Original Article Oncol Res Treat 2014;37:239–242 DOI: 10.1159/000362399
Received: February 3, 2014 Accepted: March 13, 2014 Published online: April 14, 2014
Single-Center Experience in the Treatment of Primary Testicular Lymphoma Biljana Mihaljevica,b Vojin Vukovica Mihailo Smiljanica Natasa Milicc Milena Todorovica,b Jelena Bilaa,b Bosko Andjelica Vladislava Djurasinovica Jelena Jelicica Darko Antica,b a
Clinic for Hematology, Clinical Center Serbia, Belgrade, Medical Faculty, c Institute for Medical Statistics and Informatics, Medical Faculty, University in Belgrade, Serbia b
Summary Background: Primary testicular lymphoma (PTL) is a rare and highly aggressive extranodal non-Hodgkin’s lymphoma. Patients and Methods: We evaluated the clinical and histopathological features and outcomes of 10 PTL patients treated in the period of 2003–2013 with multimodal therapy (rituximab, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), intrathecal prophylaxis, irradiation of the contralateral testis) following orchiectomy. Results: Complete remission was achieved in 8 patients after first-line therapy while 2 patients had disease progression. The median follow-up duration was 30 months (range 6–110 months). Relapse occurred in 3 patients. 1 patient relapsed in the contralateral testis, while the other 2 patients relapsed to the skin and the central nervous system (CNS), respectively. The time to relapse was 2, 8, and 9 months. Patients with disease progression and relapse received ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin) as salvage treatment, except for 1 patient who was treated with palliative radiotherapy. After second-line therapy, only 1 patient had a short partial remission of 2 months. The median overall survival was 48 months, and the mean progression-free survival was 36 months (the median was not reached). Conclusions: We evaluated 10 patients with PTL treated with rituximab plus CHOP, prophylactic intrathecal chemotherapy, and prophylactic irradiation of the contralateral testis, resulting in good outcome and low incidence of relapse in the contralateral testis; however, the benefit of intrathecal chemotherapy is not yet confirmed.
© 2014 S. Karger GmbH, Freiburg 2296-5270/14/0375-0239$39.50/0 Fax +49 761 4 52 07 14 [email protected] www.karger.com
Accessible online at: www.karger.com/ort
Introduction Primary testicular lymphoma (PTL) is a rare lymphoproliferative disease that occurs mainly in older men and constitutes up to 2% of all non-Hodgkin’s lymphomas [1]. It is the most common malignant tumor of the testis in men older than 50 years [1, 2]. The average age at diagnosis ranges from 57 to 71 years [1, 3–6]. PTL is usually characterized by the swelling of 1 testicle, which is sometimes accompanied by pain or the appearance of a hydrocele; less than 5% of the cases include bilateral testicular involvement at presentation [1, 3, 7]. Histologically, diffuse large B cell lymphoma (DLBCL) is the predominant type in more than 80% of cases, and the other histological types are seen in childhood (follicular lymphoma) or in cases with secondary testicular involvement (lymphoblastic lymphoma) [8–10]. PTLs tend to spread to other extranodal sites, especially the central nervous system (CNS) and the contralateral testis. This can be explained by the overexpression of CXCR4 on tumor cells in PTLs because there are data that confirm the role of CXCR4 activation and migration in directing metastasis toward CXCR12-expressing target organs [11, 12]. Other sites of dissemination include the Waldeyer ring, the lungs, pleura, skin, and soft tissues [2, 13, 14]. The current first-line treatment for PTL consists of anthracycline-containing regimens plus rituximab followed by intrathecal prophylaxis and irradiation of the contralateral testis. To date, only a few prospective clinical trials [15, 16] have addressed the treatment effects of PTL because of the rarity of this condition. Although the introduction of doxorubicin-containing regimens with intrathecal prophylaxis and prophylactic irradiation of the contralateral testis have had an obvious effect on the control of relapse in the contralateral testis, secondary CNS disease remains a challenge.
