The ages of patients with CNS involvement ranged from 23 to 68 years with a mean of 47.2 years (Table 1). None of these patients had immunodeficiency disorders. Five patients had stage IVE disease and only one patient had stage IIE disease at the time of diagnosis. All patients were seen to have extranodal involvement on PET/CT. ECOG performance status was at least 2 in all patients and the International Prognostic Index (IPI) was high in all patients with a median of 4. Similarly, age-adjusted IPI scores were 2–3 in these patients. Serum LDH levels were normal in four patients and significantly elevated in two (351 and 1035 IU/l). Median survival was 2.5 months after the diagnosis of CNS involvement.
MRI of the brain and/or the spine was not routinely performed in our patient population. However, two patients who had neurological symptoms (ataxia, which was proven to originate from the vestibular system in one patient and from peripheral neuropathy in another) underwent MRI imaging of the CNS. No abnormal findings were detected on MRI, and 18F-FDG PET imaging results were normal for the brain.
In this study, among the subgroup of patients who underwent 18F-FDG PET/CT for restaging of recurrent disease, six received intrathecal prophylaxis. Two patients with Burkitt’s lymphoma and four with extranodal involvement associated with high risk for CNS relapse (testicular involvement in one patient, paranasal involvement in two, and adrenal gland involvement in one patient) received intrathecal methotrexate. None of our patients with CNS relapse had CNS prophylaxis.
Secondary CNS involvement is a devastating complication of aggressive NHL. The incidence of CNS relapse in lymphoma patients varies greatly among different NHL subtypes. Following primary CNS lymphoma and primary ocular lymphoma, patients with lymphoblastic lymphoma and Burkitt’s lymphoma are at higher risk of developing CNS relapse compared with other lymphoma subtypes 7. In general, the incidence of CNS relapse is regarded as ∼5% 5,8. However, many clinical factors such as advanced stage, age over 60 years, bone marrow involvement, extranodal involvement, elevated lactate dehydrogenase levels, and poor performance status have been identified as risk factors for CNS involvement in NHL 1,9,10. In this study, similar to the historical data, we observed that 4.4% of patients with NHL presented with secondary CNS involvement at the time of diagnosis, and 5.4% of patients developed CNS relapse or progression to CNS. In our patient group, all patients with secondary CNS involvement had other sites of extranodular disease as a predisposing factor for CNS involvement of NHL. In addition, advanced stage of disease and high IPI scores were the most common predisposing factors following the presence of extranodular disease.
Accurate diagnosis of secondary CNS involvement in NHL is essential. The standard method is microscopic examination of samples for the presence of malignant cells. In general, CSF cytology is regarded as the gold standard for diagnosis 7. More recently, the diagnostic sensitivity of flow cytometry was found to be higher than that of cytomorphology, and the National Comprehensive Cancer Network (NCCN) 11 recommended the use of flow cytometry for the diagnosis of CNS lymphoma. However, recommendations for CSF examinations by lumbar puncture are generally limited to certain NHL subtypes or to certain conditions in which the patient has high-risk factors associated with CNS involvement 11.
There are conflicting results on the most common manifestations of CNS disease in patients with relapsed NHL. According to previous reports, unlike primary CNS lymphomas, secondary CNS lymphomas present as leptomeningeal metastases in two-thirds of patients and as parenchymal metastases in one-third of them 12. However, recent reports indicate that secondary CNS involvement manifests as parenchymal disease in 60% of patients with DLBCL 13. Lymphoma involving the pituitary gland is an exceedingly infrequent event 4,14,15. In this study, parenchymal involvement was more frequent than leptomeningeal disease, and pituitary gland involvement was detected in one patient. Even though the incidence of secondary CNS involvement of NHL as evidenced by 18F-FDG PET/CT in this study was found to correlate with historical data, possible underestimation of occult leptomeningeal and or parenchymal disease on 18F-FDG PET is subject to debate. Having the advantage of highest soft tissue resolution, gadolinium-enhanced MRI would be the modality of choice for CNS imaging. However, current literature lacks evidence derived from such a comparison in assessing the CNS of NHL patients, as cranial and spine MRI studies are not routinely performed for all patients with NLH in clinical practice. Similarly, a comparison between 18F-FDG PET and MRI was not possible in our study because MRI of the CNS was only limited to patients with neurological symptoms and to those with pathological 18F-FDG uptake in CNS.
