Case Report:Plasma Cell Neoplasm in Conjunction with Glioblastoma of the Conus Medullaris

Susan R. Williams,¹ John R. Parker,¹ Alvin Martin,² Todd Vitaz,3 and Joseph C. Parker, Jr.¹1Department of Pathology, University of Louisville Hospital; 2Clinical Pathology Associates, Louisville; and 3Norton Neuroscience Institute, Louisville, Kentucky

Abstract. We report a plasma cell neoplasm in conjunction with a glioblastoma multiforme (GBM) of the conus medullaris in a 42-year-old man. Glioblastoma is a World Health Organization (WHO) grade IV neoplasm that requires surgical intervention, radiation, and possibly chemotherapy. Astrocytomas of the spinal cord are rare neoplasms, with intramedullary glioblastomas comprising only 1% to 3%. Plasma cell neoplasms result from monoclonal proliferation of mature B cells; they have been reported as a primary malignancy with gliomas arising after treatment. Secondary plasma cell neoplasms arising within glioblastomas have not previously been described. However, there have been reports of glioblastomas related to other plasma cell and hematopoietic diseases such as Waldenstrom’s macroglobulinemia and myeloid sarcomas.

Introduction

Glioblastoma is a high grade (WHO IV) glial neoplasm of the central nervous system. It is characterized by an abundance of highly pleo-morphic astrocytes that possess marked nuclear atypia and mitotic activity with microvascular and endothelial cell proliferation and/or necrosis [1]. Glioblastomas occur at any age but are most common between 45 to 75 years, with the majority located in the cerebral hemispheres [1]. Plasma cell neo-plasms include a group of diseases that result from the monoclonal expansion of immunoglobulin-producing B cells. These neoplasms include monoclonal gammopathy of undetermined significance (MGUS), Waldenstrom’s macroglobulinemia, plasma cell myeloma and its variants, solitary plasmacytoma of bone, extramedullary plasmacy-toma, immunoglobulin deposition diseases, and osteosclerotic myeloma

[2]. These disorders involve various sites of the body and have been associated with connective tissue diseases, peripheral neuropathies, and other skin, endocrine, or liver diseases, as well as following solid organ or bone marrow transplant-ation [2]. We report the unique presentation of a plasma cell neo-plasm in the spinal cord after two resections and therapy for a glio-blastoma of the conus medullaris.

Case Report

A 34-yr-old man initially presented to his physician with complaints of radiating pain in the right buttock and leg. His medical history included arthroscopic knee surgery; he had no other pertinent medical or family history. He received a series of epidural blocks that provided temporary relief of his pain, and during the following six months he developed a right foot drop. Magnetic resonance imaging

(MRI) in October 2000 revealed a 3.8 x 1.9 cm intradural, intramed-ullary lesion with limited enhance-ment that nearly filled the spinal canal. There was no disc protrusion or nerve root compression. Partial resection of this mass revealed hypercellular glial tissue with mild

Address correspondence to Joseph C. Parker, Jr., M.D., Department of Pathology, University of Louisville Hospital, 530 S. Jackson St., Louisville, KY 40202, USA; e-mail Jcpark01@gwise.louisville.edu.

Fig. 1. MRI in 2007 of the hetero-geneously enhancing mass with cystic degeneration in the conus medullaris.

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nuclear pleomorphism consistent with a well differentiated astro-cytoma (WHO grade II). After surgery, he received external beam radiation, but he continued to have worsening pain that was unres-ponsive to analgesic therapy. In April 2007, the patient developed incontinence and persist-ent low back pain radiating to his groin. A hydromorphone hydro-chloride pain pump was inserted for management, but his symptoms continued. In September 2007, a MRI study showed an increase in the mass from 2.0 x 1.2 x 1.2 cm to 2.0 x 2.0 x 3.7 cm with significant filling of the spinal canal (Fig. 1).

Debulking of the tumor in September 2007 confirmed recur-rence of the glial neoplasm, which possessed scattered spindled tumor cells associated with malignant gemistocytes and uninucleated and focal multinucleated tumor cells. There was cellular pleomorphism and endothelial cell proliferation. Isolated hemorrhage and necrosis were present. In addition, hyalin-izing fibrosis was associated with focally prominent vasculature and chronic inflammation including lymphoid cells, plasma cells, and scattered macrophages. The glial fibrillary acidic protein (GFAP) immunostain was strongly positive.

