Primary testicular lymphoma (PTL) is a rare, clinically aggressive form of extranodal lymphoma. The vast majority of cases are histologically diffuse large B-cell lymphoma, but rarer subtypes are clinically important and must be recognized. In this review, we discuss the incidence, clinical presentation, and prognostic factors of PTL and present a summary of the recent advances in our understanding of its pathophysiology, which may account for the characteristic clinical features. Although outcomes for patients with PTL have historically been poor, significant gains have been made with the successive addition of radiotherapy (RT), full-course anthracycline-based chemotherapy, rituximab and central nervous system–directed prophylaxis. We describe the larger retrospective series and prospective clinical trials and critically examine the role of RT. Although rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone given every 21 days with intrathecal methotrexate and locoregional RT is the current international standard of care, a substantial minority of patients progress, representing an unmet medical need. Finally, we discuss new treatment approaches and recent discoveries that may translate into improved outcomes for patients with PTL.

Primary testicular lymphoma (PTL) is an uncommon and aggressive form of extranodal non-Hodgkin lymphoma (NHL) accounting for <5% of testicular malignancies and 1% to 2% of NHL cases.1  With a median age at diagnosis of 66 to 68 years,2-5  PTL is both the most common testicular malignancy in men age >60 years and the most common bilateral testicular neoplasm.6  Population-based studies have estimated the annual incidence at 0.09 to 0.26 per 100 000 population.1,7 

Clinical features, risk factors, and etiology

Typical presentation consists of a firm, painless testicular mass without preference for either side, inseparable from the affected testis, with median tumor size at presentation of 6 cm.8  There is an associated hydrocele in ∼40% of cases.2  Synchronous bilateral involvement occurs in 6% to 10% of cases.7,9  Constitutional symptoms at diagnosis are uncommon, but if they are present, they strongly suggest systemic disease, which is present in 20% to 30% of patients.7,9  PTL has marked extranodal tropism, and relapses frequently involve sites including the central nervous system (CNS), skin, contralateral testis, and pleura.3,5,10-12  Although there are limited data regarding specific risk factors for PTL, HIV infection is a known risk factor for aggressive NHL, with lymphomas in HIV-infected patients more commonly presenting with extranodal primary sites, including the testis.13  HIV-positive patients with PTL are younger (median age, 36 years) with immunoblastic, plasmablastic, or Burkitt-like histology being more frequent, along with a median overall survival (OS) <6 months prior to use of combined antiretroviral therapy.14  Although data are scarce, it is likely that since the introduction of combined antiretroviral therapy, outcomes for HIV-positive patients with PTL have improved in line with nodal diffuse large B-cell lymphoma (DLBCL).15 

There are several putative mechanisms for the link between PTL and CNS relapse. This may in part reflect the biologic characteristics of tumors arising in an immune privileged site. Lymphomas arising under the selective pressure of immune surveillance may develop an immune escape phenotype.16  Common to both PTL and primary CNS lymphoma (PCNSL) are high levels of immunoglobulin variable region heavy chain gene somatic hypermutation17  and loss of human leukocyte antigen expression resulting from gene deletions,18,19  which may assist evasion of the host antitumor response. In addition, a nascent PTL clone may benefit from developing in an immune privileged site behind the blood-testis barrier, which has several components designed to shield developing gametocytes. These include (1) a mechanical barrier formed by the tight junction between Sertoli and endothelial cells preventing the passage of large/hydrophilic molecules,20  (2) an efflux pump (P-glycoprotein; MRP1) for smaller/lipophilic molecules, (3) an immunologic barrier formed by Sertoli cells that hinders the passage of antibodies,21  and (4) local production of anti-inflammatory cytokines.22 

Menter et al23  studied 45 cases of PTL by using immunohistochemistry (IHC) and fluorescence in situ hybridization, finding low levels of p53 expression but high levels of phosphorylated STAT3 (pSTAT3), overexpression of pCXCR4, and upregulation of the nuclear factor κB (NF-κB) pathway. Although few patients had clinical outcome data available, expression of both CXCR4 and pCXCR4 was predictive of inferior progression-free survival (PFS) (P = .007). Little is known about the role of CXCR4 expression in lymphoma, although the chemokine receptor has myriad biologic functions, including trafficking of lymphocytes to sites of inflammation, hematopoietic cell homing, trafficking of tumor cells to target organs, proliferation and directed migration of neuronal cells, and infiltration of activated monocytes to areas of ischemic injury.24  Preclinical models have shown that directed metastasis is mediated by CXCR4 activation and migration toward CXCR12-expressing target organs.24  Thus, overexpression of CXCR4 may predispose PTL toward extranodal relapse.

Imaging modalities that may assist in diagnosis include ultrasonography, which demonstrates focal or diffuse areas of hypoechogenicity with hypervascularity in an enlarged testis,25,26  and magnetic resonance imaging, which allows simultaneous evaluation of both testes, paratesticular spaces, and spermatic cord; typical findings include T2 hypointensity and strong heterogeneous gadolinium enhancement.27  When PTL is suspected, inguinal orchiectomy is required for achievement of optimal disease control and adequacy of a pathologic specimen. In view of the rarity of PTL and frequent presentation to nonhematologists, it is important that the appropriate IHC be performed (see “Pathology”) and that expert pathology review is sought for difficult cases, because distinguishing some cases from seminoma can be difficult.28 

Recommended staging is the same as that for other forms of aggressive NHL (positron emission tomography-computed tomography, bone marrow biopsy) with the addition of specific CNS staging with lumbar puncture for cerebrospinal fluid analysis by cytology and flow cytometry (since there is evidence to support improved sensitivity29 ) and brain magnetic resonance imaging. We recommend thorough examination of the skin because cutaneous DLBCL (leg type) and testicular DLBCL have been concurrently reported,30  and the skin is a potential site of extranodal recurrence. HIV serology should be performed. As with other forms of NHL, the Ann Arbor system is used for staging, although it was not specifically designed for extranodal lymphomas. Patients with isolated bilateral involvement of the testes have a prognosis similar to that of patients with stage I/II disease31 ; therefore, we agree with existing recommendations that such cases be considered stage I.32  In the largest series, 60% to 79% of patients were stage I/II at presentation,3,7,11,33  although from a pragmatic perspective, patients with stage III/IV PTL can be considered identical to patients with systemic nodal DLBCL with secondary testicular involvement. Distinguishing between the two entities is difficult and somewhat arbitrary, because it usually cannot be determined in retrospect whether the testicular mass was truly the initial site of disease, and the prognoses for both are similar.7 

The large majority of PTLs (80% to 98%) are DLBCLs, although patients with HIV infection often present with more aggressive variants. DLBCL-type PTL typically expresses B-cell markers CD19, CD20, CD79a, and PAX5; Bcl-2 protein is expressed in 70% of cases, but Bcl-6 is rarely positive.23  The median MIB1 proliferative index is 40%, and in the non-HIV population, Epstein-Barr virus is usually negative.23  Rare histologies include mantle cell lymphoma,34-36  extranodal natural killer–cell lymphoma,37  peripheral T-cell lymphoma,38  extranodal marginal zone lymphoma,39  and activin receptor-like kinase-1–negative anaplastic large cell lymphoma.40 

Pediatric follicular lymphoma of the testis

Pediatric follicular lymphoma (FL), a rare entity, deserves special mention, because it appears to have characteristics distinct from nodal FL and requires a distinct management approach. Of the 15 cases reported, typical features included grade 3A morphology, stage IE disease, expression of CD10 and Bcl-6 by IHC but lack of Bcl-2 protein expression or BCL2 gene rearrangement and indolent clinical behavior.41-45  In contrast, adults with primary FL of the testis are reported to bear the BCL2 gene rearrangement and overexpress Bcl-2 protein.41  The optimal therapy is unclear, with most patients treated with orchiectomy plus abbreviated anthracycline-containing chemotherapy. However, two patients were managed with surgery alone and remained in ongoing clinical remission at 30 and 96 months.45,46  Although data are scarce, outcomes appear favorable without reports of CNS relapses to date.

