Patterns of Outcome and Prognostic Factors in Primary Large-Cell Lymphoma of the Testis in a Survey by the International Extranodal Lymphoma Study Group

Journal of Clinical Oncology, Vol 21, Issue 1 (January), 2003: 20-27

To determine clinical features and patterns of outcome of primary testicular diffuse large B-cell lymphomas (DLCL). Patients and Methods: A retrospective international survey of 373 patients with primary testicular DLCL.

Results: Most patients presented with localized disease (stage I to II), and the median age at diagnosis was 66 years (range, 19 to 91 years). Anthracycline-based chemotherapy was administered to 255 patients (68%), and prophylactic intrathecal chemotherapy was given to 68 patients (18%); 133 patients (36%) received prophylactic scrotal radiotherapy. Median overall survival was 4.8 years, and median progression-free survival was 4 years. The survival curves showed no clear evidence of a substantial proportion of cured patients. A favorable international prognostic index score (IPI), no B-symptoms, the use of anthracyclines, and prophylactic scrotal radiotherapy were significantly associated with longer survival at multivariate analysis. However, even for patients with stage I disease and good-risk IPI, the outcome seems worse than what was reported for DLCL at other sites. At a median follow-up of 7.6 years, 195 patients (52%) had relapsed. Extranodal recurrence was reported in 140 cases. Relapses in CNS were detected in 56 patients (15%) up to 10 years after presentation. A continuous risk of recurrence in the contralateral testis was seen in patients not receiving scrotal radiotherapy.      Because patients were treated according to the current policy of each institution at the time of diagnosis, there is a wide range of radiotherapy doses (from 18 to 50 Gy) and fields (from scrotal only to a variety of extended fields with or without contralateral testis) among the 196 patients who received radiotherapy.

Conclusion: Testicular DLCL is characterized by a particularly high risk of extranodal relapse even in cases with localized disease at diagnosis. Anthracycline-based chemotherapy, CNS prophylaxis, and contralateral testicular irradiation seem to improve the outcome. Their efficacy is under evaluation in a prospective clinical trial.

Before the widespread use of anthracycline chemotherapy, patients with stage I and II testis lymphomas were managed mainly with postorchiectomy radiotherapy to the para-aortic and pelvic lymph nodes. At present, radiotherapy to the retroperitoneal nodes has largely been abandoned in stage I patients, but it is generally given to stage II patients as part of the combined-modality approach recommended in stage II DLCL presenting in other sites. Unfortunately, the wide variability of doses and fields in our retrospective analysis prevented a reliable study of the impact of retroperitoneal radiotherapy in localized testis lymphomas, although the prognostic impact of this strategy seems to be dose-dependent.

A substantial rate of failure in the contralateral testis has been reported in the literature, and it has been confirmed in our cases where continuous high risk of recurrence in the contralateral testis is documented in patients not receiving prophylactic scrotal radiotherapy . Our data confirm that low-dose radiotherapy to the contralateral testis, which has been recommended by some authors for all patients with primary testis lymphoma,could reduce the risk of failure at this site.

Distant extranodal failures, especially in the CNS, remain a major problem, even in patients who receive a full course of doxorubicin-based chemotherapy. The issue of optimal treatment of patients at the time of isolated CNS relapses is unresolved. Whole-brain radiotherapy is most often used; however, this treatment has substantial potential neurotoxicity, especially in the elderly. A recent report indicates that high-dose intravenous methotrexate alone might be a feasible and effective alternative to whole-brain radiotherapy. The high rate of CNS progression observed in historical series has led to a recommendation for routine CNS prophylaxis with at least intrathecal chemotherapy.The value of intrathecal chemotherapy, introduced as a prophylactic measure in the 1990s, is still controversial because CNS failures occur more frequently in brain parenchyma than in meninges, and CNS relapses have been observed also in patients who received intrathecal chemotherapy. A clear propensity for parenchymal involvement is confirmed in our study  and is in marked contrast to primary nodal DLCL, where the CNS relapse rate is below 5% and the leptomeninges are the dominant site of involvement.In our series, intrathecal chemotherapy was associated with an improved PFS; however, its direct effect on preventing CNS relapses was not statistically significant, possibly because of the low number of patients who received such treatment (80% of CNS relapses did not receive any intrathecal prophylaxis).

The use of high-dose methotrexate to deliver parenchymal CNS prophylaxis has been shown to be effective among patients with primary nodal lymphomas but is not always practical or feasible in elderly patients, and even the delivery of standard intrathecal chemotherapy is often problematic. In this series, only 29 patients (8%) received high-dose intravenous methotrexate as CNS prophylaxis, apparently with no evidence of any benefit in either reducing CNS relapses or prolonging survival; but again, the small number of treated cases does not allow any conclusions to be drawn. On the contrary, the small subset of patients who received aggressive systemic chemotherapy and complete prophylaxis (intrathecal chemotherapy and scrotal irradiation) showed a significantly better outcome, with a 3-year actuarial OS rate of 88%. However, their median follow-up is short, a possible selection bias cannot be ruled out, and the efficacy of this policy has yet to be validated in prospective clinical trials.

