the unencapsulated mass is well delineated from the uninvolved lung parenchyma. B, The center of the lesion is composed of sheets of large polygonal cells, with foci of coagulative necrosis resulting in a vaguely granulomatous appearance. C, At the periphery the large cells infiltrate and expand contiguous alveolar septa, interlobular septa, and bronchovascular bundles. D, At high magnification, the large cells are characterized by abundant eosinophilic cytoplasmic inclusions (hematoxylin-eosin, original magnifications X20 [A], X100 [B and C], and X400 [D].

Caption: Figure 2. Immunohistochemical stains for CD20 (A), CD3 (B), CD138 (C), CD 68 (D), [kappa] light chain (E), and [lambda] light chain (F). In situ hybridization using probes for [kappa] (G) and [lambda] (H) light chains (hematoxylin-eosin, original magnifications X200 [A-D] and X400).

References

(1.) Dogan S, Barnes L, Cruz-Vetrano W. Crystal-storing histiocytosis: report of a case, review of the literature (80 cases) and a proposed classification. Head Neck Pathol. 2012;6(1):111-120.

(2.) 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(12):1441-1448.

(3.) Lebeau A, Zeindl-Eberhart E, Muller EC, et al. 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):1817-1827.

(4.) Papla B, Spolnik P, Rzenno E, et al. Generalized crystal-storing histiocytosis as a presentation of multiple myeloma: a case with a possible pro-aggregation defect in the immunoglobulin heavy chain. Virchows Arch. 2004;445(1):83-89.

(5.) Sethi S, Cuiffo BP, Pinkus GS, Rennke HG. Crystal-storing histiocytosis involving the kidney in a low-grade B-cell lymphoproliferative disorder. Am J Kidney Dis. 2002;39(1):183-188.

(6.) Thorson P, Hess JL. Transformation of monocytoid B-cell lymphoma to large cell lymphoma associated with crystal-storing histiocytes. Arch Pathol Lab Med. 2000;124(3):460-462.

(7.) Jones D, Renshaw AA. Recurrent crystal-storing histiocytosis of the lung in a patient without a clonal lymphoproliferative disorder. Arch Pathol Lab Med. 1996;120(10):978-980.

(8.) 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(10):920-924.

(9.) Kazzaz B, Dewar A, Corrin B. An unusual pulmonary plasmacytoma. Histopathology. 1992;21(3):285-287.

(10.) Prasad ML, Charney DA, Sarlin J, Keller SM. Pulmonary immunocytoma with massive crystal storing histiocytosis: a case report with review of literature. Am J Surg Pathol. 1998;22(9):1148-1153.

(11.) Sun Y, Tawfiqul B, Valderrama E, Kline G, Kahn LB. Pulmonary crystal-storing histiocytosis and extranodal marginal zone B-cell lymphoma associated with a fibroleiomyomatous hamartoma. Ann Diagn Pathol. 2003;7(1):47-53.

(12.) Fairweather PM, Williamson R, Tsikleas G. Pulmonary extranodal marginal zone lymphoma with massive crystal storing histiocytosis. Am J Surg Pathol. 2006;30(2):262-267.

(13.) Wang CW, Colby TV. Histiocytic lesions and proliferations in the lung. Semin Diagn Pathol. 2007;24(3):162-182.

(14.) lonescu DN, Pierson DM, Qing G, Li M, Colby TV, Leslie KO. Pulmonary crystal-storing histiocytoma. Arch Pathol Lab Med. 2005;129(9):1159-1163.

(15.) Lee WS, Kim SR, Moon H, et al. Pulmonary crystal-storing histiocytoma in a patient without a lymphoproliferative disorder. Am J Med Sci. 2009;338:421 424.

(16.) Todd WU, Drabick JJ, Benninghoff M, Frauenhoffer EE, Zander DS. Pulmonary crystal-storing histiocytosis diagnosed by computed tomography-guided fine-needle aspiration. Diagn Cytopathol. 2010;38(4):274-278.

(17.) Ko HM, da Cunha Santos G, Boerner SL, Boerner SL, Bailey DJ, Geddie WR. Negative images of crystalline immunoglobulin in crystal storing histiocytosis: a potential cytologic mimic of mycobacteria in smears. Diagn Cytopathol. Oct 2012;40(10):916-919.

(18.) Freeman C, Berg JW, Cutler SJ. Occurrence and prognosis of extranodal lymphomas. Cancer. 1972;29(1):252-260.

(19.) Kurtin PJ, Myers JL, Adlakha H, et al. Pathologic and clinical features of primary pulmonary extranodal marginal zone B-cell lymphoma of MALT type. Am J Surg Pathol. 2001;25(8):997-1008.

(20.) Davis CJ, Butchart EG, Gibbs AR. Nodular pulmonary amyloidosis occurring in association with pulmonary lymphoma. Thorax. 1991;46(3):217 218.

(21.) Koss MN, Hochholzer L, Nichols PW, Wehunt WD, Lazarus AA. Primary non-Hodgkin's lymphoma and pseudolymphoma of lung: a study of 161 patients. Hum Pathol. 1983;14(12):1024-1038.

(22.) Turner RR, Colby TV, Doggett RS. Well-differentiated lymphocytic lymphoma: a study of 47 patients with primary manifestation in the lung. Cancer. 1984;54(10):2088-2096.

(23.) Khoor A, Myers JL, Tazelaar HD, Kurtin PJ. Amyloid-like pulmonary nodules, including localized light-chain deposition: clinicopathologic analysis of three cases. Am J Clin Pathol. 2004;121(2):200-204.