Cell-of-origin studies and chromosomal translocations

In PTL with DLBCL histology, cell of origin determined by either IHC-based algorithms47  and/or DNA microarray is activated B-cell–like (ABC) in 60% to 96% of cases.4,36,48-50  The variation in frequency is dependent on both the proportion of patients with advanced-stage disease (in which it is difficult to distinguish PTL from nodal DLBCL with testicular metastases) and the IHC algorithm used.47  The true proportion of cases that are ABC type is likely to be at the higher end of the published estimates, because even though 6% to 36% of cases are CD10+ in published series36,48,50  and are classified as germinal center B-cell–like by the Hans algorithm,47  many also express the B-cell activation marker MUM1. Some scoring systems consider such cases to be ambiguous, fitting neither the ABC nor the germinal center B-cell–like subtype.51  Booman et al48  determined cell of origin by using both IHC and gene expression profiling. By IHC, 14 (64%) were clearly ABC type (CD10Bcl-6+/−MUM1+); however, 8 (36%) were classified as ambiguous (CD10+Bcl-6+MUM1+), and 7 (88%) of 8 of these ambiguous cases were reclassified as ABC type by gene expression analysis. This predominance of ABC type may partially account for the historically poor outcomes from PTL.52  Recent data in nodal DLBCL suggest that the adverse outcome conferred by the ABC subtype may be attributable to chronic active B-cell receptor signaling and constitutive NF-κB and PI3K activation.53  Interestingly, a large international consortium found that coexpression of MYC and Bcl-2 protein contributed to the inferior survival of ABC-type nodal DLBCL.54  However, the limited data available suggest that the frequency of either a proteomic or a cytogenetic double hit with MYC and Bcl-2 in PTL is low. Bernasconi et al55  performed cytogenetic analyses by using split-signal fluorescence in situ hybridization probes in 16 patients with PTL, finding 3 cases (19%) bearing MYC translocations. Menter et al23  found that only 5 (13%) of 38 PTL cases expressed c-myc protein, but all 5 also expressed Bcl-2 protein. Finally, the dependence of ABC-type DLBCL on MYD88, an adaptor protein which acts through Toll-like receptor and interleukin-1 receptor, was recently described.56  Kraan et al57  found mutations in MYD88 in >70% of PTL and PCNSL but in <20% of patients with nodal DLBCL, providing further evidence for differences in pathophysiology.

Numerous prognostic factors for PTL have been described, largely derived from small retrospective series, often including patients who had disseminated disease with testicular involvement. Thus, although the International Prognostic Index (IPI) and its components have been frequently reported as prognostic factors, they are surrogate markers of high tumor burden and disseminated disease. For the majority of patients with PTL who present with limited-stage disease, the IPI is typically <2 and therefore has limited prognostic utility.58  The adverse prognostic markers for PFS are summarized in Table 1; those for OS are similar with one study also identifying infiltration of adjacent tissues.59  The impact of non-DLBCL histology is difficult to determine because of the rarity of such cases. A Dutch series found evidence that transformed extranodal marginal zone lymphoma was associated with smaller tumor size, less frequently elevated lactate dehydrogenase, absence of B symptoms, more frequent stage IE disease, lower IPI than pure DLBCL, and a nonsignificant trend toward improved survival.39 

Table 1

Prognostic factors for PFS identified in PTL

Adverse prognostic factors for PFS in studies of PTLReferences
Age >70 y 
Advanced stage 7, 11, 12, 64 
B symptoms 11, 12, 92 
ECOG performance status >1 11, 92 
>1 extranodal site 68 
Involvement of extranodal sites other than testis 11, 68 
Tumor diameter >10 cm 11 
Raised serum LDH 11, 12 
Raised serum β2-microglobulin 11, 12 
Hypoalbuminemia 
Involvement of the left testis 7, 92, 93 
Adverse prognostic factors for PFS in studies of PTLReferences
Age >70 y 
Advanced stage 7, 11, 12, 64 
B symptoms 11, 12, 92 
ECOG performance status >1 11, 92 
>1 extranodal site 68 
Involvement of extranodal sites other than testis 11, 68 
Tumor diameter >10 cm 11 
Raised serum LDH 11, 12 
Raised serum β2-microglobulin 11, 12 
Hypoalbuminemia 
Involvement of the left testis 7, 92, 93 

ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase.

A particular characteristic of PTL is the temporal pattern of continuing relapses, even >15 years after initial treatment, which frequently involves sanctuary sites such as the contralateral testis and CNS.3  Relapses often occur at multiple extranodal sites, including lung, soft tissue, adrenal glands, liver, and bone marrow.3,5,11,12  The crude incidence of CNS involvement in PTL has been reported in smaller series as up to 44%, although estimates vary widely and use of CNS-directed prophylaxis was typically nonuniform.3,5,12,33,60  The best estimate of risk in the prerituximab era is from the large, retrospective International Extranodal Lymphoma Study Group (IELSG) series of 381 patients with PTL.11  The 5- and 10-year actuarial risks of 19% and 34% are substantially greater than those for nodal DLBCL (Figure 1).61  As is the case in nodal DLBCL,62  CNS parenchymal relapse is more frequent than leptomeningeal relapse; in the IELSG series, 64% of CNS relapses involved brain parenchyma, and 61% were isolated to the CNS, consistent with other series.11 

Systemic therapy (chemotherapy and rituximab)

Historically the outcome of PTL has been inferior to that of nodal DLBCL with no plateau in PFS and OS curves in retrospective studies (Table 2).4,5,9,11,12,33,63  As previously outlined, orchiectomy alone is indicated for both diagnostic and therapeutic purposes. However, outcomes of patients treated with orchiectomy and/or radiation alone are poor.7,64  Many chemotherapy strategies have been used, but the rarity of the tumor has prevented the conduct of prospective randomized comparisons among chemotherapy strategies. Thus, the available data are drawn from either nonrandomized phase 2 studies or from retrospective series.

Table 2

Selected retrospective studies containing ≥10 patients with testicular lymphoma

ReferenceYearNo. of patientsMedian age (range), yearsDLBCL (%)CNS prophylaxis and no. of patients (%)Adverse prognostic factorsNo. of patients with CNS relapse (%)Outcome
PFSOS
1994 39 73 (10-86) 91 N/R — Stage III/IV N/R 5-y OS, 17% 
Poor ECOG PS 
 LDH 
B symptoms 
2000 62 68 76 IT MTX 4 (6)  RT alone 13 (32) Median DFS/OS, 2.7 y 
2001 25 69 100 IT MTX 2 (3) Albumin <35 g/L  0/2 IT; 2/23 no IT 3-y EFS, 23%; 10-y OS, 32% 
11 2003 373 66 (19-91) 100 IT CT 73 (20) Stage III/IV Stage III/IV 5 y (19) 5-y PFS, 48% 
ECOG PS >1 ECOG PS >1 10 y (34) 5-y OS, 48% 
B symptoms B symptoms 
LDH LDH 
Extranodal sites other than testis Extranodal sites other than testis 
CNS involvement CNS involvement 
β2m β2m 
Bulk >10 cm Bulk >10 cm 
IPI high IPI high 
No anthracycline No anthracycline 
<4 cycles IT CT <4 cycles IT CT 
No prophylactic scrotal RT No prophylactic scrotal RT 
Age >60 y 
64 2007 45 59 (40-81) 91 IT MTX 6 (13) Stage ≥II Stage ≥II 2/6 IT Median PFS, 1.3 y 
 No involved field RT 7/39 no IT Median OS, 2.8 y 
 