Darko Antic, MD, PhD Clinic for Hematology Clinical Center Serbia Koste Tordorovica 2, 11000 Belgrade, Serbia [email protected]
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Keywords Primary testicular lymphoma · Therapy · Outcome
Patients and Methods In this retrospective study, we reviewed the medical records of 10 patients with PTL who were treated at the Clinic of Hematology, Clinical Center of Serbia, between 2003 and 2013. The study was approved by the clinical ethics committee and all persons gave their informed consent prior to inclusion in the study. The data of these patients included the epidemiological features, clinicopathological characteristics, type of management, and outcome (table 1). The clinical stage of the tumor was evaluated using the Ann Arbor staging system. All patients underwent orchiectomy with histopathological examination of the testicular tissue and immunohistochemical analysis, which included common markers such as CD20, CD79a, bcl-2, bcl-6, MUM-1, and Ki-67. The outcome was assessed by determining the depth of remission. Complete remission was defined as the absence of signs and symptoms approximately 1 month after completion of therapy, partial remission was defined as a ≥ 50% decrease in the longest perpendicular diameter of all measurable lesions, and a 25% increase in tumor size at the site of primary origin or the appearance of new lesions during therapy was considered as progressive disease. Stable disease was considered between partial remission and progressive disease. Progression-free survival (PFS) was assessed as the time from diagnosis to the occurrence of treatment failure, relapse, or death from lymphoma. Overall survival (OS) was calculated from the time of diagnosis to the time of death or the last follow-up. Descriptive analyses were used to characterize the study population. Survival analysis was performed using the Kaplan-Meier method.
vincristine, and prednisone (CHOP) plus rituximab, followed by intrathecal prophylactic chemotherapy in 8 of 10 patients and irradiation of the contralateral testis in 7 of 10 patients. Complete remission was achieved in 8 patients after firstline treatment, and 2 patients showed disease progression. The median duration of follow-up was 30 months (range, 6–110 months). Relapse occurred in 3 patients; 1 patient showed relapse in the contralateral testis, and 2 patients showed relapse in other extranodal localizations such as the skin and the CNS. 1 of the 2 patients with progressive disease showed progression to the contralateral testis in addition to a few other localizations. Neither of the patients with relapse or disease progression in the contralateral testis received prophylactic radiotherapy. The patient with CNS relapse was treated with intrathecal prophylaxis. The time to relapse was 2, 8, and 9 months. Both patients with disease progression and 2 of the patients who experienced relapse received etoposide, methylprednisolone, cytarabine, and cisplatin (ESHAP) as salvage treatment, and 1 patient (with CNS relapse) was treated only with palliative radiotherapy. After second-line therapy, only 1 patient showed a short partial remission lasting for 2 months. The median OS in our group of patients was 48 months
Results In all patients, a diagnosis of PTL was established after rchiectomy was performed. The average age of the patients o in this study was 59.7 ± 11.4 years (range, 32–76 years). 5 patients had PTL in the right testicle, 4 patients had PTL in the left testicle, and 1 patient had bilateral testicular involvement. 3 patients had B symptoms. At diagnosis, 9 patients had Ann Arbor stage I or II, and 1 patient had stage IV disease. The mean international prognostic index (IPI) score at diagnosis was 2.2 ± 1.1 (range, 0–4). Histopathological analysis revealed DLBCL in all patients, and most patients had non-germinal center B cell histological features. Ki-67 positivity ranged from 60 to 80%, indicating high malignancy. After orchiectomy, all the patients were administered 4–8 cycles of chemo immunotherapy consisting of cyclophosphamide, doxorubicin,
Fig. 1. Median OS of patients with primary testicular lymphoma.
Table 1. Epidemiological features, clinicopathological characteristics, type of management, and outcome of patients with primary testicular lymphoma Patient no.
Age, years
Stage
Location
Surgery
Rituximab
Chemotherapy
RT IPI
CR/PR/PD
Relapse (months)
OS, months
Outcome, alive
1 2 3 4 5 6 7 8 9 10
62 58 64 67 62 64 76 58 54 32
II-EA I-EB I-EA I-EB II-EB II-EA I-EA IV-EA II-EA I-EA
right right left bilateral right left right left left right
orchiectomy orchiectomy orchiectomy orchiectomy orchiectomy orchiectomy orchiectomy orchiectomy orchiectomy orchiectomy
+ + + + + + + + + +
8 CHOP 8 CHOP 4 CHOP 8 CHOP 8 CHOP 6 CHOP 4 CHOP 8 CHOP 8 CHOP 6 CHOP
+ – + + – – + + + +
CR CR CR CR PD CR CR PD CR CR
– + (9) – + (8) – – – – + (2) –
39 48 39 16 20 110 40 21 18 6
+ – + – + + + – – +
4 2 2 3 2 2 3 3 1 0
240
Oncol Res Treat 2014;37:239–242
Mihaljevic/Vukovic/Smiljanic/Milic/Todorovic/ Bila/Andjelic/Djurasinovic/Jelicic/Antic
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RT = radiotherapy, IPI = international prognostic index, CR = complete remission, PR = partial remission, PD = progressive disease, OS = overall survival, CHOP = cyclophosphamide, doxorubicin, vincristine, and prednisone.
