Clin Neuroradiol DOI 10.1007/s00062-013-0280-4

Correspondence

ALK Positive Anaplastic Large Cell Lymphoma With Pure Leptomeningeal Involvement: Unique Case Report and Review of the Literature P. C. Bricker · W. S. Lesley · R. Surapaneni

Received: 7 August 2013 / Accepted: 23 December 2013 © Springer-Verlag Berlin Heidelberg 2014

Introduction Both primary and secondary anaplastic large cell lymphoma (ALCL) involvement of the central nervous system (CNS) is rarely encountered. ALCL is characterized by CD30-positive cells and subclassified by anaplastic lymphoma kinase reactivity (ALK positive [ALK+] or negative [ALK−] cytogenics). Only 13 patients with ALCL have been reported with spread to the CNS. Of these, only one demonstrated pure leptomeningeal involvement with nonspecified ALK status. The following case report details the first instance of ALK+ ALCL with pure leptomeningeal spread. Case Description A 44-year-old African descent woman was admitted for cough, fever, and anemia. She had diffuse adenopathy in all nodal regions of the chest, abdomen, and pelvis. She also had multiple lumps in the breasts, which were felt to represent enlarged lymph nodes. Bone marrow biopsy was negative, and she had no obvious extranodal sites. Her lactate dehydrogenase (LDH) was elevated at 395 IU/L (N = 60– 200 IU/L), Eastern Cooperative Oncology Group (ECOG) W. S. Lesley, MD, CPE, FACR () Departments of Radiology and Surgery, Scott and White HealthCare, 2401 South 31st Street, Suite 2X, Temple, TX 76508, USA e-mail: [email protected] P. C. Bricker · W. S. Lesley, MD, CPE, FACR · R. Surapaneni, MD Texas A&M HSC College of Medicine, 2401 South 31st Street, Suite 2X, Temple, TX 76508, USA R. Surapaneni, MD Department of Hematology Oncology, Scott and White HealthCare, 2401 South 31st Street, Suite 2X, Temple, TX 76508, USA

performance status was 2 and Ann Arbor stage III. Inguinal node biopsy demonstrated neoplastic cells that were immunopositive for CD30, CD5, CD45RO, and immunonegative for CD3, CD8, CD10, and CD15. Cytogenics evaluation revealed t(2;5)(p23;q35). Subsequent ALK analysis was positive, and a final diagnosis of ALK+ ALCL, common monomorphic type was established. She was started on CHOP chemotherapy (cyclophosphamide, Adriamycin, vincristine and prednisone) cycled every 3-weeks. After 2 cycles she had a Positron emission tomography–computed tomography (PET–CT), which showed good response and a decrease in size of all the enlarged nodes. She presented with a 3-day history of fever, chills, nausea, vomiting, and headache 1 week after her third cycle. An infectious cause was initially pursued by workup at readmission. This evaluation included a magnetic resonance imaging (MRI) of the brain and subsequent lumbar puncture. MRI (Fig. 1) demonstrated early intracranial leptomeningeal disease. Bedside lumbar puncture revealed no evidence of cerebrospinal fluid (CSF)-based infection or lymphoma. However, empiric cefepime and vancomycin were initiated for possible meningitis without any improvement in symptoms. Based on infectious disease consult recommendations, full treatment with cefepime, vancomycin, anti-TB therapy, voriconazole, ampicillin, and acyclovir was begun. No improvement was seen on the antibiotic regimen, and all infectious studies continued to be negative. On the second day of admission, the patient became lethargic. On day 4 she was stuporous, and by day 11 she was unresponsive. An Ommaya reservoir was placed on day 5 of her hospitalization. At that time, biopsy of the right frontal convexity brain and dura was done which did not demonstrate tumor. Repeat MRI (Fig. 2) performed on day 8 revealed more robust and widespread leptomeningeal disease due to frank leptomeningeal carcinomatosis.

