Central Nervous System Anaplastic Large Cell Lymphoma in an Adult: Successful Treatment With a Combination of Radiation and Chemotherapy
By Carmichael, Mark G
Anaplastic large cell lymphoma (ALCL) is 1 of 17 mature T cell neoplasms described by the World Health Organization. Primary central nervous system (PCNS) ALCL represents a distinct rare form of this family of non-Hodgkin lymphoma and discussions of prognosis and management are limited to case reports and case series. Therapies for this disease largely parallel that of other PCNS lymphomas. We report the case of a 38-year-old male soldier who presented with a parieto-occipital mass lesion and neurological sequelae without evidence of systemic disease. Pathologic evaluation of tissue from brain biopsy confirmed ALCL. We elected treatment with an intensive combination of systemic and intrathecal chemotherapy with radiotherapy. Our patient is in complete remission 15 months following therapy. Tailored therapies for PCNS ALCL are unavailable and this regimen may be an option for patients who can tolerate intensive treatments. Introduction
Anaplastic large cell lymphoma (ALCL) of the central nervous system (CNS) is a rare T cell lymphoma accounting for <3.6% of primary CNS lymphoma (PCNSL) cases.1 ALCL in adults typically occurs as cutaneous or systemic/nodal disease, with extranodal or CNS involvement being uncommon. PCNS ALCL represents a distinctly rare entity, with approximately 20 cases reported in the literature.2-5 Reports of PCNS ALCL and its treatment are sometimes included as subsets of PCNSL case series and individual case reports, but definitive therapeutic recommendations are lacking.2,6,7 As such, specific treatment for ALCL of the CNS is not optimally defined. We report the case of PCNS ALCL in a human immunodeficiency virus- negative adult successfully treated with a combination of systemic and intrathecal chemotherapy following whole-brain radiotherapy resulting in a complete response. Freedom from disease and overall survival have yet to be determined with our patient in clinical remission 15 months following therapy.
Case Report
A 38-year-old male soldier presented for medical attention with the acute onset of seizure, syncope, left-sided hemiparesis, visual field deficit, and ataxia consistent with a large right intraparenchymal parieto-occipital mass best seen by magnetic resonance imaging (MRI) of the brain (Fig. 1). Neurosurgical evaluation and a brain biopsy confirmed neoplasia, but final pathology results were not immediately available. Initial differential diagnosis primarily focused on glioblastoma and nonHodgkin lymphoma (NHL).
There was no report of peripheral adenopathy, recent illness, weight loss, night sweats, or fatigue suggestive of systemic lymphoma. Physical examination, to include testicular examination and complete ophthalmologic examination, was significant for left hemiparesis, ataxia, and a left lower homonymous quadrantanopsia, but was negative for evidence of lymphoma. Complete blood count and serum chemistries and lactate dehydrogenase were normal. Computed tomography of the chest, abdomen, and pelvis and whole-body positron emission tomography were normal.
The patient’s clinical condition rapidly deteriorated over several days with worsening left homonymous quadrantanopsia, left hemiparesis, and persistent seizure activity despite treatment with high-dose dexamethasone and phenytoin. Treatment was started with whole-brain radiotherapy despite the uncertainty of the diagnosis with a plan to reduce the radiation fields if glioblastoma was confirmed. His condition rapidly stabilized throughout the course of radiotherapy.
Pathologic evaluation by the Armed Forces Institute of Pathology and Johns Hopkins University Medical Center confirmed ALCL. Both institutions described the tumor as having malignant cells consistent with ALCL that were phenotypically positive for CD30, CD45, and ALK1 by immunohistochemistiy.
Whole-brain radiotherapy was administered to a total dose of 2800 cGy. Following a brief period of recovery from radiotherapy, an Ommaya reservoir was placed for delivery of intrathecal chemotherapy. Systemic chemotherapy with high-dose methotrexate/ leucovorin, vincristine, procarbazine, and dexamethasone with intra- Ommaya methotrexate was followed by highdose systemic cytarabine according to the DeAngelis protocol.6 We deviated from the protocol only in our sequencing of therapy delivered: the protocol calls for systemic high-dose and intrathecal chemotherapy to be administered first, whole-brain radiotherapy second, and high-dose cytarabine last. Our patient completed the radiation portion of the regimen first, receiving the remainder of the regimen as published.