In general, secondary CNS involvement tends to occur at a median of 5–12 months after the diagnosis of NHL 12,16. In half of the patients, CNS involvement is associated with systemic relapse, and CNS disease generally occurs as an early manifestation of relapsed lymphoma. Either isolated or in the context of systemic relapsed disease, the prognosis of CNS recurrence is poor with a median survival of 2–6.5 months 16,17. In this study, time to relapse with CNS involvement was 8–12 months and two-thirds of patients with CNS relapse had systemic disease manifestation as well. Similar to historical data, we observed that median survival time after relapse with CNS involvement was 2.5 months.
When CNS relapse occurs as a part of systemic disease manifestation or during disease progression, it often indicates an end-stage disease with resistance to most therapeutic strategies 2,8,9. In contrast, isolated CNS disease with no evidence of systemic involvement may be potentially treatable when combined systemic and intraventricular chemotherapy is administered along with radiation therapy 5,8,9,17. Compared with primary CNS lymphoma and isolated CNS relapse of systemic lymphoma, secondary CNS lymphoma has an even worse prognosis, with a median survival of only months and very few reported long-term survivors 19. Distinguishing secondary CNS lymphoma from primary CNS lymphoma is essential not only to define a therapeutic approach but also to assess therapy response on follow-up. For both of these groups of patients, there has been interest in defining patients with high risk for CNS relapse.
Several studies have been conducted to discriminate patients who may benefit from CNS prophylaxis. This is a fundamental, yet open, issue. The routine use of intrathecal CNS prophylaxis is well described in patients with Burkitt’s and lymphoblastic lymphomas, whereas subsequent need for prophylaxis is less well described in patients with DLBCL 9. The effectiveness of intrathecal prophylaxis and the combination of high-dose systemic methotrexate and intrathecal chemotherapy are controversial issues 15,18,20–23. Current literature agrees on the need for further investigations to better identify patients who are at high risk and to protect them from potential complications associated with such aggressive administrations 8.
The discrimination between isolated CNS relapse and CNS involvement with systemic disease progression may have significant value for guiding therapy. In addition, differential diagnosis of primary CNS lymphoma and secondary CNS lymphoma or systemic spread of primary CNS lymphoma is crucial not only to define a therapeutic approach but also to assess therapy response on follow-up 24. To this end, differential diagnosis must be made as rapidly as possible to allow the early institution of effective therapy.
The use of 18F-FDG PET/CT in the management of patients with NHL has become essential for initial staging and restaging. The superiority of 18F-FDG PET over CT for assessment of extranodal involvement is, today, well established 25. In addition, the impact of 18F-FDG PET/CT has been well recognized for evaluation of therapy response in NHL. Several reports have emphasized the impact of pretreatment 18F-FDG PET and early 18F-FDG PET imaging after one or two cycles of induction chemotherapy 26,27. Furthermore, PET has been integrated into the revised response criteria for malignant lymphoma 28.
Similar to its role in systemic lymphoma, the use of 18F-FDG PET/CT in the pretreatment setting of patients with primary CNS lymphoma is also well established 29. In addition, recent studies have evaluated the prognostic value of 18F-FDG PET/CT in primary CNS lymphoma and authors have found that pretreatment 18F-FDG uptake may have a prognostic value in newly diagnosed primary CNS lymphoma 30. However, current literature lacks sufficient data on the use of 18F-FDG PET in CNS relapse of lymphoma. In contrast to clinical studies on systemic lymphoma and primary CNS lymphoma, the rarity of secondary CNS lymphoma makes prospective studies of this entity difficult to perform. Reports on the use of 18F-FDG PET to detect CNS involvement in NHL are limited to a few case studies. There are no large case series or prospective trials on this rare and fatal complication of lymphomas. In addition, there are no studies that evaluate the prognostic performance of 18F-FDG PET/CT in CNS involvement of lymphoma in comparison with CSF cytology. Although retrospective, our study demonstrates the incidence of CNS involvement in a group of patients with aggressive NHL who underwent 18F-FDG PET/CT and allows us to assemble the largest series to date of patients with CNS involvement as detected on PET/CT.
However, there are some limitations to this study because of its retrospective nature. First, there may have been clinical bias in referring patients for a PET/CT scan. Second, because lumbar puncture is not a routine procedure, it was not performed in all cases; hence, results of a real comparison between CSF cytology and PET/CT findings are not available for most patients. For this reason, the question whether subclinical or microscopic CNS involvement might have been underdiagnosed on PET/CT remains unclarified and is still subject to further research. To this end, although comparable to historical data, the results of this study should not be considered as the real incidence of CNS involvement in patients with NHL.
