Pulmonary Crystal-Storing Histiocytoma
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1 Case Reports Pulmonary Crystal-Storing Histiocytoma Diana N. Ionescu, MD; Diane M. Pierson, DO; Gefei Qing, MD; Maomi Li, MD; Thomas V. Colby, MD; Kevin O. Leslie, MD We describe the case of a 50-year-old woman with a lung tumor composed of crystal-storing histiocytes. These cells and associated plasma cells failed to show clonal light chain restriction, and the patient had no associated hematologic disorder. The differential diagnosis included crystal-storing histiocytosis, characterized by accumulation of crystallized immunoglobulins, a rare manifestation of monoclonal gammopathies/plasma cell dyscrasias. Crystalladen histiocytes have previously been described in many organs. Four reports have described crystal-storing histiocytosis in the lung, always associated with a lymphoproliferative disorder. The present patient, other case from our archive, and case reported in the literature, all without an association with lymphoproliferative disorder, make a full description and definition of this lesion appropriate. The morphology, immunohistochemical profile, and electron microscopic features are described herein, and the term pulmonary crystal-storing histiocytoma is proposed. A practical algorithm is presented for the assessment of solitary lung masses composed of large histiocytic cells. (Arch Pathol Lab Med. 2005;29:59 63) REPORT OF A CASE A 50-year-old woman with a long history of rheumatoid factor negative rheumatoid arthritis had been treated for more than 2 years with methotrexate when she required additional immunosuppression therapy with infliximab for exacerbation of her disease. Radiologic studies revealed a.9.6-cm mass in the left upper lobe lung. A thoracotomy with lymph node sampling and a left upper lobe wedge resection was performed at an outside hospital without complications. The clinical and radiologic differential diagnosis was infection or neoplasm. The patient was also an active 30-pack-a-year smoker, but her past medical history was otherwise unremarkable. She had no history of occupational exposures or pulmonary infections. Results of laboratory investigations, including a serum protein electrophoresis test, were all within normal limits. Accepted for publication May 7, From the Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pa (Dr Ionescu); the Department of Pathology, Mayo Clinic, Scottsdale, Ariz (Drs Pierson, Colby, and Leslie); the Department of Pathology, University of Manitoba (Dr Qing); and the Department of Pathology, Montefiore Hospital, New York, NY (Dr Li). The authors have no relevant financial interest in the products or companies described in this article. Reprints: Diana N. Ionescu, MD, Department of Pathology, University of Pittsburgh Medical Center, Presbyterian Hospital, 200 Lothrop St, Room A60, Pittsburgh, PA 523 ( ionescudn@upmc.edu). PATHOLOGIC FINDINGS Morphologic Findings The surgical specimen was a wedge biopsy of lung, measuring cm, that contained a 2.5-cm tan nodule with focal anthracotic pigmentation. The specimen was fixed in 0% formalin and routinely processed for histologic examination, and tissue was placed in glutaraldehyde for electron microscopy. Histologic sections stained with hematoxylin-eosin showed a nodular mass of large histiocytic cells expanding the alveoli and infiltrating the alveolar septa (Figure ). In areas, a more solid growth pattern was seen, with sheets of oval to spindle-shaped cells replacing the lung parenchyma. These cells focally destroyed bronchioles. At the periphery of the tumor, the crystal-laden cells infiltrated the interstitium and also occupied the alveoli in a desquamative interstitial pneumonia like pattern. Scattered nodular lymphoid aggregates with well-defined germinal centers were present, surrounded by rare plasma cells with occasional periodic acid-schiff positive Russell bodies. Mucostasis was seen within large and smaller bronchioles. In these areas, the lumens were partially obstructed by mucus, desquamated epithelial cells, pigmented macrophages, and a small number of admixed crystal-laden macrophages. At higher magnification, the bright eosinophilic cytoplasm of tumor cells was filled with numerous nonbirefringent, needle-shaped, eosinophilic crystals (Figure 2). The nuclei were