- Email: [email protected]
Secondary Diffuse Choroid Plexus B-Cell Lymphoma: Case Report and Review of Literature
Case Report
Secondary Diffuse Choroid Plexus B-Cell Lymphoma: Case Report and Review of Literature Bi Yi Chen1, Vivien Chen1, Shafqat Inam1, Charlotte Yin2, Omprakash Damodaran1
Key words Chemotherapy - Intraventricular lymphoma - Secondary central nervous system lymphoma -
Abbreviations and Acronyms CNS: Central nervous system CSF: Cerebrospinal fluid DLBCL: Diffuse large B cell lymphoma MRI: Magnetic resonance imaging PET: Positron emission tomography R-CHOP: Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone From the 1Concord General Repatriation Hospital, Concord; and 2Royal North Shore Hospital, St Leonards, Australia To whom correspondence should be addressed: Bi Yi Chen, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2019) 128:18-22. https://doi.org/10.1016/j.wneu.2019.04.203
- BACKGROUND:
Central nervous system (CNS) relapse is an uncommon complication of diffuse large B cell lymphoma and is associated with significant mortality and morbidity. It is becoming a more prevalent pathologic entity in the rituximab era. Our case provides insight into the pathophysiology, diagnosis, prevention, and management of secondary intraventricular CNS lymphomas.
- CASE
DESCRIPTION: We report an unusual case of a 64-year-old man who presented with an isolated secondary CNS lymphoma involving the choroid plexus in a diffuse pattern. He initially presented with obstructive hydrocephalus from diffuse choroid plexus lesions and was commenced on systemic therapy after confirmation of diagnosis via samples obtained from an open biopsy.
- CONCLUSIONS:
This case highlights the lack of high-quality evidence behind the use of high-dose intravenous methotrexate as CNS prophylaxis. The case provides additional insight into the pathophysiology of intraventricular CNS lymphomas and the importance of establishing a histopathologic diagnosis via an open biopsy before the administration of high-dose steroids.
Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter Crown Copyright ª 2019 Published by Elsevier Inc. All rights reserved.
INTRODUCTION Isolated central nervous system (CNS) lymphoma relapse is uncommon in patients with previously treated diffuse large B cell lymphoma (DLBCL) and portends a poor prognosis. We present an unusual case of an isolated secondary CNS lymphoma involving the choroid plexus in a diffuse pattern. We describe the successful management and diagnosis of this unusual case at our institution. The report also aims to provide insight into the pathophysiology, diagnosis, prevention, and management of secondary intraventricular CNS lymphomas. CASE A 64-year-old man presented with 2 weeks’ history of worsening morning headaches, cognitive decline, and ataxia. He was diagnosed with stage IVA DLBCL 3 years prior. Positron emission tomography (PET) scan showed no evidence of CNS
18
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involvement. The patient subsequently received radiation therapy to his thoracic paravertebral lesion, as well as prophylactic intrathecal methotrexate; 2 cycles of doseadjusted rituximab, etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin chemotherapy; 4 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP-14); and 2 cycles of high-dose intravenous methotrexate therapy as prophylaxis to prevent CNS relapse. He achieved complete metabolic and clinical remission at the completion of 6 months of chemotherapy. On this admission, he had no B symptoms. He had an Eastern Cooperative Oncology Group performance score of 0 before his recent deterioration. On examination, he had a Glasgow Coma Scale score of 15 and mobilized with an ataxic gait. He struggled with short-term recall. His examinations was otherwise unremarkable. Computed tomography of the brain showed diffuse infiltration of the choroid plexus in the lateral, third, and fourth ventricles with homogenously contrastenhancing lesions causing acute obstructive
hydrocephalus (Figure 1). Magnetic resonance imaging (MRI) of the brain showed restricted diffusion within the intraventricular masses, favoring lymphoma (Figure 2). Neurologic PET showed markedly increased metabolism in the intraventricular lesion, again favoring a high-grade lesion. His body PET demonstrated no other sites of active disease. His lactate dehydrogenase was 201 U/L, white cell count was 8.2 109/L, hemoglobin was 163 g/L, and platelet was 223 109/L. The patient underwent an open biopsy of the right intraventricular lesion via a rightsided craniotomy. A transcortical approached through the superior parietal lobule was used to access the trigone of the right lateral ventricle under stereotactic guidance. Biopsy samples were taken and proteinaceous fluid was drained. Histopathology confirmed diffuse large B cell lymphoma (non GCB/ABC phenotype). After surgery, the patient was commenced on high-dose dexamethasone of 40 mg daily and experienced significant clinical improvement. He was subsequently commenced on salvage chemotherapy with methotrexate, cytarabine,
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2019.04.203
CASE REPORT BI YI CHEN ET AL.
