Successful treatment of isolated central nervous system recurrence of primary testicular lymphoma by autologous stem cell transplantation using a conditioning regimen of thiotepa and busulfan

Abstract

Primary testicular lymphoma (PTL) frequently relapses in the central nervous system (CNS) despite prophylactic intrathecal chemotherapy, and the outcome for CNS recurrence of PTL is very poor. We report a case of isolated CNS recurrence of bilateral PTL. Our patient achieved complete response (CR) after rituximab-combination chemotherapy for PTL. Approximately five years later, isolated CNS recurrence of PTL occurred. Our patient achieved CR again after high-dose methotrexate therapy and autologous stem cell transplantation (ASCT) with a conditioning regimen of thiotepa and busulfan as a consolidation therapy. The secondary failure of platelet recovery, probably caused by busulfan, occurred after the platelet engraftment. Our patient has remained in CR for over three years. The treatment strategy for CNS recurrence of PTL is mainly whole-brain radiotherapy or high-dose methotrexate-based chemotherapy; however, CNS recurrence of PTL may occur again even after achieving CR. ASCT with a conditioning regimen of thiotepa and busulfan is the optimal consolidation therapy for secondary CNS lymphoma. To the best of our knowledge, this is the second reported case of a patient with isolated CNS recurrence of PTL successfully treated by ASCT with a conditioning regimen of thiotepa and busulfan as a consolidation therapy.

INTRODUCTION

Primary testicular lymphoma (PTL) is a rare type of non-Hodgkin lymphoma and usually involves a unilateral testis, but occasionally involves the bilateral testes. Diffuse large B-cell lymphoma is the most common histopathological type. Rituximab-combination chemotherapy is effective for achieving complete response (CR), and prophylactic irradiation is usually performed on the contralateral testis. However, central nervous system (CNS) recurrence frequently occurs even after over five years despite prophylactic intrathecal chemotherapy. The treatment for CNS recurrence is mainly high-dose methotrexate-based chemotherapy or whole-brain radiotherapy (WBRT).¹ Autologous stem cell transplantation (ASCT) is not usually indicated because patients with PTL are commonly elderly and their performance status is not suitable for transplantation. Thus, the prognosis of CNS recurrence of PTL is very poor.

Here, we report a case of a male patient with isolated CNS recurrence of bilateral PTL. Our patient achieved CR after high-dose methotrexate chemotherapy and underwent ASCT with a conditioning regimen of thiotepa and busulfan as a consolidation therapy. The secondary failure of platelet recovery was complicated probably owing to busulfan, and the platelet count was successfully elevated to within the normal range with prednisolone treatment.² To the best of our knowledge, this is the second reported case of isolated CNS recurrence of PTL successfully treated by ASCT with a conditioning regimen of thiotepa and busulfan.

CASE REPORT

A 53-year-old male was admitted to the Department of Urology in our hospital in August 2014 because of a right swollen testis. His medical history was unremarkable. Contrast-enhanced computed tomography (CT) showed heterogenous enhancement in his bilateral testes, suggesting bilateral lesions (Fig. 1a). High orchidectomy was performed in September 2014. Histopathological examinations of the resected bilateral testes revealed the proliferation of medium-sized abnormal cells with scant cytoplasm around the seminiferous tubules in both testes (Fig. 2a, b). Immunohistochemical analysis showed that the medium-sized abnormal cells were positive for CD20 (Fig. 2c), CD79a, and Bcl-6 (Fig. 2d), and negative for CD3, CD10 (Fig. 2e), and MUM-1 (Fig. 2f). These results led to the diagnosis of diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), germinal center B-cell (GCB) type in accordance with Hans’ criteria³ and the World Health Organization (WHO) 2008 classification.⁴ Chromosomal analysis using G banding and immunoglobulin heavy chain rearrangement analysis were not carried out. After the high orchidectomy, positron emission tomography–computed tomography (PET-CT) images showed no abnormal accumulation of fluorodeoxyglucose (Fig. 1b). The patient was then transferred to our department. No abnormal cells were detected in the bone marrow and cerebrospinal fluid. Thus, he was diagnosed as having primary bilateral testicular lymphoma (PTL), stage I AE. Laboratory examination showed no elevations of lactate dehydrogenase (LDH), C-reactive protein (CRP), and soluble interleukin-2 receptor (sIL-2R) levels. Rituximab-combination CHOP (rituximab 600 mg per body; cyclophosphamide, 1200 mg per body; doxorubicin, 80 mg per body; vincristine, 2 mg per body; prednisolone, 60 mg per body for five days) chemotherapy (R-CHOP regimen) was administered every three weeks. After six courses of R-CHOP regimen and three of intrathecal chemotherapy with triple agents (cytarabine 40 mg, methotrexate 15 mg and prednisolone 20 mg per body), he achieved a complete metabolic response (CMR), as shown by PET-CT images in May 2015.