(24.) Li G, Hansmann ML, Zwingers T, Lennert K. Primary lymphomas of the lung: morphological, immunohistochemical and clinical features. Histopathology. 1990;16(6):519-531.

(25.) Zioni F, Giovanardi P, Bozzoli M, Artusi T, Bonacorsi G, Sighinolfi P. Massive bone marrow crystal-storing histiocytosis in a patient with IgA-lambda multiple myeloma and extensive extramedullary disease: a case report. Tumori. 2004;90(3):348-351.

(26.) Sukpanichnant S, Hargrove NS, Kachintorn U, et al. Clofazimine-induced crystal-storing histiocytosis producing chronic abdominal pain in a leprosy patient. Am J Surg Pathol. 2000;24(1):129-135.

(27.) 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):481-485.

(28.) Gebrail F, Knapp M, Perotta G, Cualing H. Crystalline histiocytosis in hereditary cystinosis. Arch Pathol Lab Med. 2002;126(9):1135.

(29.) Amir G, Ron N. Pulmonary pathology in Gaucher's disease. Hum Pathol. 1999;30(6):666-670.

(30.) Nicholson AG, Florio R, Hansell DM, et al. Pulmonary involvement by Niemann-Pick disease: a report of six cases. Histopathology. 2006;48(5):596 603.

(31.) Kwon KY, Colby TV. Rhodococcus equi pneumonia and pulmonary malakoplakia in acquired immunodeficiency syndrome: pathologic features. Arch Pathol Lab Med. 1994;118(7):744-748.

(32.) Deavers M, Guinee D, Koss MN, et al. Granular cell tumors of the lung: clinicopathologic study of 20 cases. Am J Surg Pathol. 1995;19(6):627-635.

(33.) Kapadia SB, Enzinger FM, Heffner DK, Travis WD. Crystal-storing histiocytosis associated with lymphoplasmacytic neoplasms: report of three cases mimicking adult rhabdomyoma. Am J Surg Pathol. 1993;17(5):461-467.

(34.) Friedman MT, Molho L, Valderrama E, Kahn LB. Crystal-storing histiocytosis associated with a lymphoplasmacytic neoplasm mimicking adult rhabdomyoma: a case report and review of the literature. Arch Pathol Lab Med. 1996; 120(12):1133-1136.

Chen Zhang, MD; Jeffrey L. Myers, MD

Accepted for publication May 22, 2013.

From the Department of Pathology, University of Michigan, Ann Arbor. Dr Zhang is now with the Department of Pathology, Indiana University, Indianapolis.

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

Presented at New Frontiers in Pathology: An Update for Practicing Pathologists meeting; Homestead Resort; August 3-5, 2012; Glen Arbor, Michigan.

Reprints: Jeffrey L. Myers, MD, Department of Pathology, University of Michigan, 1500 E Medical Center Dr, Ann Arbor, MI 48109 (e-mail: myerjeff@med.umich.edu).

Summary of 10 Previously Reported Patients With Pulmonary
Crystal-Storing Histiocytosis (CSH)

                                      Solitary
                                    or Multiple          Maximum
                                      Nodules            Nodule
Source, y                 y/Sex        (No.)            Size, cm

Kazzaz et al, (9) 1992    60/M    Multiple (2)             2.0
Jones and                 54/F    Solitary           3.0 (recurrence
  Renshaw, (7) 1996                                        2.0)
Prasad et al, (10) 1998   72/F    Solitary                 2.2
Sun et al, (11) 2003      59/M    Multiple (3)             2.0
Papla et al, (4) 2004     51/M    Solitary (a)             NA
lonescu et                50/F    Solitary                 2.0
  al, (14) 2005
Fairweather               69/F    Solitary                 2.0
  et al, (12) 2006
Lee et al, (15) 2009      64/M    Solitary                 NA
Todd et al, (16) 2010     75/F    Solitary                 1.1
Ko et al, (17) 2012       64/M    Multiple (2) (b)         NA

                          Underlying LP-PCD           Outcome
                           (Other Relevant      (Interval Following
Source, y                     History)           Diagnosis of CSH)

Kazzaz et al, (9) 1992    Plasmacytoma        NA
Jones and                 None                recurrent nodule (10
  Renshaw, (7) 1996                           yrs);NED (11.2 yrs)
Prasad et al, (10) 1998   Lymphoplasmacytic   NA
                          lymphoma
Sun et al, (11) 2003      MALT lymphoma       NED (9 months)
Papla et al, (4) 2004     Multiple myeloma    Dead (postoperative)
lonescu et                None (rheumatoid    NA
  al, (14) 2005             arthritis)
Fairweather               MALT lymphoma       NED (4 months)
  et al, (12) 2006
Lee et al, (15) 2009      None (treated       NA
                            tuberculosis)
Todd et al, (16) 2010     MGUS                Stable nodule (2 years)
Ko et al, (17) 2012       MALT lymphoma       NA

Abbreviations: LP-PCD, lymphoproliferative/plasma cell disorder;
MALT, mucosa-associated lymphoid tissue; MGUS, monoclonal gammopathy
of undetermined significance; NA, not available; NED, no evidence of
disease.

(a) CSH was an incidental discovery in lobectomy resected for
adenocarcinoma.

(b) One nodule, MALT lymphoma ([lambda] light-chain restricted) without
CSH; 1 nodule, MALT lymphoma ([kappa] light-chain restricted) with CSH.


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Author:Zhang, Chen; Myers, Jeffrey L.
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Case study
Date:Sep 1, 2013
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