This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tondini, C. Articles by Bonadonna, G. Search for Related Content PubMed PubMed Citation Articles by Tondini, C. Articles by Bonadonna, G. Social Bookmarking                            What's this?

Diffuse Large-Cell Lymphoma of the Testis

From the Division of Medical Oncology and Division of Pathology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.

Address reprint requests to Carlo Tondini, MD, Divisione di Oncologia Medica, Istituto Nazionale per lo Studio e la Cura dei Tumori, Via G. Venezian 1, 20133 Milano, Italia; email tondini{at}istitutotumori.mi.it

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To evaluate clinical outcome of patients with testicular diffuse large-cell lymphoma treated with conventional-dose systemic chemotherapy.

PATIENTS AND METHODS: This study is a retrospective analysis of adult patients with testicular diffuse large-cell lymphoma who were treated with a doxorubicin-based chemotherapy regimen at our institution, the Istituto Nazionale Tumori of Milan. Twenty-nine assessable patients, with a median age of 61 years, were identified. Sixteen patients had limited stage (Ann Arbor stage I/II) disease, whereas 13 patients had a testicular mass and distant organ involvement (Ann Arbor stage IV). Patients were retrospectively classified according to the International Prognostic Index.

RESULTS: After a median follow-up of 82 months, 22 patients presented disease progression and 22 patients had died. Actuarial median time to treatment failure and overall survival were 44 and 41 months for patients with limited stage and 9 and 16 months for patients with advanced stage, respectively. Eight patients failed initial treatment, and 14 patients relapsed from clinical remission after a median disease-free time of 17 months (range, 6 to 98 months). Median survival time after progression of lymphoma was 5 months (range, 0 to 22 months). In nine (41%) of the 22 failing patients, the initial site of relapse was either the CNS or the contralateral testis; the remaining patients experienced relapse in multiple extranodal sites.

CONCLUSION: Poor prognosis of patients with diffuse large-cell lymphoma calls for more effective treatment strategies, such as high-dose chemotherapy programs for younger patients or specifically designed chemotherapy regimens for patients not suitable for high-dose treatment, with the purpose to provide control of both systemic disease and disease of the CNS and contralateral testis. The potential benefit of contralateral testicular irradiation has to be taken into account in the treatment planning.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PRIMARY MALIGNANT lymphoma of the testis is a rare disease that accounts approximately for 5% of all testicular neoplasm and only 1% of lymphoma presentations. However, it is the most common testicular malignancy in patients older than 60 years of age.^1,2

Retrospective analyses^3-6 have shown that, after locoregional treatment only (orchiectomy and radiation therapy), relapse is high, ranging approximately from 50% to 80%, with a third of the patients relapsing in the CNS or in the contralateral testis. Recent publications have attempted to define the utility of early treatment with conventional-dose chemotherapy programs for these patients, but results are controversial.^7-10 In fact, the rarity of testicular diffuse large-cell lymphoma (DLCL) has prevented the carefully designed prospective trials that would evaluate clinical outcome of specifically targeted treatment programs. Therefore, clinical approach to the treatment of these cases has generally followed the evolution of knowledge in the treatment of similar, extratesticular presentation cases, with variable recommendation for introduction of prophylactic intrathecal chemotherapy or contralateral testicular irradiation.¹

With the present retrospective analysis of all cases of testicular DLCL seen at our institution in a 20-year time span, we intend to contribute our experience to define prognosis, outcome, and patterns of failure of patients presenting with a primary testicular DLCL after a conventional-dose therapeutic approach.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
A retrospective survey of all adult patients with a diagnosis of lymphoma seen and prospectively observed at our institution from 1973 through 1993 was conducted. Patients with a diagnosis of testicular lymphoma were identified. Assessment criteria for this retrospective study were a diagnosis of DLCL, initial complaint of a testicular mass, age older than 17 years, and staging and treatment at our institution with a doxorubicin-based chemotherapy regimen. After a human immunodeficiency virus (HIV) screening test became available at our institution in 1985, only HIV-negative patients have been included in the present analysis.