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Fig. 1  Initial magnetic resonance imaging brain demonstrates faint but abnormal leptomeningeal enhancement on the coronal (a, arrows) and axial (b, arrows) T1-Gadolinium enhanced images. Subtle, but abnormally increased sulcal signal is also present on the fluid-attenuated inversion recovery sequence (c, arrows)

Results A fluoroscopically guided lumbar puncture was done on the 13th day and cytological studies and immunohistochemistry were performed. These CSF studies now found CD30 positive lymphoma cells plus ALK+ with nuclear staining. Altogether, the findings confirmed the radiologic and clinical diagnosis of leptomeningeal involvement by ALK+ ALCL. The patient was weaned off the antibiotics and whole brain radiation was performed for 4 days with no improvement in symptoms. Intrathecal cytarabine and intravenous methotrexate were then administered on day 21. Despite all these measures, the patient’s mental status fluctuated with eventual decline. On day 34, the patient was discharged to inpatient hospice where she succumbed shortly thereafter. Discussion ALCL is an infrequent but aggressive T-cell lymphoma with characteristic CD30-positive cells and either ALK+ or ALK− cytogenics [1]. In 2008, the World Health Orga-

Fig. 2 Follow-up magnetic resonance imaging brain (a, axial T1gadolinium; b, axial fluid-attenuated inversion recovery) demonstrates the Ommaya tract (a and b, black arrows), and more widespread and robust leptomeningeal involvement (a and b, white arrows) consistent with leptomeningeal carcinomatosis

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nization determined that based on current evidence, ALK+ and ALK− subtypes were distinct entities which warranted separate delineation [2]. ALK+ ALCL entails a chromosomal translocation of the ALK gene and the expression of ALK protein. ALK+ ALCL more commonly affects males and young adults (median 35 years; average 34 years) and frequently presents at an advanced stage with systemic symptoms and extranodal involvement [3]. Overall, the prognosis of ALK+ ALCL is better than other T-cell lymphomas including ALK− ALCL. CNS involvement by ALCL is considered rare by most accounts in the literature, but the actual prevalence ranges between 1.9 and 3.8 % based on larger studies of patients with either ALK+ or ALK− ALCL [4–6]. Nonsystemic, primary CNS ALK+ ALCL remains exceptionally rare with only nine cases reported and recently summarized by Park et al. [7]. The average age of this cohort is 17.4 years with a male to female ratio of 8:1. Of these, two cases mostly affected the leptomeninges while a third case involved just the dura. The remaining patients had variable parenchymal neuroaxis involvement. Whether ALK+ ALCL primarily or secondarily involves the CNS, pure leptomeningeal disease is exceptionally rare. Unfortunately, most reports of ALCL that affect the CNS have not provided sufficient details either in regards to ALK status or exact CNS anatomic site. Most relevantly, a review of the literature failed to find any report of ALK+ ALCL with pure leptomeningeal extranodal spread. Therefore, the presented case uniquely details an unheard of clinical progression of ALK+ ALCL from nodes to leptomeninges. Despite demonstrating clinical remission from nodal disease, and while receiving CHOP chemotherapy, this patient relapsed with diagnostically subtle but rapidly progressive leptomeningeal carcinomatosis. This case also highlights the earlier sensitivity of gadolinium enhanced MRI in detecting early leptomeningeal disease compared with CSF analysis and in this situation, brain biopsy, even though the MRI was obtained with a low-end strength magnet (1.5 T). Nevertheless, MRI remains nonspecific in identifying an exact pathoetiologic cause for