The Ki-67 immunostain varied from <2% to focal 20% positivity (Fig. 2). These findings were consist-ent with a glioblastoma of the conus medullaris. Temozolomide therapy was initiated at a dose of 200 mg/m². The patient experienced bruis-ability, with his platelet count dropping to 9,000/dl in February 2008. At that time temozolomide therapy was stopped, but a second cycle at 150 mg/m² was begun when the thrombocytopenia resolved. Progressive paraplegia occurred over the following months. In Nov-ember 2008, MRI studies revealed that the tumor diameter had increased to 3 cm. Surgical removal

Fig. 2. Ki-67 (200x) positive staining of glia in the 2007 GBM, compared to 2-3% staining of the 2000 astrocytoma (inset).Fig. 3. H&E stain (600x) demonstrating cellular pleomorphism and mitoses (arrows) in the 2008 GBM.Fig. 4. H&E stain (200x) demonstrating necrosis in the 2008 GBM.Fig. 5. H&E stain (400x) demonstrating sheets of plasma cells within the 2008 GBM with CD 138 positive staining (inset).

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of the tumor to preserve the patient’s life included a T8-S1 laminectomy in November 2008, with removal of the T8 spinal cord down to the cauda equina. Initial H&E-stained sections showed recurrent glio-blastoma (Figs. 3, 4) with sheets of plasma cells (Fig. 5). The tumor specimen was stained for GFAP and CD 138 antibodies using an automated immunohistochemical technique with epiptope enhance-ment, and it was stained for kappa and lambda messenger RNA via non-isotopic in situ hybridization (ISH). These stains demonstrated GFAP positivity of the pleomorphic glial cells in the glioblastoma multi-forme (Fig. 6), with sheets of plasma

cells decorated with CD 138 anti-body (Fig. 5 inset). These plasma cells had monoclonal expression of kappa messenger RNA (Fig. 7), with very few plasma cells that stained for lambda messenger RNA. To define this clonal plasma cell neoplasm, additional antibody stains were done including MUM-1, cyclin D1, CD 20, PAX-5, IgG, IgM, IgA, and CD 19, using appropriate epiptope enhancement. The plasma cells stained positively with MUM-1 and CD 19 (Fig. 8), and monoclonal IgD (Fig. 9); there were scattered CD 20 positive cells. The CD 20 positivity raised the possibility of a marginal zone lymphoma with plasmacytic differ-

entiation. Examinations failed to reveal an M protein in the patient’s urine or blood, and his blood counts remained in the appropriate range. Bone marrow aspiration failed to reveal any features of multiple myeloma or lymphoma. These immunohistochemical and labor-atory findings favored a diagnosis of a plasma cell neoplasm in con-junction with a glioblastoma of the conus medullaris. A marginal zone lymphoma with plasmacytic differ-entiation could not be excluded. Immunotains for PAX-5, CD 138, CD 3, CD 20, p53, IgD, Ki-67, and ISH for kappa and lambda were performed to elucidate the progres-sion of the astrocytoma to glioblast-

Fig. 6. GFAP (100x) positive staining of the pleomorphic glia in the 2008 GBM.Fig. 7. Kappa ISH (200x) demonstrating monoclonal expression for kappa messenger RNA in the 2008 GBM.Fig. 8. CD19 (100x) positive staining of the plasma cells in the 2008 GBM.Fig. 9. IgD (400x) monoclonal expression of the plasma cells associated with the 2008 GBM.

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oma and to investigate the presence of lymphoid or plasma cells in the earlier resections. The original neuroglial tumor examined in 2000 was devoid of inflammatory cells and had rare p53 nuclear staining. The Ki-67 cell cycle label varied from 2% to 3% (Fig. 2 inset). The recurrent glioblastoma in 2007 did not display any inflammatory or monoclonal infiltrate, and its Ki-67 cell cycle labeling ranged from 2% up to 20% focally.

