Primary Lymphoma of the Spinal Cord

Case Report Primary Lymphoma of the Spinal Cord STEVEN

E. SCHILD, M.D.,

ROBERT

E. WHAREN, JR., M.D., DAVID M.

MENKE, M.D., W. NEATH FOLGER, M.D.,

AND GERARDO COLON-OTERO, M.D.

Non-Hodgkin's lymphomas arising in the spinal cord are extremely rare. Only eight single case reports have been well confirmed in the literature. Herein we describe a 59-year-old woman with symptoms attributable to a spinal cord lesion. Physical examination revealed neurologic deficits but no evidence of tumor elsewhere. Although several imaging studies were performed, only magnetic resonance imaging with use of gadolinium revealed the exact site and extent of the lesion. Laminectomy and direct examination of the spinal cord disclosed a discolored region at the level of the 11th thoracic vertebra. A biopsy specimen was obtained, and pathologic examination revealed an intermediate grade, mixed cell lymphoma of T-cell origin. Radiotherapy was administered to the lesion and

Primary lymphomas arising in the central nervous system (CNS) are rare; they constitute about I % of intracranial neoplasms'f and 2% of malignant lymphomas.' Although patients of all ages have been diagnosed with CNS lymphomas, the incidence peaks during the sixth decade of life, with a male predominance.' Patients whose immune system is compromised because of the human immunodeficiency virus (HIV), autoimmune diseases, congenital immune deficiencies, and immunosuppressive medications have been described as having an increased risk of primary lymphoma of the CNS. 4 ,5 A relationship may exist between the Epstein-Barr virus and the development of such lymphomas." Primary lymphomas of the CNS are most often categorized as diffuse histiocytic lesions on the basis of the Rappaport classification and as large cell and immunoblastic on the basis of the Working Formulation classification.' Most of these lymphomas are composed of B cells.' From the Department of Radiation Oncology (S,E.S,), Mayo Clinic Scottsdale, Scottsdale, Arizona; Department of Neurosurgery (RE.W,), Department of Pathology (D,M,M,), and Division of Hematology/Oncology (G,C-O,), Mayo Clinic Jacksonville, Jacksonville, Florida; and Department of Neurology (W,N.F.), Mayo Clinic Rochester, Rochester, Minnesota, Address reprint requests to Dr. S, E. Schild, Department of Radiation Oncology, Mayo Clinic Scottsdale, 13400 East Shea Boulevard, Scottsdale, AZ 85259, Mayo Clin Proc 1995; 70:256-260

adjacent region of the spinal cord with use of 6-MV photons and an anteroposterior-posteroanterior technique; the total dose was 45 Gy in 23 fractions. No chemotherapy was given. After 3 years of follow-up, the neurologic signs and symptoms were stable, and repeated magnetic resonance imaging with use of gadolinium showed no residual tumor. In addition to the case report, we review the literature on primary lymphomas of the central nervous system and discuss treatment recommendations. (Mayo Clin Proc 1995; 70:256-260) eNS = central nervous system; CSF = cerebrospinal fluid; HIV = human immunodeficiency virus; MRI = magnetic resonance imaging

Primary lymphomas of the CNS most frequently involve the brain and only infrequently involve the spinal cord or other extracranial sites.' Lymphomas arising as primary tumors of the spinal cord are extremely rare and have been described in only a few isolated reports.t" Herein we report a case of a primary spinal cord lymphoma of T-cell phenotype, review the literature, and provide treatment recommendations based on the available data.

REPORT OF CASE A 59-year-old woman sought medical attention because of a 2-year history of progressive lower extremity weakness and numbness associated with bowel and bladder dysfunction. Her initial symptom was the spontaneous onset of numbness involving the right lateral calf. During a 2-month period, the numbness progressed to involve the right foot, Throughout the next 6 months, progressive weakness of the right foot developed, and in April 1989, she fractured her right ankle. An assessment performed elsewhere included magnetic resonance imaging (MRI) (without use of contrast medium) of the lumbar spine, myelography, computed tomography of the pelvis and abdomen, and thermography, results of which showed normal findings except for a protruding disk in the L-5 to Sol interspace. That disk was surgically removed. Postoperatively, the weakness progressed, and severe burning pain developed in the right leg. 256

