Monoclonal gammopathy of undetermined significance

We report the case of a 64-year-old woman who, 12 years after receiving a diagnosis of Gaucher's disease with concurrent monoclonal gammopathy of undetermined significance, developed worsening thrombocytopenia and bone pain. Bone marrow biopsy at this time revealed 50% plasma cells with a serum monoclonal immunoglobulin A-Lambda level of 3.2 g/L. Roentgenography revealed a lytic clavicular lesion, and a diagnosis of multiple myeloma was made. To our knowledge, this case is the first to document the evolution of a monoclonal gammopathy of undetermined significance to multiple myeloma in a patient with Gaucher's disease. The importance of investigating cytopenias and increased bone pain in such patients, perhaps by bone marrow biopsy, to rule out potentially malignant plasma cell dyscrasias is stressed. (Arch Pathol Lab Med. 1997;121 OS-1111 )

PATHOLOGIC FINDINGS

Bone marrow aspirates were air dried and stained with a traditional Wright-Giemsa stain. Core biopsies were fixed in 10% buffered formalin and embedded in paraffin. Biopsy material was routinely processed and stained with hematoxylin-eosin and examined under light microscopy on an Olympus microscope with a lOx eyepiece. Material from the 1990 bone marrow biopsy was placed in glutaraldehyde for fixation prior to evaluation with electron microscopy. A Jol lOOS electron microscopy was used, and images were taken at x12 500 and x25 000 magnification.

Aspirate smears from the bone marrow obtained in 1978 showed mixed hematopoiesis with numerous enlarged macrophages filled with fibrillary cytoplasmic material easily visible on light microscopy. Plasma cells with normal morphology were increased to approximately 9%.

Other marrow elements had normal morphology and were present in the usual proportions. The core biopsy showed a hypocellular marrow with numerous Gaucher's cells, found individually and in clusters, each containing a small nucleus and fibrillary cytoplasm. The bone marrow biopsy in 1990 showed many Gaucher's cells and 50% plasma cells. Many of these plasma cells had immature nuclei with occasional nucleoli. Multinucleated plasma cells were also seen (Fig 1).

On electron microscopy, typical fibrillary and cylindrical structures were found in the cytoplasm of the Gaucher's cells, primarily within lysosomes. The cylindrical structures were both densely and loosely packed (Fig 2). They measured from 40 to 60 nm in diameter. No dense round deposits, often found in pseudo-Gaucher's cells, were seen. COMMENT

Although Gaucher's disease may be associated with bone pain and cytopenias, roentgenographic findings are characteristic. Myeloma patients have punched-out, lytic lesions, whereas patients with Gaucher's disease exhibit a spectrum of lesions, ranging from bony infarctions to Erlenmeyer-flask deformities due to increased marrow volume.1 Bone marrow biopsy is no longer routinely used to diagnose Gaucher's disease; however, should lytic lesions be noted on roentgenography, it would be reasonable to pursue that course and to obtain additional serum and urine protein analyses. The incidence of clonal B-cell disorders, including MM and MGUS,412 appears higher in this patient group than in the general population.2- Lymphomas and solid tumors appear to occur at a higher incidence in this group as well.4

Theories regarding the mechanism for B-cell proliferation generally focus on antigenic stimulation of these cells by lipid-laden macrophages.' However, Shiran et al4 recently reported that in 48 patients with Gaucher's disease, rates of solid and lymphoid tumors were increased, as well as the rate of MM. These findings may point to a more global immune dysregulation.

As for the apparent increase in myeloma in patients with Gaucher's disease, we theorize that perhaps interleukin-6 (IL-6) may play a role in the proliferation of plasma cells. Experimental evidence in IL-6 transgenic mice has demonstrated that a polyclonal IgG plasmacytosis may occur in the spleen, lymph nodes, and thymus when IL-6 is constitutively produced by the liver.'3 In humans, IL-6 is produced by macrophages, as well as by other hematopoietic cells and keratinocytes.14 In vitro data using human myeloma cell lines showed that all three cell lines studied showed proliferation in the presence of IL-6.15 It therefore seems possible that patients with Gaucher's disease, who have macrophages that are potentially stimulated by the presence of accumulated sphingolipids, may produce increased levels of IL-6, which may lead to plasmacytosis of varying degrees and even myeloma. In vivo studies to determine whether IL-6 is in fact increased in these patients would be of interest.

Accepted for publication April 28, 1997.

References

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12. Lamon JM, Miller W, Tavassoli M, Longmire R, Beutler E. Multiple myeloma complicating Gaucher's disease. West] Med. 1982;136:122-128. 13. Fattori E, Rocca CD, Costa P. Development of progressive kidney damage and myeloma kidney in interleukin-6 transgenic mice. Blood.1994;83:25702579.

14. Yamamoto T, Soejima K, Katayama I, Nishioka K. Intralesional steroid-therapy-induced reduction of plasma interleukin-6 and improvement of cutaneous plasmacytosis. Dermatology. 1995;190:242-244.

15. Sponreno E, Savino R, Ciapponi L. Human interleukin-6 receptor superantagonists with high potency and wide spectrum on multiple myeloma cells. Blood. 1996;87:4510-4519.

From the Departments of Laboratory Medicine (Drs Brady and Corash) and Pathology (Dr Bhargava), University of California, San Francisco.

Reprint requests to Department of Laboratory Medicine, University of California, San Francisco, 505 Parnassus Ave, Box 0100, San Francisco, CA 94143-0506 (Dr Brady).

Copyright College of American Pathologists Oct 1997
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