In conclusion, this retrospective IELSG survey represents the largest body of information on outcomes of patients with testis lymphoma to date. It confirms the findings of smaller studies and provides interesting data concerning the best treatment strategy, but because of its retrospective nature, it does not provide a definitive answer as to the optimal approach to this disease.

The management of patients with testicular lymphoma presents several challenges. Because of the poor prognosis, an aggressive treatment approach is warranted. However, testicular lymphoma is predominantly a disease of older men who often have limited ability to tolerate aggressive treatment. Improved understanding of the genetic and molecular characteristics of testicular lymphoma may help in the future to identify patients at risk of CNS failure and to tailor the treatment to the individual patient.

The rarity of the disease makes randomized trials virtually impossible. Hence, an international collaboration is crucial to properly address the management of testicular lymphoma. On the basis of the results of this study, an international prospective trial has been launched by the IELSG to assess the feasibility and efficacy of prophylactic radiotherapy to the contralateral testis and intrathecal methotrexate in addition to rituximab plus CHOP chemotherapy. This study should test the results of this retrospective analysis and can provide further evidence to support the use of systemic chemotherapy and complete prophylaxis (intrathecal chemotherapy and scrotal irradiation), thus helping to define some standard guidelines for the management of testicular DLCL. We are aware that the potential benefit of rituximab for a lymphoma arising in immune privileged sites remains questionable (despite data suggesting its crossing of the blood-brain barrier, it does not seem to penetrate into CNS well when administered intravenously, and its intrathecal administration is poorly studied). However, the association of rituximab plus CHOP has been shown to be significantly better than CHOP alone,and it is considered the standard treatment of DLCL at any site in several institutions. Given the observed propensity for parenchymal involvement of CNS relapses, other regimens, capable of circumventing the blood-brain barrier, might be more appropriate in view of the CNS penetration of methotrexate and cytarabine, but it may be difficult to test an aggressive regimen in a large multicentric study of mainly elderly patients.

Outcome and patterns of failure in testicular lymphoma: a multicenter rare cancer network study .
Zouhair.IJROBP 2002;52:652

Primary extranodal lymphoma of the testis is a lethal disease, second only to primary brain lymphoma; median survival is 12 to 24 months. It accounts for approximately 1% of non-Hodgkin’s lymphomas, 4% of all extranodal non-Hodgkin’s lymphomas, and 5% of all testicular malignancies . Primary testicular lymphoma is essentially an intermediate or high-grade lymphoma, and diffuse large-cell type is the most common . In contrast to other testicular malignancies, primary testicular lymphoma occurs mostly in patients older than 50 years of age. After adequate locoregional and systemic treatment, central nervous system (CNS) remains the most frequent site of recurrence (up to 30%). Therefore, prophylactic intrathecal (IT) chemotherapy (CT) combined with systemic treatment has been introduced to improve outcome

To assess the outcome and patterns of failure in patients with testicular lymphoma treated by chemotherapy (CT) and/or radiation therapy (RT). Data from a series of 36 adult patients with Ann Arbor Stage I ( n = 21), II ( n = 9), III ( n = 3), or IV ( n = 3) primary testicular lymphoma, consecutively treated between 1980 and 1999, were collected in a retrospective multicenter study by the Rare Cancer Network. Median age was 64 years (range: 21–91 years).  Most patients ( n = 29) had CT, consisting in most cases of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) with ( n = 17) or without intrathecal CT. External RT was delivered to scrotum alone ( n = 12) or testicular, iliac, and para-aortic regions ( n = 8). The median RT dose was 31 Gy (range: 20–44 Gy) in a median of 17 fractions (10–24), using a median of 1.8 Gy (range: 1.5–2.5 Gy) per fraction. The median follow-up period was 42 months (range: 6–138 months).

External radiation therapy was given to 22 (61%) patients  . Irradiation volume consisted of the scrotum alone in 13 patients (bilateral in all) and the scrotal, iliac, and para-aortic regions in 9 patients (4 Stage I, 5 Stage II). Megavoltage photons and/or electrons were used in all patients. . A median total dose of 31.0 Gy (range: 20.0–44.0 Gy) was given in a median of 1.8 Gy/fraction (range: 1.5–2.5 Gy/fraction) over a median period of 26 days (range: 12–42 days). One patient received prophylactic whole-brain radiotherapy to a total dose of 12 Gy in 6 fractions.