small and bland, and there were no mitoses. Spotty areas of coagulative necrosis were identified, which stained negative for acidfast bacilli and fungi. of the examined tissues contained intravascular crystals, as would be expected if the patient had cryocrystalglobulinemia. Eosinophils and neutrophils were rare, and there was no tissue reaction, such as fibroblastic proliferation or desmoplastic reaction, seen within or around the mass. Multiple mediastinal lymph nodes (levels 6 through 2) excised during thoracotomy showed preserved lymph node architecture accompanied by mild sinus histiocytosis and moderate anthracotic deposition. No crystal-laden macrophages were found on thorough examination of these hematoxylin-eosin stained sections. Histochemical Studies Histochemical stains for periodic acid Schiff, with and without diastase digestion, and Masson trichrome were performed to evaluate the crystals. In the more spindled areas, the appearance of the eosinophilic cytoplasm raised concern for intracytoplasmic collagen matrix. The Masson trichrome stain showed that Arch Pathol Lab Med Vol 29, September 2005 Pulmonary Crystal-Storing Histiocytoma Ionescu et al 59
2 Figure. Crystal-storing histiocytoma, a lung mass composed entirely of large, polygonal histiocytes with abundant intracytoplasmic crystal deposition (hematoxylin-eosin, original magnification 40). Figure 2. Sharp-edged, brightly eosinophilic, needle-shaped crystals within histiocytes (hematoxylin-eosin, original magnification 400). Figure 3. The intracytoplasmic crystal inclusions are mildly immunoreactive for. The surrounding plasma cells are polyclonal (original magnification 200). 60 Arch Pathol Lab Med Vol 29, September 2005 Pulmonary Crystal-Storing Histiocytoma Ionescu et al
3 Table. Crystal-Storing Histiocytoma, Histochemical and Immunohistochemical Profile Stain* Histochemical Periodic acid Schiff Periodic acid Schiff with diastase digestion Masson s trichrome Acid-fast bacilli Gram Grocott Immunohistochemical CD68 CD43 Lysosome Myeloperoxidase Keratin AE/AE3 S00 Melan-A Smooth muscle actin Desmin CD20 CD3 Double - IgM IgG IgA IgD * Ig indicates immunoglobulin. Results Figure 6. Electron photomicrograph demonstrating electron-dense polygon-shaped amorphous crystals, characteristic of immunoglobulin deposition within histiocytes (original magnification 3500). it was indeed not collagen, and the crystals were negative by periodic acid Schiff. Stains for acid-fast bacilli and fungi were performed and failed to reveal infectious microorganisms. Immunohistochemistry Formalin-fixed, paraffin-embedded tissue was stained using the avidin-biotin peroxidase complex technique and heat-induced epitope retrieval buffer. The antibodies used included CD68 (KP); CD20 (L26); CD3; keratin AE/ AE3; S00 protein; smooth muscle actin; desmin; monoclonal antibodies for (Figure 3) and (Figure 4); and immunoglobulin heavy chain for immunoglobulin (Ig) M (Figure 5), IgG, IgA, and IgD. In situ hybridization for double - was also performed. The crystal-laden macrophages showed immunoreactivity with histiocytic markers including CD68, CD43, and lysosome, although their reactivity was weaker compared with that of the smoker s macrophages seen in the vicinity of the mass, within air spaces. The lesional cells were negative for S00 protein, lymphocyte markers (CD20 and CD3), keratin (AE/AE3), desmin, and smooth muscle actin. The intracytoplasmic crystal inclusions were mildly immunoreactive for and. The surrounding plasma cells were polyclonal. The small lymphocytes showed a mixture of B and T lymphocytes in an approximately equal proportion. Strong positivity for IgM heavy chain was seen in the intracytoplasmic crystals. These were negative for the other immunoglobulin heavy-chain stains performed (IgG, IgA, and IgD). The results for the histochemical and immunohistochemical stains are presented in Table. Electron Microscopy Fresh tissue was sent for electron microscopic evaluation, which was subsequently fixed in 2.5% glutaraldehyde, embedded in Epon-Araldite resin (Electron Microscopy Sciences, Hatfield, Pa), cut into 500-nm sections, and stained with uranyl acetate lead citrate. The grids were examined with a JEOL 00S transmission electron microscope (JEOL USA Inc, Peabody, Mass). Electron microscopy showed intralysosomal deposition of polygonshaped amorphous crystals, characteristic of immunoglobulin in the histiocytic cells (Figure 6). COMMENT Crystal-storing histiocytosis with massive accumulation of crystallized immunoglobulins is a rare manifestation of monoclonal gammopathies/plasma cell dyscrasias. Crystal-storing histiocytosis may complicate multiple myeloma, isolated plasma cell tumors, other lymphoid neoplasms (particularly lymphoplasmacytic lymphoma), transient polyclonal plasma cell hyperplasia after bone marrow transplantation, and monoclonal gammopathy. 