2009 769 68 100 Unknown Diagnosis pre-1986 Diagnosis pre-1986 Unknown 5-y DSS, 62% 
Age >70 y Age >70 y 
Stage III/IV Stage III/IV 
Therapy other than surgery and RT Therapy other than surgery and RT 
Left testis 
12, 94 1995, 2010 75 62 (22-82) 100 IT CT 30 (40) Stage III/IV Stage III/IV IT (9) 5-y OS, 87% (R-CHOP) 
LDH LDH No IT (16) (P = .397) 52% (CHOP-like) 
B symptoms B symptoms 15% (no anthracycline) 
IPI high IPI high 
β2m 
ReferenceYearNo. of patientsMedian age (range), yearsDLBCL (%)CNS prophylaxis and no. of patients (%)Adverse prognostic factorsNo. of patients with CNS relapse (%)Outcome
PFSOS
1994 39 73 (10-86) 91 N/R — Stage III/IV N/R 5-y OS, 17% 
Poor ECOG PS 
 LDH 
B symptoms 
2000 62 68 76 IT MTX 4 (6)  RT alone 13 (32) Median DFS/OS, 2.7 y 
2001 25 69 100 IT MTX 2 (3) Albumin <35 g/L  0/2 IT; 2/23 no IT 3-y EFS, 23%; 10-y OS, 32% 
11 2003 373 66 (19-91) 100 IT CT 73 (20) Stage III/IV Stage III/IV 5 y (19) 5-y PFS, 48% 
ECOG PS >1 ECOG PS >1 10 y (34) 5-y OS, 48% 
B symptoms B symptoms 
LDH LDH 
Extranodal sites other than testis Extranodal sites other than testis 
CNS involvement CNS involvement 
β2m β2m 
Bulk >10 cm Bulk >10 cm 
IPI high IPI high 
No anthracycline No anthracycline 
<4 cycles IT CT <4 cycles IT CT 
No prophylactic scrotal RT No prophylactic scrotal RT 
Age >60 y 
64 2007 45 59 (40-81) 91 IT MTX 6 (13) Stage ≥II Stage ≥II 2/6 IT Median PFS, 1.3 y 
 No involved field RT 7/39 no IT Median OS, 2.8 y 
 
2009 769 68 100 Unknown Diagnosis pre-1986 Diagnosis pre-1986 Unknown 5-y DSS, 62% 
Age >70 y Age >70 y 
Stage III/IV Stage III/IV 
Therapy other than surgery and RT Therapy other than surgery and RT 
Left testis 
12, 94 1995, 2010 75 62 (22-82) 100 IT CT 30 (40) Stage III/IV Stage III/IV IT (9) 5-y OS, 87% (R-CHOP) 
LDH LDH No IT (16) (P = .397) 52% (CHOP-like) 
B symptoms B symptoms 15% (no anthracycline) 
IPI high IPI high 
β2m 

β2m, β-2-microglobulin; CT, chemotherapy (various); DFS, disease-free survival; DSS, disease-specific survival; EFS, event-free survival; IT, intrathecal; MTX, methotrexate; N/R, not reported; PS, performance status.

The outcome of patients with PTL has been gradually improving. A retrospective MD Anderson Cancer Center (MDACC) series showed incremental improvements in PFS and OS over time with refinement of treatment strategy (Figure 2).12  This trend is mirrored by the Surveillance, Epidemiology, and End Results registry in which analysis by treatment era (defined by 5-year intervals) showed incremental improvements in OS, with a median OS of 1.8 years for patients diagnosed in 1980-1985 but median not yet reached for those diagnosed 20 years later (5-year disease-specific survival, 62.4%).7  On the basis of nodal DLBCL, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) at 21-day intervals was the most widely used regimen for PTL prior to the introduction of rituximab, achieving 5-year OS of 30% to 52%.12,65  Attempts to improve on this with the addition of bleomycin,10,66  increasing dose-density,10  or use of more intensive strategies such as hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone given as course A, followed by methotrexate and cytarabine given as course B) 63  have been limited to small retrospective series that did not demonstrate any appreciable improvements. In addition, the deliverability of such dose-intensive strategies is limited, given the demographic features of the majority of patients with PTL.

Figure 1

Time to CNS recurrence in the IELSG retrospective study, demonstrating ongoing risk of late CNS relapses. Reprinted from Zucca et al11  with permission.

Figure 1

Time to CNS recurrence in the IELSG retrospective study, demonstrating ongoing risk of late CNS relapses. Reprinted from Zucca et al11  with permission.

Close modal

The impact of rituximab on outcomes in PTL remains unclear, but appears less definitive than in nodal DLBCL. A retrospective analysis from the British Columbia Cancer Agency (BCCA) of 88 patients with PTL treated with CHOP either with (n = 48) or without (n = 40) rituximab found (after a median follow up of 60 months) that there was no difference in 5-year rates of progression or OS.67  However, the rituximab plus CHOP (R-CHOP) group contained more patients with adverse prognostic factors, and multivariate analysis found that the use of rituximab was a favorable prognostic factor for both time to progression (P = .006) and OS (P = .009). Rituximab had no evident impact on CNS relapse in this study. The improvement in outcome was also noted in the MDACC retrospective series, in which the addition of rituximab to anthracycline-based chemotherapy resulted in significant improvements in 5-year OS (56% vs 87%; P = .019) despite no such improvement in PFS (52% vs 59%; P = .138), suggesting that improved salvage therapies may have been responsible.12 

CNS prophylaxis

The apparent lack of impact of rituximab on CNS relapse risk in the BCCA series is not surprising, given that levels of rituximab in cerebrospinal fluid are only 0.1% that of serum levels,68  and a recent meta-analysis suggested only minor reduction in CNS relapse in nodal DLBCL.61  In an attempt to ameliorate the high risk of CNS relapse, intrathecal chemotherapy has been used in many retrospective series.3-5,12  However, given the nonuniform application inherent in retrospective case series, drawing firm conclusions about the efficacy of intrathecal methotrexate is difficult. Of the prospective clinical trials performed, two used intrathecal chemotherapy alone and reported CNS relapse rates of 6%,58,69  while one used both intrathecal and systemic methotrexate and reported no CNS relapses among 38 patients.70  In all 3 studies, the crude incidence of CNS relapse was significantly less than that for historical controls. Given that many relapses are parenchymal rather than leptomeningeal and that the penetration into brain parenchyma and distribution around the neuroaxis of methotrexate injected by lumbar puncture is limited,71  there is a conceptual appeal to the use of high-dose systemic methotrexate for CNS prophylaxis because it achieves higher drug levels in brain parenchyma.72  Furthermore, in nodal DLBCL, the addition of high-dose systemic methotrexate appears to lower the risk of CNS relapse.73-75  The merits of this approach are reflected by treatment guidelines,76  and the ongoing IELSG-30 prospective protocol incorporates intravenous methotrexate (1.5 g/m2) in addition to intrathecal liposomal cytarabine (ClinicalTrials.gov identifier: NCT00945724). Dose reductions should be made for patients with renal impairment and for the elderly.

Prospective clinical trials in PTL

Few prospective clinical trials in PTL have been conducted (Table 3). The Groupe Ouest Est d'Etude des Leucémies et Autres Maladies du Sang (GOELAMS) 02 study used 3 cycles of VCAP in patients age 18 to 60 years, or VCEP-bleo (vindesine, cyclophosphamide, epirubicin, prednisolone, and bleomycin) in patients age 61 to 75 years. All patients received radiotherapy (RT) to inguinal, iliac, and para-aortic lymph nodes, whole brain RT, and intrathecal prophylaxis.69  With a median follow-up of 73.5 months, DFS and OS were 70% and 65%, respectively, with one CNS relapse (6%).

