Case 3 -

Extranodal Marginal Zone Plasmocytic Lymphoma with Crystal-Storing Histiocytosis Helmut H. Popper Medical University of Graz Graz, Austria

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Clinical History The male patient, born in 1916, died because of sclerosis and stenosis of the coronary arteries with multiple infarcts resulting in congestive heart failure, leading to decompensation. Pneumonia was clinically suspected. The medical history also included chronic renal insufficiency. At autopsy, the following macroscopic and microscopic changes were observed: Heart and large blood vessels: general arteriosclerosis of all large- and medium-sized arteries; severe sclerosis and stenosis of the coronary arteries and their main branches; multiple scars in the posterior myocardium with formation of an aneurysm; a heart stimulating device (VVI) implanted in the right posterior ventricle wall Pleura and pleural cavities: 200 ml pleural effusions and focal pleural fibrosis on both sides Lungs: emphysematous changes in both lungs; two round grayish-white nodules measuring 1.5 and 2 cm in diameter in the left lower and right upper lobes, respectively; mild arteriosclerosis of the pulmonary arteries Other pathology: cholelithiasis, fracture of the left distal radius Sections from both nodules were submitted for consultation, and a section of one is provided. Both demonstrated identical histologic features. Case 3 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 3 - Figure 1 Case 3 - Figure 2 Case 3 - Figure 3 Case 3 - Figure 4 Case 3 - Figure 5 Case 3 - Figure 6 Case 3 - Figure 7 CD163 (IHC) Case 3 - Figure 8 HLA-DR (IHC) Case 3 - Figure 9 IgG (IHC) Case 3 - Figure 10 PAS Morphology On low power magnification, both nodules showed a dense interstitial and intraalveolar infiltrate, the former with a predominant perivascular pattern, the latter most often completely obstructing the lumina of alveoli and bronchioles. The interstitial infiltrate occasionally showed lymphoid follicle-like structures. On closer examination, the intraalveolar infiltrate was mainly composed of macrophages, whereas in the interstitial component plasmacytic cells, small lymphocytes and some intermingled blasts predominated. Occasional lymphoepithelial lesions were noted. On high power magnification, macrophages displayed abundant cytoplasm filled with needle-like crystals, which stained positively with PAS. Differential Diagnosis Based on morphology, several different scenarios can be considered: An infectious process caused by persistent intracytoplasmic organisms A storage disease associated with a benign reactive lymphoid infiltrate A lymphoid neoplasm associated with a storage disease or another type of macrophage reaction Based on the morphology, lymphoma was considered most likely. Additional immunohistochemical stains were performed to characterize the infiltrates, with the following results: anti-IgG Plasma cells and B-lymphocytes pos anti-IgA Neg anti-IgM Neg anti-IgD Neg Anti-kappa Plasma cells and B-lymphocytes pos Anti-lambda Neg Anti-HLADR Plasma cells pos CD 3 Neg (only few scattered T-lymphocytes) CD 5 Neg CD 10 Neg CD 14 Lymphocytes and plasma cells neg CD 20 B-lymphocytes pos, plasma cells neg CD 21 Few B-lymphocytes pos CD 23 Only single plasma cells and lymphocytes pos CD 38 Plasma cells pos CD 68 Macrophages pos CD 79a Few B-lymphocytes and plasma cells pos CD 138 Plasma cells pos CD 163 Macrophages pos Pan-CK Neg, but highlighting the lymphoepithelial lesions MIB1 < 10% The plasmacytic cell population predominated, and only approximately 10% CD20-positive and HLA-DR-negative B-lymphocytes were seen. There was an IgG and kappa light chain restriction in the lymphoid and plasma cell population. Focally, lymphoid cells were positive for CD21 and CD79a, whereas the plasma cell population stained also for CD38 and CD138. The lymphoid cells were negative for CD5, CD10 and CD23. CD20 and cytokeratin antibodies highlighted a few lymphoepithelial lesions, which supports the interpretation of extranodal marginal zone lymphoma. High-grade B-cell lymphomas can be excluded, because there were no sheets of blasts and a significant number of the tumor cells showed plasmacytic differentiation. Lymphoplasmacytic lymphoma is another, sometimes very difficult differential diagnoses. These lymphomas, however, are usually IgM heavy-chain-positive neoplasms. Therefore, lymphoplasmacytic lymphoma can be excluded in our case. Reactive inflammatory infiltration would be polyclonal, and can therefore be excluded from our differential. Follicular lymphoma can in rare occasions be found in the lung, but these will show a different immunophenotype, with positivity of almost all cells for CD10, CD20, and CD79a, and a lack of plasmacytic cells. Small lymphocytic lymphoma/chronic lymphocytic leukemia can also produce lung infiltrates. This lymphoma is morphologically characterized by small lymphoid cells and lacks plasmacytic differentiation. Extraosseous plasmacytoma usually presents with sheets of tumor cells without intermingled monoclonal B-lymphocytes and thus can also be excluded. The crystalline material within the macrophages was immunopositive for IgG, supporting a diagnosis of crystal-storing histiocytosis. Extranodal marginal zone lymphoma of BALT type (EMZL-BALT) is one of the most common lymphomas arising primarily within the lung. The combination with crystal-storing histiocytosis (CSH) is an unusual combination. So far, only three cases involving the lung have been described in the literature. CSH has been described with EMZL of