SECONDARY CHOROID B-CELL LYMPHOMA
Figure 1. Computed tomography of the brain showing diffuse homogenously enhancing choroid plexus lesions with acute hydrocephalus.
thiotepa, and rituximab (MATRix), of which he has finished 4 cycles. A progress PET scan after 4 cycles of chemotherapy showed good partial remission with complete resolution of the choroid plexus tumor, but residual subtle increased metabolism in the left frontal lobe. The patient progressed to an uncomplicated autologous transplant with thiotepa and carmustine conditioning as consolidation therapy. He remains well 1 year after his initial presentation.
DISCUSSION Isolated CNS relapse of DLBCL is an uncommon complication after remission, occurring in only 3% of DLBCL patients.1 CNS relapse is associated with significant mortality and morbidity as a result of the disease’s aggressive nature and toxicities
associated with chemotherapy.1,2 Median survival after CNS relapse is 2e6.5 months in patients diagnosed with nonHodgkin lymphoma.1 Secondary CNS lymphoma typically presents intracranially as pachymeningeal or leptomeningeal infiltrates and rarely occurs in periventricular or intraventricular locations.3 Diffuse choroid plexus involvement with primary or secondary lymphoma is a rare phenomenon. A search on Medline was conducted to identify cases with secondary intraventricular lymphoma. There were no restrictions on language. The search terms “cerebral ventricle neoplasms” AND “lymphoma” and “choroid plexus” AND “lymphoma” were used. Identified papers were screened on the basis of the title and abstract by 2 independent investigators, and an indepth review of each selected article was
Figure 2. Magnetic resonance imaging of the brain showing changes on susceptibility-weighted imaging consistent with hemorrhage. There is
WORLD NEUROSURGERY 128: 18-22, AUGUST 2019
performed with important information extracted. A total of 95 articles were identified on the initial search. Ninety-three articles were excluded after reading the title and abstract. Only 2 cases of intraventricular involvement in systemic lymphoma by Suzuki et al4 and Ravichandran et al5 were described (Table 1). Suzuki et al’s4 case had significant periventricular involvement, whereas in our case and Ravichandran et al’s5 case, this was absent, possibly reflecting a different pathway of disease spread. Isolated secondary CNS lymphoma relapse, without other areas of hypermetabolism on body PET, is infrequent.6 Our patient had isolated secondary CNS lymphoma, but the pattern of disease, involving pure the choroid plexus in a diffuse pattern, was rare. This is, in fact,
restricted diffusion on diffusion-weighted imaging, and there are T2 flair changes throughout the ventricular system.
www.journals.elsevier.com/world-neurosurgery
19
CASE REPORT
20
Resolution of lymphoma cells in CSF and resolution of abnormal enhancement on imaging with R-CHOP treatment CSF sample
www.SCIENCEDIRECT.com
CSF, cerebrospinal fluid; CT, computed tomography; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone.
Further R-CHOP therapy Adrenal, retroperitoneal, bones/B cell lymphoma 3 years prior 71/Male Suzuki et al., 20154
1 Month of cognitive impairment/R-CHOP therapy
Near-complete resolution of the lesion on CT 1 week after treatment CSF via ventriculostomy Intravenous dexamethasone, ventriculostomy, and radiation therapy Breast/diffuse large B cell lymphoma 3 years prior 78/Female Ravichandran et al., 19985
2 weeks’ history of impaired mentation and ataxia/did not specify
Primary Location/Pathology Age/Sex
Presentation/Previous Therapy
SECONDARY CHOROID B-CELL LYMPHOMA
Author
Table 1. Literature Review of Patients with Secondary Intraventricular Lymphoma
Treatment
Method of Obtaining Diagnosis
Outcome
BI YI CHEN ET AL.