Discussion PTL is a rare malignancy comprising 1–7% of all testicular neoplasms and 2% of all non-Hodgkin’s lymphomas; it most often occurs in men older than 50 years [1]. Patients with PTL usually present with painless unilateral testicle swelling. Bilateral involvement ranges from 5% at presentation to 35% later in the course of the disease [2, 6, 17]. According to some reported data, involvement of the left testicle seems to be a predictor of worse survival, whereas germ cell tumors of the testis with left-sided appearance indicate a better outcome [4]. There is no clear explanation for the described laterality, although anatomic diversity in the testicular venous drainage system through an unknown mechanism is considered as the main cause for this curious aspect. The main histological type of PTL is DLBCL, which is observed in 80% of testicular lymphomas. On the other side, this histological type comprises approximately 40% of the non-Hodgkin’s lymphomas in general [1, 2]. Histological analysis revealed that all 10 patients in our study had DLBCL. Because of the rarity of PTL, only a few prospective trials have studied the treatment and outcome of patients with this disease and they are based on previously reported retrospective studies. In most of the previous reports there is no survival curve plateau that indicates occurrence of late relapses. In a retrospective review of 373 patients treated from 1968 to 1998 at 23 institutions, Zucca et al. [1] reported a median OS of 4.8 years and a PFS of 4 years in a heterogeneous group treated with a variety of therapeutic modalities. Use of anthracycline-containing regimens, irradiation of the contralateral testis, and CNS prophylactic chemotherapy significantly extended the PFS and OS, with a decrease in relapse in the contralateral testis of irradiated patients but no significant reduction in CNS disease. Multivariate analysis revealed that a favorable IPI score, absence of B symptoms, anthracyclinecontaining chemotherapy, and prophylactic scrotal irradiation were significantly associated with better OS and PFS [1]. Another large retrospective analysis was performed by Gundrum et al. [4] who reviewed the Surveillance, Epidemiology, and End Results (SEER) database and the medical records of 769 patients with PTL from 1980 to 2005. In another study [18], there was no improvement in the disease-specific survival for PTL when rituximab was introduced in combination with chemotherapy after 2000, which was unlike that observed for nodal DLBCL. The role of rituximab is also questionable with respect to reducing relapse or progression to the CNS. There are some doubts regarding the ability of rituximab to break through the brain-blood barrier and consequently prevent dissemination to the CNS [2]. This point of view was corroborated by Feugier et al. [19] in a randomized trial of 399 pa-
Primary Testicular Lymphoma
tients with DLBCL; they compared the effect of CHOP plus rituximab (R-CHOP) versus that of CHOP and showed that the addition of rituximab did not reduce the risk of dissemination to the CNS at relapse. Based on the results of these retrospective studies, the International Extranodal Lymphoma Study Group (IELSG) conducted a prospective phase II trial [13], enrolling 53 patients who received CHOP-21 plus rituximab followed by prophylactic irradiation of the contralateral testis and intrathecal chemotherapy prophylaxis of 4 doses of methotrexate. Patients with stage II disease also received involved-field radiotherapy. After a median follow-up of 65 months, the 5-year PFS and OS rates were 74% and 85%, respectively, with 3 cases of CNS relapse and no cases of relapse in the contralateral testis. The 5-year cumulative incidence of CNS relapse was 6% [15]. These results should be interpreted in light of the exclusion criteria, such as an Ann Arbor stage > II and an Eastern Cooperative Oncology Group (ECOG) performance status ≥ 2. As a contribution to the fight against CNS relapse, we highlight the findings of Aviles et al. [16] who treated 34 patients with PTL by performing orchiectomy followed by 6 cycles of anthracycline-based combined chemotherapy, radiotherapy, and prophylaxis to the CNS with 4 monthly cycles of a high dose of methotrexate (6 g/m2). In addition, the IELSG30 phase II trial in progress attempts to reduce the risk of CNS disease by administering 4 intrathecal injections of cytarabine in the treatment phase and 2 cycles of systemic intermediatedose methotrexate (1.5 g/m2) as consolidation [20]. In our group of patients, 2 patients showed progression to the contralateral testis; both of them did not receive prophylactic irradiation, which is in accordance with the conclusions of most studies on PTL. In addition, 1 case of CNS relapse occurred in a patient who was treated with intrathecal prophylactic chemotherapy, which supports the presumption that the currently used CNS prophylaxis is insufficient. Bearing in mind the poor prognosis for relapsed patients, there is the necessity for the development of new potential therapeutic approaches. Recent data about low levels of p53 expression, high levels of phosphorylated STAT3 (signal transducer and activator of transcription 3), overexpression of CXCR4, and up-regulation of the nuclear factor kB (NF-kB) pathway in patients with PTL suggest that the CXCR4 inhibitor plerixafor as well as inhibitors of the Janus kinase (JAK)STAT and NF-kB pathways need to be tested in prospective clinical trials with PTL patients [11].