2,3 Figure 4. Figure 5. Intracytoplasmic immunohistochemical stain for and polyclonal staining in the surrounding plasma cells (original magnification 200). Immunohistochemical stain for immunoglobulin heavy chain for immunoglobulin M (original magnification 400). Arch Pathol Lab Med Vol 29, September 2005 Pulmonary Crystal-Storing Histiocytoma Ionescu et al 6
4 Table 2. Pulmonary Crystal-Storing Histiocytosis With and Without Underlying Lymphoproliferative Disorders (LPD)* No. of Source, y Cases Associated with lymphoproliferative disorders Kazzaz et al, Colby et al, Prasad et al, Age, y/ Sex LPD Type Immunoglobulin Type 60/M 79/F 72/F Plasmacytoma B-cell lymphoma Immunocytoma Sun et al, /M Extranodal marginal zone B-cell lymphoma Kraus and Wick, Extranodal marginal zone B-cell lymphoma Papla et al, /M Multiple myeloma IgG, Without underlying lymphoproliferative disorders Jones and Renshaw, Present case Unpublished case 54/F 50/F Immunoglobulin light chain, IgM, Immunoglobulin heavy-chain rearrangement Polyclonal IgM * indicates not available; Ig, immunoglobulin. Case from the file of Charles Carrington, MD (deceased), Department of Pathology, Stanford University Medical Center, Stanford, Calif. Figure 7. A practical approach to an entity presenting as a nodular histiocytic proliferation in the lung. Crystal-storing histiocytosis is usually a systemic process, although the initial presentation may be confined to one organ or tissue compartment. Aggregates of crystalladen histiocytes in crystal-storing histiocytosis have been previously described in the bone, bone marrow, head and neck, skin, kidney, stomach, thymus, and liver. 4 Three reports describe crystal-storing histiocytosis in the lung: as a solitary mass, 5 as 2 discrete incidental nodules, 6 and as involvement as part of a systemic disease 7 ; 2 additional cases are illustrated in textbooks. 4,8 In all cases, an immunoproliferative disease was concomitantly present in the evaluated specimen. In the lung, a case of marginal zone lymphoma with extensive plasmacytic differentiation was described as being accompanied by crystal-storing histiocytes. 4 Table 2 summarizes the cases of pulmonary crystal-storing histiocytosis with and without underlying lymphoproliferative disorders. We present a patient with an isolated lung mass without apparent systemic disease (other than rheumatoid arthritis). The dense proliferation, composed exclusively of crystal-laden macrophages, infiltrated and expanded the alveoli and formed a true mass with solid growth and destruction of lung parenchyma. A review of our archive of consultation cases revealed only similar case, diagnosed more than 25 years ago. That patient showed a similar single lung mass composed of brightly eosinophilic macrophages containing large numbers of intracytoplasmic crystals. Electron microscopy confirmed that the rodlike intracytoplasmic structures had a crystalline ultrastructure. No associated neoplasm was identified, and the patient had no evidence of multiple myeloma, monoclonal plasma protein, or a connective tissue disorder. No recurrent disease was reported. A brief communication published in 996 described a similar example of crystal-storing histiocytes recurrent in the lung in a patient without a clonal lymphoproliferative disorder. 9 The long asymptomatic course of this patient, as well as the lack of an associated hematologic disorder 62 Arch Pathol Lab Med Vol 29, September 2005 Pulmonary Crystal-Storing Histiocytoma Ionescu et al