the second of such case to be reported in the literature and, as such, provides novel insight into the pathophysiology, diagnosis, and management of secondary intraventricular CNS lymphomas. The pathophysiology of intraventricular lymphoma is currently not well elucidated. The CNS does not contain resident lymphocytes and lack lymphatic vessels under normal circumstances.7 Given leptomeningeal spread is the most common location of CNS disease in systemic lymphoma, the possibility of lymphoma infiltrating the perivascular spaces secondary to hematogenous spread should be entertained. Furthermore, the choroid plexus is a relatively vascular structure consisting of choroid epithelium surrounding numerous capillaries intermingled in loose connective tissue. The capillaries of the choroid plexus are lined by fenestrated endothelium, which allows tumor cells to enter the CNS via a hematogenous route.8,9 Choroid plexus tumor is a site where the blood-brain barrier is broken down, as evidenced by the pronounced tumor blush seen on angiograms. This site of disrupted blood-brain barrier is freely exposed to the ventricular cavity, allowing tumor cells to seed throughout the ventricular system. Despite the significant burden of disease in the choroid plexus and normal direction of cerebrospinal fluid (CSF) flow from the fourth ventricle to the subarachnoid space, the remaining neural axis was surprisingly disease free on MRI, though there was subtle increase metabolism in the frontal lobes seen on the neural PET scan. The clarity of CSF in the subarachnoid space compared with the turbid and thick fluid observed in the lateral ventricle intraoperatively demonstrates an obstructive phenomenon occurring in the lateral and median apertures of the fourth ventricle. This obstruction likely stems from diseased choroid plexus in the fourth ventricle. The relative lack of disease in the subarachnoid space is further highlighted by T2 flair changes in the ventricles on MRI and lack of such changes in the subarachnoid space (Figure 2). Obstructive hydrocephalus secondary to choroid plexus metastatic infiltrates facilitates the spread of lymphoma within the ventricular system to other parts of the choroid plexus. This explains the diffuse pattern of choroid plexus involvement observed.
Multiple extranodal sites at diagnosis is a well-known risk factor for CNS relapse in non-Hodgkin lymphoma.10,11 High-dose intravenous methotrexate is typically given in these patients as CNS prophylaxis to prevent recurrence. However, the efficacy of intravenous methotrexate as CNS prophylaxis remains uncertain.10,12,13 Our patient received 2 cycles of high-dose intravenous methotrexate but did not receive intrathecal therapy. Intrathecal methotrexate prophylaxis, although previously shown to reduce rates of CNS relapse, has fallen out of favor due to contradictory evidence regarding its efficacy provided in retrospective studies.12,14 Theoretically, drugs delivered intrathecally are rapidly transported out of the CNS via arachnoid granulations, which limits its CSF concentration and flow into the ventricular system.15 Higher sustained cytotoxic methotrexate levels in CSF are achieved after intravenous dosing compared with intrathecal dosing, making high-dose intravenous methotrexate the standard of care as CNS prophylaxis for patients at high risk of CNS relapse.16,17 However, the evidence behind such practice is limited. There are no prospective or randomized studies to demonstrate the efficacy behind high-dose intravenous or intrathecal methotrexate as CNS prophylaxis. Our patient relapsed in the CNS despite 2 doses of intravenous methotrexate. More prospective and randomized research is thus required to establish the true efficacy of intrathecal and intravenous methotrexate as CNS prophylaxis, especially with higher CNS relapse in the rituximab era.18 The introduction of rituximab has improved the overall prognosis for DLBCL patients, though due to its limited CNS penetration, the proportion of relapses with isolated CNS disease has increased notably.19 Phase I trials are under way for intrathecal rituximab to evaluate its efficacy and side effect profile in CNS lymphoma.20 Diagnostic evaluation of secondary lymphoma often relies on a combination of imaging and histopathologic assessment. Imaging helps to characterize the intracranial lesion and determine the extent of systemic disease, providing valuable prognostic and therapeutic information. Our patient’s diffusion-weighted brain MRI demonstrates high signal intensity along the choroid plexus in the lateral, third, and
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2019.04.203
CASE REPORT BI YI CHEN ET AL.