Conclusions The standard of treatment for PTL is orchiectomy followed by chemoimmunotherapy, irradiation of the contralateral testis, and intrathecal prophylactic chemotherapy. Despite notable improvement in the PFS and OS after the introduction of multimodal treatment, 2 goals remain for the near future:
Oncol Res Treat 2014;37:239–242
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(fig. 1), and the mean PFS was 36 months (the median was not reached).
(i) achieving a plateau in the survival curve and (ii) eradicating diseases of the CNS. If we accomplish the second goal, the first goal will probably be within reach. We believe that the ongoing IELSG30 phase II trial with modified CNS prophylaxis could give us some essential information. In the future, the development of biological therapeutic agents should be considered.
Disclosure Statement The authors declare that they have no conflict of interest.
References
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6 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;30A:1760–1764. 7 Mazloom A, Fowler N, Medeiros J, Iyengar I, Horace P, Dabaja SM: 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;51:1217–1224. 8 Verma N, Lazarchick J, Gudena V, Turner J, Chaudhary UB: Testicular lymphoma: an update for clinicians. Am J Med Sci 2008;336:336–341. 9 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;19:1521–1527. 10 Miedler JD, MacLennan GT: Primary testicular lymphoma. J Urol 2007;178:2645. 11 Cheah CY, Wirth A, Seymour JF: Primary testicular lymphoma. Blood 2014;123:486–493. 12 Domanska UM, Kruizinga RC, Nagengast WB, Timmer-Bosscha H, Huls G, de Vries EG, Walenkamp AM, et al.: A review on CXCR4/ CXCL12 axis in oncology: no place to hide. Eur J Cancer 2013;49:219–230. 13 Zucca E, Roggero E, Bertoni F, et al.: Primary extranodal non-Hodgkin’s lymphomas: Part 1. Gastrointestinal, cutaneous and genitourinary lymphomas. Ann Oncol 1997;8:727–737. 14 Martenson JA Jr, Buskirk SJ, Ilstrup DM, et al.: Patterns of failure in primary testicular nonHodgkin’s lymphoma. J Clin Oncol 1988;6:297–302.
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15 Vitolo U, Chiappella A, Ferreri AJM, Martelli M, Baldi I, Balzarotti M, Bottelli C, Conconi A, Gomez H, Guillermo AL, Martinelli G, Merli F, Novero D, Orsucci L, Pavone V, Ricardi U, Storti S, Gospodarowicz MK, Cavalli F, Sarris AH, Zucca E: 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;29:2766–2772. 16 Aviles A, Neri N, Huerta-Guzman J, Perez F, Fernandez R: Testicular lymphoma: organ-specific treatment did not improve outcome. Oncology 2004;67:211–214. 17 Shahab N, Doll DC: Testicular lymphoma. Semin Oncol 1999;26:259–269. 18 Sehn LH, Donaldson J, Chhanabhai M, et al.: Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol 2005:23:5027–5033. 19 Feugier P, Virion JM, Tilly H, et al.: Incidence and risk factors for central nervous system occurrence in elderly patients with diffuse large-B-cell lymphoma: influence of rituximab. Ann Oncol 2004; 15:129–133. 20 Ahmad SS, Idris SF, Follows GA, Williams MV: Primary testicular lymphoma. Clin Oncol 2012; 24:358–365.
Mihaljevic/Vukovic/Smiljanic/Milic/Todorovic/ Bila/Andjelic/Djurasinovic/Jelicic/Antic
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1 Zucca E, Conconi A, Mughal TI, Sarris AH, Seymour JF, Vitolo U, Klasa R, Ozsahin M, Mead GM, Gianni MA, Cortelazzo S, Ferreri AJM, Ambrosetti A, Martelli M, Thiéblemont C, Gomez Moreno H, Pinotti G, Martinelli G, Mozzana R, Grisanti S, Provencio M, Balzarotti M, Laveder F, Oltean G, Callea V, Roy P, Cavalli F, Gospodarowicz MK: 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;21:20–27. 2 Vitolo U, Ferreri AJM, Zucca E: Primary testicular lymphoma. Crit Rev Oncol Hematol 2008;65:183– 189. 3 Cao B, Ji D, Zhou X, Zhao T, Guo Y, Wang Z, Cao J, Hu X, Hong X: A clinical analysis of primary testicular diffuse large B-cell lymphoma in China. Hematology 2011;16:291–297. 4 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;27:5227–5232. 5 Lagrange JL, Ramaioli A, Theodore CH, TerrierLacombe MJ, Beckendorf V, Biron P, Chevreau CH, Chinet-Charrot P, Dumont J, Delobel-Deroide A, D’Anjou J, Chassagne C, Parache RM, Karsenty JM, Mercier J, Droz JP; 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;12:1313–1319.
