Use of rituximab in lymphomatoid granulomatosis with isolated central nervous system involvement
- 1 Texas A&M Health Science Center College of Medicine, Houston, Texas, USA
- 2 Houston Methodist Cancer Center, Houston, Texas, USA
- 3 Department of Hematopathology, Houston Methodist Hospital, Houston, Texas, USA
- Correspondence to Dr Cesar Gentille; cgentillesanchez@houstonmethodist.org
Abstract
A 33-year-old woman presented to the emergency room with severe headaches. A CT scan of the head revealed two brain lesions with associated vasogenic oedema. Diagnostic resection of one of the lesions followed by pathological analysis revealed grade III lymphomatoid granulomatosis (LYG). Staging investigations elsewhere in the body were negative, isolating this case of LYG to the central nervous system, an atypical presentation. After the resection, she was treated with single-agent rituximab 375 mg/m2. The follow-up MRI demonstrated the resolution of brain lesions and no progression of the disease.
Background
Lymphomatoid granulomatosis (LYG) is a rare B-cell lymphoproliferative disease driven by the Epstein-Barr virus (EBV). Histologically, it is characterised by angiocentric and angiodestructive lesions with atypical B cells in a polymorphous inflammatory background.1 The mean age of LYG presentation is approximately 48 years and there is a male predominance with a male-to-female ratio of 2:1.2 Immunocompromised patients with conditions such as AIDS, post-transplant and/or on chronic immunosuppressive drugs are at risk; however, LYG has also been seen in immunocompetent patients.3 4 LYG almost always presents as pulmonary disease with the most common extrapulmonary sites being the skin (35%) and nervous system (27%). LYG of the kidney, spleen and liver has also been described, though less commonly.5 Isolated central nervous system (CNS)-LYG is a rarely documented phenomenon, and thus, treatment is largely based on case reports and case series. Prior studies have suggested using chemotherapy in cases of high-grade systemic LYG. However, in cases of isolated CNS-LYG, there are little data available other than case reports. To our knowledge, we report the first case of isolated high-grade CNS-LYG treated successfully with single-agent rituximab.
Case presentation
A 33-year-old woman presented to the emergency department for an episode of severe headache with nausea. Her medical history was significant for systemic lupus erythematosus on prednisone (10 mg/day) and mycophenolate mofetil (1000 mg two times per day) and end-stage renal disease on dialysis secondary to lupus nephritis. Her headaches were intermittent and started approximately 1 month prior; otherwise no vomiting, focal weakness, weight loss, fever, night sweats or other issues. Her headache progressively worsened over the course of 3 days until she brought herself to the hospital. Her physical examination, including extensive neurological examination, was unremarkable.
Investigations
A CT scan of the head revealed areas of vasogenic oedema in the left parietal and right frontal lobes. Further evaluation with brain MRI revealed T2 heterogeneous lesions in the regions of oedema, with an additional area of hyperintensity in the left frontal subcortical white matter (figure 1A). CT angiogram of the neck demonstrated innumerable enlarged supraclavicular and cervical lymph nodes. A cervical lymph node biopsy was inconclusive but showed a small B-lymphocyte predominance with concurrent flow cytometry negative for lymphoma. A supraclavicular excisional lymph node biopsy showed benign reactive findings with concurrent flow cytometry again negative for lymphoma. Given these inconclusive results, neurosurgery proceeded with diagnostic resection of the right frontal lobe mass. Histopathological evaluation revealed a nodular lesion composed of an atypical and pleomorphic mononuclear infiltrate of intermediate to large cells with irregular nuclear contours, vesicular chromatin with occasional prominent nucleoli and scant cytoplasm, in a polymorphous background of small mature lymphocytes and plasma cells. The atypical infiltrate was predominantly arranged in a perivascular distribution, with infiltration and destruction of associated vessels, with areas of necrosis. The large atypical cells stained positive for CD20, PAX5, CD30, BCL2, BCL6, MUM-1 and EBV by Epstein-Barr-encoding region (EBER) in situ hybridisation (>50/hpf), with a proliferative index of >80% by Ki-67, and negative for CD3, CD10, CD15, cMyc and ALK1. CD20 also highlighted the background small mature B lymphocytes (figure 2). These findings were consistent with LYG grade III.
(A) MRI on presentation showing two brain lesions: the right middle frontal gyrus lesion measuring 5 mm with haemorrhage and calcification; the second similar-appearing lesion is in the left parieto-occipital region centred in the cortex and sulci. (B) Follow-up MRI post-resection showing the new left frontoparietal lesion with associated oedema.