Fig. 1.

CT and PET-CT images of PTL at diagnosis

(a) Contrast-enhanced CT images show heterogenous enhancement in bilateral testes, suggesting bilateral lesions.

(b) PET-CT images after the high orchidectomy show no abnormal accumulation of fluorodeoxyglucose in the whole body.

Fig. 2.

Histopathological findings of the resected testes.

(a, b) Hematoxylin-eosin staining showed the proliferation of medium-sized abnormal cells with scant cytoplasm around the seminiferous tubules in both testes (original magnification, a X200, b X400). Immunohistochemical analysis showed that medium-sized abnormal cells were positive for CD20 (c), and Bcl-6 (d), and negative for CD10 (e), and MUM-1 (f) (original magnification, X400).

Approximately five years after achieving CMR, in March 2020, he was admitted again to our hospital because of diplopia, left ptosis, and dysgraphia. Brain magnetic resonance imaging (MRI) showed low-intensity areas on the T1-weighted image (Fig.3a) and irregular high-intensity areas on the T2-weighted image (Fig.3b) and fluid-attenuated inversion recovery (FLAIR) image (Fig.3c) in both the thalamus and left middle cerebral peduncle. No abnormal cells were detected in the cerebrospinal fluid. Laboratory examination showed no elevation of LDH, CRP, and sIL-2R levels. CT images showed no abnormalities in the thoracic and abdominal regions, including the testes. Brain biopsy was not performed because of the complication and sequelae of surgical intervention, as well as his refusal. Thus, we clinically diagnosed him as having isolated parenchymal central nervous system (CNS) recurrence of PTL because it usually occurs late onset. High-dose methotrexate (HD-MTX, 3.5 g per square meter) was administered every three weeks. After one course of HD-MTX therapy, his symptoms immediately disappeared, and after four courses of HD-MTX therapy, brain MRI images showed no abnormalities, suggesting the achievement of complete remission (CR) (Fig. 3d, e, f). High-dose cytarabine (3 g per square meter twice a day) was administered as a mobilizing regimen. Granulocyte-colony stimulating factor (G-CSF, 600 µg per body) was started daily from day 11, and apheresis was performed on day 15. The number of CD34-positive cells collected was 8.0 X 10⁶ per kg. Autologous stem cell transplantation (ASCT) with a conditioning regimen of thiotepa and busulfan (busulfan, 3.2 mg per kg on days -8 to -5; thiotepa, 5 mg per kg on days -4 to -3) was performed in August 2020.⁵ He did not experience mucositis and liver dysfunction, but septic shock due to methicillin-resistant coagulase-negative Staphylococcus and Klebsiella oxytoca occurred as a complication during the nadir (grade 4 febrile neutropenia). Any neuropsychological adverse effects were not observed after ASCT. The time post-ASCT to neutrophil recovery >0.5X10⁹ per L was 9 days and to platelet recovery >50X10⁹ per L was 16 days. However, the platelet count started to decrease on day 29 after platelet engraftment and was below 30X10⁹ per L on day 36 despite stopping or changing many drugs. We considered that immune-mediated platelet destruction was due to the conditioning regimen of busulfan. Prednisolone (0.5 mg per kg) was started for thrombocytopenia on day 44, and his platelet count immediately increased to the normal range. He has remained in CMR, as shown by the PET-CT images, for over three years after ASCT, and his platelet count remained within the normal range after the withdrawal of prednisolone.

Fig. 3.

Brain MRI findings of the isolated CNS lesions.

Brain MRI at the time of the diagnosis of isolated CNS recurrence showed low- intensity areas on the T1-weighted image (a) and irregular high-intensity areas on the T2-weighted image (b) and fluid-attenuated inversion recovery (FLAIR) image (c) in both the thalamus and the left middle cerebral peduncle. After four courses of HD-MTX therapy, brain MRI showed the disappearance of abnormal signals on the T1-weighted (d), the T2-weighted (e), and FLAIR (f) images, suggesting CR.

DISCUSSION

Here, we reported a case of isolated parenchymal CNS recurrence of bilateral PTL successfully treated by ASCT with a conditioning regimen of thiotepa and busulfan.

