Introduction

Post-transplant lymphoproliferative disorders (PTLD) are a heterogeneous group of lymphoid or plasmacytic proliferations occurring in recipients of solid organ transplants and hematopoietic stem cell transplantation (HSCT) [1]. The clinical presentation of PTLD is highly variable, and ranges from an indolent self-limited form of lymphoproliferation to fulminant disease and from localized to widely disseminated disease. PTLD based on the revised classification by the World Health Organization are grouped into four categories; early lesions, polymorphic PTLD, monomorphic PTLD, and classic Hodgkin lymphoma-type PTLD [2]. The pathogenesis of PTLD in most patients is related to B-cell proliferation induced by infection with Epstein-Barr virus (EBV) in the setting of chronic immunosuppression [3, 4].

Extra nodal involvement is common in PTLD, but isolated involvement of the central nervous system (CNS) is extremely rare. In solid organ transplant recipients the median time from transplantation to primary CNS-PTLD is 4.4 years [5]. The cerebral hemispheres are the most common site of CNS-PTLD, with the the subcortical white matter and basal ganglia, being most commonly affected. CNS-PTLD after solid organ transplants is usually monomorphic EBV positive disease of B-cell origin and median survival is 47 months from diagnosis.

Primary CNS-PTLD after HSCT is also rare and has not been well described. Here we report an adult allogeneic HSCT recipient who developed primary CNS-PTLD, review the literature and discuss treatment options.

Case report

A 27-year old female underwent human leukocyte antigen-matched unrelated donor HSCT for acute leukemia of ambiguous lineage. The conditioning regimen consisted of cyclophosphamide and total body irradiation. Cyclosporine and methotrexate were given for prophylaxis of graft-versus-host disease (GVHD). On day 25 post-transplant the patient developed acute GVHD of the gut and skin that responded to high-dose steroids. On day 34 post-transplant the cyclosporine was changed to mycophenolate mofetil due to thrombotic microangiopathy. Post-transplant evaluation of the bone marrow did not demonstrate evidence of leukemia. By day 152 post-transplant the patient’s steroids were discontinued and the dose of mycophenolate mofetil was tapered to 500 mg per day orally.

On day 173 post-transplant the patient developed bilateral aching headache pain, worse when recumbent and exacerbated by eye movements. The headaches were present constantly, and were not associated with visual, sensory, or motor symptoms, but were associated with photophobia and phonophobia. The patient reported intermittent blurred vision but not diplopia. Cognitive testing using the MMSE was normal. The cranial nerve exam was unremarkable and fundoscopy normal. Muscle tone was normal, reflexes were depressed throughout. Motor strength was full in all muscle groups tested. Cerebellar testing and sensory examination were normal.

MRI of the brain with and without gadolinium contrast demonstrated multiple intraparenchymal contrast enhancing lesions with surrounding T2Flair hyperintensities. Several of the lesions were adjacent to the leptomeningeal surface but there was no leptomeningeal enhancement at other sites (Fig. 1). MRI of the total spine demonstrated no evidence of leptomeningeal, intradural, or intraparenchymal spinal cord abnormalities.

Fig. 1
figure 1

a T1 weighted post-gadolinium MRI at diagnosis demonstrating enhancing lesions in the right frontal and left occipital lobes. b T1 weighted post-gadolilnium MRI of comparable axial level after 4 weekly doses of rituximab demonstrating partial response with subgyral enhancement remaining in the right frontal lobe and left occipital lobes. c T1 weighted post-gadolilnium MRI obtained 3 months after completion of treatment demonstrating only small residual focus of enhancement in the right frontal lobe. d T1 weighted post-gadolinium MRI obtained 6 months after completion of treatment demonstrating complete resolution of all lesions

Full size image

A diagnostic lumbar puncture demonstrated a CSF protein of 90 μg/dl, glucose 47 mg/dl, 7 WBC/μl, 75% lymphocytes, 25% mononuclear cells. Cerebrospinal fluid (CSF) cytology demonstrated no malignant cells. CSF analysis was also negative for bacterial, fungal, viral, or parasitic organisms. Real time PCR for EBV DNA on whole blood and CSF were negative. Brain biopsy was performed, which demonstrated a perivascular and interstitial infiltrate of abnormal large, mononuclear cells, some with irregular nuclear contours, dense chromatin and/or prominent nucleoli. Numerous mitotic figures were seen. Immunohistochemical stains confirmed a B-cell origin (PAX-5 positive) with positive staining for CD20 and CD79a. In situ hybridization demonstrated positive staining for latent EBV-associated early RNA (EBER) (Fig. 2). A diagnosis of post-transplant lymphoproliferative disorder, monomorphic-type, with diffuse large B-cell morphology was made. CT/PET scan of the chest, abdomen, and pelvis showed no evidence of nodal or organ involvement. Bone marrow biopsy showed no evidence of leukemia or PTLD.