Received: February 3, 2014 Accepted: March 13, 2014 Published online: April 14, 2014
Single-Center Experience in the Treatment of Primary Testicular Lymphoma Biljana Mihaljevica,b Vojin Vukovica Mihailo Smiljanica Natasa Milicc Milena Todorovica,b Jelena Bilaa,b Bosko Andjelica Vladislava Djurasinovica Jelena Jelicica Darko Antica,b a
Clinic for Hematology, Clinical Center Serbia, Belgrade, Medical Faculty, c Institute for Medical Statistics and Informatics, Medical Faculty, University in Belgrade, Serbia b
Summary Background: Primary testicular lymphoma (PTL) is a rare and highly aggressive extranodal non-Hodgkin’s lymphoma. Patients and Methods: We evaluated the clinical and histopathological features and outcomes of 10 PTL patients treated in the period of 2003–2013 with multimodal therapy (rituximab, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), intrathecal prophylaxis, irradiation of the contralateral testis) following orchiectomy. Results: Complete remission was achieved in 8 patients after first-line therapy while 2 patients had disease progression. The median follow-up duration was 30 months (range 6–110 months). Relapse occurred in 3 patients. 1 patient relapsed in the contralateral testis, while the other 2 patients relapsed to the skin and the central nervous system (CNS), respectively. The time to relapse was 2, 8, and 9 months. Patients with disease progression and relapse received ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin) as salvage treatment, except for 1 patient who was treated with palliative radiotherapy. After second-line therapy, only 1 patient had a short partial remission of 2 months. The median overall survival was 48 months, and the mean progression-free survival was 36 months (the median was not reached). Conclusions: We evaluated 10 patients with PTL treated with rituximab plus CHOP, prophylactic intrathecal chemotherapy, and prophylactic irradiation of the contralateral testis, resulting in good outcome and low incidence of relapse in the contralateral testis; however, the benefit of intrathecal chemotherapy is not yet confirmed.
© 2014 S. Karger GmbH, Freiburg 2296-5270/14/0375-0239$39.50/0 Fax +49 761 4 52 07 14 [email protected] www.karger.com
Accessible online at: www.karger.com/ort
Introduction Primary testicular lymphoma (PTL) is a rare lymphoproliferative disease that occurs mainly in older men and constitutes up to 2% of all non-Hodgkin’s lymphomas [1]. It is the most common malignant tumor of the testis in men older than 50 years [1, 2]. The average age at diagnosis ranges from 57 to 71 years [1, 3–6]. PTL is usually characterized by the swelling of 1 testicle, which is sometimes accompanied by pain or the appearance of a hydrocele; less than 5% of the cases include bilateral testicular involvement at presentation [1, 3, 7]. Histologically, diffuse large B cell lymphoma (DLBCL) is the predominant type in more than 80% of cases, and the other histological types are seen in childhood (follicular lymphoma) or in cases with secondary testicular involvement (lymphoblastic lymphoma) [8–10]. PTLs tend to spread to other extranodal sites, especially the central nervous system (CNS) and the contralateral testis. This can be explained by the overexpression of CXCR4 on tumor cells in PTLs because there are data that confirm the role of CXCR4 activation and migration in directing metastasis toward CXCR12-expressing target organs [11, 12]. Other sites of dissemination include the Waldeyer ring, the lungs, pleura, skin, and soft tissues [2, 13, 14]. The current first-line treatment for PTL consists of anthracycline-containing regimens plus rituximab followed by intrathecal prophylaxis and irradiation of the contralateral testis. To date, only a few prospective clinical trials [15, 16] have addressed the treatment effects of PTL because of the rarity of this condition. Although the introduction of doxorubicin-containing regimens with intrathecal prophylaxis and prophylactic irradiation of the contralateral testis have had an obvious effect on the control of relapse in the contralateral testis, secondary CNS disease remains a challenge.