Table 3

Prospective studies in PTL

ReferenceYearNo. of patientsMedian age, yearsRangeDLBCL (%)TreatmentCNS prophylaxisPrognostic factorsNo. of patients with CNS relapse (%)Outcome
70 2002 16 62 29-73 100 Age 18-60 y: VCAP IT MTX all N/R 1 (6) 6-y OS, 65% 
Age 61-75 y: VECP-bleo 
Regional RT 
71 2009 38 51.8 53-70 100 R-CEOP 14 MTX 6 g/m2 IV × 4 N/R (0) 5-y EFS, 70% 
59 2011 56 64 22-79 100 R-CHOP 21 IT MTX × 4 N/R (6) 5-y PFS, 74% 
5-y OS, 85% 
ReferenceYearNo. of patientsMedian age, yearsRangeDLBCL (%)TreatmentCNS prophylaxisPrognostic factorsNo. of patients with CNS relapse (%)Outcome
70 2002 16 62 29-73 100 Age 18-60 y: VCAP IT MTX all N/R 1 (6) 6-y OS, 65% 
Age 61-75 y: VECP-bleo 
Regional RT 
71 2009 38 51.8 53-70 100 R-CEOP 14 MTX 6 g/m2 IV × 4 N/R (0) 5-y EFS, 70% 
59 2011 56 64 22-79 100 R-CHOP 21 IT MTX × 4 N/R (6) 5-y PFS, 74% 
5-y OS, 85% 

EFS, event-free survival; IT, intrathecal; MTX, methotrexate; N/R, not reported; VCAP, vindesine, doxorubicin, cyclophosphamide, prednisolone; VECP-bleo, vindesine, epirubicin, cyclophosphamide, prednisolone, bleomycin. Additional abbreviations are explained in Table 2.

Avilés et al70  conducted a single-arm, open-label study using 6 cycles of rituximab, cyclophosphamide (1500 mg/m2), epirubicin (120 mg/m2), vincristine, prednisolone (R-CEOP) dosed at 14-day intervals, with patients who achieved complete response (CR) receiving 30 Gy RT to the scrotum and contralateral testis. CNS prophylaxis comprised 4 cycles of high-dose intravenous methotrexate (6 g/m2) with leucovorin rescue. Of the 38 patients enrolled, 86% achieved CR, and the actuarial 5-year event-free survival and OS were 70% and 66%, respectively. No CNS relapses were reported in this study.

The IELSG-10 study was a multicenter phase 2 study that evaluated R-CHOP delivered at 21-day intervals followed by locoregional irradiation.58  Intrathecal methotrexate was used for CNS prophylaxis during the first 2 chemotherapy cycles. Fifty-three patients with stage I/II DLBCL-type PTL were included (patients with bilateral testicular involvement were considered stage I); 98% achieved CR and, after median follow up of 65 months, the 5-year PFS and OS were 74% and 85%, respectively. The 5-year actuarial incidence of CNS relapse was 6%. The excellent results in this study established R-CHOP every 21 days with intrathecal methotrexate and locoregional RT as the reference treatment for patients with limited-stage PTL, including those with bilateral testicular involvement. Thus, we regard R-CHOP every 21 days with intrathecal methotrexate with scrotal RT after completion of chemotherapy as the recommended treatment of these patients also.

There are limited data regarding the use of abbreviated chemotherapy in PTL. An early report from BCCA treated 15 patients with stage I/II PTL with either 3 cycles of CHOP or a 6-week regimen modified from MACOP-B (methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin), termed ACOB (cyclophosphamide, doxorubicin, vincristine, bleomycin, and prednisolone).66  They reported a remarkable 4-year PFS and OS of 93%, with no CNS relapses. This result should be considered in the context of the small number of patients and it has not been replicated. Conversely, there are data suggesting that abbreviated chemotherapy compromises outcomes. Seymour et al,5  in a retrospective series of 25 patients, reported a shorter median time to treatment failure (1.2 vs 8.4 years; P = .03) in patients who received <6 cycles of chemotherapy. Supporting this, patients in the IELSG retrospective series who received ≥6 cycles of chemotherapy had a better long-term outcome than those treated for a shorter period (10-year OS, 44% vs 19%; P = .03).11 

RT

Early studies of PTL included patients treated with orchiectomy and locoregional RT only and were associated with uniformly high rates of relapse.2  The use of RT alone for PTL would be considered only for patients who refused or were unfit for systemic chemotherapy.2  Recent efforts to improve the management of PTL have focused on prophylactic therapy for sanctuary sites, such as the CNS and contralateral testis.58 

Testicular irradiation.

Patients treated by orchiectomy and anthracycline-based chemotherapy have an appreciable risk of relapse in the contralateral testis.1,3,9  In the IELSG series, testicular relapse was a component of 43 (45%) of 195 treatment failures, with 15-year actuarial incidence of contralateral testicular relapse of 42% in the absence of scrotal irradiation.11  Prophylactic scrotal radiation was associated with significant reduction in the incidence of testicular relapse (P = .011) and improvement in both 5-year PFS (70% vs 36%; P = .00001) and OS (66% vs 38%; P = .00001).11  Other studies have also suggested that the addition of adjuvant RT improves survival, although it is uncertain to what extent this reflects patient selection for adjuvant irradiation.7,77 

In the IELSG-10 study, adjuvant testicular radiation (median, 30 Gy; range, 24 to 40 Gy) was used routinely with no testicular relapses observed.58  RT should thus be considered mandatory in stage I to II disease. Adjuvant scrotal radiation may have more value in limited-stage disease, because in the IELSG series, testicular relapse occurred in 28% of treatment failures for stage I and was the sole initial site of failure in 10%, whereas for patients with initial stage III to IV disease, testicular relapse occurred in 16% of failures but was the sole site of failure in only 2%. Nonetheless, given the relatively low morbidity of this treatment, it should be considered standard care for all patients who are receiving potentially curative chemotherapy. Despite this, the Surveillance, Epidemiology, and End Results data showed that only 30% to 40% of patients received RT, without apparent improvement over time.7 

Nodal irradiation.

In stage I PTL, there is no role for adjuvant irradiation to uninvolved para-aortic or pelvic nodes. In stage II PTL, the benefit of RT to involved nodes in patients treated with R-CHOP is uncertain. For example, in the IELSG-10 study of 13 stage II patients, 9 received nodal RT, and the single relapse occurred within the RT field in one of these patients.58  The 4 patients not treated with RT were all in remission at the time of reporting; however, the small number of patients and nonrandomized allocation of RT means that this question remains open. There are limited data to suggest benefit of regional nodal irradiation in stage III/IV disease; thus, it is not recommended.

Toxicity.

Testicular irradiation causes acute cutaneous toxicity, which may last several weeks. The major long-term toxicities of scrotal irradiation are dose-dependent and include infertility and hypogonadism.78  The acute toxicities of abdominal and pelvic irradiation include lethargy, nausea, disturbance of bowel function, and cytopenias, while late toxicity primary consists of increased risk of second primary malignancies.

Management of relapsed disease

The prognosis of patients with PTL who experience relapse is poor. The median survival after relapse is infrequently reported but was <2 months in the Danish series.1  The narrow gap between reported PFS and OS in most other studies suggests that this estimate is probably accurate. The likely explanations for this dismal outlook are the high frequency of CNS relapse and the average patient is elderly and has comorbidities precluding aggressive salvage strategies and/or stem cell transplantation.