(A) Angiocentric polymorphic infiltrate with angioinvasion and destruction by large atypical lymphoid cells (H&E, ×20). (B) CD20 immunohistochemistry highlighting small B lymphocytes (left), and clusters of large atypical lymphoid cells (right) (×10). (C) EBER (in situ hybridisation) highlighting large EBV-positive cells, angiocentric and diffuse (×10). EBER, Epstein-Barr-encodingregion; EBV, Epstein-Barr virus.
Staging with CT chest/abdomen/pelvis showed no other lesions, except for hyperdense mass in the upper pole of the left kidney that was found to be a chromophobe renal cell carcinoma. Follow-up MRI demonstrated complete resolution of oedema in the areas of resection. Given her asymptomatic state and the absence of new masses on brain imaging, it was decided to hold an intervention for LYG until after her nephrectomy.
Differential diagnosis
Differential diagnoses following MRI (figure 1) of included lymphoma, or metastatic disease, both of which are more common than LYG. The ultimate determinant of LYG diagnosis was made following resection of the right frontoparietal lesion and histopathological evaluation of the specimen. In traditional cases of systemic LYG or those with isolated involvement, histological evaluation is necessary for the diagnosis.
Treatment
Two months later, her headaches became more frequent and a new small lesion in the left frontoparietal area with surrounding oedema was found on follow-up brain MRI (figure 1B). Given her new-onset symptoms in combination with increased tumour size, it was decided to initiate therapy. She was treated with rituximab monotherapy at 375 mg/m2 due to her comorbidities and the absence of lesions in other sites. Four weekly doses were given with no major issues.
Outcome and follow-up
One month after the completion of therapy, a follow-up brain MRI showed resolution of the previous oedema as well as stable T2 signal changes with no new lesions (figure 3A,B). Her headaches also significantly improved with only seldom episodes. Radiation oncology did not deem radiotherapy to be necessary at this time. Six-month follow-up showed stable lesions with no progression.
(A) Post-rituximab MRI showing resolution of oedema in the right middle frontal gyrus and the left parietooccipital region. (B) Post-rituximab MRI showing the resolution of the left frontoparietal lesion and oedema.
Discussion and review of literature
Isolated CNS-LYG is a rare phenomenon. Symptoms reported in previous cases include headache, ataxia, personality disturbances, visual changes, seizures, memory loss and hemiparesis. MRI is suggested to be the best imaging modality to detect and monitor LYG involvement of the CNS.6 Neuroimaging findings are variable. Features of LYG that have been reported include multiple focal intraparenchymal lesions with T2 enhancement and punctate/linear enhancement, involvement of the leptomeninges and cranial nerves, mass lesions and ring-enhancing lesions.1 5 6 A literature review by Lucantoni et al 5 suggests that mass lesions might have a higher incidence in primary CNS-LYG as compared with systemic LYG with later CNS involvement. Reported radiological findings of LYG are non-specific however, and differentials include but are not limited to metastasis, lymphoma, infection, vasculitis and multiple sclerosis, all of which are more common than LYG.
The diagnosis of LYG is dependent on histological evaluation. Classic findings include mononuclear cell infiltrates with angioinvasion and CD20-positive large B lymphocytes on a background of CD3-positive T lymphocytes. Findings supporting a diagnosis of LYG, though not always present, include necrosis within the cellular infiltrate, and positive in situ hybridisation for EBER. There is debate on whether EBV positivity is necessary for diagnosis, as there have been reported cases, particularly of isolated CNS-LYG, which have been EBV negative.5 Grading of LYG is divided into a three-tier system and is useful for the therapeutic management of the disease. Grade I lesions have no large atypical cells, minimal necrosis and EBV-positive cells are rarely seen. Grade II lesions have occasional large atypical cells, moderate necrosis and EBV-positive cells 5–20/hpf. Grade III lesions have numerous large atypical cells (>50/hpf) that are easily identified and are associated with extensive necrosis.7
There have been no large prospective randomised controlled trials for the treatment of LYG due to the rarity of the disease, and thus, treatment is largely based on small retrospective studies or case reports. A risk-adapted approach to management was designed by the US National Cancer Institute. Grade I and II lesions were treated with interferon-alpha given subcutaneously at 7.5 million units three times weekly and then dose escalated.8 In 31 patients given interferon-alpha with low-grade LYG, 60% achieved complete remission. Follow-up at 5 years showed a progression-free survival (PFS) rate of low-grade LYG of 56% and a median time to remission of 9 months. Grade III LYG was treated with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (DA-EPOCH-R). Chemotherapy was given over six cycles and patients who tolerate therapy without substantial drops in their absolute neutrophil count received increased dosing of doxorubicin, etoposide and cyclophosphamide. The complete response rate to DA-EPOCH-R was 66% with PFS of 40% at 28 months.1 8