Darko Antic, MD, PhD Clinic for Hematology Clinical Center Serbia Koste Tordorovica 2, 11000 Belgrade, Serbia [email protected]
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Keywords Primary testicular lymphoma · Therapy · Outcome
Patients and Methods In this retrospective study, we reviewed the medical records of 10 patients with PTL who were treated at the Clinic of Hematology, Clinical Center of Serbia, between 2003 and 2013. The study was approved by the clinical ethics committee and all persons gave their informed consent prior to inclusion in the study. The data of these patients included the epidemiological features, clinicopathological characteristics, type of management, and outcome (table 1). The clinical stage of the tumor was evaluated using the Ann Arbor staging system. All patients underwent orchiectomy with histopathological examination of the testicular tissue and immunohistochemical analysis, which included common markers such as CD20, CD79a, bcl-2, bcl-6, MUM-1, and Ki-67. The outcome was assessed by determining the depth of remission. Complete remission was defined as the absence of signs and symptoms approximately 1 month after completion of therapy, partial remission was defined as a ≥ 50% decrease in the longest perpendicular diameter of all measurable lesions, and a 25% increase in tumor size at the site of primary origin or the appearance of new lesions during therapy was considered as progressive disease. Stable disease was considered between partial remission and progressive disease. Progression-free survival (PFS) was assessed as the time from diagnosis to the occurrence of treatment failure, relapse, or death from lymphoma. Overall survival (OS) was calculated from the time of diagnosis to the time of death or the last follow-up. Descriptive analyses were used to characterize the study population. Survival analysis was performed using the Kaplan-Meier method.
vincristine, and prednisone (CHOP) plus rituximab, followed by intrathecal prophylactic chemotherapy in 8 of 10 patients and irradiation of the contralateral testis in 7 of 10 patients. Complete remission was achieved in 8 patients after firstline treatment, and 2 patients showed disease progression. The median duration of follow-up was 30 months (range, 6–110 months). Relapse occurred in 3 patients; 1 patient showed relapse in the contralateral testis, and 2 patients showed relapse in other extranodal localizations such as the skin and the CNS. 1 of the 2 patients with progressive disease showed progression to the contralateral testis in addition to a few other localizations. Neither of the patients with relapse or disease progression in the contralateral testis received prophylactic radiotherapy. The patient with CNS relapse was treated with intrathecal prophylaxis. The time to relapse was 2, 8, and 9 months. Both patients with disease progression and 2 of the patients who experienced relapse received etoposide, methylprednisolone, cytarabine, and cisplatin (ESHAP) as salvage treatment, and 1 patient (with CNS relapse) was treated only with palliative radiotherapy. After second-line therapy, only 1 patient showed a short partial remission lasting for 2 months. The median OS in our group of patients was 48 months
Results In all patients, a diagnosis of PTL was established after rchiectomy was performed. The average age of the patients o in this study was 59.7 ± 11.4 years (range, 32–76 years). 5 patients had PTL in the right testicle, 4 patients had PTL in the left testicle, and 1 patient had bilateral testicular involvement. 3 patients had B symptoms. At diagnosis, 9 patients had Ann Arbor stage I or II, and 1 patient had stage IV disease. The mean international prognostic index (IPI) score at diagnosis was 2.2 ± 1.1 (range, 0–4). Histopathological analysis revealed DLBCL in all patients, and most patients had non-germinal center B cell histological features. Ki-67 positivity ranged from 60 to 80%, indicating high malignancy. After orchiectomy, all the patients were administered 4–8 cycles of chemo immunotherapy consisting of cyclophosphamide, doxorubicin,
Fig. 1. Median OS of patients with primary testicular lymphoma.
Table 1. Epidemiological features, clinicopathological characteristics, type of management, and outcome of patients with primary testicular lymphoma Patient no.
Age, years
Stage
Location
Surgery
Rituximab
Chemotherapy
RT IPI
CR/PR/PD
Relapse (months)
OS, months
Outcome, alive
1 2 3 4 5 6 7 8 9 10
62 58 64 67 62 64 76 58 54 32
II-EA I-EB I-EA I-EB II-EB II-EA I-EA IV-EA II-EA I-EA
right right left bilateral right left right left left right
orchiectomy orchiectomy orchiectomy orchiectomy orchiectomy orchiectomy orchiectomy orchiectomy orchiectomy orchiectomy
+ + + + + + + + + +
8 CHOP 8 CHOP 4 CHOP 8 CHOP 8 CHOP 6 CHOP 4 CHOP 8 CHOP 8 CHOP 6 CHOP
+ – + + – – + + + +
CR CR CR CR PD CR CR PD CR CR
– + (9) – + (8) – – – – + (2) –
39 48 39 16 20 110 40 21 18 6
+ – + – + + + – – +
4 2 2 3 2 2 3 3 1 0
240
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RT = radiotherapy, IPI = international prognostic index, CR = complete remission, PR = partial remission, PD = progressive disease, OS = overall survival, CHOP = cyclophosphamide, doxorubicin, vincristine, and prednisone.