It is difficult to make robust evidence-based recommendations for the optimal approach for patients with relapsed PTL. Four (22%) of 18 patients with relapsed lymphoma in the MDACC series underwent autologous stem cell transplantation, but their outcomes were not reported.12  Interestingly, of the 9 patients with relapsed lymphoma in the IELSG-10 study, 4 (44%) remained alive in second remission after unspecified salvage therapy,58  perhaps suggesting that prevention of CNS relapse may result in greater potential to salvage patients in the future.

New insights into the distinctive pathophysiology of PTL may facilitate novel therapeutic strategies. There is evidence that both lenalidomide79  and the inhibitor of Bruton’s tyrosine kinase ibrutinib80  are active in ABC-type DLBCL. Several groups are exploring R-CHOP in combination with lenalidomide (R2-CHOP)81-84  and ibrutinib in nodal DLBCL. The data available so far suggest that these combinations are well tolerated and effective, although to the best of our knowledge, patients with PTL are not specifically being studied. The presence of lenalidomide has been demonstrated in the semen of male patients,85  and a case of multiple myeloma invading the testis was successfully treated using lenalidomide and dexamethasone, suggesting penetration of the blood-testis barrier.86  Data regarding the CNS penetration of lenalidomide are lacking; however, 2 phase 1 studies in patients with refractory CNS tumors have demonstrated low toxicity but poor response rates.87,88  Pomalidomide, another immunomodulatory drug has demonstrated both synergistic enhancement of antigen-dependent cellular cytotoxicity with rituximab89  and excellent CNS penetration and impressive activity against a Raji xenograft model of PCNSL.90  Thus, given the promising activity of R2-CHOP, combining pomalidomide with rituximab and/or chemotherapy in patients with PTL may have appeal.

If CXCR4 is found to have a pathophysiologic role in mediating extranodal relapse, development of the CXCR4 inhibitor plerixafor (currently licensed for peripheral blood stem cell mobilization) may prove attractive as a therapeutic adjuvant to chemotherapy. Finally, the overactivation of NF-κB and STAT3 signaling pathways may be exploited as a target; a small-molecule inhibitor of JAK-STAT signaling has shown in vitro activity against ABC-type DLBCL cell lines and is synergistic with NF-κB pathway inhibitors.91  Further improvements in the outcome of patients with PTL are likely to be achieved only by collaborative enrollment of patients into thoughtfully designed, prospective clinical trials.

In conclusion, significant gains have been made in PTL with the successive addition of RT, anthracycline-based chemotherapy, rituximab, and CNS-directed prophylaxis. Although R-CHOP every 21 days with intrathecal methotrexate and locoregional RT is the current international standard of care, there is unmet medical need for patients for whom this approach fails. A greater understanding of the pathophysiologic processes underlying the characteristic tropism of PTL has the potential for further improvements in treatment of this rare but aggressive disease.

Figure 2

OS of patients with PTL treated at MDACC, by chemotherapy strategy. Adriamycin (doxorubicin). Reprinted from Mazloom et al12  with permission.

Figure 2

OS of patients with PTL treated at MDACC, by chemotherapy strategy. Adriamycin (doxorubicin). Reprinted from Mazloom et al12  with permission.

Close modal

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.

The authors wish to thank Jan Delabie for his critical review of the manuscript.

This work was supported by the Victorian Cancer Agency (grant number CTCB11_18) and the Haematology Society of Australia and New Zealand (New Investigator Scholarship).

Contribution: C.Y.C., A.W., and J.F.S. performed the literature review and wrote and approved the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: John F. Seymour, Department of Haematology, Peter MacCallum Cancer Centre, Locked Bag 1, A’Beckett St, East Melbourne 8006, VIC, Australia; e-mail: [email protected].

1
Møller
 
MB
d’Amore
 
F
Christensen
 
BE
Testicular lymphoma: a population-based study of incidence, clinicopathological correlations and prognosis. The Danish Lymphoma Study Group, LYFO.
Eur J Cancer
1994
, vol. 
30A
 
12
(pg. 
1760
-
1764
)
2
Shahab
 
N
Doll
 
DC
Testicular lymphoma.
Semin Oncol
1999
, vol. 
26
 
3
(pg. 
259
-
269
)
3
Fonseca
 
R
Habermann
 
TM
Colgan
 
JP
et al. 
Testicular lymphoma is associated with a high incidence of extranodal recurrence.
Cancer
2000
, vol. 
88
 
1
(pg. 
154
-
161
)
4
Hasselblom
 
S
Ridell
 
B
Wedel
 
H
Norrby
 
K
Sender Baum
 
M
Ekman
 
T
Testicular lymphoma—a retrospective, population-based, clinical and immunohistochemical study.
Acta Oncol
2004
, vol. 
43
 
8
(pg. 
758
-
765
)
5
Seymour
 
JF
Solomon
 
B
Wolf
 
MM
Janusczewicz
 
EH
Wirth
 
A
Prince
 
HM
Primary large-cell non-Hodgkin’s lymphoma of the testis: a retrospective analysis of patterns of failure and prognostic factors.
Clin Lymphoma
2001
, vol. 
2
 
2
(pg. 
109
-
115
)
6
Vitolo
 
U
Ferreri
 
AJ
Zucca
 
E
Primary testicular lymphoma.
Crit Rev Oncol Hematol
2008
, vol. 
65
 
2
(pg. 
183
-
189
)
7
Gundrum
 
JD
Mathiason
 
MA
Moore
 
DB
Go
 
RS
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
, vol. 
27
 
31
(pg. 
5227
-
5232
)
8
Horne
 
MJ
Adeniran
 
AJ
Primary diffuse large B-cell lymphoma of the testis.
Arch Pathol Lab Med
2011
, vol. 
135
 
10
(pg. 
1363
-
1367
)
9
Crellin
 
AM
Hudson
 
BV
Bennett
 
MH
Harland
 
S
Hudson
 
GV
Non-Hodgkin’s lymphoma of the testis.
Radiother Oncol
1993
, vol. 
27
 
2
(pg. 
99
-
106
)
10
Avilés
 
A
Neri
 
N
Huerta-Guzmán
 
J
Pérez
 
F
Fernández
 
R
Testicular lymphoma: organ-specific treatment did not improve outcome.
Oncology
2004
, vol. 
67
 
3-4
(pg. 
211
-
214
)
11
Zucca
 
E
Conconi
 
A
Mughal
 
TI
et al. 
International Extranodal Lymphoma Study Group
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
2003
, vol. 
21
 
1
(pg. 
20
-
27
)
12
Mazloom
 
A
Fowler
 
N
Medeiros
 
LJ
Iyengar
 
P
Horace
 
P
Dabaja
 
BS
Outcome of patients with diffuse large B-cell lymphoma of the testis by era of treatment: the M. D. Anderson Cancer Center experience.
Leuk Lymphoma
2010
, vol. 
51
 
7
(pg. 
1217
-
1224
)
13
Coté
 
TR
Biggar
 
RJ
Rosenberg
 
PS
et al. 
AIDS/Cancer Study Group
Non-Hodgkin’s lymphoma among people with AIDS: incidence, presentation and public health burden.
Int J Cancer
1997
, vol. 
73
 
5
(pg. 
645
-
650
)
14
Verma
 
N
Chaudhary
 
UB
Costa
 
LJ
Gudena
 
V
Lazarchick
 
J
Primary testicular lymphoma and AIDS.
Ann Clin Lab Sci
2010
, vol. 
40
 
1
(pg. 
75
-
79
)
15
Barta
 
SK
Xue
 
X
Wang
 
D
et al. 
Treatment factors affecting outcomes in HIV-associated non-Hodgkin lymphomas: a pooled analysis of 1546 patients.
Blood
2013
, vol. 
122
 
