Brain Pathology Case of the Month - March 2009

DIAGNOSIS  CNS manifestation of multiple myeloma

DISCUSSION

On the basis of morphological and immunohistochemical findings we favored the diagnosis of a diffuse infiltration of the CNS by the MM diagnosed and treated three years ago. Polymerase chain reaction (PCR) analysis confirmed the diagnosis by revealing monoclonality of the immunoglobulin heavy chain.

Multiple myeloma is characterized by the presence of neoplastic proliferating plasma cells; the tumor is generally restricted to the bone marrow. In less than 1 % of the cases a CNS involvement is observed including localized intraparenchymal lesions, solitary cerebral plasmocytoma or CNS myelomatosis (= presence of monoclonal cells in the CSF) (2;4;6;7). The etiology of CNS infiltrating multiple myeloma is unknown and the hypothesis includes a continuous spread from eroded lytic skull lesions or hematogenous spread of tumor cells favored by the fact that most MM drugs do not reach the brain parenchyma (5). In our patient no skull lesions were found suggesting a haematogenous spread of tumor cells. In patients with CNS manifestations of MM a high incidence of p53 deletions was observed which might indicate relevance for the metastatic features of myeloma cells (1). The prognosis of patients with MM CNS manifestation is in general poor; Nieuwenhuizen reported a survival time between 0.1 and 25 months (5).

Histopathologically, localized intraparenchymal lesions of CNS MM are characterized by the presence of neoplastic, proliferating plasma cells which are occasionally multinucleated as observed in our cases. However, in our patient the infiltration of neoplastic plasma cells was associated by extensive demyelination which to our knowledge has not been described in the literature to date as a feature of CNS MM. The presence of a demyelinating lesion with relative axon preservation, perivascular infiltrates and numerous foamy macrophages leads to the consideration of a variety of differential diagnoses. These include as progressive multifocal leukencephalopathy (especially in immunosuppressed patients as in our case), sentinel lesions or less likely multiple sclerosis. However, the high number of pleomorphic plasma cells of which some were proliferating was highly suggestive for CNS MM. The presence of lambda and kappa light chain-producing plasma cells may be explained by an additional inflammatory component. The diagnosis of CNS MM could be definitively confirmed by PCR revealing the monoclonality of the immunoglobulin heavy chain.

REFERENCES

1. Chang H, Sloan S, Li D, Keith SA (2004) Multiple myeloma involving central nervous system: high frequency of chromosome 17p13.1 (p53) deletions. Br J Haematol 127: 280-284.
2. Fassas AB, Muwalla F, Berryman T et al (2002) Myeloma of the central nervous system: association with high-risk chromosomal abnormalities, plasmablastic morphology and extramedullary manifestations. Br J Haematol 117: 103-108.
3. Kuhlmann T, Remington L, Maruschak B, Owens T, Bruck W (2007) Nogo-A is a reliable oligodendroglial marker in adult human and mouse CNS and in demyelinated lesions. J Neuropathol Exp Neurol 66: 238-246.
4. Lupu VD, Saini N, Balish M (2005) CNS myelomatosis. Neurology 64: 1007.
5. Nieuwenhuizen L, Biesma DH (2008) Central nervous system myelomatosis: review of the literature. Eur J Haematol 80: 1-9.
6. Seftel MD, Maguire J, Voss N, Woodhurst WB, Dalal BI, Shepherd JD (2002) Intra-cerebral relapse following prolonged remission after autologous stem cell transplantation for multiple myeloma. Leuk Lymphoma 43: 2399-2403.
7. Veinstein A, Brizard A, Randriamalala E, Babin P, Preud'homme JL, Guilhot F (1997) Central nervous system relapses after autologous stem cell transplantation for myeloma. Report of two cases. Hematol Cell Ther 39: 327-330.

Contributed by T. Kuhlmann, S. Vogelgesang, B. Gunawan, J. Scheunemann, A. Wolters, W. Brück

International Society of Neuropathology