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Testicular Disease in Childhood B-Cell Non-Hodgkin’s Lymphoma: The French Society of Pediatric Oncology Experience

From Service d’Oncologie Pédiatrique and Département d’Oncologie Pédiatrique, Institut Gustave Roussy, Villejuif; Unité d’Oncologie et Hématologie Pédiatrique, Centre Hospitalier Universitaire de Nantes, Nantes; Département d’Oncologie Pédiatrique, Institut Curie, Paris; Unité d’Oncologie et Hématologie Pédiatrique, Centre Hospitalier Universitaire de Marseille, Marseille; Unité d’Oncologie et Hématologie Pédiatrique, CHU de Limoges, Limoges; Unité d’Oncologie et Hématologie Pédiatrique, CHU de Toulouse, Toulouse; and Unité d’Oncologie et Hématologie Pédiatrique, CHU de Nancy, Nancy, France.

Address reprint requests to Jean-Hugues Dalle, MD, Service des Maladies du Sang, Unité de greffe de moelle, Centre Hospitalier Regional Universitaire de Lille, 59037 Lille Cedex, France; email: jhdalle{at}wanadoo.fr

	ABSTRACT

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PURPOSE: To investigate whether testicular disease in childhood B-cell lymphoma should continue to be considered a sanctuary site, as it is with other lymphoid malignancies such as acute lymphoblastic leukemia.

PATIENTS AND METHODS: Seven hundred forty-two children with B-cell non-Hodgkin’s lymphoma were included in the LMB protocols of the French Society of Pediatric Oncology from February 1981 to May 1994. Thirty patients (5.3%) had testicular involvement at diagnosis. We describe the clinical presentation and outcome of these 30 patients, who were treated without local radiation therapy.

RESULTS: Five patients underwent diagnostic orchidectomy. The median patient age was 8.5 years (range, 2 to 14 years), and their cancers were stage III (18 patients), stage IV (five patients), and B-cell acute lymphoblastic leukemia (seven patients). Five patients had central nervous system involvement. Twenty-eight patients (95%) achieved complete remission. Twenty-six patients are alive without progressive disease (median follow-up, 6.5 years).

CONCLUSION: Testicular disease does not seem to confer a poor prognosis, and it is curable with intensive combination chemotherapy alone. Local treatment (surgery or radiation) is avoidable; therefore, gonadal function can be preserved.

	INTRODUCTION

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FOR CHILDREN WITH B-cell non-Hodgkin’s lymphoma (B-NHL), therapy and outcomes have improved dramatically during the past 15 years, particularly in patients with advanced-stage cancers (stages III and IV) and B-cell acute lymphoblastic leukemia (B-ALL). Intensive combination chemotherapy programs from 1981 to 1989 have increased the survival rate from 35% to greater than 80%.^1-2 Involvement of the testis, like that of other "sanctuaries," was thought to confer a poor prognosis, essentially by analogy with ALL.^3-5

Since 1981, the French Society of Pediatric Oncology (SFOP) has considered this location treatable with combination chemotherapy alone, as for other disease sites with the exception of central nervous system (CNS) involvement. The LMB 81, 84, 86, and 89 SFOP studies precluded local radiotherapy and surgery.^6-9

Two published studies reported conflicting conclusions on the best therapeutic approach to testicular disease. Haddy et al³ emphasized the importance of additional local therapy in childhood lymphoma with testicular involvement, whereas Kellie et al⁴ suggested that local therapy was pointless. However, both included small numbers of patients with different NHL histology at diagnosis and relapse. We examine the "sanctuary" hypothesis of testicular involvement and describe the clinical presentation and treatment outcome of a large group of consecutive and unselected patients with B-NHL.

	PATIENTS AND METHODS

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Patients
Seven hundred forty-two consecutive patients with newly diagnosed B-NHL or ALL were enrolled in the SFOP LMB studies from February 1981 to May 1994. There were 569 boys and 173 girls (sex ratio, 3.3:1). Patients were entered onto one of the four successive multicenter LMB studies by the different SFOP participating centers according to disease stage. Clinical stage was determined at diagnosis by use of Murphy’s staging system.¹⁰ Testicular disease was documented in 30 cases. Because this involvement did not change the therapy, complementary confirmation by histology was not mandatory. In 14 patients, however, the diagnosis was confirmed by histologic examination after orchidectomy, percutaneous needle biopsy, or aspiration. In 16 other cases, testicular involvement was determined by physical examination and, as for localization of all other clinical lymphomas, it was defined as an abnormal increase in size, irregular swelling, and/or abnormal consistency.