SECONDARY CHOROID B-CELL LYMPHOMA
fourth ventricles (Figure 2). The lesions showed abnormal enhancement on gadolinium-enhanced T1-weighted MRI (see Figure 2). These features are typical of lymphoma. High-dose steroids are required for the treatment and symptomatic management of obstructive hydrocephalus from choroid plexus lymphoma. However, steroids increase the risk of a nondiagnostic brain biopsy.21 CNS lymphoma thus requires histopathologic substantiation before commencement of high-dose steroids. This case poses a diagnostic challenge because obstructive hydrocephalus is a contraindication for lumbar puncture. Therefore tissue is required from the choroid plexus to establish a diagnosis. A stereotactic open biopsy was successfully performed. We advocate for this approach because it allows the operator to visualize the choroid plexus lesion and reduce sampling error, as well as relieve pressure in the temporal horn of the lateral ventricle on the side of the biopsy. A multidisciplinary team of neurosurgeons and hematologists is required for successful management of CNS lymphoma relapse. The treatment for secondary CNS lymphoma is predominately with intravenous chemotherapy; however, experimentation with intrathecal and intraventricular therapies is beginning to emerge.16,22 Dose-intensive chemotherapy with autologous stem cell transplant is also currently attracting attention as an option for treating CNS relapse.23,24 Due to the poor prognosis and a lack of established therapeutic algorithms, there is no current standard of care for these patients. Our patient received the MATRix regimen, which is well-established for the treatment of primary CNS lymphoma, but good-quality evidence in secondary CNS lymphoma is lacking.25
pattern. This case highlights the lack of high-quality evidence behind the use of high-dose intravenous methotrexate as CNS prophylaxis. The case provides additional insight into the pathophysiology of intraventricular CNS lymphomas and the importance of establishing a histopathologic diagnosis via an open biopsy before the administration of high-dose steroids.
CONCLUSION
10. Hollender A, Kvaloy S, Nome O, Skovlund E, Lote K, Holte H. Central nervous system involvement following diagnosis of non-Hodgkin’s lymphoma: a risk model. Ann Oncol. 2002;13: 1099-1107.
In the rituximab era, isolated CNS lymphoma relapse is becoming an increasingly encountered pathology in oncologic practice. This, coupled with the significant mortality associated with condition, makes it an important pathologic entity to be aware of. Our case is the first case in the literature to describe isolated CNS relapse in the setting of lymphoma involving the choroid plexus in a diffuse
REFERENCES 1. Herr MBP, Rich D, Mohile N. Clinical features, treatment, and survival of secondary central nervous system lymphoma. Blood. 2014;124:5389. 2. Herman TS, Hammond N, Jones SE, Butler JJ, Byrne GE Jr, McKelvey EM. Involvement of the central nervous system by non-Hodgkin’s lymphoma: the Southwest Oncology Group experience. Cancer. 1979;43:390-397. 3. Slone HW, Blake JJ, Shah R, Guttikonda S, Bourekas EC. CT and MRI findings of intracranial lymphoma. AJR Am J Roentgenol. 2005;184: 1679-1685. 4. Suzuki M, Kobayashi Z, Ito T, Akaza M, Tomimitsu H, Shintani S. Lymphoma presenting with choroid plexus infiltration and periventricular dissemination. J Neurol Sci. 2015;353: 179-180. 5. Ravichandran TP, Fredericks EJ, Goldman RL, Abernathy EC, Ergin MT. Intraventricular B-cell lymphoma from the breast. Neuroradiology. 1998; 40:522-523. 6. DeRosa P, Cappuzzo JM, Sherman JH. Isolated recurrence of secondary CNS lymphoma: case report and literature review. J Neurol Surg Rep. 2014;75:e154-e159. 7. Sierra del Rio M, Rousseau A, Soussain C, Ricard D, Hoang-Xuan K. Primary CNS lymphoma in immunocompetent patients. Oncologist. 2009; 14:526-539. 8. Spector R, Keep RF, Robert Snodgrass S, Smith QR, Johanson CE. A balanced view of choroid plexus structure and function: focus on adult humans. Exp Neurol. 2015;267:78-86. 9. Levine S. Choroid plexus: target for systemic disease and pathway to the brain. Lab Invest. 1987; 56:231-233.
11. 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.