Different treatment modalities including steroids, interferon alpha and chemotherapy have been reported in isolated CNS-LYG. A case series of three patients with LYG grade II–III described good outcomes after steroids either in conjunction with interferon-alpha (one patient) or cyclosporine and mycophenolate mofetil (two patients with a history of renal transplantation). Despite the high-grade lesions, all of them had a response to treatment and were alive 1 ½−2 years after treatment.9 This report suggests that isolated CNS LYG could have a better prognosis than secondary CNS involvement of systemic LYG despite the grade of the lesion. However, other studies have used more intensive treatment such as chemotherapy with high-dose methotrexate or cyclophosphamide for grade II and III lesions. The use of radiation therapy has also been reported either alone or in conjunction with chemotherapy (cyclophosphamide, cisplatin, CHOP and methotrexate) and/or steroids. Most of these patients were alive after 1 year of follow-up.5
As stated above, rituximab has been used for systemic LYG as part of DA-EPOCH-R as well as other regimens such as: CHOP,3 10 high-dose cytarabine-based chemotherapy,11 high-dose methotrexate-based chemotherapy,12 temozolomide4 and cyclophosphamide, vincristine and prednisone (CVP).10 A single-institution experience reported overall response rates of 63.6% in 11 patients with systemic LYG (2 of them with CNS involvement) after rituximab-based chemotherapy (mostly in conjunction with CHOP and CVP) as well as a median overall survival and PFS of 23 and 12.2 months, respectively .10 Rituximab monotherapy has been used in systemic cases with CNS compromise. Five cases of systemic LYG involving CNS (one with LYG grade III) treated with single-agent rituximab have been reported (table 1).13–17 All of them had some degree of response; three with complete remission. These patients were alive for at least 12 months after follow-up; the longest follow-up was 4 years with no signs of recurrence. No data have been published regarding the use of single-agent rituximab in isolated CNS-LYG. Given our patient’s comorbidities and low burden of disease, we proceeded with rituximab monotherapy. Our case is the first one to our knowledge where rituximab has been used as a single agent for high-grade CNS-LYG with good results although further follow-up will be needed to assess long-term outcomes.
Reported cases of LYG with CNS involvement where rituximab monotherapy was used
| Case | Age | Sex | Site involvement | EBV status | Grade | Treatment | Results | Outcome (months) | Author |
| 1 | 48 | M | CNS, lung | + | I–II | Rituximab | Complete remission | 18 | Ishiura et al |
| 2 | 70 | F | CNS, lung | + | III | Rituximab | Complete remission | 48 | Castrale et al |
| 3 | 51 | M | CNS, lung | + | II | Rituximab | Complete remission | 36 | Zaidi et al |
| 4 | 35 | M | CNS, spleen, kidney | – | I | Rituximab+steroids | Improvement | 34 | Costiniuk et al |
| 5 | 4 | M | CNS, skin | + | I–II | Rituximab+steroids | Improvement | 12 | Hernandez et al |
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CNS, central nervous system; EBV, Epstein-Barr virus; LYG, lymphomatoid granulomatosis .
LYG is a rare EBV-associated lymphoproliferative disease. Histological and immunohistochemical analyses are essential in making the diagnosis. Treatment of systemic LYG can be guided by grading of the lesion with prior reports recommending chemotherapy in cases of high-grade systemic LYG. Rituximab has been used either in conjunction with chemotherapy or as a single agent. However, in cases of isolated CNS-LYG, there are little data available. Despite being considered high-grade CNS-LYG, our patient had a great response to rituximab monotherapy, which supports this regimen as an alternative to chemotherapy in patients where there is a concern for poor tolerance or where the potential benefits of front-line chemotherapy are not clear.
Learning points
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Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus-associated lymphoproliferative disease, with diagnosis dependent on histological evaluation.
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Cases of LYG isolated of the central nervous system (CNS) are rare, and there is no well-established treatment paradigm at this time.
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Single-agent rituximab should be considered for isolated high-grade CNS-LYG, especially when there is a concern for poor tolerance or where the potential benefits of front-line chemotherapy are not clear.
Footnotes
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Contributors JM performed review of the literature, as well as contributed to the writing of the manuscript. CGS analysed and interpreted patient information, reviewed literature and edited the writing of the manuscript. AB performed histological evaluation of the CNS-LYG lesion, provided the histological slides found in the manuscript as well as the descriptions. SS was the primary physician for the case presented. He edited the final manuscript. All authors have reviewed and approved of the final manuscript for submission.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Competing interests None declared.
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Patient consent for publication Obtained.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.
References
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