Treatment Programs
The four LMB 81, 84, 86, and 89 studies have been described in detail previously.^6-9 In summary, patients were grouped as follows:

1. Patients with advanced-stage B-cell (small-noncleaved-cell) lymphoma (ie, head and neck stage II and stages III or IV), or B-ALL by Murphy’s classification, were entered onto LMB 81 (1981 to 1984).¹⁰
   
2. Patients with advanced B-cell (small-noncleaved-cell) lymphoma without CNS involvement or B-ALL (ie, more than 70% bone marrow [BM] involvement in the absence of an abdominal or head and neck primary cancer) were entered onto LMB 84 (1984 to 1989). The duration of treatment was randomized (short arm, 3.5 months; long arm, 7 months).⁷
   
3. Patients with CNS involvement or B-ALL (as defined above) were entered onto LMB 86 (1985 to 1989).⁸
   
4. Patients with B-cell lymphoma or B-ALL of any stage or histologic subtype were stratified into three risk groups and entered onto LMB 89 (after 1989).⁹ Testicular irradiation was not mandatory in any LMB protocol.
   

All LMB programs used intensive chemotherapy and had the same treatment schedule.^6-9 In protocols LMB 81, 84, and 89 group B, the first two induction courses, called COPADM, were identical with high-dose methotrexate (3 g/m² in a 3-hour infusion), fractionated cyclophosphamide (1.5 g/m² in the first course or 3 g/m² in the second course, in six fractions during a 3-day period), vincristine (2 mg/m²), adriamycin (60 mg/m²), and prednisone (60 mg/m²/d). The following two consolidation courses contained cytarabine in a continuous infusion during a 5-day period. The main difference between the protocols was the duration of maintenance therapy: the total duration of treatment was decreased from 1 year in 1981 to 3.5 months in 1989 as result of the LMB 84 trial. More intensive protocols were designed for patients with CNS disease or ALL. In the LMB 86 and LMB 89 group C protocols, high-dose methotrexate was given at the dosage of 8 g/m² in a 4-hour infusion, and the consolidation courses were intensified by the addition of high doses of cytarabine (3g/m²/d, days 2 through 5) combined with etoposide in a cytarabine and etoposide (CYVE) course. In the LMB 86 protocol, all patients received cranial irradiation, although in LMB 89 group C, only patients with CNS disease at initial diagnosis received cranial radiation therapy.

Statistical Analysis
The duration of survival was calculated from the date of diagnosis to death or the last date at which the patient was known to be alive. Event-free survival and overall survival curves were plotted by use of the Kaplan-Meier method.¹¹

	RESULTS

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Patients
Thirty (5.3%) of the 569 boys with B-NHL or B-ALL had testicular disease at diagnosis and were treated in 15 French oncology centers and one Dutch hospital. The median age was 8.5 years (range, 2 to 14 years).

Clinical Presentation
Testicular involvement was unilateral in 24 patients and bilateral in six (patient nos. 3, 9, 15, 20, 25, and 30) ( Table 1). In five patients, testicular involvement was the initial sign of their disease at presentation. Orchidectomy was performed in five children, one of whom had an inguinal tumor in an ectopic testis (patient no. 12). In the other 25 patients, testicular involvement was found at the initial work-up. Testicular involvement was diagnosed clinically and always was associated with another clinical site of disease except in one case (patient no. 18). In this child, the extension checkpoint demonstrated mediastinal localization of disease; had the checkpoint been performed before orchidectomy, it could have been avoided. Two boys had an ectopic testis (patient nos. 5 and 12). {tabft}Abbreviations: FSH, follicle-stimulating hormone; LH, luteinizing hormone; SNC, small noncleaved cells; CNS+, CNS involvement; -, negative; CR: complete remission; DOD, died of disease.

