Case 4--Lesion 2

In other areas of the honeycombed lesion, there are prominent sheets of cells with pink cytoplasm. These cells stained with the macrophage marker, CD68. Note the presence of some lymphoid cells centrally.

This entire lesion was composed only of cells: there was no light chain deposition as seen in lesion 1.

At high magnification, the macrophages contain crystals that are rhomboid (3 arrows) or hexagonal (2 arrowheads).

Immunoperoxidase stains for kappa light chains (left) and lambda chains (right).

The crystals (arrows) do not stain for either light chain in this paraffin-embedded tissue.

Electron microscopy of such lesions shows that the crystals are in secondary lysosomes.

Kappa

Lambda

Lung parenchyma away from the nodules showed patchy lymphoplasmacytic infiltrates along bronchovascular bundles and in the interlobular septa. In the areas of light chain deposition, lymphoid cells were present but sparse. The cause of the destruction of alveolar walls in each type of lesion is not apparent. Hilar lymph nodes showed sinus histiocytosis and increased numbers of plasma cells but no crystals or deposits. No lymphoid cellular infiltrates, deposits, or crystals were found in other organs at autopsy.

Diagnosis: Clonal B-cell proliferation with crystal formation and multifocal light chain deposits (kappa)

Comment: Again, as in the previous 3 cases, the clonality of the more cellular lesion suggests that it represents a low-grade lymphoma of bronchus-associated lymphoid tissue. Perhaps this patient's long-standing neutropenia, possibly autoimmune in nature, predisposed to this disease.

Crystal-storing Lymphoproliferative Diseases

Occurrence: Intracytoplasmic crystals are an occasional finding in lymphoproliferative disorders including plasmacytoma, multiple myeloma, low-grade lymphomas, chronic lymphocytic leukemia, and in reactive lymph nodes [1,2]. Their existence in patients with low-grade B-cell lymphoplasmacytic neoplasms has been recently reviewed [3]. Eight cases have been reported, in three of which the lung was involved [1-3]. Outcome was good with only one death from disseminated disease [3]. The clinical or histologic changes sometimes mimic those of other diseases--Weber-Christian disease [1], adult rhabdomyoma [4], or Gaucher's disease [5,6]. The crystals may be found in the neoplastic plasma cells or lymphocytes [3,7] or in macrophages or other hematopoietic cells [3,8,9]. Sometimes they are found extracellularly. They may also be found in renal epithelial cells where they cause myeloma-associated Fanconi's syndrome (renal tubular acidosis) [10]. The crystals are rhomboid, rectangular, or hexagonal [3,10]. Their ultrastructure varies from homogeneous and electron dense [4] to lattice-like to fibrillar [11,12].

Light chain types in crystals: The vast majority of cases with crystals have a paraprotein with a kappa light chain, but the heavy chains can be varied [12-17]. An exception is in patients with B-chronic lymphocytic leukemia (B-CLL). Crystals are found in circulating tumor cells of approximately 5% of these patients. In a study of 12 patients with crystals, the crystals as well as the surface membrane immunoglobulins were mostly lambda type by immunofluorescent staining despite the fact that most patients with B-CLL have kappa light chains on the surface membrane [7]. In a case of myeloma-associated Fanconi's syndrome, the crystals were shown to contain kappa chains by immunoelectron microscopic labeling with specific antibody [18].

Pathogenesis: Studies of the paraproteins that are found in patients with crystals have found a) structural abnormalities with altered interchain disulfide bonds, which predispose to crystallization in vitro [19] or b) protease-resistant peptides. The protease-resistant peptide chains were found in a patient with myeloma-associated Fanconi's syndrome by comparing the structure of the protein generated from his myeloma plasma cells to that of crystals derived from the urine. Protease digestion of the whole kappa chain produced a fragment, also found in the crystals, that was resistant to further proteolysis and prone to crystal formation [10].

Crystals may be formed in the neoplastic lymphocytes or plasma cells, but the pathogenesis of the crystals in other hematopoietic cell types and epithelial cells is unclear. Uptake of preformed crystals or, more likely, formation intracellularly in lysosomes from ingested protein are two possibilities [10,12].

Crystals and amyloid or LCDD: An even rarer condition is the combination of crystal-storing cells and amyloidosis [12,14]. In one patient with multiple myeloma, crystals were present in the myeloma cells, histiocytes, and renal proximal tubular cells. Amyloid deposits were mostly perivascular in multiple organs [14]. In another patient with multiple myeloma, crystal-storing histiocytes were mixed with tumor in the marrow and other sites and separate from nodular amyloid deposits. No crystals were found in the myeloma cells in that case [12]. In summary, of the patients with crystals and deposits, two had myeloma and amyloidosis, AL kappa, and one had LCDD with a kappa restricted lymphoproliferative disorder and separate nodules of non-amyloid light chain deposits in the lung (this patient).