After a median period of 11 months (range: 1–76 months), 14 patients presented lymphoma progression, mostly in the central nervous system (CNS) ( n = 8). Among the 17 patients who received intrathecal CT, 4 had a CNS relapse ( p = NS). No testicular, iliac, or para-aortic relapse was observed in patients receiving RT to these regions. The 5-year overall, lymphoma-specific, and disease-free survival was 47%, 66%, and 43%, respectively. In univariate analyses, statistically significant factors favorably influencing the outcome were early-stage and combined modality treatment. Neither RT technique nor total dose influenced the outcome. Multivariate analysis revealed that the most favorable independent factors predicting the outcome were younger age, early-stage disease, and combined modality treatment.

In this multicenter retrospective study, CNS was found to be the principal site of relapse, and no extra-CNS lymphoma progression was observed in the irradiated volumes. More effective CNS prophylaxis, including combined modalities, should be prospectively explored in this uncommon site of extranodal lymphoma.

a) Overall survival according to treatment modality (CT + RT vs. other) in 36 patients with testicular lymphoma ( p = 0.06, log-rank test. (b) Disease-free survival (DFS) according to treatment modality (CT + RT vs. other) in 36 patients with testicular lymphoma

Primary testicular non-Hodgkin’s lymphoma is an uncommon disease, and its treatment is not standardized. Orchidectomy is the standard initial treatment of suspected primary tumors of the testis . Lymphomas are the most frequent cause of testicular tumors in men more than 50 years of age  . In our series, the median age was 64 years (range: 21–91 years).

The prognosis of testicular lymphoma is relatively poor compared to other nodal or extranodal lymphomas . Because of the rarity of this disease, the majority of the patients reported in retrospective series were probably not staged completely as recommended, which may reflect the poor outcome  . Even in our series, a full staging workup could not be completed in 50% of patients.

The overall poor outcome of this disease has been linked to various prognostic factors, including advanced age at presentation , constitutional symptoms , bulky primary tumor , spermatic cord involvement , presence of vascular invasion  , and degree of sclerosis . The most important predictive factors are the stage and pathologic grading  . Patients with Stage IE and IIE disease have better outcome than those with advanced-stage disease .

Among the various prognostic factors studied in our series, i.e., age, stage, spermatic cord infiltration, grade, LDH, ß-2-microglobulin, and type of treatment, only younger age and early stage were independent prognostic factors influencing favorably the overall and disease-free survival. These two factors are part of the International Prognostic Index .

The universally accepted treatment modality for Stage I and II aggressive nodal lymphoma is combined chemotherapy and radiation therapy  However, an optimal treatment approach has not been defined for extranodal lymphomas. Neither have randomized studies been performed evaluating the superiority of combined modality treatment to RT or CT alone, especially in testicular lymphoma. Connors  , in their study of 15 patients with Stage I and II disease given combined modality treatment, observed 93% actuarial relapse-free survival. However, in a retrospective study by Fonseca that included 62 patients, no beneficial effect of combined treatment compared to single modality was observed. In their study, only 10 patients, including 3 with Stage I disease, received combined modality treatment. Moreover, only 4 patients received IT-CT, and 2 of these already had leptomeningeal involvement at diagnosis. It is, therefore, difficult to draw a conclusion about the inefficiency of combined treatment.

In the present series, univariate analyses revealed that patients treated with combined CT and RT did better than those treated with CT or RT alone in terms of overall, disease-free, and lymphoma-specific survival. Moreover, multivariate analysis revealed that combined treatment was an independent factor for lymphoma-specific survival.

The patterns of failure after the initial treatment of testicular lymphoma include mainly the CNS, contralateral testis, Waldeyer’s ring, skin, pleura, lung, liver, spleen, bone, and bone marrow  . Lymphoma progression is rarely observed in irradiated volumes . CNS relapse, both as intracerebral and/or leptomeningeal, was reported by many authors, with an incidence of up to 30% . IT-CT is indicated in patients with proven leptomeningeal involvement . The role of CNS prophylaxis in patients without CNS involvement remains to be proven, and its beneficial effect is still controversial . It may be important to distinguish intraparenchymal failures from the leptomeningeal ones, which are rarely detailed in the literature.

In our series, no patients relapsed in irradiated volumes. The majority of relapses (12 out of 14) were in extranodal sites. Eight (22%) patients had CNS relapse: 4 intracerebral and 4 leptomeningeal. Half ( n = 4) of these relapses were at the unique site of lymphoma progression. IT-CT did not significantly prevent CNS relapse: Of the 17 patients who received prophylactic IT-CT, 4 patients relapsed (intracerebral in 2, meningeal in 2), whereas of the 19 patients who did not have prophylactic IT-CT, a total of 4 also relapsed (intracerebral in 2, meningeal in 2).

In this retrospective multicentric study including patients with primary testicular lymphoma, we conclude that CNS is the principal site of relapse, and no lymphoma progression was observed in irradiated volumes. Patients treated with combined modality, including chemotherapy and radiation therapy, did better than those treated with a single modality. On the other hand, to prevent intraparenchymal failure, more effective CNS prophylaxis, such as low-dose whole-brain irradiation or high-dose methotrexate, must be prospectively explored.