CNS recurrence of PTL usually occurs as a late relapse, and the majority of cases of isolated CNS recurrence are parenchymal brain lesions. Kridel et al.⁶ reported that 25% of PTL patients developed CNS recurrence within a median time of 2.3 years, and that patients at the limited stage developed predominantly parenchymal lesions of CNS as a late relapse while patients at the advanced stage were more likely to have leptomeningeal recurrence as an early relapse. Our patient had relapsed for isolated parenchymal lesions of the CNS five years after achieving CMR. The pattern of recurrence was compatible with Kridel’s report. The risk factor for CNS recurrence of PTL was not determined, and prophylactic intrathecal chemotherapy did not prevent CNS recurrence, as reported by Vitolo et al.⁷ Therefore, we should consider the treatment strategy for CNS recurrence of PTL.

CNS recurrence is an uncommon presentation of DLBCL with an approximate incidence of 5% incidence, but it shows a poor prognosis with a median overall survival of seven months from the time of CNS recurrence.⁸ The treatment option for CNS recurrence is mainly high-dose methotrexate-based chemotherapy or whole-brain radiotherapy. In the case of primary CNS lymphoma, Montemurro et al.⁹ reported that HD-MTX induction followed by ASCT with a conditioning regimen of thiotepa and busulfan showed a similar outcome to WBRT, but that WBRT was associated with a high incidence of severe neurotoxicity. Thus, ASCT may be feasible for younger patients with CNS recurrence as a consolidation therapy. In the case of secondary CNS involvement in DLBCL, Cote et al.¹⁰ reported for the first time the outcome of 16 secondary CNS lymphoma patients who underwent high-dose chemotherapy with ASCT following a conditioning regimen of thiotepa, busulfan, and cyclophosphamide. After the report of Cote et al., many other retrospective studies were conducted of high-dose chemotherapy with ASCT following a thiotepa-based conditioning regimen for secondary CNS lymphoma.^11–15 Yamashita et al.¹⁶ reported the outcome of 8 CNS lymphoma patients who underwent high-dose chemotherapy with ASCT following a busulfan-based conditioning regimen. Among them, a 46-year-old male patient with PTL relapsed in the CNS 5643 days after achieving CR treated with CHOP chemotherapy. He achieved CR again after HD-MTX chemotherapy followed by ASCT with a conditioning regimen of thiotepa, busulfan, and cyclophosphamide. The adverse events were grade 3 mucositis, grade 3 liver dysfunction, and grade 3 febrile neutropenia. They did not mention the long-term outcome of his case. Thus, to the best of our knowledge, this is the second case of a patient with isolated CNS recurrence of PTL successfully treated by ASCT with a conditioning regimen of high-dose thiotepa and busulfan. Our patient remained in CMR for over three years. Our patient experienced less severe adverse events because of the omission of cyclophosphamide from the conditioning regime. Thus, we should consider high-dose chemotherapy with ASCT following a conditioning regimen of high-dose thiotepa and busulfan to patients with isolated parenchymal CNS recurrence of PTL as a consolidation therapy after CR was achieved by salvage chemotherapy such as high-dose methotrexate-based chemotherapy.

Our patient developed thrombocytopenia after platelet engraftment. There are many causes of thrombocytopenia after ASCT, such as drug-induced, late graft failure, and immune-mediated platelet destruction. Wada et al.² reported the cases of three patients with secondary failure of platelet recovery (SFPR) after high-dose thiotepa and busulfan following by ASCT. The median time of ASCT to the onset of SFPR was 38 days, the use of busulfan was one of the possible risk factors for SFPR, and low-to-intermediate-dose prednisolone was effective for SFPR. In our patient, the conditioning regimen included busulfan, the time of ASCT to the onset of SFPR was 36 days, and intermediate-dose prednisolone (0.5 mg per kg) was effective for the elevation of his platelet count. These findings were compatible with those in the report by Wada et al. Thus, we considered that the cause of thrombocytopenia was probably SFPR.

In conclusion, we reported a second case of isolated parenchymal CNS recurrence of bilateral PTL successfully treated by ASCT with a conditioning regimen of thiotepa and busulfan. SFPR may occur after ASCT with a condition regimen using busulfan. Our patient maintained CMR for over three years after ASCT. High-dose chemotherapy with ASCT following a conditioning regimen of thiotepa and busulfan is beneficial for CNS recurrence of PTL as a consolidation therapy after CR is achieved by high-dose methotrexate-based chemotherapy.