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In August 1990, the patient came to Mayo Clinic J acksonville and described a constant burning sensation and a loss of feeling involving the right buttock, posterior thigh, ankle, and foot. She had difficulty initiating urination and nocturia. She noted urgency for defecation but no incontinence. Her medical history included Hashimoto's thyroiditis. A neurologic examination disclosed mild to moderate weakness involving distal right L-5 innervated muscles (especially the anterior tibial, posterior tibial, and long and short peroneal muscles). The right quadriceps and ankle reflexes were decreased on the right side, and Babinski's sign was present on the same side. The superficial anal reflexes were absent bilaterally. Her gait was ataxic with searching steps, and Romberg's sign was present. Proprioceptive and vibration senses were impaired in both lower extremities, although impairment was worse in the right extremity. Light touch and pin sensation were diminished in an L-3 to S-4 segmental distribution on the right side as well. MRI of the thoracolumbar region (Fig. 1 A) revealed an intrinsic lesion of the spinal cord, predominantly on the right side at the level of the 11th thoracic vertebra. The lesion was isointense on the unenhanced scan and had intense homogeneous enhancement after administration of gadolinium. No enlargement of the spinal cord was noted. Results of myelography were normal, as were findings on examination of the cerebrospinal fluid (CSF). On Sept. 29,1990, laminectomy was performed from the 10th through the 12th thoracic vertebrae. A purplish discolored region was noted on the right side of the spinal cord at the level of the 11th thoracic vertebra. A biopsy specimen was obtained from an avascular region of the spinal cord at the site of the lesion. This small piece of tissue, 2 mm in greatest diameter, was the entire specimen available for histologic and special studies. The tissue was frozen in liquid nitrogen for assessment of diagnostic adequacy, immunostaining, and gene rearrangement studies. Routine light microscopy revealed a dense, cytologically atypical lymphoid infiltrate that obliterated the native architecture (Fig. 2 A). Immunostains showed neoplastic lymphocytes that strongly expressed the T-cell marker CD2 (Fig. 2 B) and weakly expressed the T-cell marker CD5 (Fig. 2 C). These same lymphocytes were negative for the B-cell markers CDl9 (Fig. 2 D) and CD22. Insufficient DNA was available after frozen-section immunostaining for T-cell receptor gene rearrangement analysis. On the basis of the obliterative nature of the mixed large and small T-cell lymphoid infiltrates and aberrantly weak staining by CD5, an intermediate grade, diffuse, mixed cell lymphoma of T-cell origin was diagnosed. Postoperatively, further staging evaluation was performed, including bone marrow biopsy and aspiration; MRI of the brain and entire spinal cord; ophthalmologic examination; computed tomography of the chest, abdomen,

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Fig. 1. Magnetic resonance images of spine, with use of gadolinium, of 59-year-old woman. A, Enhancing lesion at 11th thoracic vertebra (arrow). B, Appearance 3 years after radiotherapy; no residual lesion noted in spinal cord (arrows).

and pelvis; and a whole-body radionuclide bone scan, which revealed no evidence of distant disease. Results of serum HIV and human T-celllymphotropic virus type 1 antibody studies were negative. Serum immunoelectrophoresis demonstrated no paraproteins. Postoperatively, the patient received radiotherapy-45 Gy administered in 23 fractions (36 Gy in 18 fractions immediately followed by an additional 9 Gy in 5 fractions). Treatment was delivered to a segment of the spine (10th thoracic

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SPINAL CORD LYMPHOMA

/

'. c

D

Fig. 2. Biopsy specimens of frozen sections of spinal cord. A, Hematoxylin-eosin; original magnification, x400. B, CD2 immunoperoxidase stain; original magnification, x400. C, CD5 immunoperoxidase stain; original magnification, x400. D, CD19 immunoperoxidase stain; original magnification, x400. through the 1st lumbar vertebrae ) with 6-MV photons and use of an anteroposterior-posteroanterior technique. During radiotherapy , she experienced fatigue and nausea. No chemotherapy was administered . Follow-up examinations have revealed no change in the symptoms or physical finding s. Repeated MRI of the spine with use of gadolinium performed on Sept. 23, 1993, revealed no evidence of the previou sly noted enhancing lesion in the spinal cord at the 11th thoracic vertebra (Fig. 1 B ).