We were able to identify 33 adult patients with primary testicular lymphoma. Four patients were excluded from the present analysis because they were found to have low-grade lymphoma (two patients) or because they did not complete treatment at our institution (two patients). The remaining 29 assessable patients, with the exception of one who had a lymph node biopsy, had diagnosis of lymphoma by orchiectomy. All pathologic slides were reviewed at our institution and classified according to the International Working Formulation (IWF)¹¹ as DLCL, either centroblastic or immunoblastic type (IWF subtype G and H). After diagnostic surgery, all patients were staged with chest x-ray, lymphangiogram, upper digestive tract contrast study, either ultrasound or computed tomography study of the abdomen, bone marrow biopsy, and examination of the CSF. All patients were treated at our institution with a doxorubicin-based chemotherapy program. We retrospectively classified patients, according to the International Prognostic Index (IPI) score,¹² into four risk groups: low (IPI score 0 to 1), low-intermediate (IPI score of 2), high-intermediate (IPI score of 3), and high risk (IPI score of 4 to 5).

Statistical analysis was conducted with computation of actuarial survival curves according to the Kaplan-Meier method,¹³ and statistical significance of differences between groups was determined with the log-rank test.¹⁴ Time to treatment failure (TTF) was calculated from the date of chemotherapy initiation to the time of first evidence of failure, ie, disease progression or death from any cause. Overall survival (OS) was calculated from the time of chemotherapy initiation to the time of death from any cause.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Population Characteristics
Main patient and disease characteristics are listed in Table 1. Median age of all patients was 61 years (range, 19 to 79 years). Sixteen patients presented with limited stage disease (Ann Arbor I/II); seven patients were found to have disease localized to the testis, whereas nine patients presented involvement of locoregional lymph nodes (lumboaortic in seven, inguina-iliac in two). Median age of the limited stage group was 64 years (range, 33 to 79 years). Only two of these patients presented with a bulky testicular mass (> 10 cm). Lactate dehydrogenase serum level was more than 1.25 times the normal upper values in one patient with stage I disease and in two patients with stage II disease.

Thirteen patients presented with advanced stage disease (Ann Arbor IV) with distant organ involvement, including skin, lungs, kidneys, bone, thyroid, liver, maxilla, spleen, and Waldeyer's ring. In three patients, the contralateral testis was involved. In one patient, bone marrow infiltration was detected microscopically at staging. One patient with advanced stage was found to have a positive CSF cytology. Lactate dehydrogenase serum level was more than 1.25 times the normal upper values in five of the 13 patients. Median age of stage IV patients was 55 years (range, 19 to 70 years). Only four of these patients ranked in the IPI low-intermediate risk group, whereas six and three ranked in the high-intermediate or high IPI risk group, respectively.

Treatment and Response
All patients received a doxorubicin-based chemotherapy regimen. The 16 patients with limited stage disease were treated with four to six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP; nine patients) or CHOP-like (four patients) regimens, whereas the remaining three patients received six cycles of alternating cyclophosphamide, vincristine, prednisone/doxorubicin, bleomycin, and prednisone (CVP/ABP; one patient) or methotrexate-leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B; two patients). Seven patients were disease-free after orchiectomy, whereas seven of nine stage II patients achieved complete response (CR) with chemotherapy, for a total of 14 complete responders (87%, 95% confidence interval (CI), 62% to 98%). Two patients who progressed during initial chemotherapy died shortly after. Prophylactic radiation therapy to retroperitoneal lymph nodes was administered to 12 of the 14 complete responders in this group of patients, with a median dose of 36 Gy (range, 32 to 44 Gy). Prophylactic radiation therapy to ipsilateral hemiscrotum with shielding of the contralateral testis was administered to patients presenting with bulky testicular mass to reduce the risk of potential residual disease after surgical debulking.

The 13 patients with advanced stage disease were treated with CHOP or CHOP-like regimens (eight patients), alternating CVP/ABP (two patients), MACOP-B (one patient), prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide/cytarabine, bleomycin, vincristine, and methotrexate (ProMACE/CytaBOM; one patient), and ProMACE/mechlorethamine, vincristine, procarbazine, and prednisone (one patient). Complete remission was achieved in seven patients (54%, 95% CI, 25% to 81%), whereas four patients achieved only a partial remission, and two patients proved refractory to initial treatment. No patient in the present series received prophylactic intrathecal chemotherapy or irradiation to the contralateral testis.