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12. Arkenau HT, Chong G, Cunningham D, et al. The role of intrathecal chemotherapy prophylaxis in patients with diffuse large B-cell lymphoma. Ann Oncol. 2007;18:541-545. 13. McMillan A. Central nervous system-directed preventative therapy in adults with lymphoma. Br J Haematol. 2005;131:13-21. 14. Kumar A, Vanderplas A, LaCasce AS, et al. Lack of benefit of central nervous system prophylaxis for diffuse large B-cell lymphoma in the rituximab era: findings from a large national database. Cancer. 2012;118:2944-2951. 15. Pardridge WM. Drug transport in brain via the cerebrospinal fluid. Fluids Barriers CNS. 2011;8:7. 16. Glantz MJ, Cole BF, Recht L, et al. High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary? J Clin Oncol. 1998;16: 1561-1567. 17. Abramson JS, Hellmann M, Barnes JA, et al. Intravenous methotrexate as central nervous system (CNS) 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. 18. Tai WM, Chung J, Tang PL, et al. Central nervous system (CNS) relapse in diffuse large B cell lymphoma (DLBCL): pre- and post-rituximab. Ann Hematol. 2011;90:809-818. 19. Deng L, Song Y, Zhu J, et al. Secondary central nervous system involvement in 599 patients with diffuse large B-cell lymphoma: are there any changes in the rituximab era? Int J Hematol. 2013; 98:664-671. 20. Rubenstein JL, Li J, Chen L, et al. Multicenter phase 1 trial of intraventricular immunochemotherapy in recurrent CNS lymphoma. Blood. 2013; 121:745-751. 21. Porter AB, Giannini C, Kaufmann T, et al. Primary central nervous system lymphoma can be histologically diagnosed after previous corticosteroid use: a pilot study to determine whether corticosteroids prevent the diagnosis of primary central nervous system lymphoma. Ann Neurol. 2008;63: 662-667. 22. Szczepanek D, Wasik-Szczepanek E, Szymczyk A, et al. Intraventricular treatment of secondary central nervous system lymphoma—case study and literature overview. Neurol Neurochir Pol. 2018; 52:410-414. 23. Soussain C, Suzan F, Hoang-Xuan K, et al. Results of intensive chemotherapy followed by hematopoietic stem-cell rescue in 22 patients with refractory or recurrent primary CNS lymphoma or intraocular lymphoma. J Clin Oncol. 2001;19: 742-749. 24. Bromberg JE, Doorduijn JK, Illerhaus G, et al. Central nervous system recurrence of systemic lymphoma in the era of stem cell transplantation—an International Primary Central Nervous System Lymphoma Study Group project. Haematologica. 2013;98:808-813.
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25. Ferreri AJ, Cwynarski K, Pulczynski E, et al. Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial. Lancet Haematol. 2016;3:e217-e227.
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SECONDARY CHOROID B-CELL LYMPHOMA
Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 4 March 2019; accepted 22 April 2019
Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter Crown Copyright ª 2019 Published by Elsevier Inc. All rights reserved.
Citation: World Neurosurg. (2019) 128:18-22. https://doi.org/10.1016/j.wneu.2019.04.203
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2019.04.203
Secondary Diffuse Choroid Plexus B-Cell Lymphoma: Case Report and Review of Literature Bi Yi Chen1, Vivien Chen1, Shafqat Inam1, Charlotte Yin2, Omprakash Damodaran1
Key words Chemotherapy - Intraventricular lymphoma - Secondary central nervous system lymphoma -
Abbreviations and Acronyms CNS: Central nervous system CSF: Cerebrospinal fluid DLBCL: Diffuse large B cell lymphoma MRI: Magnetic resonance imaging PET: Positron emission tomography R-CHOP: Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone From the 1Concord General Repatriation Hospital, Concord; and 2Royal North Shore Hospital, St Leonards, Australia To whom correspondence should be addressed: Bi Yi Chen, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2019) 128:18-22. https://doi.org/10.1016/j.wneu.2019.04.203
- BACKGROUND:
Central nervous system (CNS) relapse is an uncommon complication of diffuse large B cell lymphoma and is associated with significant mortality and morbidity. It is becoming a more prevalent pathologic entity in the rituximab era. Our case provides insight into the pathophysiology, diagnosis, prevention, and management of secondary intraventricular CNS lymphomas.
- CASE
DESCRIPTION: We report an unusual case of a 64-year-old man who presented with an isolated secondary CNS lymphoma involving the choroid plexus in a diffuse pattern. He initially presented with obstructive hydrocephalus from diffuse choroid plexus lesions and was commenced on systemic therapy after confirmation of diagnosis via samples obtained from an open biopsy.
- CONCLUSIONS:
This case highlights the lack of high-quality evidence behind the use of high-dose intravenous methotrexate as CNS prophylaxis. The case provides additional insight into the pathophysiology of intraventricular CNS lymphomas and the importance of establishing a histopathologic diagnosis via an open biopsy before the administration of high-dose steroids.
Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter Crown Copyright ª 2019 Published by Elsevier Inc. All rights reserved.