ALK Positive Anaplastic Large Cell Lymphoma With Pure Leptomeningeal Involvement

meningeal inflammation. In this patient, infectious meningitis mistakenly remained the presumptive diagnosis until CSF showed ALK+ ALCL leptomeningeal carcinomatosis. Biopsy may have been falsely negative as a result of biopsy site selection, which was done at the location of the Ommaya port access (right mid-frontal convexity) and not at the area of suspected inflammation on MRI (frontoparietal junction). Regarding the false negative CSF analysis in the presence of an abnormal MRI, Novello et al. [8] had a similar experience with a case of ALK+ ALCL presenting as an intradural, extramedullary spinal mass. In that case report, a pachymeningeal (i.e., dural not leptomeningeal) tumor presented with mid thoracic cord compression. While CSF analysis was normal, MRI found a conspicuous, enhancing mass with features favoring meningioma. Biopsy, on the other hand, was positive for recurring ALCL 3-years after treatment of primary parailiac lymph node involvement. Consensus is lacking regarding treatment for intracranial ALK+ ALCL as evidenced by various management regimens found in the literature. While systemic ALK+ ALCL is frequently responsive to chemotherapy, such is not the case when ALK+ ALCL spreads intracranially [7]. As shown in the presented case, combined intrathecal chemotherapy and radiation therapy proved ineffective in controlling disease progression. Autologous hematopoietic stem cell transplant (auto-SCT) may be useful in intracranial ALK+ ALCL as reported by Zhang et al. [9]. In that account, auto-SCT was associated with greater than 1-year survival in a patient with mixed neuroaxial and leptomeningeal ALK+ ALCL. Conclusion In conclusion, pure leptomeningeal spread by ALK+ ALCL is exceptionally rare and previously undocumented. MRI is more sensitive though nonspecific in detecting leptomeningeal ALK+ ALCL than CSF cytology analysis. Acknowledgements  The authors have no financial or other conflicts of interest to disclose.

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Conflict of Interest  The authors declare that there are no actual or potential conflicts of interest in relation to this article.

References 1. Delsol G, Ralfkiaer E, Stein H. Anaplastic large cell lymphoma. In: Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. Pathology and Genetics of tumors of haematopoietic and lymphoid tissues: World Health Organization classification of tumors. Lyon: IARC Press; 2001. pp. 230–5. 2. Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood. 2011;117:5019–32. 3. Ferreri AJ, Govi S, Pileri SA, Savage KJ. Anaplastic large cell lymphoma, ALK-positive. Crit Rev Oncol Hematol. 2012;83:293–302. 4. Falini B, Pileri S, Zinzani PL, Carbone A, Zagonel V, Wolf-Peeters C, Verhoef G, Menestrina F, Todeschini G, Paulli M, Lazzarino M, Giardini R, Aiello A, Foss HD, Araujo I, Fizzotti M, Pelicci PG, Flenghi L, Martelli MF, Santucci A. ALK+ lymphoma: clinicopathologic findings and outcome. Blood. 1999;93:2697–706. 5. Savage KJ, Harris NL, Vose JM, Ullrich F, Jaffe ES, Connors JM, Rimsza L, Pileri SA, Chhanabhai M, Gascoyne RD, Armitage JO. Weisenburger DD; International Peripheral T-Cell Project. ALKanaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-cell Lymphoma Project. Blood. 2008;111:5496–504. 6. Williams D, Mori T, Reiter A, Woessman W, Rosolen A, Wrobel G, Zsiros J, Uyttebroeck A, Marky I, Le Deley MC, Brugières L; for the European Intergroup for Childhood Non-Hodgkin Lymphoma, the Japanese Pediatric Leukemia/Lymphoma Study Group. Central nervous system involvement in anaplastic large cell lymphoma in childhood: results from a multicentre European and Japanese study. Pediatr Blood Cancer. 2013;60:E118–21. 7. Park JS, Park H, Park S, Kim SJ, Seol HJ, Ko YH. Primary central nervous system ALK positive anaplastic large cell lymphoma with predominantly leptomeningeal involvement in an adult. Yonsei Med J. 2013;54:791–6. 8. Novello M, Lauriola L, Della Pepa GM, Giuseppe LR, Coli A, Visocchi M. ALK-positive anaplastic large cell lymphoma presenting as intradural spinal mass: first reported case and review of literature. Neuropathology. 2013;33:418–23. 9. Zhang X, Bui M, Caracciolo J, Field T, Zhang L. Adult anaplastic large cell lymphoma involving the central nervous system: a rare clinical scenario. Ann Hematol. 2011;90:721–3.

Ethics Declaration  Case reports are not considered research by the authors’ governing Institutional Review Board (IRB), and therefore are discharged from the authors’ IRB oversight. Nevertheless, this report was compiled and presented in accordance with the 1964 Declaration of Helsinki and its later amendments.

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ALK Positive Anaplastic Large Cell Lymphoma With Pure Leptomeningeal Involvement: Unique Case Report and Review of the Literature.

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