Outcome
After a median follow-up period for surviving patients of 82 months (range, 62 to 201 months), 22 patients of the entire patient population presented disease progression and 22 patients have died, 21 from progressive non-Hodgkin's lymphoma and one from treatment-related complications. For patients with limited stage disease, actuarial median TTF and OS were 44 months and 41 months, respectively. For patients with advanced stage disease, TTF and OS were 9 months and 16 months, respectively. Statistical analysis of differences between limited and advanced stage disease showed a trend toward significance for TTF (P = .08) but not for OS (P = .14) (Fig 1). An analysis ranking patients according to the IPI score showed that the median TTF was 61, 15, 7, and 9 months (P = .056) and OS was 82, 25, 9, and 11 months (P = .031) for the low, low-intermediate, high-intermediate, and high IPI risk group, respectively (Fig 2).

View larger version (12K): [in this window] [in a new window]   Fig 1. Overall survival according to Ann Arbor stage.

View larger version (14K): [in this window] [in a new window]   Fig 2. Overall survival according to International Prognostic Index risk group.

Pattern of Relapse and Salvage Treatment
Sites of disease failure are listed in Table 2, according to limited or advanced stage presentation. Two of the 16 patients with limited stage presentation died shortly after initial chemotherapy treatment. Eight of the remaining 14 patients in this group relapsed from CR after a median time of 17 months (range, 7 to 75 months). Sites of failure in these 10 patients included isolated CNS progression (three patients), isolated contralateral testis (one patient), or both (one patient). In the other five patients, sites of failure included other extranodal organs, such as kidney, intestine, bone, Waldeyer's ring, and skin. Of the 10 failing patients with initially limited stage disease, only two patients achieved a second CR. One patient relapsed in the Waldeyer's ring after a disease-free interval of 47 months and is presently disease-free more than 12 months after second-line treatment. The other patient with isolated brain relapse achieved a transient CR, but the disease fatally progressed in the CNS after 1 year in second remission.

Of the 13 patients with advanced disease at presentation, six patients failed initial treatment, and disease rapidly progressed. Six of the remaining seven patients in this group relapsed from CR after a median time of 22 months (range, 6 to 98 months). Only one patient is in continuous CR at 86 months of follow-up. Sites of relapse included isolated CNS in two patients, isolated relapse in the contralateral testis in one patient, and both in one patient. Seven patients presented other extranodal sites of relapse, such as skin, Waldeyer's ring, bone, kidney, and lung. Bone marrow was involved at the time of relapse in two patients. In one patient, we did not have information on the sites of relapse. All patients with advanced stage disease failed salvage treatment and died shortly after.

In conclusion, 22 of 29 patients have failed treatment. Median survival for these patients after progression of lymphoma was 5 months (range, 0 to 22 months), with no differences between patients presenting with limited or advanced disease. Overall, of all 29 patients, nine (31%) failed in the CNS and six (20%) in the contralateral testis. Only two of the nine patients with CNS progression presented with CSF-positive cytology, whereas the other seven patients presented with parenchymal disease.

Twenty patients received salvage systemic chemotherapy at our institution, including retreatment with doxorubicin-based regimens, mesna, ifosfamide, mitoxantrone, and etoposide,¹⁵ or a six-drug salvage regimen developed at our institution.¹⁶ Radiation therapy and intrathecal chemotherapy were added for patients presenting with CNS involvement.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
We report a retrospective analysis of patients with testicular DLCL seen at the Istituto Nazionale Tumori of Milan from 1973 through 1993. We were able to identify 29 adult patients who were uniformly staged and treated at our institution. All patients were treated with a doxorubicin-based chemotherapy regimen, and 85% of those with limited disease received prophylactic radiotherapy on retroperitoneal and inguinal nodal stations. No patients received prophylactic radiation therapy on the uninvolved contralateral testis or prophylactic intrathecal chemotherapy. Therefore, these patients were managed like equivalent DLCL cases with extra-testicular presentation. After a median follow-up of 7 years, actuarial analysis shows that only one third of the patients presenting with limited stage disease and slightly more than 10% of the patients with advanced stage disease are alive. According to the IPI classification, outcome looks poor for all risk groups, with roughly 40% of the patients in the low-risk group and 25% in the low-intermediate–risk group alive, respectively, and no survivors in the high-intermediate– and high-risk groups. In nine (41%) of the 22 failing patients, the initial site of relapse was either the CNS or the contralateral testis, whereas the remaining patients experienced relapse in multiple extranodal sites. These data compare unfavorably with outcome data of patients with similar extratesticular DLCL, which indicates that more than 80% of patients with limited stage and 30% to 40% of patients with more advanced stage disease are expected to be long-term, disease-free survivors with conventional-dose, doxorubicin-based chemotherapy regimens.^12,17,18