19
(pg. 
3251
-
3262
)
16
Dunn
 
GP
Bruce
 
AT
Ikeda
 
H
Old
 
LJ
Schreiber
 
RD
Cancer immunoediting: from immunosurveillance to tumor escape.
Nat Immunol
2002
, vol. 
3
 
11
(pg. 
991
-
998
)
17
Thompsett
 
AR
Ellison
 
DW
Stevenson
 
FK
Zhu
 
D
V(H) gene sequences from primary central nervous system lymphomas indicate derivation from highly mutated germinal center B cells with ongoing mutational activity.
Blood
1999
, vol. 
94
 
5
(pg. 
1738
-
1746
)
18
Booman
 
M
Douwes
 
J
Glas
 
AM
et al. 
Mechanisms and effects of loss of human leukocyte antigen class II expression in immune-privileged site-associated B-cell lymphoma.
Clin Cancer Res
2006
, vol. 
12
 
9
(pg. 
2698
-
2705
)
19
Riemersma
 
SA
Jordanova
 
ES
Schop
 
RF
et al. 
Extensive genetic alterations of the HLA region, including homozygous deletions of HLA class II genes in B-cell lymphomas arising in immune-privileged sites.
Blood
2000
, vol. 
96
 
10
(pg. 
3569
-
3577
)
20
Bart
 
J
Groen
 
HJM
van der Graaf
 
WTA
et al. 
An oncological view on the blood-testis barrier.
Lancet Oncol
2002
, vol. 
3
 
6
(pg. 
357
-
363
)
21
Mital
 
P
Hinton
 
BT
Dufour
 
JM
The blood-testis and blood-epididymis barriers are more than just their tight junctions.
Biol Reprod
2011
, vol. 
84
 
5
(pg. 
851
-
858
)
22
Fijak
 
M
Bhushan
 
S
Meinhardt
 
A
Immunoprivileged sites: the testis.
Methods Mol Biol
2011
, vol. 
677
 (pg. 
459
-
470
)
23
Menter
 
T
Ernst
 
M
Drachneris
 
J
et al. 
Phenotype profiling of primary testicular diffuse large B-cell lymphomas [published online ahead of print August 16, 2013].
Hematol Oncol
 
24
Domanska
 
UM
Kruizinga
 
RC
Nagengast
 
WB
et al. 
A review on CXCR4/CXCL12 axis in oncology: no place to hide.
Eur J Cancer
2013
, vol. 
49
 
1
(pg. 
219
-
230
)
25
Moorjani
 
V
Mashankar
 
A
Goel
 
S
Khandelwal
 
K
Patange
 
V
Merchant
 
N
Sonographic appearance of primary testicular lymphoma.
AJR Am J Roentgenol
1991
, vol. 
157
 
6
(pg. 
1225
-
1226
)
26
Srisuwan
 
T
Muttarak
 
M
Kitirattrakarn
 
P
Ya-in
 
C
Clinics in diagnostic imaging (134). Testicular lymphoma.
Singapore Med J
2011
, vol. 
52
 
3
(pg. 
204
-
208
)
27
Tsili
 
AC
Argyropoulou
 
MI
Giannakis
 
D
Sofikitis
 
N
Tsampoulas
 
K
Primary diffuse large B-cell testicular lymphoma: magnetic resonance imaging findings.
Andrologia
2012
, vol. 
44
 
Suppl 1
(pg. 
845
-
847
)
28
Ponti
 
G
Ponzoni
 
M
Ferreri
 
AJ
Foppoli
 
M
Mazzucchelli
 
L
Zucca
 
E
The impact of histopathologic diagnosis on the proper management of testis neoplasms.
Nat Clin Pract Oncol
2008
, vol. 
5
 
10
(pg. 
619
-
622
)
29
Benevolo
 
G
Stacchini
 
A
Spina
 
M
et al. 
Fondazione Italiana Linfomi
Final results of a multicenter trial addressing role of CSF flow cytometric analysis in NHL patients at high risk for CNS dissemination.
Blood
2012
, vol. 
120
 
16
(pg. 
3222
-
3228
)
30
Muniesa
 
C
Pujol
 
RM
Estrach
 
MT
et al. 
Primary cutaneous diffuse large B-cell lymphoma, leg type and secondary cutaneous involvement by testicular B-cell lymphoma share identical clinicopathological and immunophenotypical features.
J Am Acad Dermatol
2012
, vol. 
66
 
4
(pg. 
650
-
654
)
31
Go
 
RS
Gundrum
 
JD
Uncertainty and discordance in the staging and prognosis of diffuse large B-cell lymphoma with isolated bilateral testicular involvement.
Am J Hematol
2009
, vol. 
84
 
11
(pg. 
762
-
763
)
32
Wittekind
 
C
Henson
 
DE
Hutter
 
RPV
Sobin
 
LH
 
UICC-TNM Supplement. A Commentary on Uniform Use. 2nd ed. New York, NY: Wiley-Liss; 2001
33
Lagrange
 
JL
Ramaioli
 
A
Theodore
 
CH
et al. 
Radiation Therapy Group and the Genito-Urinary Group of the French Federation of Cancer Centres
Non-Hodgkin’s lymphoma of the testis: a retrospective study of 84 patients treated in the French anticancer centres.
Ann Oncol
2001
, vol. 
12
 
9
(pg. 
1313
-
1319
)
34
Epstein
 
AS
Hedvat
 
C
Habib
 
F
Hamlin
 
P
Testis-isolated mantle cell lymphoma: a unique case.
Clin Lymphoma Myeloma Leuk
2011
, vol. 
11
 
5
(pg. 
439
-
441
)
35
Licci
 
S
Morelli
 
L
Covello
 
R
Primary mantle cell lymphoma of the testis.
Ann Hematol
2011
, vol. 
90
 
4
(pg. 
483
-
484
)
36
Kemmerling
 
R
Stintzing
 
S
Mühlmann
 
J
Dietze
 
O
Neureiter
 
D
Primary testicular lymphoma: a strictly homogeneous hematological disease?
Oncol Rep
2010
, vol. 
23
 
5
(pg. 
1261
-
1267
)
37
Liang
 
DN
Yang
 
ZR
Wang
 
WY
et al. 
Extranodal nasal type natural killer/T-cell lymphoma of testis: report of seven cases with review of literature.
Leuk Lymphoma
2012
, vol. 
53
 
6
(pg. 
1117
-
1123
)
38
Jun
 
HJ
Kim
 
WS
Yang
 
JH
et al. 
Orbital infiltration as the first site of relapse of primary testicular T-cell lymphoma.
Cancer Res Treat
2007
, vol. 
39
 
1
(pg. 
40
-
43
)
39
Kuper-Hommel
 
MJ
Janssen-Heijnen
 
ML
Vreugdenhil
 
G
et al. 
Clinical and pathological features of testicular diffuse large B-cell lymphoma: a heterogeneous disease.
Leuk Lymphoma
2012
, vol. 
53
 
2
(pg. 
242
-
246
)
40
Lagmay
 
J
Termuhlen
 
A
Fung
 
B
Ranalli
 
M
Primary testicular presentation of ALK-1-negative anaplastic large cell lymphoma in a pediatric patient.
J Pediatr Hematol Oncol
2009
, vol. 
31
 
5
(pg. 
330
-
332
)
41
Bacon
 
CM
Ye
 
H
Diss
 
TC
et al. 
Primary follicular lymphoma of the testis and epididymis in adults.
Am J Surg Pathol
2007
, vol. 
31
 
7
(pg. 
1050
-
1058
)
42
Finn
 
LS
Viswanatha
 
DS
Belasco
 
JB
et al. 
Primary follicular lymphoma of the testis in childhood.
Cancer
1999
, vol. 
85
 