Fig. 2
figure 2

a Brain biopsy demonstrated an abnormal, pleomorphic infiltrate of large centroblastic cells (×1000, H & E stain), which showed strong nuclear staining for the B-cell transcription factor PAX-5 (b, ×500, immunohistochemical stain), nuclear staining for EBER (c, ×1000, in situ hybridization), and a high proliferative index on Ki67/Mib-1 staining (d, ×500, immunohistochemical stain)

Full size image

The patient was treated with rituximab administered intravenously weekly for 4 weeks. The dose of rituximab was escalated after the first dose from 375 to 500 mg/m2. In addition, the mycophenolate mofetil was rapidly tapered and discontinued within 4 weeks with no exacerbation of GVHD. The patient’s symptoms improved after the first dose of rituximab and resolved by the completion of therapy. Decrease in size of all of the lesions was seen on MRI imaging at the completion of therapy. Follow up brain MRI 3 months after treatment began demonstrated near complete resolution of all of the previously seen lesions and complete resolution by 6 months (Fig. 1).

Discussion

Although PTLD represent a relatively uncommon complication in HSCT patients, this complication is a significant cause of morbidity and mortality. Incidence rates for PTLD peak at 2–3 months after allo-HSCT, and then decline sharply with increasing time since transplantation. The risk of development of PTLD following allo-HSCT is associated with T cell depletion of the donor marrow, antithymocyte globulin use, unrelated or HLA-mismatched grafts, acute and chronic GVHD and advanced age at transplantation [6].

Treatment options for systemic PTLD include reduction of immunosuppression, EBV-specific cytotoxic T lymphocytes (CTL), monoclonal antibodies, chemotherapy, and radiation therapy [7–9]. Primary CNS-PTLD following allo-HSCT presents a particular challenge as there is limited clinical experience, few reported cases and lack of prospective studies. Only a small number of cases isolated CNS-PTLD following allo-HSCT have been reported [10–18] (Table 1). The latency between transplantation and development of CNS-PTLD ranged from 2 to 23 months. CNS-PTLD presented as multiple bilateral lesions in the majority of cases.

Table 1 Clinical features of patients with CNS-PTLD following allo-HSCT
Full size table

Given the rarity of primary CNS-PTLD following allo-HSCT there is no consensus on optimal treatment. Reduction of immunosuppression to restore immune function should be considered if the patient’s symptoms are not life threatening and the risk of developing or exacerbating GVHD is low. However, reduction of the immunosuppression alone may not be sufficient to restore immune responses to EBV in the early post-HSCT period as patients may have not fully reconstituted their immune cells and their ability to mount immune responses [19]. If a significant response is not achieved with reduction of immunosuppression or there is a need for immediate therapy based on the patient’s symptomatology, choice of additional therapy depends on the patient’s performance status and organ function. High-dose methotrexate may be of particular value of PTLD involving the CNS. Multiple clinical trials have demonstrated the efficacy of high-dose methotrexate in treatment of primary CNS lymphoma [20]. In addition, chemotherapy with high-dose methotrexate has also induced responses in patients with CNS-PTLD after liver and renal transplantation [21, 22]. For our patient, concerns about hepatotoxicity and renal toxicity for the high-dose methotrexate, as well as concern about potential bone marrow suppression in a allo-HSCT recipient who was already immunocompromised were reasons not to use high-dose methotrexate as first-line treatment. The use of EBV-specific CTL in allo-HSCT recipients has been proven to be safe with no appreciable alloreactivity and without the development of acute GVHD [23]. However, the availability and time needed for generation of EBV-specific CTL was a limiting factor in treating our patient at presentation of her symptoms.

As most cases of PTLD after HSCT are derived from donor B-cells, monoclonal anti-B-cell antibodies have been used to treat PTLD. The most widely antibody used for the treatment of PTLD is rituximab, a chimeric murine/human monoclonal anti-CD20 antibody [24–28].

In a prospective multicenter phase II trial of 60 patients with PTLD after solid organ transplants treated with rituximab after not responding to reduction of immunosuppression the 1 year progression free survival was 42% [25]. The median time to progression was 6.0 months with 38% of patients being primarily refractory and 12% experiencing progression after a partial response, stable disease, or complete response. In patients that received solid organ transplants and developed primary CNS-PTLD rituximab either at standard doses or higher doses has been used with some success [5, 29]. In addition, rituximab as a single agent as well as in combination with cytotoxic chemotherapy, has been employed in the treatment of primary CNS lymphoma [20, 30–34] and intra-ventricular rituximab has been used in patients with lymphomatous meningitis [35–37].

In our patient, with a negative CSF cytology and no MRI evidence of leptomeningeal lymphoma, we decided to use first systemic rituximab with concomitant reduction of the immunosuppression that resulted in complete resolution of the patient’s symptoms and radiographic findings. Whether maintenance rituximab would be effective after the contrast enhancing lesions have resolved, and the blood brain barrier is presumably reconstitituted, is unclear.

Post-transplant lymphoproliferative disorder isolated to the CNS following allo-HSCT is a rare presentation of an uncommon disease. The optimal therapy for treatment of CNS-PTLD after allo-HSCT remains to be determined. Prospective trials that incorporate stepwise treatment approaches i.e., first reduction of immunosuppression followed with rituximab and then intensive chemotherapy are needed to further define effective therapies for primary CNS-PTLD.