Recently, there has been discordant evidence emerging from retrospective analyses of case series of patients with primary testicular DLCL. Although it is clear that locoregional treatment is insufficient even for patients with disease limited to a single testis,^3-6,19 the real benefit deriving from conventional-dose chemotherapy has not been established. In 15 patients with stage I and II testicular DLCL treated with orchiectomy, a doxorubicin-based chemotherapeutic program of 6- to 9-week duration (CHOP or doxorubicin, cyclophosphamide, vincristine, and bleomycin), and prophylactic radiotherapy to the uninvolved contralateral testis, Connors et al⁷ reported a 4-year actuarial survival of 93%. None of these patients relapsed in the contralateral testis, as opposed to three of their 14 historical controls. More recently, Touroutoglou et al⁸ reviewed the M.D. Anderson Cancer Center (MDACC) experience of patients with a diagnosis of primary testicular lymphoma seen between 1969 and 1993. They identified 22 patients treated with one of several systemic conventional-dose, doxorubicin-based chemotherapy programs in use at their center. Only one patient received prophylactic radiation treatment to the contralateral testis, and no patient received prophylactic treatment to the CNS. With a median follow-up of almost 10 years, they reported an actuarial disease-free survival of 40% for patients with stage I disease and favorable presentation (IPI score 1). All the remaining patients with more advanced disease (stage II or IPI score 2) had died of lymphoma progression at the time of the analysis. Of note, two of the patients with a favorable IPI score and four patients with a less favorable (> 1) IPI score presented isolated relapse in the unirradiated contralateral testis as first site of failure. Furthermore, three patients with favorable presentation and four patients with less favorable IPI score relapsed in the CNS. Therefore, our experience is similar to that reported from MDACC. Other series of patients with limited stage primary testicular lymphoma treated with systemic chemotherapy reported intermediate results, with relapse rates ranging between 15%² and 44%.^9,20

Outcome of patients presenting with advanced stage testicular lymphoma is dismal. Our experience with 13 such patients is very similar to that reported by Touroutoglou et al⁸ and by Crellin et al.⁹ Median survival for these patients is reported to be between 9 and 13 months, with occasional patients being long-term survivors. Disease course in these patients is usually very aggressive, with widespread organ involvement and frequent early CNS progression.

In conclusion, our study confirms the poor prognosis of testicular DLCL patients, both for primary and for advanced disease. More effective systemic treatment for all patients is definitely warranted. Although it is likely that prophylactic locoregional treatment, such as contralateral testicular irradiation or intrathecal therapy, can contribute to prevent initial testicular or CSF relapse and should be considered for all patients with testicular lymphoma, we believe that more effective systemic treatment is necessary to contrast the dismal course of the disease. In fact, only two of our patients experienced isolated testicular relapse, and only two of the nine patients with CNS relapse presented with CSF-positive cytology, whereas the other seven patients presented with parenchymal disease. All other patients showed widespread systemic disease progression, with involvement of other extranodal sites. This aggressive course calls for a more effective systemic treatment able to control occult disease both systemically and in protected areas, such as CNS and the contralateral testis. We believe that more effective treatment programs, such as high-dose chemotherapy with stem-cell support, should be tested in younger patients with primary testicular lymphoma. In our series, 50% of patients were older than 60 years, but only one of them was older than 70 years. For elderly patients in good general condition, a properly devised chemotherapeutic regimen able to control disease both in the CNS and in the contralateral testis should be devised.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Zucca E, Roggero E, Bertoni F, et al: Primary extranodal non-Hodgkin's lymphomas: Part 1. Gastrointestinal, cutaneous, and genitourinary lymphomas. Ann Oncol 8:727-737, 1997[Free Full Text]