DISCUSSION Besides the current case, primary spinal cord lymphoma s have been clearly verified in only eight reported cases. Our patient may have been predisposed to the development of a CNS lymphoma because of abnormal immune function. She had Hashimoto's thyroiditis , an autoimmune disorder that has been associated with the development of B-cell lymphomas of the thyroid. 16 In the previously reported cases

of primary spinal cord lymphoma (Table 1), two patients had autoimmune disorders; one had myasthenia gravis, 13 and one had a "lupuslike" illness." The detection of our patient 's spinal cord lymphoma was possible only with MRI with use of gadolinium. The pathologic diagno sis can be made with either CSF cytologic study or biopsy. If the diagnosis can be obtained with CSF cytology, a biopsy of the spinal cord and its attendant risks can be avoided. The outcome s associated with various therapies in patients with lymphom as arising in the brain are dismal. In a study by Henry and associates,' patients who received supportive care survived for a median of 3.3 months, and those who underwent a surgical procedure survived for a median of 4.6 months; however, the patients who received radiotherapy survived a median of 15.2 months. The use of chemotherapy for primary CNS lymphomas is controversial; some investigators have reported benefits.":" whereas others have found no benefits .20•21

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Table I.-Literature Review of Primary Spinal Cord Lymphomas* Reference

Age (yr) and sex

Histologic findings

Site of lesion

Reznik,"

33M

Reticulum cell sarcoma

Herbst et al," 1976

51 M

Diffuse, mixed cell lymphoma

Bruni et al," 1977

53M

Lymphoma

Mitsumotoet al," 1980

63 F

Diffuse, histiocytic lymphoma

Slager et al," 1982

45F

Diffuse, mixed cell lymphoma

Cervical cord

Hautzer et alp 1983

26F

Diffuse, mixed cell lymphoma

Entire spinal cord

Supportivecaret

Itami et al," 1986

24F

Cervical and thoracic cord

CraniospinalRT (40.5 Gy for 5 wk)

Toner et al," 1989

59M

Diffuse, poorly differentiated lymphocytic lymphoma Diffuse, large cell lymphoma

Lumbar spine

Schild et ai, current case

59F

Diffuse, mixed cell lymphoma

Thoracic spine

Local RT to 30 Gy. IT methotrexateand ara-C and IV chemotherapy§ Local RT to 45 Gy in 23 Fx

1975

Cervical and thoracic cord Medullary cone

Treatment]

Cervical and thoracic cord Lumbar cord

Surgical procedure Local RT (40 Gy in 20 Fx). 2nd course of RT (38 Gy in 19 Fx) and IT methotrexate Supportive caret Dexamethasone-improvement. Later, brain metastatic lesion found; craniospinalRT Supportivecaret

Outcome Death, 1 mo postoperatively. Autopsy-lymphoma in spinal cord only Free of disease at 4-yr follow-up

Death, 8 mo after first symptoms. Autopsy-involvement of entire spinal cord Death during craniospinalRT. Autopsy-involvement of spine and brain metastatic lesion Death, 7 mo after first symptoms. Autopsy-involvement of cervical spine and direct invasion of brain stem Death, 10 mo after first symptoms. Autopsy-involvement of spine, optic nerves, and thalamus Free of disease at 18-mo follow-up Free of disease at 22-mo follow-up Free of disease at 3-yr follow-up

*Only cases of lymphomasarising in the spinal cord as the first site of involvementwere included. tFx = fractions; IT = intrathecallyadministered; IV = intravenouslyadministered; RT = radiotherapy. tDiagnosis made at autopsy. §Cyclophosphamide, doxorubicin, vincristine,prednisone,and etoposide. The literature on primary spinal cord lymphomas, in contrast to that on intracranial primary CNS lymphomas, is scant (Table 1). Patients who received supportive care died rapidly. Patients with primary spinal cord lymphomas may have a better prognosis than those with primary lymphomas of the brain, which are associated with dismal long-term prognoses." Of the eight previously well-confirmed cases of primary spinal cord lymphoma, four patients received radiotherapy with or without chemotherapy, three of whom were alive with no evidence of disease on follow-up that ranged from 18 to 48 months. Minimal data are available on the role of chemotherapy for primary spinal cord lymphomas. Of two patients who received cytotoxic chemotherapy and radiotherapy, neither had evidence of recurrence at last followup. In all cases of spinal cord lymphomas, radiotherapy is the primary therapy for potential preservation of neurologic function and extension of survival. The dose of irradiation

necessary for local control of spinal cord lymphomas has not been well established; however, local control has been achieved in all three previously reported cases, with doses ranging from 30 to 40.5 Gy (Table 1). The optimal radiotherapy field arrangement depends on the extent of disease. CNS lymphomas have a propensity for multifocality, an outcome that could be used to support the administration of craniospinal irradiation in patients with multifocal disease or in those with tumor cells found in the CSF. Craniospinal irradiation has been administered to two patients with primary spinal cord lymphomas: one died during therapy, and the other was free of disease at last follow-up. Focal spinal irradiation has been administered to two patients; in one, treatment to one site in the spine failed, but a second course of focal irradiation and chemotherapy were successful. The other patient has been reported to be free of disease. For our patient, an extensive workup revealed only one detectable focus of disease. Therefore, we used only local radio-