References

1. Harada M, Shimada M, Fukayama M, Kaneko T, Kitazume K, Weiss S. Crystal-storing histiocytosis associated with lymphoplasmacytic lymphoma mimicking Weber-Christian disease: immunohistochemical, ultrastructural, and gene-rearrangement studies. Hum Pathol 1996; 27:84-87.

2. Kazzaz B, Dewar A, Corrin B. An unusual pulmonary plasmacytoma. Histopathology 1992; 21:285-287.

3. Prasad M, Charney D, Sarlin J, Keller S. Pulmonary immunocytoma with massive crystal storing histiocytosis. A case report with review of literature. Am J Surg Pathol 1998; 22:1148-1153.

4. Kapadia S, Enzinger F, Heffner D, Hyams V, Frizzera G. Crystal-storing histiocytosis associated with lymphoplasmacytic neoplasms. Report of three cases mimicking adult rhabdomyoma. Am J Surg Pathol 1993; 17:461-467.

5. Padmalatha C, Warner T, Hafez G. Pseudo-Gaucher cell in IgMk plasmacytoid lymphoma. Am J Surg Pathol 1981; 5:501-505.

6. Scullin Jr D, Shelburne J, Cohen H. Pseudo-Gaucher cells in multiple myeloma. Am J Med 1979; 67:347-352.

7. Peters O, Thielemans C, Steenssens L, De Waele M, Hijmans W, Van Camp B. Intracellular inclusion bodies in 14 patients with B cell lymphoproliferative disorders. J Clin Pathol 1984; 37:45-50.

8. Gabriel L, Escribano L, Perales J, Bellas C, Odriozola J, Navarro J-L. Multiple myeloma with crystalline inclusions in most hemopoietic cells. Am J Hematol 1985; 18:405-411.

9. Suarez P, El-Naggar A, Batsakis J. Intracellular crystalline deposits in lymphoplasmacellular disorders. Ann Otol Rhinol Laryngol 1997; 106:170-172.

10. Aucouturier P, Bauwens M, Khamlichi A, Denoroy L, Spinelli S, Touchard G, Preud'homme J, et al. Monoclonal Ig L chain and L chain V domain fragment crystallization in myeloma-associated Fanconi's syndrome. J Immunol 1993; 150:3561-3568.

11. Raman S, van Slyck E. Nature of intracytoplasmic crystalline inclusions in myeloma cells (morphologic, cytochemical, ultrastructural, and immunofluorescent studies). Am J Clin Pathol 1983; 80:224-228.

12. Takahashi K, Naito M, Takatsuki K, Kono F, Chitose M, Ooshima S, Mori N, et al. Multiple myeloma, IgA k type, accompanying crystal-storing histiocytosis and amyloidosis. Acta Pathol Jpn 1987; 37:141-154.

13. Grossniklaus H, Stulting R, L'Hernault N. Corneal and conjunctival crystals in paraproteinemia. Hum Pathol 1990; 21:1181-1183.

14. Kjeldsberg C, Eyre H, Totzke H. Evidence for intracellular amyloid formation in myeloma. Blood 1977; 50:493-504.

15. Cordier A, Scolari L, Vaerman J-P, Dutrieux-Fauchet M-C, Dutrieux C, Haumont S. Ultrastructural aspects of crystal-like inclusions in a case of IgA plasma cell proliferation. Scand J Haematol 1976; 17:143-152.

16. Yamamoto T, Hishida A, Honda N, Ito I, Shirasawa H, Nagase M. Crystal-storing histiocytosis and crystalline tissue deposition in multiple myeloma. Arch Pathol Lab Med 1991; 115:351-354.

17. Tsuchikawa K, Yokomichi H, Satoh I, Suzuki C, Watanabe Y, Tajima G. A Study of intracytoplasmic inclusions in myeloma cells from two patients with multiple myeloma. Tohoku J Exp Med 1987; 153:11-20.

18. Truong L, Mawad J, Cagle P, Mattioli C. Cytoplasmic crystals in multiple myeloma-associated Fanconi's syndrome. Arch Pathol Lab Med 1989; 113:781-785.

19. Green E, Morrison L, Love P, DeSchryver-Kecskemeti K, Waltman S, Smith M, Scott M. A structurally aberrant immunoglobulin paraprotein in a patient with multiple myeloma and corneal crystal deposits. Am J Med 1990; 88:304-311.

Clinical summary Discussion

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