5 and the presence of polyclonal plasma cells, suggests, as in our patients, a reactive rather than neoplastic nature of this lesion. An interesting observation related to our patient is that she presented with a long history of rheumatoid arthritis. A similar case of a solitary crystal-storing histiocytic lesion of the tongue has been described in a patient with rheumatoid arthritis and polyclonal hypergammaglobulinemia. 0 Accumulation and crystallization of paraprotein within histiocytes may mimic the appearance of Gaucher cells or of the so-called pseudo-gaucher cells seen in chronic myelogenous leukemia. Because of their light microscopic appearance and ultrastructural differences between Gaucher cells and pseudo-gaucher cells, paraproteinemia-related crystal-storing macrophages might be termed pseudo-pseudo-gaucher cells. In the absence of findings consistent with localized or diffuse immunoproliferative disease, the differential diagnosis for lesions such as that of our patient includes several neoplastic and nonneoplastic diseases. A practical approach to an entity presenting as a nodular histiocytic proliferation with microscopic features of large, polygonal histiocytic cells is presented in Figure 7. Does this lesion represent a benign histiocytic lesion, such as that described by Katzenstein and Maurer 2 in 979? Is this lesion a subtle manifestation of an unrecognized lymphoproliferative disease? Is pulmonary crystalstoring histiocytoma the equivalent in humans of the acidophilic macrophage pneumonia of unknown etiology described in laboratory mice 3? Because of the common association of lymphoproliferative disease with lesions composed of crystal-laden histiocytes, an extensive clinical workup should always be performed to rule out this possibility, including radiologic studies to search for systemic involvement by crystal-storing histiocytosis or a plasmacytoma, a bone marrow biopsy to exclude plasma cell myeloma or lymphoma, serum protein electrophoresis, and so forth. In the cases suspected to be associated with multiple myeloma and negative upon the first bone marrow biopsy, additional bone marrow biopsies may be diagnostic. 7 Crystal-storing histiocytosis in the context of systemic lymphoproliferative disease is typically associated with a poor prognosis, regardless of the type of neoplasm. 2 However, pulmonary crystal-storing histiocytoma, as described in this article, may be a reactive entity presenting as an asymptomatic mass, without evidence of associated hematolymphoid disorders. The lesion appears to have a good prognosis, although it can recur many years following the initial diagnosis. References. Ball NJ, Wickert W, Marx LH, et al. Crystalglobulinemia syndrome. Cancer. 993;7: Lebeau A, Zeindl-Eberhart E, Müller 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;00: Jones D, Bhatia VK, Krausz T, et al. Crystal-storing histiocytosis: a disorder occurring in plasmacytic tumors expressing immunoglobulin kappa light chain. Hum Pathol. 999;30: Kraus MD, Wick MR. Hematolymphoid proliferations involving the lung. In: Leslie KO, Wick MR, eds. Practical Pulmonary Pathology. Philadelphia, Pa: Churchill Livingstone; 2005: Prasad ML, Charney DA, Sarlin J, et al. Pulmonary immunocytoma with massive crystal storing histiocytosis: a case report with review of literature. Am J Surg Pathol. 998;22: Kazzaz B, Dewar A, Corrin B. An unusual pulmonary plasmacytoma. Histopathology. 992;2: 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: Colby TV, Koss MN, Travis WD. Tumors of the Lower Respiratory Tract. Washington, DC: Armed Forces Institute of Pathology; 995. Atlas of Tumor Pathology; 3rd series, fascicle Jones D, Renshaw AA. Recurrent crystal-storing histiocytosis of the lung in a patient without a clonal lymphoproliferative disorder. Arch Pathol Lab Med. 996;20: 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. 998;22: Schaefer HE. Gammopathy-related crystal-storing histiocytosis, pseudoand pseudo-pseudo-gaucher cells: critical commentary and mini-review. Pathol Res Pract. 996;92: Katzenstein AL, Maurer JJ. Benign histiocytic tumor of lung: a light- and electron-microscopic study. Am J Surg Pathol. 979;3: Murray AB, Luz A. Acidophilic macrophage pneumonia in laboratory mice. Vet Pathol. 990;27: Sun Y, Tawfiqul B, Valderrama E, Kline G, Kahn LB. Pulmonary crystalstoring histiocytosis and extranodal marginal zone B-cell lymphoma associated with a fibroleiomyomatous hamartoma. Ann Diagn Pathol. 2003;7: Arch Pathol Lab Med Vol 29, September 2005 Pulmonary Crystal-Storing Histiocytoma Ionescu et al 63
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