Primary testicular lymphoma: the site matters

Primary testicular lymphoma (PTL) is a rare entity with distinct natural history and inferior outcome compared to nodal and other extranodal diffuse large B-cell lymphoma (DLBCL). This lymphoma is characterized by unique clinical features, including a tendency to recur in the contralateral testis, central nervous system (CNS), lung, pleura, and soft tissues, as well as the occurrence of late relapses without an apparent survival plateau. All the above imply that PTL has a distinct tumor biology calling for specific strategies for management.

Over the last several decades, the treatment and prognosis of patients with DLBCL have improved significantly, owing to incorporation of anthracyclines and the monoclonal antibody rituximab [1]. In contrast to other DLBCL, the relative rarity of PTL has hampered investigation in terms of prospective randomized clinical trials. Because of this, retrospective case series have formed a basis for comparison of different treatment modalities in PTL, leading to the development of a multimodality treatment approach consisting of surgical removal of the primary tumor, prophylactic radiotherapy to the contralateral testis, and intrathecal chemotherapy prophylaxis, in addition to systemic combination chemotherapy. However, controversies regarding the optimal management of both early and advanced disease still remain, and a significant number of patients eventually relapse and succumb to the disease.

Mazloom et al. [2] retrospectively analyzed the clinicopathologic characteristics and outcomes of 75 patients with PTL treated at a single institution, with particular attention given to the impact of changes in the therapeutic approach on patient outcome over more than four decades. Their results confirm that advanced stage disease, elevated serum lactate dehydrogenase (LDH) level, the presence of B symptoms, and high-intermediate and high International Prognostic Index (IPI) all score as negative prognostic factors for both progression-free survival (PFS) and overall survival (OS), confirming the findings of other investigators [3]. The authors also demonstrate significant improvements in 5-year OS for both early and advanced stage disease, depending on the era of treatment. This study does not show what impact the addition or omission of radiotherapy has had on patient outcomes in the different treatment eras, nor do the data demonstrate a benefit for prophylactic intrathecal chemotherapy. Interestingly, the results of Mazloom et al. do not reveal significant differences in PFS since the introduction of rituximab, which raises the question of whether the observed differences in OS may actually be attributable to factors other than the use of rituximab, such as the development of more effective treatment modalities for relapsed disease. Overall, the findings from this single-institution analysis confirm prior observations from the pre-rituximab area; however, a number of important questions regarding PTL and its optimal treatment still remain unanswered.

While several retrospective studies from other medical centers [3–5] have also indicated that treatment with anthracycline-based chemotherapy in addition to standard orchiectomy and local or regional irradiation improves relapse-free survival in PTL, other investigators [6–8] have been unable to confirm such a benefit. In the light of this, we may indeed speculate whether these discrepancies are due to differences in dose administration or delays of chemotherapy, inconsistent application of additional radiotherapy, insufficient numbers of studied subjects, or differences in the underlying biology of the testicular tumors. There are also conflicting data in the literature regarding the potential role of rituximab in conferring an additional survival benefit over anthracycline-based chemotherapy alone, and this issue should be addressed in a prospective randomized trial. However, due to the rarity of PTL and the universal use of rituximab, it is unlikely that such a study will ever be performed. A recent report from the Surveillance, Epidemiology, and End Results (SEER) database [9] has provided a substantial body of evidence on the epidemiology, survival trends, and clinical outcome of 769 patients with PTL between 1980 and 2005. While the disease incidence has been increasing, both median OS and disease-specific survival (DSS) for all stages were actually superior for patients with nodal DLBCL compared to PTL (4.6 years vs. 1.8 years), illustrating the continuous risk of late disease-related deaths in the latter entity. Moreover, there was no improvement in DSS recorded in patients with testicular DLBCL after the year 2000, whereas in nodal DLBCL, DSS improved dramatically, presumably reflecting the impact of rituximab. These observations are in keeping with those of Mazloom et al., and since follow-up after 2000 is relatively short, it remains to be seen whether the occurrence of late relapses in patients from the SEER database is affected by the addition of rituximab.

As discussed by Mazloom et al., the efficacy of prophylactic radiotherapy in preventing lymphoma recurrence in the contralateral testis has been convincingly demonstrated in a number of studies. Nevertheless, there is currently no evidence in the literature to show that the administration of prophylactic intrathecal chemotherapy reduces the risk of CNS recurrence in patients with PTL, since a significant proportion of CNS relapses are located in the brain parenchyma, and occur up to 10 years after initial presentation. Some authors have advocated the use of intermediate- or high-dose methotrexate as part of the initial treatment for patients with advanced stage or high-risk PTL [3], and this approach is currently being prospectively investigated by the International Extranodal Lymphoma Study Group (IELSG).

How could we further improve the outcome of patients with PTL? Improved understanding of the underlying tumor biology may lead to the discovery of molecules that could be targeted specifically and novel treatment approaches, while identification of reliable prognostic biomarkers would help in patient risk stratification and allow for the development of individualized therapy. Currently, such investigations are ongoing, but are still far from being translated into differentiated therapeutic approaches. A few studies dealing with small numbers of patients with PTL have demonstrated a predominance of the prognostically unfavorable non-germinal center subtype, but the currently available data do not allow any conclusions to be drawn regarding differences in survival [10,11]. In view of the consistently observed high rate of extranodal relapses and the unique predilection for sanctuary sites, it must be assumed that other tumor features, such as the lack of expression of adhesion molecules and major histocompatibility antigens, contribute to this phenomenon and have a major impact on patient outcome. Further investigations are clearly needed to elucidate the molecular biology and validate prognostic tissue markers in this rare subtype of DLBCL.