Complications and toxicity included a moderately severe steroid myopathy, peripheral neuropathy, mucositis, mild cytopenias, and a large pulmonary artery saddle embolus following the placement of the Ommaya reservoir that was treated with lowmolecular-weight heparin and placement of an inferior vena caval filter. There were no delays in administration of chemotherapy. Growth factor support with fllgrastim was used. MRI of the brain following completion of chemotherapy was significant for complete resolution of tumor mass, edema, and midline shift (Fig. 2).
Six months after completing chemotherapy, our patient has residual but improved neurological deficits. His left hemiparesis is mild, with four-fifths strength in both extremities. Bilateral lower extremity proximal muscle weakness is improved with cessation of steroids and physical therapy assistance. His gait is steadied with a cane and his left lower homonymous quadrantanopsia is less severe than at presentation. He is otherwise functional, with intact mental status. Formal neuropsychiatric testing was not performed.
Discussion
The World Health Organization recognizes ALCL as 1 of 17 classes of mature T/natural killer cell neoplasms. ALCL represents 3% of NHL in adults with a male:female ratio of 6.5:1 during the second and third decades of life. ALCL in adults typically occurs as systemic/ nodal or cutaneous disease, with skin, bone, soft tissue, lung, and liver affected most often in extranodal disease. CNS involvement, particularly PCNS involvement, is rare.8 Our search revealed 10 individual case reports and a case series of 9 patients from the Mayo Clinic of PCNS ALCL in adults.2-5
Recommendations regarding therapies are unavailable given the small numbers of disparately treated cases. Most reports do describe therapies and outcomes, but consensus statements about the best therapeutic intervention are not available. Patients with ALK1- positive tumors do, however, show consistently better outcomes independent of the therapy used. ALK1 positivity as such seems to offer important prognostic information.5,8 Most cases are treated with regimens typically used in PCNS NHL of B cell origin.9
Unlike adult T cell lymphoma, ALCL is not associated with human T cell leukemia virus 1 infection, and, as in other T cell neoplasms, a clear association with Epstein-Barrr virus or human immunodeficiency virus is likewise not shown.8
Compared to other T cell lymphomas, systemic ALCL has a more favorable prognosis, with high proportions of patients achieving complete remissions with anthracycline-based regimens. 10 A large percentage of these responses are durable, with overall survival at 5 years approaching 50%.11-13 Responses to therapy and survival data for PCNS ALCL are unavailable due to the small number of cases.
The results of Radiation Therapy Oncology Group Study 9310, published in 2002 by DeAngelis et al.,6 described an intensive combined modality therapy regimen for PCNSL. This key study established the superiority of combined modality treatment (chemotherapy and radiotherapy) to radiotherapy alone. The report did not distinguish between subtypes of NHL and, as such, did not offer insight into the treatment response and survival data of patients with PCNS ALCL. The trial did show that patients under 60 years old achieved a median overall survival of 50 months, while those older than 60 had a median survival of 21 months, a clinically and statistically significant difference. More than one-half of the patients in the trial experienced severe or life-threatening toxicity, with half of the toxicities being hematologic. The most concerning toxicity, a delayed leukoencephalopathy, occurred in 15% of the patients. The details of the regimen are well described and are not repeated here.6
We elected the DeAngelis protocol as primary therapy for our patient after a careful review of the literature. Given the patient’s performance status at the completion of radiotherapy, we felt he could tolerate, and would benefit from, an aggressive and potentially effective course of systemic and intrathecal chemotherapy. Toxicities were manageable and overall well tolerated. Most of the residual neurological deficits attributed to the primary lesion actually improved over the course of therapy. Although this represents a single experience, we feel the DeAngelis protocol represents a viable treatment option for patients with PCNS ALCL.
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Guarantor: MAJ Mark G. Carmichael, MC USA
Contributor: MAJ Mark G. Carmichael, MC USA
Hematology and Oncology Service, Walter Reed Army Medical Center, 6900 Georgia Avenue NW, Washington, DC 20307-5001.
This manuscript was received for review in May 2006 and accepted for publication in September 2006.
Reprint & Copyright (c) by Association of Military Surgeons of U.S., 2007.
Copyright Association of Military Surgeons of the United States Jun 2007
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