INTRODUCTION Isolated central nervous system (CNS) lymphoma relapse is uncommon in patients with previously treated diffuse large B cell lymphoma (DLBCL) and portends a poor prognosis. We present an unusual case of an isolated secondary CNS lymphoma involving the choroid plexus in a diffuse pattern. We describe the successful management and diagnosis of this unusual case at our institution. The report also aims to provide insight into the pathophysiology, diagnosis, prevention, and management of secondary intraventricular CNS lymphomas. CASE A 64-year-old man presented with 2 weeks’ history of worsening morning headaches, cognitive decline, and ataxia. He was diagnosed with stage IVA DLBCL 3 years prior. Positron emission tomography (PET) scan showed no evidence of CNS
18
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involvement. The patient subsequently received radiation therapy to his thoracic paravertebral lesion, as well as prophylactic intrathecal methotrexate; 2 cycles of doseadjusted rituximab, etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin chemotherapy; 4 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP-14); and 2 cycles of high-dose intravenous methotrexate therapy as prophylaxis to prevent CNS relapse. He achieved complete metabolic and clinical remission at the completion of 6 months of chemotherapy. On this admission, he had no B symptoms. He had an Eastern Cooperative Oncology Group performance score of 0 before his recent deterioration. On examination, he had a Glasgow Coma Scale score of 15 and mobilized with an ataxic gait. He struggled with short-term recall. His examinations was otherwise unremarkable. Computed tomography of the brain showed diffuse infiltration of the choroid plexus in the lateral, third, and fourth ventricles with homogenously contrastenhancing lesions causing acute obstructive
hydrocephalus (Figure 1). Magnetic resonance imaging (MRI) of the brain showed restricted diffusion within the intraventricular masses, favoring lymphoma (Figure 2). Neurologic PET showed markedly increased metabolism in the intraventricular lesion, again favoring a high-grade lesion. His body PET demonstrated no other sites of active disease. His lactate dehydrogenase was 201 U/L, white cell count was 8.2 109/L, hemoglobin was 163 g/L, and platelet was 223 109/L. The patient underwent an open biopsy of the right intraventricular lesion via a rightsided craniotomy. A transcortical approached through the superior parietal lobule was used to access the trigone of the right lateral ventricle under stereotactic guidance. Biopsy samples were taken and proteinaceous fluid was drained. Histopathology confirmed diffuse large B cell lymphoma (non GCB/ABC phenotype). After surgery, the patient was commenced on high-dose dexamethasone of 40 mg daily and experienced significant clinical improvement. He was subsequently commenced on salvage chemotherapy with methotrexate, cytarabine,
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2019.04.203
CASE REPORT BI YI CHEN ET AL.
SECONDARY CHOROID B-CELL LYMPHOMA
Figure 1. Computed tomography of the brain showing diffuse homogenously enhancing choroid plexus lesions with acute hydrocephalus.
thiotepa, and rituximab (MATRix), of which he has finished 4 cycles. A progress PET scan after 4 cycles of chemotherapy showed good partial remission with complete resolution of the choroid plexus tumor, but residual subtle increased metabolism in the left frontal lobe. The patient progressed to an uncomplicated autologous transplant with thiotepa and carmustine conditioning as consolidation therapy. He remains well 1 year after his initial presentation.
DISCUSSION Isolated CNS relapse of DLBCL is an uncommon complication after remission, occurring in only 3% of DLBCL patients.1 CNS relapse is associated with significant mortality and morbidity as a result of the disease’s aggressive nature and toxicities
associated with chemotherapy.1,2 Median survival after CNS relapse is 2e6.5 months in patients diagnosed with nonHodgkin lymphoma.1 Secondary CNS lymphoma typically presents intracranially as pachymeningeal or leptomeningeal infiltrates and rarely occurs in periventricular or intraventricular locations.3 Diffuse choroid plexus involvement with primary or secondary lymphoma is a rare phenomenon. A search on Medline was conducted to identify cases with secondary intraventricular lymphoma. There were no restrictions on language. The search terms “cerebral ventricle neoplasms” AND “lymphoma” and “choroid plexus” AND “lymphoma” were used. Identified papers were screened on the basis of the title and abstract by 2 independent investigators, and an indepth review of each selected article was
Figure 2. Magnetic resonance imaging of the brain showing changes on susceptibility-weighted imaging consistent with hemorrhage. There is
WORLD NEUROSURGERY 128: 18-22, AUGUST 2019
performed with important information extracted. A total of 95 articles were identified on the initial search. Ninety-three articles were excluded after reading the title and abstract. Only 2 cases of intraventricular involvement in systemic lymphoma by Suzuki et al4 and Ravichandran et al5 were described (Table 1). Suzuki et al’s4 case had significant periventricular involvement, whereas in our case and Ravichandran et al’s5 case, this was absent, possibly reflecting a different pathway of disease spread. Isolated secondary CNS lymphoma relapse, without other areas of hypermetabolism on body PET, is infrequent.6 Our patient had isolated secondary CNS lymphoma, but the pattern of disease, involving pure the choroid plexus in a diffuse pattern, was rare. This is, in fact,
restricted diffusion on diffusion-weighted imaging, and there are T2 flair changes throughout the ventricular system.