7
(pg. 
1626
-
1635
)
43
Pakzad
 
K
MacLennan
 
GT
Elder
 
JS
et al. 
Follicular large cell lymphoma localized to the testis in children.
J Urol
2002
, vol. 
168
 
1
(pg. 
225
-
228
)
44
Pileri
 
SA
Sabattini
 
E
Rosito
 
P
et al. 
Primary follicular lymphoma of the testis in childhood: an entity with peculiar clinical and molecular characteristics.
J Clin Pathol
2002
, vol. 
55
 
9
(pg. 
684
-
688
)
45
Liu
 
Q
Salaverria
 
I
Pittaluga
 
S
et al. 
Follicular lymphomas in children and young adults: a comparison of the pediatric variant with usual follicular lymphoma.
Am J Surg Pathol
2013
, vol. 
37
 
3
(pg. 
333
-
343
)
46
Heller
 
KN
Teruya-Feldstein
 
J
La Quaglia
 
MP
Wexler
 
LH
Primary follicular lymphoma of the testis: excellent outcome following surgical resection without adjuvant chemotherapy.
J Pediatr Hematol Oncol
2004
, vol. 
26
 
2
(pg. 
104
-
107
)
47
Hans
 
CP
Weisenburger
 
DD
Greiner
 
TC
et al. 
Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray.
Blood
2004
, vol. 
103
 
1
(pg. 
275
-
282
)
48
Booman
 
M
Douwes
 
J
Glas
 
AM
de Jong
 
D
Schuuring
 
E
Kluin
 
PM
Primary testicular diffuse large B-cell lymphomas have activated B-cell-like subtype characteristics.
J Pathol
2006
, vol. 
210
 
2
(pg. 
163
-
171
)
49
Li
 
D
Xie
 
P
Mi
 
C
Primary testicular diffuse large B-cell lymphoma shows an activated B-cell-like phenotype.
Pathol Res Pract
2010
, vol. 
206
 
9
(pg. 
611
-
615
)
50
Al-Abbadi
 
MA
Hattab
 
EM
Tarawneh
 
MS
Amr
 
SS
Orazi
 
A
Ulbright
 
TM
Primary testicular diffuse large B-cell lymphoma belongs to the nongerminal center B-cell-like subgroup: A study of 18 cases.
Mod Pathol
2006
, vol. 
19
 
12
(pg. 
1521
-
1527
)
51
Colomo
 
L
López-Guillermo
 
A
Perales
 
M
et al. 
Clinical impact of the differentiation profile assessed by immunophenotyping in patients with diffuse large B-cell lymphoma.
Blood
2003
, vol. 
101
 
1
(pg. 
78
-
84
)
52
Alizadeh
 
AA
Eisen
 
MB
Davis
 
RE
et al. 
Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling.
Nature
2000
, vol. 
403
 
6769
(pg. 
503
-
511
)
53
Davis
 
RE
Ngo
 
VN
Lenz
 
G
et al. 
Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma.
Nature
2010
, vol. 
463
 
7277
(pg. 
88
-
92
)
54
Hu
 
S
Xu-Monette
 
ZY
Tzankov
 
A
et al. 
MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program.
Blood
2013
, vol. 
121
 
20
(pg. 
4021
-
4031, quiz 4250
)
55
Bernasconi
 
B
Uccella
 
S
Martin
 
V
et al. 
Gene translocations in testicular lymphomas [published online ahead of print August 16, 2013].
Leuk Lymphoma
 
56
Ngo
 
VN
Young
 
RM
Schmitz
 
R
et al. 
Oncogenically active MYD88 mutations in human lymphoma.
Nature
2011
, vol. 
470
 
7332
(pg. 
115
-
119
)
57
Kraan
 
W
Horlings
 
HM
van Keimpema
 
M
et al. 
High prevalence of oncogenic MYD88 and CD79B mutations in diffuse large B-cell lymphomas presenting at immune-privileged sites.
Blood Cancer J
2013
, vol. 
3
 pg. 
e139
 
58
Vitolo
 
U
Chiappella
 
A
Ferreri
 
AJ
et al. 
First-line treatment for primary testicular diffuse large B-cell lymphoma with rituximab-CHOP, CNS prophylaxis, and contralateral testis irradiation: final results of an international phase II trial.
J Clin Oncol
2011
, vol. 
29
 
20
(pg. 
2766
-
2772
)
59
Wang
 
Y
Li
 
ZM
Huang
 
JJ
et al. 
Three prognostic factors influence clinical outcomes of primary testicular lymphoma.
Tumour Biol
2013
, vol. 
34
 
1
(pg. 
55
-
63
)
60
Lote
 
K
Holte
 
H
Kvaloy
 
S
Testicular lymphoma is associated with a high risk of extranodal recurrence.
Cancer
2000
, vol. 
89
 
3
(pg. 
713
-
714
)
61
Zhang
 
J
Chen
 
B
Xu
 
X
 
Impact of rituximab on incidence of and risk factors for central nervous system relapse in patients with diffuse large B-cell lymphoma: a systematic review and meta-analysis [published online ahead of print July 29, 2013]. Leuk Lymphoma. doi: 10.3109/10428194.2013.811239
62
Siegal
 
T
Goldschmidt
 
N
CNS prophylaxis in diffuse large B-cell lymphoma: if, when, how and for whom?
Blood Rev
2012
, vol. 
26
 
3
(pg. 
97
-
106
)
63
Park
 
B-B
Kim
 
JG
Sohn
 
SK
et al. 
Consideration of aggressive therapeutic strategies for primary testicular lymphoma.
Am J Hematol
2007
, vol. 
82
 
9
(pg. 
840
-
845
)
64
Buskirk
 
SJ
Evans
 
RG
Banks
 
PM
O’Connell
 
MJ
Earle
 
JD
Primary lymphoma of the testis.
Int J Radiat Oncol Biol Phys
1982
, vol. 
8
 
10
(pg. 
1699
-
1703
)
65
Tondini
 
C
Ferreri
 
AJ
Siracusano
 
L
et al. 
Diffuse large-cell lymphoma of the testis.
J Clin Oncol
1999
, vol. 
17
 
9
(pg. 
2854
-
2858
)
66
Connors
 
JM
Klimo
 
P
Voss
 
N
Fairey
 
RN
Jackson
 
S
Testicular lymphoma: improved outcome with early brief chemotherapy.
J Clin Oncol
1988
, vol. 
6
 
5
(pg. 
776
-
781
)
67
Telio
 
D
Villa
 
D
Shenkier
 
T
et al. 
 
Diffuse large B-cell lymphoma with testicular involvement: outcome and risk of CNS relapse in the rituximab era [abstract]. Blood. 2011;118(21). Abstract 780
68
Rubenstein
 
JL
Fridlyand
 
J
Abrey
 
L
et al. 
Phase I study of intraventricular administration of rituximab in patients with recurrent CNS and intraocular lymphoma.
J Clin Oncol
2007
, vol. 
25
 
11
(pg. 
1350
-
1356
)
69
Linassier
 
C
Desablens
 
B
Lefrancq
 
T
et al. 
GOELAMS Study Group
Stage I-IIE primary non-Hodgkin’s lymphoma of the testis: results of a prospective trial by the GOELAMS Study Group.
Clin Lymphoma
2002
, vol. 
3
 
3
(pg. 
167
-
172
)
70
Avilés
 
A
Nambo
 
MJ
Cleto
 
S
Neri
 
N
Huerta-Guzmán
 
J
Rituximab and dose-dense chemotherapy in primary testicular lymphoma.
Clin Lymphoma Myeloma
2009
, vol. 
9
 