other sites, most often the head and neck region, the lymph nodes, the kidney, and the bone marrow. The phagocytosis of the crystalline material by macrophages has been explained by an excess of immunoglobulin production, in most cases with a kappa light chain restriction, with ingestion of this crystallized material by macrophages. In addition, the following stains were performed to evaluate for infectious organisms, with the following results: Acid fast stain (mycobacteria) Neg Grocott Methenamine (fungi) Neg PAS (fungi, Whipple's disease) Positively stained crystals Warthin-Starry (bacteria) Neg Giemsa (bacteria and fungi) Neg A subset of infectious organisms can persist within cells, either due to a specialized cell membrane and/or capsule, which enables them to escape the attack of lysosomal enzymes, or because they have acquired adaptations by which they inhibit the fusion of lysosomes and phagosomes. These agents typically produce accumulations of macrophages and should therefore be considered in the differential diagnosis. Mycobacteria are best known for this capability. Infection by M. avium complex can induce this type of macrophage accumulation without formation of epithelioid granulomas. Due to the negative acid fast staining of the crystalline material, however, mycobacteria can be excluded. Other bacteria, which can induce macrophage accumulation, are Listeria and Bartonella species, and Tropheryma whippelii (Whipple's disease). Although lung involvement is exceedingly rare in these infections, it can occur. PAS is positive in Whipple's disease, but the organisms form aggregates of small thin rods, and not crystals. The organisms should also stain with the Warthin-Starry stain. Fungi can also cause this type of reaction. Although Pneumocystis jirovecii (carinii) usually causes protein-rich exudation and a mild interstitial inflammatory response, a granulomatous reaction with epithelioid cells has been described in this setting. Macrophage accumulation may occur early in the process, but there are no crystalline inclusions as seen in the current case. Finally, parasites can persist within macrophages and can cause macrophage accumulation. However, in these cases there is usually concomitant infiltration by eosinophils or neutrophils and there are no crystalline inclusions. Malakoplakia and storage diseases can also be considered in the differential diagnosis. Malakoplakia is characterized by an accumulation of macrophages with concentric laminated inclusions (Michaelis-Gutmann bodies) in the cytoplasm, which do not resemble the crystals seen in the current case. These unique crystals are also not seen in storage diseases that involve the lung (Niemann-Pick disease, Gaucher's disease, Fabry's disease, Hermansky-Pudlak Syndrome). Finally hemophagocytic syndrome can be considered in the differential diagnosis, since it is also characterized by an accumulation of macrophages. However, in hemophagocytic syndrome, macrophages will show inclusions of red blood cells and an acute interstitial pneumonia with diffuse alveolar damage, which was not apparent in our case. Diagnosis Extranodal marginal zone plasmocytic lymphoma with crystal-storing histiocytosis References Popper HH: Epithelioid cell granulomatosis of the lung: new insights and concepts, Sarcoidosis Vasc Diffuse Lung Dis 1999, 16:32-46 Tokudome S, Kono S, Ikeda M, Kuratsune M, Kumamaru S: Cancer and other causes of death among leprosy patients, J Natl Cancer Inst 1981, 67:285-289 Jayalakshmi P, Looi LM, Lim KJ, Rajogopalan K: Autopsy findings in 35 cases of leprosy in Malaysia, Int J Lepr Other Mycobact Dis 1987, 55:510-514 Winberg CD, Rose ME, Rappaport H: Whipple's disease of the lung, Am J Med 1978, 65:873-880 Symmons DP, Shepherd AN, Boardman PL, Bacon PA: Pulmonary manifestations of Whipple's disease, Q J Med 1985, 56:497-504 Kelly CA, Egan M, Rawlinson J: Whipple's disease presenting with lung involvement, Thorax 1996, 51:343-344 Travis WD, Pittaluga S, Lipschik GY, Ognibene FP, Suffredini AF, Masur H, Feuerstein I, Kovacs J, Pass HI, Condron KS, et al.: Atypical pathologic manifestations of Pneumocystis carinii pneumonia in the acquired immune deficiency syndrome. 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Pathologic features, Arch Pathol Lab Med 1994, 118:744-748 Yuoh G, Hove MG, Wen J, Haque AK: Pulmonary malakoplakia in acquired immunodeficiency syndrome: an ultrastructural study of morphogenesis of Michaelis-Gutmann bodies, Mod Pathol 1996, 9:476-483 Bastas A, Markou N, Botsi C, Myrianthefs P, Trigidou R, Poulakis N, Polyzogopoulos D: Malakoplakia of the lung caused by Pasteurella multocida in a patient with AIDS, Scand J Infect Dis 2002, 34:536-538 Popper HH, Zenz W, Mache C, Ohlinger W: Familial haemophagocytic lymphohistiocytosis. A report of three cases with unusual lung involvement, Histopathology 1994, 25:439-445 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, 22:1148-1153 Fairweather PM, Williamson R, Tsikleas G: Pulmonary extranodal marginal zone lymphoma with massive crystal storing histiocytosis, Am J Surg Pathol 2006, 30:262-267 Kapadia SB, Enzinger FM, Heffner DK, Hyams VJ, Frizzera G: Crystal-storing histiocytosis associated with lymphoplasmacytic neoplasms. Report of three cases mimicking adult rhabdomyoma, Am J Surg Pathol 1993, 17:461-467 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, 120:1133-1136 Suarez P, el-Naggar AK, Batsakis JG: Intracellular crystalline deposits in lymphoplasmacellular disorders, Ann Otol Rhinol Laryngol 1997, 106:170-172 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