Discussion PTL is a rare malignancy comprising 1–7% of all testicular neoplasms and 2% of all non-Hodgkin’s lymphomas; it most often occurs in men older than 50 years [1]. Patients with PTL usually present with painless unilateral testicle swelling. Bilateral involvement ranges from 5% at presentation to 35% later in the course of the disease [2, 6, 17]. According to some reported data, involvement of the left testicle seems to be a predictor of worse survival, whereas germ cell tumors of the testis with left-sided appearance indicate a better outcome [4]. There is no clear explanation for the described laterality, although anatomic diversity in the testicular venous drainage system through an unknown mechanism is considered as the main cause for this curious aspect. The main histological type of PTL is DLBCL, which is observed in 80% of testicular lymphomas. On the other side, this histological type comprises approximately 40% of the non-Hodgkin’s lymphomas in general [1, 2]. Histological analysis revealed that all 10 patients in our study had DLBCL. Because of the rarity of PTL, only a few prospective trials have studied the treatment and outcome of patients with this disease and they are based on previously reported retrospective studies. In most of the previous reports there is no survival curve plateau that indicates occurrence of late relapses. In a retrospective review of 373 patients treated from 1968 to 1998 at 23 institutions, Zucca et al. [1] reported a median OS of 4.8 years and a PFS of 4 years in a heterogeneous group treated with a variety of therapeutic modalities. Use of anthracycline-containing regimens, irradiation of the contralateral testis, and CNS prophylactic chemotherapy significantly extended the PFS and OS, with a decrease in relapse in the contralateral testis of irradiated patients but no significant reduction in CNS disease. Multivariate analysis revealed that a favorable IPI score, absence of B symptoms, anthracyclinecontaining chemotherapy, and prophylactic scrotal irradiation were significantly associated with better OS and PFS [1]. Another large retrospective analysis was performed by Gundrum et al. [4] who reviewed the Surveillance, Epidemiology, and End Results (SEER) database and the medical records of 769 patients with PTL from 1980 to 2005. In another study [18], there was no improvement in the disease-specific survival for PTL when rituximab was introduced in combination with chemotherapy after 2000, which was unlike that observed for nodal DLBCL. The role of rituximab is also questionable with respect to reducing relapse or progression to the CNS. There are some doubts regarding the ability of rituximab to break through the brain-blood barrier and consequently prevent dissemination to the CNS [2]. This point of view was corroborated by Feugier et al. [19] in a randomized trial of 399 pa-
Primary Testicular Lymphoma
tients with DLBCL; they compared the effect of CHOP plus rituximab (R-CHOP) versus that of CHOP and showed that the addition of rituximab did not reduce the risk of dissemination to the CNS at relapse. Based on the results of these retrospective studies, the International Extranodal Lymphoma Study Group (IELSG) conducted a prospective phase II trial [13], enrolling 53 patients who received CHOP-21 plus rituximab followed by prophylactic irradiation of the contralateral testis and intrathecal chemotherapy prophylaxis of 4 doses of methotrexate. Patients with stage II disease also received involved-field radiotherapy. After a median follow-up of 65 months, the 5-year PFS and OS rates were 74% and 85%, respectively, with 3 cases of CNS relapse and no cases of relapse in the contralateral testis. The 5-year cumulative incidence of CNS relapse was 6% [15]. These results should be interpreted in light of the exclusion criteria, such as an Ann Arbor stage > II and an Eastern Cooperative Oncology Group (ECOG) performance status ≥ 2. As a contribution to the fight against CNS relapse, we highlight the findings of Aviles et al. [16] who treated 34 patients with PTL by performing orchiectomy followed by 6 cycles of anthracycline-based combined chemotherapy, radiotherapy, and prophylaxis to the CNS with 4 monthly cycles of a high dose of methotrexate (6 g/m2). In addition, the IELSG30 phase II trial in progress attempts to reduce the risk of CNS disease by administering 4 intrathecal injections of cytarabine in the treatment phase and 2 cycles of systemic intermediatedose methotrexate (1.5 g/m2) as consolidation [20]. In our group of patients, 2 patients showed progression to the contralateral testis; both of them did not receive prophylactic irradiation, which is in accordance with the conclusions of most studies on PTL. In addition, 1 case of CNS relapse occurred in a patient who was treated with intrathecal prophylactic chemotherapy, which supports the presumption that the currently used CNS prophylaxis is insufficient. Bearing in mind the poor prognosis for relapsed patients, there is the necessity for the development of new potential therapeutic approaches. Recent data about low levels of p53 expression, high levels of phosphorylated STAT3 (signal transducer and activator of transcription 3), overexpression of CXCR4, and up-regulation of the nuclear factor kB (NF-kB) pathway in patients with PTL suggest that the CXCR4 inhibitor plerixafor as well as inhibitors of the Janus kinase (JAK)STAT and NF-kB pathways need to be tested in prospective clinical trials with PTL patients [11].