To our knowledge, this is the first study to demonstrate the incidence of CNS disease detected by PET/CT in patients with NHL and to emphasize the value of 18F-FDG PET/CT in the detection of CNS involvement. Further, although response evaluation and prognostication cannot be justified by a single case, the pretreatment and post-treatment 18F-FDG images of case no. 2 may highlight the value of 18F-FDG PET/CT in the evaluation of response to cranial radiation therapy. In addition, this study demonstrates the pituitary gland involvement detected on PET/CT as a very rare site of CNS involvement in patients with NHL (Fig. 3).
CNS dissemination is a rare but usually fatal complication of aggressive lymphomas. Prophylaxis modalities to prevent CNS dissemination in aggressive lymphomas cannot be widely applied to every lymphoma patient as they are associated with increased risk for neurotoxicity. Therefore, early identification of patients with CNS involvement is crucial in the management of these malignancies. Whole-body PET/CT, starting from the vertex, should be used in the case of patients with aggressive high-grade lymphomas for accurate initial staging and restaging. PET/CT is a sensitive and valuable method for the detection of CNS involvement in patients with NHL. Further, we believe that improved metabolic imaging with PET will presumably play an important role in the planning of new targeted therapies and for prognostication in the future.
Conflicts of interest
There are no conflicts of interest.
1. Villa D, Connors JM, Shenkier TN, Gascoyne RD, Sehn LH, Savage KJ. Incidence and risk factors for central nervous system relapse in patients with diffuse large B-cell lymphoma: the impact of the addition of rituximab to CHOP chemotherapy. Ann Oncol. 2010;21:1046–1052
2. Bierman P, Giglio P. Diagnosis and treatment of central nervous system involvement
in non-Hodgkin’s lymphoma
. Hematol Oncol Clin North Am. 2005;19:597–609
3. Patrij K, Reiser M, Wätzel L, Pels H, Kowoll A, Herrlinger U, et al. Isolated central nervous system relapse of systemic lymphoma (SCNSL): clinical features and outcome of a retrospective analysis. Ger Med Sci. 2011;9:Doc11
4. Komninos J, Vlassopoulou V, Protopapa D, Korfias S, Kontogeorges G, Sakas DE, et al. Tumors metastatic to the pituitary gland
: case report and literature review. J Clin Endocrinol Metab. 2004;89:574–580
5. Van Besien K, Gisselbrecht C, Pfreundschuh M, Zucca E. Secondary lymphomas of the central nervous system: risk, prophylaxis and treatment. Leuk Lymphoma. 2008;49(Suppl 1):52–58
6. Jaffe ES. The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Hematology Am Soc Hematol Educ Program. 2009:523–531
7. Pui CH, Thiel E. Central nervous system disease in hematologic malignancies: historical perspective and practical applications. Semin Oncol. 2009;36(Suppl 2):S2–S16
8. Doolittle ND, Abrey LE, Shenkier TN, Tali S, Bromberg JE, Neuwelt EA, et al. Brain parenchyma involvement as isolated central nervous system relapse of systemic non-Hodgkin lymphoma: an International Primary CNS Lymphoma Collaborative Group report. Blood. 2008;111:1085–1093
9. Feugier P, Virion JM, Tilly H, Haioun C, Marit G, Macro M, et al. Incidence and risk factors for central nervous system occurrence in elderly patients with diffuse large-B-cell lymphoma: influence of rituximab. Ann Oncol. 2004;15:129–133
10. Boehme V, Schmitz N, Zeynalova S, Loeffler M, Pfreundschuh M. CNS events in elderly patients with aggressive lymphoma treated with modern chemotherapy (CHOP-14) with or without rituximab: an analysis of patients treated in the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Blood. 2009;113:3896–3902
11. Clinical practice guidelines in oncology (NCCN Guidelines). Non-Hodgkin’s lymphomas. Version 3. 2012 NCCN Available at: http:// http://www.nccn.org /professionals/physician_gls/pdf/nhl.pdf