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therapy. Our patient was free of disease at her most recent follow-up assessment. Prompt detection of primary spinal cord lymphomas with modem imaging techniques, specifically gadolinium-enhanced MRI, and diagnosis by biopsy or CSF cytologic study are necessary to ensure that specific antitumor therapy can be administered early to preserve neurologic function and extend survival. ACKNOWLEDGMENT We thank Drs. Brian P. O'Neill and William W. Wong for their assistance in the preparation of the submitted manuscript. REFERENCES 1. Freeman C, Berg JW, Cutler SJ. Occurrence and prognosis of extranodallymphomas. Cancer 1972; 29:252-260 2. Schiffer D, Chio A, Giordana MT, Novero D, Palestro G, Soffietti R, et al. Primary lymphomas of the brain: a clinico-pathologic review of 37 cases. Tumori 1987; 73:585592 3. Henry JM, Heffner RR Jr, Dillard SH, Earle KM, Davis RL. Primary malignant lymphomas of the central nervous system. Cancer 1974; 34:1293-1302 4. Helle TL, Britt RH, Colby TV. Primary lymphoma of the central nervous system: clinicopathological study of experience at Stanford. J Neurosurg 1984; 60:94-103 5. Loeffler JS, Ervin TJ, Mauch P, Skarin A, Weinstein HJ, Canellos G, et al. Primary lymphomas of the central nervous system: patterns offailure and factors that influence survival. J Clin Oncol 1985; 3:490-494 6. Hochberg FH, Miller G, Schooley RT, Hirsch MS, Feorino P, Henle W. Central-nervous-system lymphoma related to Epstein-Barr virus. N Engl J Med 1983; 309:745748 7. Hochberg FH, Miller DC. Primary central nervous system lymphoma. J Neurosurg 1988; 68:835-853 8. Reznik M. Pathology of primary reticulum cell sarcoma of the human central nervous system. Acta Neuropathol Suppl 1975; 6:91-94 9. Herbst KD, Corder MP, Justice GR. Successful therapy with methotrexate of a multicentric mixed lymphoma of

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the central nervous system. Cancer 1976; 38: 14761478 10. Bruni J, Bilbao JM, Gray T. Primary intramedullary malignant lymphoma of the spinal cord. Neurology 1977; 27:896898 11. Mitsumoto H, Breuer AC, Lederman RJ. Malignant lymphoma of the central nervous system: a case of primary spinal intramedullary involvement. Cancer 1980; 46: 12581262 12. Slager UT, Kaufman RL, Cohen KL, Tuddenham WJ. Primary lymphoma of the spinal cord. J Neuropathol Exp Neurol 1982; 41:437-445 13. Hautzer NW, Aiyesimoju A, Robitaille Y. "Primary" spinal intramedullary lymphomas: a review. Ann Neurol 1983; 14:62-66 14. Itami J, Mori S, Arimizu N, Inoue S, Lee M, Uno K. Primary intramedullary spinal cord lymphoma: report of a case. Jpn J Clin Oncol 1986; 16:407-412 15. Toner GC, Holmes R, Sinclair RA, Tang SK, Schwarz MA. Central nervous system lymphoma: primary lumbar nerve root infiltration. Acta Haematol 1989; 81:44-47 16. Aozasa K. Hashimoto's thyroiditis as a risk factor of thyroid lymphoma. Acta Pathol Jpn 1990; 40:459-468 17. Pollack IF, Lunsford LD, Flickinger JC, Dameshek HL. Prognostic factors in the diagnosis and treatment of primary central nervous system lymphoma. Cancer 1989; 63:939947 18. Chamberlain MC, Levin VA. Adjuvant chemotherapy for primary lymphoma of the central nervous system. Arch Neurol 1990; 47:1113-1116 19. DeAngelis LM, Yahalom J. Combined modality treatment of primary central nervous system lymphoma (PCNSL) [abstract]. Program Proc Am Soc Clin Oncol 1991; 10: 125 20. Brada M, Deamaley D, Horwich A, Bloom HJ. Management of primary cerebral lymphoma with initial chemotherapy: preliminary results and comparison with patients treated with radiotherapy alone. Int J Radiat Oncol Bioi Phys 1990; 18:787-792 21. Laperriere NJ, Cerezo L, Simpson WJ, Payne D, Panzarella A. Primary lymphoma of brain: results of radiation therapy in a modem cohort [abstract]. Int J Radiat Oncol Bioi Phys 1992; 24(Suppl):301 22. O'Neill BP, Illig JJ. Primary central nervous system lymphoma. Mayo Clin Proc 1989; 64:1005-1020

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