Conclusions The standard of treatment for PTL is orchiectomy followed by chemoimmunotherapy, irradiation of the contralateral testis, and intrathecal prophylactic chemotherapy. Despite notable improvement in the PFS and OS after the introduction of multimodal treatment, 2 goals remain for the near future:
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(fig. 1), and the mean PFS was 36 months (the median was not reached).
(i) achieving a plateau in the survival curve and (ii) eradicating diseases of the CNS. If we accomplish the second goal, the first goal will probably be within reach. We believe that the ongoing IELSG30 phase II trial with modified CNS prophylaxis could give us some essential information. In the future, the development of biological therapeutic agents should be considered.
Disclosure Statement The authors declare that they have no conflict of interest.
References
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6 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;30A:1760–1764. 7 Mazloom A, Fowler N, Medeiros J, Iyengar I, Horace P, Dabaja SM: 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;51:1217–1224. 8 Verma N, Lazarchick J, Gudena V, Turner J, Chaudhary UB: Testicular lymphoma: an update for clinicians. Am J Med Sci 2008;336:336–341. 9 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;19:1521–1527. 10 Miedler JD, MacLennan GT: Primary testicular lymphoma. J Urol 2007;178:2645. 11 Cheah CY, Wirth A, Seymour JF: Primary testicular lymphoma. Blood 2014;123:486–493. 12 Domanska UM, Kruizinga RC, Nagengast WB, Timmer-Bosscha H, Huls G, de Vries EG, Walenkamp AM, et al.: A review on CXCR4/ CXCL12 axis in oncology: no place to hide. Eur J Cancer 2013;49:219–230. 13 Zucca E, Roggero E, Bertoni F, et al.: Primary extranodal non-Hodgkin’s lymphomas: Part 1. Gastrointestinal, cutaneous and genitourinary lymphomas. Ann Oncol 1997;8:727–737. 14 Martenson JA Jr, Buskirk SJ, Ilstrup DM, et al.: Patterns of failure in primary testicular nonHodgkin’s lymphoma. J Clin Oncol 1988;6:297–302.
Oncol Res Treat 2014;37:239–242
15 Vitolo U, Chiappella A, Ferreri AJM, Martelli M, Baldi I, Balzarotti M, Bottelli C, Conconi A, Gomez H, Guillermo AL, Martinelli G, Merli F, Novero D, Orsucci L, Pavone V, Ricardi U, Storti S, Gospodarowicz MK, Cavalli F, Sarris AH, Zucca E: 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;29:2766–2772. 16 Aviles A, Neri N, Huerta-Guzman J, Perez F, Fernandez R: Testicular lymphoma: organ-specific treatment did not improve outcome. Oncology 2004;67:211–214. 17 Shahab N, Doll DC: Testicular lymphoma. Semin Oncol 1999;26:259–269. 18 Sehn LH, Donaldson J, Chhanabhai M, et al.: Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol 2005:23:5027–5033. 19 Feugier P, Virion JM, Tilly H, et al.: Incidence and risk factors for central nervous system occurrence in elderly patients with diffuse large-B-cell lymphoma: influence of rituximab. Ann Oncol 2004; 15:129–133. 20 Ahmad SS, Idris SF, Follows GA, Williams MV: Primary testicular lymphoma. Clin Oncol 2012; 24:358–365.
Mihaljevic/Vukovic/Smiljanic/Milic/Todorovic/ Bila/Andjelic/Djurasinovic/Jelicic/Antic
Downloaded by: 198.143.55.33 - 8/19/2015 1:05:59 PM
1 Zucca E, Conconi A, Mughal TI, Sarris AH, Seymour JF, Vitolo U, Klasa R, Ozsahin M, Mead GM, Gianni MA, Cortelazzo S, Ferreri AJM, Ambrosetti A, Martelli M, Thiéblemont C, Gomez Moreno H, Pinotti G, Martinelli G, Mozzana R, Grisanti S, Provencio M, Balzarotti M, Laveder F, Oltean G, Callea V, Roy P, Cavalli F, Gospodarowicz MK: 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;21:20–27. 2 Vitolo U, Ferreri AJM, Zucca E: Primary testicular lymphoma. Crit Rev Oncol Hematol 2008;65:183– 189. 3 Cao B, Ji D, Zhou X, Zhao T, Guo Y, Wang Z, Cao J, Hu X, Hong X: A clinical analysis of primary testicular diffuse large B-cell lymphoma in China. Hematology 2011;16:291–297. 4 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;27:5227–5232. 5 Lagrange JL, Ramaioli A, Theodore CH, TerrierLacombe MJ, Beckendorf V, Biron P, Chevreau CH, Chinet-Charrot P, Dumont J, Delobel-Deroide A, D’Anjou J, Chassagne C, Parache RM, Karsenty JM, Mercier J, Droz JP; 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;12:1313–1319.