5
(pg. 
386
-
389
)
71
Balis
 
FM
Blaney
 
SM
McCully
 
CL
Bacher
 
JD
Murphy
 
RF
Poplack
 
DG
Methotrexate distribution within the subarachnoid space after intraventricular and intravenous administration.
Cancer Chemother Pharmacol
2000
, vol. 
45
 
3
(pg. 
259
-
264
)
72
Zylber-Katz
 
E
Gomori
 
JM
Schwartz
 
A
Lossos
 
A
Bokstein
 
F
Siegal
 
T
Pharmacokinetics of methotrexate in cerebrospinal fluid and serum after osmotic blood-brain barrier disruption in patients with brain lymphoma.
Clin Pharmacol Ther
2000
, vol. 
67
 
6
(pg. 
631
-
641
)
73
Tilly
 
H
Lepage
 
E
Coiffier
 
B
et al. 
Groupe d’Etude des Lymphomes de l’Adulte
Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma.
Blood
2003
, vol. 
102
 
13
(pg. 
4284
-
4289
)
74
Holte
 
H
Leppä
 
S
Björkholm
 
M
et al. 
Dose-densified chemoimmunotherapy followed by systemic central nervous system prophylaxis for younger high-risk diffuse large B-cell/follicular grade 3 lymphoma patients: results of a phase II Nordic Lymphoma Group study.
Ann Oncol
2013
, vol. 
24
 
5
(pg. 
1385
-
1392
)
75
Abramson
 
JS
Hellmann
 
M
Barnes
 
JA
et al. 
Intravenous methotrexate as central nervous system (CNS) prophylaxis is associated with a low risk of CNS recurrence in high-risk patients with diffuse large B-cell lymphoma.
Cancer
2010
, vol. 
116
 
18
(pg. 
4283
-
4290
)
76
McMillan
 
A
Ardeshna
 
KM
Cwynarski
 
K
Lyttelton
 
M
McKay
 
P
Montoto
 
S
Guideline on the prevention of secondary central nervous system lymphoma: British Committee for Standards in Haematology.
Br J Haematol
2013
, vol. 
163
 
2
(pg. 
168
-
181
)
77
Visco
 
C
Medeiros
 
LJ
Mesina
 
OM
et al. 
Non-Hodgkin’s lymphoma affecting the testis: is it curable with doxorubicin-based therapy?
Clin Lymphoma
2001
, vol. 
2
 
1
(pg. 
40
-
46
)
78
Shapiro
 
E
Kinsella
 
TJ
Makuch
 
RW
et al. 
Effects of fractionated irradiation of endocrine aspects of testicular function.
J Clin Oncol
1985
, vol. 
3
 
9
(pg. 
1232
-
1239
)
79
Zhang
 
LH
Kosek
 
J
Wang
 
M
Heise
 
C
Schafer
 
PH
Chopra
 
R
Lenalidomide efficacy in activated B-cell-like subtype diffuse large B-cell lymphoma is dependent upon IRF4 and cereblon expression.
Br J Haematol
2013
, vol. 
160
 
4
(pg. 
487
-
502
)
80
Wilson
 
WH
Gerecitano
 
JF
Goy
 
A
et al. 
 
The Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib (PCI-32765), has preferential activity in the ABC subtype of relapsed/refractory de novo diffuse large B-cell lymphoma (DLBCL): interim results of a multicenter, open-label, phase 2 study [abstract]. Blood. 2012;120(21). Abstract 686
81
Nowakowski
 
GS
LaPlant
 
B
Habermann
 
TM
et al. 
Lenalidomide can be safely combined with R-CHOP (R2CHOP) in the initial chemotherapy for aggressive B-cell lymphomas: phase I study.
Leukemia
2011
, vol. 
25
 
12
(pg. 
1877
-
1881
)
82
Chiappella
 
A
Tucci
 
A
Castellino
 
A
et al. 
Lenalidomide plus cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab is safe and effective in untreated elderly patients with diffuse large B-cell lymphoma: a phase I study by the Fondazione Italiana Linfomi.
Haematologica
2013
 
98(11):1732-1738
83
Tilly
 
H
Morschhauser
 
F
Salles
 
G
et al. 
Phase 1b study of lenalidomide in combination with rituximab-CHOP (R2-CHOP) in patients with B-cell lymphoma.
Leukemia
2013
, vol. 
27
 
1
(pg. 
252
-
255
)
84
Wang
 
M
Fowler
 
N
Wagner-Bartak
 
N
et al. 
Oral lenalidomide with rituximab in relapsed or refractory diffuse large cell, follicular and transformed lymphoma: a phase II clinical trial.
Leukemia
2013
, vol. 
27
 
9
(pg. 
1902
-
1909
)
85
Chen
 
N
Lau
 
H
Choudhury
 
S
Wang
 
X
Assaf
 
M
Laskin
 
OL
Distribution of lenalidomide into semen of healthy men after multiple oral doses.
J Clin Pharmacol
2010
, vol. 
50
 
7
(pg. 
767
-
774
)
86
Miyao
 
K
Sakemura
 
R
Sakai
 
T
et al. 
Testicular invading refractory multiple myeloma during bortezomib treatment successfully treated with lenalidomide: a case report [published online ahead of print July 3, 2013].
Ann Hematol
 
87
Fine
 
HA
Kim
 
L
Albert
 
PS
et al. 
A phase I trial of lenalidomide in patients with recurrent primary central nervous system tumors.
Clin Cancer Res
2007
, vol. 
13
 
23
(pg. 
7101
-
7106
)
88
Warren
 
KE
Goldman
 
S
Pollack
 
IF
et al. 
Phase I trial of lenalidomide in pediatric patients with recurrent, refractory, or progressive primary CNS tumors: Pediatric Brain Tumor Consortium study PBTC-018.
J Clin Oncol
2011
, vol. 
29
 
3
(pg. 
324
-
329
)
89
Hernandez-Ilizaliturri
 
FJ
Reddy
 
N
Holkova
 
B
Ottman
 
E
Czuczman
 
MS
Immunomodulatory drug CC-5013 or CC-4047 and rituximab enhance antitumor activity in a severe combined immunodeficient mouse lymphoma model.
Clin Cancer Res
2005
, vol. 
11
 
16
(pg. 
5984
-
5992
)
90
Li
 
Z
Qiu
 
Y
Personett
 
D
et al. 
Pomalidomide shows significant therapeutic activity against CNS lymphoma with a major impact on the tumor microenvironment in murine models.
PLoS ONE
2013
, vol. 
8
 
8
pg. 
e71754
 
91
Lam
 
LT
Wright
 
G
Davis
 
RE
et al. 
Cooperative signaling through the signal transducer and activator of transcription 3 and nuclear factor-kappaB pathways in subtypes of diffuse large B-cell lymphoma.
Blood
2008
, vol. 
111
 
7
(pg. 
3701
-
3713
)
92
Cao
 
B
Ji
 
DM
Zhou
 
XY
et al. 
A clinical analysis of primary testicular diffuse large B-cell lymphoma in China.
Hematology
2011
, vol. 
16
 
5
(pg. 
291
-
297
)
93
Ferry
 
JA
Harris
 
NL
Young
 
RH
Coen
 
J
Zietman
 
A
Scully
 
RE
Malignant lymphoma of the testis, epididymis, and spermatic cord. A clinicopathologic study of 69 cases with immunophenotypic analysis.
Am J Surg Pathol
1994
, vol. 
18
 
4
(pg. 
376
-
390
)
94
Touroutoglou
 
N
Dimopoulos
 
MA
Younes
 
A
et al. 
Testicular lymphoma: late relapses and poor outcome despite doxorubicin-based therapy.
J Clin Oncol
1995
, vol. 
13
 
6
(pg. 
1361
-
1367
)
Sign in via your Institution