Original ResearchIntravenous but not intrathecal central nervous system–directed chemotherapy improves survival in patients with testicular diffuse large B-cell lymphoma
Introduction
Primary testicular lymphoma is a rare malignancy with an estimated yearly incidence of less than 0.3/100,000 [1]. Testicular involvement is seen in 1–2% of patients with lymphoma. The median age of patients with testicular lymphoma is on the later 7th decade of life, and lymphoma is the most common testicular malignancy in men older than 50 years of age. Most lymphomas with testicular involvement represent diffuse large B-cell lymphoma (DLBCL) [1], [2], [3], [4].
Common prognostic factors of DLBCL, such as International Prognostic Index (IPI) and high tumour burden, have been shown to correlate with survival also in testicular DLBCL (T-DLBCL). However, even after aggressive chemotherapy relapse rate of T-DLBCL is higher and overall prognosis of T-DLBCL is worse than those of nodal DLBCL, relapses often occur in the central nervous system (CNS), and the prognosis for patients with CNS involvement is dismal [5], [6].
T-DLBCLs represent most commonly non–germinal centre B-cell (non-GCB) subtype [2]. BCL2 positivity is also common, whereas expression of BCL6 and MYC is infrequent [7]. Prognostic role of these three proteins remains to be shown. Molecular studies in T-DLBCL are still based on small series. Nevertheless, as recently elegantly summarised by Twa et al [8], T-DLBCL is likely to represent a biologically distinct lymphoma entity. In addition to the molecular features of the lymphoma cells, elements of the microenvironment have been shown to have prognostic impact [9], [10] and therapeutic potential [11].
T-DLBCL is considered a curable disease with modern treatment comprising anthracycline-based immunochemotherapy, CHOP (cyclophosphamide, Adriamycin, vincristine, prednisolone) with CD20 antibody rituximab (R--CHOP). However, the optimal therapy is unclear. As for many DLBCL subtypes, no randomised trials specifically in T-DLBCL have been conducted, and treatment guidelines are based on phase II trials [12], [13]. In addition to R--CHOP, eligible patients commonly receive CNS prophylaxis with either intravenous (i.v.) or intrathecal (i.t.) methotrexate (MTX) or cytarabine (AraC) [14]. Thus far, however, no prospective randomised studies on the benefit of this approach have been published. In a retrospective series of 373 patients from the prerituximab era, i.t. chemotherapy resulted in improved progression-free survival (PFS) without benefit in overall survival (OS) or disease-specific survival (DSS) rates [3]. Furthermore, the contralateral testis also serves as a sanctuary to lymphoma cells, leading to risk of testicular relapse after immunochemotherapy. Therefore, contralateral orchiectomy or irradiation is recommended for eligible patients [12], [15]. Owing to these recommendations, T-DLBCL is underrepresented in prospective clinical trials not allowing the use of CNS prophylaxis or irradiation, which may be the reason the testes were not recognised as a risk factor for CNS recurrence in the CNS-IPI model [16].
In the Nordic countries, the most applied current therapy for T-DLBCL consists of R--CHOP–/CHOP-like regimen in combination with systemic CNS prophylaxis (high-dose(HD)-MTX or HD-cytarabine) and prophylactic contralateral orchiectomy or irradiation. However, the efficacy of this approach has never been evaluated. In the present Nordic collaborative study looking at population-based cohorts from Denmark and Finland, we investigated the impact of different treatment eras on survival and risk of CNS progression in patients with T-DLBCL.
Section snippets
Patients
We searched for patients with T-DLBCL from the pathology databases of three Southern Finland University Hospitals and the Danish Lymphoma Registry. Only the patients with testicular involvement at primary diagnosis were included, and those with primary CNS lymphoma involvement were excluded. For the Finnish cohort, the clinical data were collected from patient records, and a tissue microarray (TMA) from the diagnostic tumour samples was assembled. The TMA was subjected to standard diagnostic
Baseline and treatment characteristics
Clinical data were available from 235 patients diagnosed with T-DLBCL between 1987 and 2013. The median age at diagnosis was 71 years (range, 37–93 years). Two hundred thirty-three patients (98%) underwent orchiectomy. The disease was limited to the testis in 95 (41%) patients and regarded as primary testicular (PT)–DLBCL (stage I-II) in 146 (63%) patients according to standard staging criteria. In eight patients (11%) of the Finnish cases (N = 75), both testes were affected, which was
Discussion
This is to our knowledge the largest cohort of patients with testicular DLBCL involvement reported so far covering both prerituximab and rituximab eras and characterised by a long-term follow-up and comprehensive clinical data. In our cohort, i.v. CNS-directed chemotherapy and prophylactic treatment of the contralateral testis were associated with favourable survival independently of classical risk factors. In the lack of prospective clinical trials, this type of real-life data may support
Acknowledgement
The authors thank Anne Aarnio and Marika Tuukkanen for technical assistance. This work was supported by grants from the Academy of Finland (to S.L.), Finnish Cancer Foundation (to S.L.), Sigrid Juselius Foundation (to S.L.), University of Helsinki (to S.L. and P.V.), Helsinki University Hospital (to S.L. and S.M) and Finnish Oncology Association (to M.P. and P.V.).
References (28)
- et al.
Primary testicular lymphoma
Blood
(2014) - et al.
The pathobiology of primary testicular diffuse large B-cell lymphoma: implications for novel therapies
Blood Rev
(2018) - et al.
PD-1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma
Blood
(2017) - et al.
Rituximab and dose-dense chemotherapy in primary testicular lymphoma
Clinical Lymphoma and Myeloma
(2009) - et al.
Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray
Blood
(2004) - et al.
Prognostic impact of activated B-cell focused classification in diffuse large B-cell lymphoma patients treated with R-CHOP
Mod Pathol
(2009) - et al.
CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group
Lancet Oncol
(2006) - et al.
CNS disease in younger patients with aggressive B-cell lymphoma: an analysis of patients treated on the Mabthera International Trial and trials of the German High-Grade Non-Hodgkin Lymphoma Study Group
Ann Oncol
(2012) - et al.
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) - et al.
Primary testicular diffuse large B-cell lymphoma: a population-based study on the incidence, natural history, and survival comparison with primary nodal counterpart before and after the introduction of rituximab
J Clin Oncol
(2009)
Primary testicular diffuse large B-cell lymphoma displays distinct clinical and biological features for treatment failure in rituximab era: a report from the International PTL Consortium
Leukemia
Patterns of outcome and prognostic factors in primary large-cell lymphoma of the testis in a survey by the international extranodal lymphoma study group
J Clin Oncol
Clinical and histological features of primary testicular diffuse large B-cell lymphoma: a single center experience in China
Oncotarget
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
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