Discussion

Astrocytomas of the CNS are neoplasms of astrocytes that are immunoreactive for GFAP. Increased proliferative activity is evident in high grade tumors with Ki-67/MIB-1 mean values of 15% to 20% [1]. Our patient’s tumor possessed prominent GFAP expres-sion and a Ki-67 label of 2 to 3% in the initial tumor, which was consis-tent with a low grade astrocytoma (WHO grade II). The 2008 recur-rent tumor, with Ki-67 labeling focally approaching 20%, also had necrosis and endothelial cell prolif-eration, warranting the diagnosis of glioblastoma. Despite multiple resections and chemoradiation, the tumor recurred on two occasions. Spinal cord astrocytomas are rare neoplasms that require surgical treatment and may necessitate rad-iation and chemotherapy. Glioblas-toma multiforme comprises about 1% to 3% of intramedullary spinal cord gliomas and is diagnosed based on the degree of cellular pleomorph-ism, mitoses, endothelial cell proliferation, and/or necrosis [9-11]. Surgery and radiation are initial treatments, however, high-grade lesions with infiltrative borders may be difficult to resect. Local or lepto-meningeal dissemination will neces-sitate chemotherapy [3]. With an incidence of only 0.8 to 2.5/100,000, chemotherapeutic options for spinal cord astrocytomas have not been well investigated [3].

Since 1999, phase II and III trials have reported the benefits of temozolomide in patients with WHO grade III astrocytomas and in first relapse patients with a glio-blastoma [4-8]. Temozolomide is an alkylating agent that is hydrolyzed to methyl-triazeno-imidazole-carb-oxamide (MTIC) and subsequently to the inactive 5-aminoimidazole-4-carboxamide (AIC) and the alkylating methyldiazonium cation. This cation methylates DNA and is responsible for the cytotoxicity [4]. Myelosuppression has been reported in patients including lymphopenia (55%), thrombocytopenia (4-19%), neutropenia (8-14%), and leuko-penia (11%) [4]. While cytopenias are a recognized complication of this drug, there are few reports of secondary lymphoproliferative dis-orders. Plasmacytomas have not been described. Plasma cell neoplasms result from the monoclonal expansion of a mature, immunoglobulin-secreting B-cell that possesses both CD 19 and CD 138 antigens. Immunoglob-ulins are comprised of kappa or lambda light chains and a class-identifying heavy chain (IgM, IgA, IgD, IgE, IgG). The MUM-1 and scattered CD 20 positive cells classify this lesion as a B-cell neo-plasm, raising the possibility of a diffuse large B cell or marginal zone lymphoma with plasmacytic differ-entiation [12]. In view of the benign clinical follow-up, the unusual extranodal location, and IgD kappa expression, extramedullary plasma-cytoma may be favored, but differentiation between the two is extremely difficult. Secondary malignancies that develop after aggressive treatment for a primary malignancy have been well described. Leukemias have been reported following the use of alkylating agents and epipodo-phyllotoxins [13,14]. CNS gliomas have appeared after radiation therapy for a primary malignant

neoplasm [15,16]. Myelodysplastic syndromes and acute myeloid leukemia have occurred following temozolamide therapy for gliomas [17]. Our patient received both treatments and developed a plasma cell proliferation with monoclonal expression of IgD. Rare cases of Waldenstrom’s macroglobulinemia associated with a cerebral glioblastoma have been reported, with some diagnosed simultaneously [18,19]. Diffuse non-monoclonal plasmacytosis has been reported following multi-agent chemotherapy and granulocyte-macrophage colony-stimulating factor (GM-CSF) [20]. Recently, a myeloid sarcoma within a glio-blastoma was reported in a patient with a previous history of acute myelogenous leukemia [21]. In addition, gliomas occurring in patients with previous lymphoid malignancies include some glioblast-omas complicating the course of myelomas [22-25]. Lymphoid prolif-erations may have some effect on vascular permeability and suscep-tibility of degenerated white matter to reactive gliosis [19]. While plausible, our case defies such reasoning because the astrocytoma and glioblastoma were lesions that arose years before the plasmacytic proliferation occurred. This is the first reported case of a plasma cell neoplasm arising in association with a glioblastoma in the conus medullaris.

Acknowledgements

We thank Sheron Lear and Clinical Pathology Associates in Louisville, Kentucky, for assistance with the immunohistochemical stains.

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