www.journals.elsevier.com/world-neurosurgery
19
CASE REPORT
20
Resolution of lymphoma cells in CSF and resolution of abnormal enhancement on imaging with R-CHOP treatment CSF sample
www.SCIENCEDIRECT.com
CSF, cerebrospinal fluid; CT, computed tomography; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone.
Further R-CHOP therapy Adrenal, retroperitoneal, bones/B cell lymphoma 3 years prior 71/Male Suzuki et al., 20154
1 Month of cognitive impairment/R-CHOP therapy
Near-complete resolution of the lesion on CT 1 week after treatment CSF via ventriculostomy Intravenous dexamethasone, ventriculostomy, and radiation therapy Breast/diffuse large B cell lymphoma 3 years prior 78/Female Ravichandran et al., 19985
2 weeks’ history of impaired mentation and ataxia/did not specify
Primary Location/Pathology Age/Sex
Presentation/Previous Therapy
SECONDARY CHOROID B-CELL LYMPHOMA
Author
Table 1. Literature Review of Patients with Secondary Intraventricular Lymphoma
Treatment
Method of Obtaining Diagnosis
Outcome
BI YI CHEN ET AL.
the second of such case to be reported in the literature and, as such, provides novel insight into the pathophysiology, diagnosis, and management of secondary intraventricular CNS lymphomas. The pathophysiology of intraventricular lymphoma is currently not well elucidated. The CNS does not contain resident lymphocytes and lack lymphatic vessels under normal circumstances.7 Given leptomeningeal spread is the most common location of CNS disease in systemic lymphoma, the possibility of lymphoma infiltrating the perivascular spaces secondary to hematogenous spread should be entertained. Furthermore, the choroid plexus is a relatively vascular structure consisting of choroid epithelium surrounding numerous capillaries intermingled in loose connective tissue. The capillaries of the choroid plexus are lined by fenestrated endothelium, which allows tumor cells to enter the CNS via a hematogenous route.8,9 Choroid plexus tumor is a site where the blood-brain barrier is broken down, as evidenced by the pronounced tumor blush seen on angiograms. This site of disrupted blood-brain barrier is freely exposed to the ventricular cavity, allowing tumor cells to seed throughout the ventricular system. Despite the significant burden of disease in the choroid plexus and normal direction of cerebrospinal fluid (CSF) flow from the fourth ventricle to the subarachnoid space, the remaining neural axis was surprisingly disease free on MRI, though there was subtle increase metabolism in the frontal lobes seen on the neural PET scan. The clarity of CSF in the subarachnoid space compared with the turbid and thick fluid observed in the lateral ventricle intraoperatively demonstrates an obstructive phenomenon occurring in the lateral and median apertures of the fourth ventricle. This obstruction likely stems from diseased choroid plexus in the fourth ventricle. The relative lack of disease in the subarachnoid space is further highlighted by T2 flair changes in the ventricles on MRI and lack of such changes in the subarachnoid space (Figure 2). Obstructive hydrocephalus secondary to choroid plexus metastatic infiltrates facilitates the spread of lymphoma within the ventricular system to other parts of the choroid plexus. This explains the diffuse pattern of choroid plexus involvement observed.