2. Moller 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 30:1760-1764, 1994

3. Read G: Lymphomas of the testis: Results of treatment 1960-77. Clin Radiol 32:687-692, 1981[Medline]

4. Buskirk SG, Evans RG, Banks PM, et al: Primary lymphoma of testis. Int J Radiat Oncol Biol Phys 8:1699-1703, 1982[Medline]

5. Duncan PR, Checa F, Gowing NF, et al: Extranodal non-Hodgkin's lymphoma presenting in the testicle: A clinical and pathologic study of 24 cases. Cancer 45:1578-1584, 1980[Medline]

6. Martenson JAJ, Buskirk SJ, Ilstrup DM, et al: Patterns of failure in primary testicular non-Hodgkin's lymphoma. J Clin Oncol 6:297-302, 1988[Abstract]

7. Connors JM, Klimo P, Voss N, et al: Testicular lymphoma: Improved outcome with early brief chemotherapy. J Clin Oncol 6:776-781, 1988[Abstract/Free Full Text]

8. Touroutoglou N, Dimopoulos MA, Younes A, et al: Testicular lymphoma: Late relapses and poor outcome despite doxorubicin-based therapy. J Clin Oncol 13:1361-1367, 1995[Abstract]

9. Crellin AM, Hudson BV, Bennett MH, et al: Non-Hodgkin's lymphoma of the testis. Radiother Oncol 27:99-106, 1993[Medline]

10. Roche H, Suc E, Pons A, et al: Stage IE nonHodgkin's lymphoma of the testis: A need for a brief aggressive chemotherapy. J Urol 141:554-556, 1989[Medline]

11. The Non-Hodgkin's Lymphoma Classification Project: National Cancer Institute sponsored study of classification of non-Hodgkin's lymphomas: Summary and description of a working formulation for clinical use. Cancer 49:2112-2135, 1982[Medline]

12. The International Non-Hodgkin Lymphoma Prognostic Factor Project: A predictive model for aggressive non-Hodgkin lymphoma. N Engl J Med 329:987-994, 1993[Abstract/Free Full Text]

13. Kaplan EI, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958

14. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomized clinical trials requiring prolonged observation of each patient: II. Analysis and examples. Br J Cancer 35:1-39, 1977[Medline]

15. Rodriguez MA, Cabanillas FC, Hagemeister FB, et al: A phase II trial of mesna/ifosfamide, mitoxantrone and etoposide for refractory lymphomas. Ann Oncol 6:609-611, 1995[Abstract/Free Full Text]

16. Buzzoni R, Colleoni M, Bajetta E, et al: Effective salvage chemotherapy in relapsed or refractory non-Hodgkin's lymphoma. Ann Oncol 4:251-253, 1993[Abstract/Free Full Text]

17. Tondini C, Giardini R, Bozzetti F, et al: Combined modality therapy for primary gastrointestinal non-Hodgkin's lymphoma (GI-NHL): The Milan Cancer Institute experience. Ann Oncol 4:831-837, 1993[Abstract/Free Full Text]

18. Fisher R, Gaynor ER, Dahlberg S, et al: Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med 328:1002-1006, 1993[Abstract/Free Full Text]

19. Poulsen MG, Roberts SJ, Taylor K: Testicular lymphoma: The need for a new approach. Australas Radiol 35:257-260, 1991[Medline]

20. Sasai K, Yamabe H, Tsutsui K, et al. Primary testicular non-Hodgkin's lymphoma: A clinical study and review of the literature. Am J Clin Oncol 20:59-62, 1997[Medline]

Submitted November 9, 1998; accepted April 28, 1999.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				M. K. Tummala, P. F. Hausner, W. P. McGuire, T. Gipson, and A. Berkman CASE 1. Testis: A Sanctuary Site in Merkel Cell Carcinoma J. Clin. Oncol., February 20, 2006; 24(6): 1008 - 1009. [Full Text] [PDF]

				E. Zucca, A. Conconi, T.I. Mughal, A.H. Sarris, J.F. Seymour, U. Vitolo, R. Klasa, M. Ozsahin, G.M. Mead, M.A. Gianni, et al. 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., January 1, 2003; 21(1): 20 - 27. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tondini, C. Articles by Bonadonna, G. Search for Related Content PubMed PubMed Citation Articles by Tondini, C. Articles by Bonadonna, G. Social Bookmarking                            What's this?