12. Haldorsen IS, Espeland A, Larsson EM. Central nervous system lymphoma: characteristic findings on traditional and advanced imaging. Am J Neuroradiol. 2011;32:984–992
13. Siegal T, Goldschmidt N. CNS prophylaxis in diffuse large B-cell lymphoma: if, when, how and for whom? Blood Rev. 2012;26:97–106
14. Megan Ogilvie C, Payne S, Evanson J, Lister TA, Grossman AB. Lymphoma metastasizing to the pituitary: an unusual presentation of a treatable disease. Pituitary. 2005;8:139–146
15. Morita K, Nakamura F, Kamikubo Y, Mizuno N, Miyauchi M, Yamamoto G, et al. Pituitary lymphoma developing within pituitary adenoma. Int J Hematol. 2012;95:721–724
16. Hill QA, Owen RG. CNS prophylaxis in lymphoma: who to target and what therapy to use. Blood Rev. 2006;20:319–332
17. Stefoni V, Broccoli A, Pellegrini C, Derenzini E, Fina M, Zinzani PL. CNS recurrence of primary mediastinal large b-cell lymphoma after complete remission. J Neurooncol. 2009;95:135–139
18. Batchelor T, Leahy N, Kaufman D. High-dose methotrexate for isolated central nervous system relapse in patients with testicular non-Hodgkin's lymphoma. Clin Lymphoma. 2001;2:116–119
19. Cote GM, Hochberg EP, Muzikansky A, Hochberg FH, Drappatz J, McAfee SL, et al. Autologous stem cell transplantation with thiotepa, busulfan, and cyclophosphamide (TBC) conditioning in patients with CNS involvement by non-Hodgkin lymphoma. Biol Blood Marrow Transplant. 2012;18:76–83
20. Abramson JS, Hellmann M, Barnes JA, Hammerman P, Toomey C, Takvorian T, et al. Intravenous methotrexate as central nervous system prophylaxis is associated with a low risk of CNS recurrence in high-risk patients with diffuse large B-cell lymphoma. Cancer. 2010;116:4283–4290
21. Boehme V, Zeynalova S, Kloess M, Loeffler M, Kaiser U, Pfreundschuh M, et al. Incidence and risk factors of central nervous system recurrence in aggressive lymphoma – a survey of 1693 patients treated in protocols of the German High-Grade Non-Hodgkin’s Lymphoma
Study Group (DSHNHL). Ann Oncol. 2007;18:149–157
22. McMillan A. Central nervous system-directed preventative therapy in adults with lymphoma. Br J Haematol. 2005;131:13–21
23. Chua SL, Seymour JF, Streater J, Wolf MM, Januszewicz EH, Prince HM. Intrathecal chemotherapy alone is inadequate central nervous system prophylaxis in patients with intermediate grade non-Hodgkin’s lymphoma
. Leuk Lymphoma. 2002;43:1783–1788
24. Cimarelli S, Sebban C, Thiesse P, Sunyach MP, Blay JY, Ghesquières H. Use of F-18 FDG PET/CT in non-Hodgkin lymphoma with central nervous system involvement
. Clin Nucl Med. 2011;36:e45–e49
25. Even-Sapir E, Lievshitz G, Perry C, Herishanu Y, Lerman H, Metser U. Fluorine-18 fluorodeoxyglucose PET/CT patterns of extranodal involvement in patients with non-Hodgkin lymphoma and Hodgkin’s disease. Radiol Clin North Am. 2007;45:697–709
26. Kostakoglu L, Goldsmith SJ, Leonard JP, Christos P, Furman RR, Atasever T, et al. FDG-PET after 1 cycle of therapy predicts outcome in diffuse large cell lymphoma and classic Hodgkin disease. Cancer. 2006;107:2678–2687
27. Mikhaeel NG, Hutchings M, Fields PA, O'Doherty MJ, Timothy AR. The deleted FDG-PET after two to three cycles of chemotherapy predicts progression-free and overall survival in high-grade non-Hodgkin lymphoma. Ann Oncol. 2005;16:1514–1523
28. Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25:579–586
29. Rosenfeld SS, Hoffman JM, Coleman RE, Glantz MJ, Hanson MW, Schold SC. Studies of primary central nervous system lymphoma with fluorine-18-fluorodeoxyglucose positron emission tomography. J Nucl Med. 1992;33:532–536
30. Kawai N, Zhen HN, Miyake K, Yamamaoto Y, Nishiyama Y, Tamiya T. Prognostic value of pretreatment 18
F-FDG PET in patients with primary central nervous system lymphoma: SUV-based assessment. J Neurooncol. 2010;100:225–232
Keywords:© 2013 Lippincott Williams & Wilkins, Inc.
central nervous system involvement; 18F-FDG; non-Hodgkin’s lymphoma; positron emission tomography/computed tomography; pituitary gland