Multiple extranodal sites at diagnosis is a well-known risk factor for CNS relapse in non-Hodgkin lymphoma.10,11 High-dose intravenous methotrexate is typically given in these patients as CNS prophylaxis to prevent recurrence. However, the efficacy of intravenous methotrexate as CNS prophylaxis remains uncertain.10,12,13 Our patient received 2 cycles of high-dose intravenous methotrexate but did not receive intrathecal therapy. Intrathecal methotrexate prophylaxis, although previously shown to reduce rates of CNS relapse, has fallen out of favor due to contradictory evidence regarding its efficacy provided in retrospective studies.12,14 Theoretically, drugs delivered intrathecally are rapidly transported out of the CNS via arachnoid granulations, which limits its CSF concentration and flow into the ventricular system.15 Higher sustained cytotoxic methotrexate levels in CSF are achieved after intravenous dosing compared with intrathecal dosing, making high-dose intravenous methotrexate the standard of care as CNS prophylaxis for patients at high risk of CNS relapse.16,17 However, the evidence behind such practice is limited. There are no prospective or randomized studies to demonstrate the efficacy behind high-dose intravenous or intrathecal methotrexate as CNS prophylaxis. Our patient relapsed in the CNS despite 2 doses of intravenous methotrexate. More prospective and randomized research is thus required to establish the true efficacy of intrathecal and intravenous methotrexate as CNS prophylaxis, especially with higher CNS relapse in the rituximab era.18 The introduction of rituximab has improved the overall prognosis for DLBCL patients, though due to its limited CNS penetration, the proportion of relapses with isolated CNS disease has increased notably.19 Phase I trials are under way for intrathecal rituximab to evaluate its efficacy and side effect profile in CNS lymphoma.20 Diagnostic evaluation of secondary lymphoma often relies on a combination of imaging and histopathologic assessment. Imaging helps to characterize the intracranial lesion and determine the extent of systemic disease, providing valuable prognostic and therapeutic information. Our patient’s diffusion-weighted brain MRI demonstrates high signal intensity along the choroid plexus in the lateral, third, and
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2019.04.203
CASE REPORT BI YI CHEN ET AL.
SECONDARY CHOROID B-CELL LYMPHOMA
fourth ventricles (Figure 2). The lesions showed abnormal enhancement on gadolinium-enhanced T1-weighted MRI (see Figure 2). These features are typical of lymphoma. High-dose steroids are required for the treatment and symptomatic management of obstructive hydrocephalus from choroid plexus lymphoma. However, steroids increase the risk of a nondiagnostic brain biopsy.21 CNS lymphoma thus requires histopathologic substantiation before commencement of high-dose steroids. This case poses a diagnostic challenge because obstructive hydrocephalus is a contraindication for lumbar puncture. Therefore tissue is required from the choroid plexus to establish a diagnosis. A stereotactic open biopsy was successfully performed. We advocate for this approach because it allows the operator to visualize the choroid plexus lesion and reduce sampling error, as well as relieve pressure in the temporal horn of the lateral ventricle on the side of the biopsy. A multidisciplinary team of neurosurgeons and hematologists is required for successful management of CNS lymphoma relapse. The treatment for secondary CNS lymphoma is predominately with intravenous chemotherapy; however, experimentation with intrathecal and intraventricular therapies is beginning to emerge.16,22 Dose-intensive chemotherapy with autologous stem cell transplant is also currently attracting attention as an option for treating CNS relapse.23,24 Due to the poor prognosis and a lack of established therapeutic algorithms, there is no current standard of care for these patients. Our patient received the MATRix regimen, which is well-established for the treatment of primary CNS lymphoma, but good-quality evidence in secondary CNS lymphoma is lacking.25
pattern. This case highlights the lack of high-quality evidence behind the use of high-dose intravenous methotrexate as CNS prophylaxis. The case provides additional insight into the pathophysiology of intraventricular CNS lymphomas and the importance of establishing a histopathologic diagnosis via an open biopsy before the administration of high-dose steroids.
CONCLUSION
10. Hollender A, Kvaloy S, Nome O, Skovlund E, Lote K, Holte H. Central nervous system involvement following diagnosis of non-Hodgkin’s lymphoma: a risk model. Ann Oncol. 2002;13: 1099-1107.
In the rituximab era, isolated CNS lymphoma relapse is becoming an increasingly encountered pathology in oncologic practice. This, coupled with the significant mortality associated with condition, makes it an important pathologic entity to be aware of. Our case is the first case in the literature to describe isolated CNS relapse in the setting of lymphoma involving the choroid plexus in a diffuse
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Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 4 March 2019; accepted 22 April 2019
Journal homepage: www.journals.elsevier.com/worldneurosurgery Available online: www.sciencedirect.com 1878-8750/$ - see front matter Crown Copyright ª 2019 Published by Elsevier Inc. All rights reserved.
Citation: World Neurosurg. (2019) 128:18-22. https://doi.org/10.1016/j.wneu.2019.04.203
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2019.04.203