In 14 cases, testicular involvement was confirmed by histology or cytology (orchidectomy, five patients; testicular needle biopsy, seven patients; and tunica vaginalis biopsy, two patients). In 11 of the 14 patients, the testicular parenchyma was replaced completely by tumor cells, and in three patients, the examined testicular parenchyma was normal and disease was either localized to the epididymis (patient no. 12) or the tunica vaginalis biopsy (patient nos. 7 and 13).

The primary site of lymphoma was abdominal in 23 cases, Waldeyer’s ring in three cases, and the testis, BM, superior maxillary bone, and unknown (diffuse lymphoma with many tumors in different sites, patient no. 20) in one case each. Eighteen patients had stage III disease. Five patients had stage IV disease (isolated CNS involvement in four, and combined CNS and BM in one). Seven patients had B-ALL (with CNS involvement in one).

Histologic, Immunologic, and Cytogenetic Analysis
B-NHL diagnosis was confirmed by cytologic examination of BM aspirates, pleural or ascitic fluids in nine cases, and by histologic examination in 21 patients. Twenty-nine cases were Burkitt’s lymphoma, Burkitt’s-like-B-NHL (small-noncleaved-cell lymphoma), or B-ALL, and one was a diffuse large-cell B-NHL (centroblastic) (patient no. 5).

Surface immunoglobulin test results were positive in 19 of 21 patients tested: kappa (n = 9), lambda (n = 6), and unspecified (n = 4). Karyotypes were obtained in 12 cases: seven had translocation t(8;14), one had translocation t(8;22), one was normal diploid, and three studies were unsuccessful. Serum LDH level was higher than twice the normal upper institutional value for age in 12 of 15 children tested on the LMB 89 study.

Treatment
Patient nos. 1 through 9 were treated in the LMB 81 study (six, stage III; one, stage IV; and two, B-ALL). Patient nos. 10 through 14 were treated in the LMB 84 study (four stage III, one B-ALL; two patients on the short arm and three on the long arm). Patient no. 15 was treated on the LMB 86 study. Patient nos. 16 through 30 were treated on the LMB 89 study (eight stage III, four stage IV, and three B-ALL); nine were placed in group B and six in group C. Four patients received cranial irradiation (patient nos. 9, 20, 26, and 30) for CNS disease at diagnosis and one for inclusion in protocol LMB 86 (patient no. 15).

Therapeutic Outcome
Twenty-eight patients (94%) achieved a complete remission including the testes. In three cases (patient nos. 16, 22, and 25) residual extratesticular tumor was biopsied; no viable tumor was found.

Two patients with abdominal disease (patient nos. 4 and 7) who were treated on the LMB 81 protocol never achieved a complete remission, although they responded in the testes, and both ultimately died. Of note, one of them had seizures and renal impairment attributed to high-dose methotrexate after the first induction course, and methotrexate was discontinued during the subsequent courses. Two children (patient nos. 16 and 20) had recurrent disease without any testicular involvement at relapse, and both died.

All 30 boys, including the four who died, obtained a clinical remission of the testis with return to the normal size. Dependent on physician decision, this remission was confirmed by histologic examination in nine patients (including patient nos. 4 and 16). Testicular disease was controlled by combination chemotherapy alone, and no local testicular relapse occurred.

Survival
Twenty-six boys (15 with stage III disease, four with stage IV disease, and seven with B-ALL) are alive with a median follow-up of 112 months (range, 53 to 201 months). Four patients died of progressive disease within the first year after diagnosis. No toxicity-related death occurred (Table 1). The Kaplan-Meier event-free survival of all patients was 87% ± 10, with a plateau at 10 months, 83% ± 15% for stages III and IV, and 92% ± 15 for B-ALL ( Figs 1 and 2).

View larger version (10K): [in this window] [in a new window]   Fig 1. Global event-free survival of 30 children.

View larger version (11K): [in this window] [in a new window]   Fig 2. Detailed event-free survival for stage III (–|–|–)and stage IV (— —) disease.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Testicular involvement in children with newly diagnosed NHL is infrequent, and it accounts for 3% to 12% of cases.^3-5 In our study, 30 (5.3%) of 539 boys with B-NHL or B-ALL had testicular involvement, which is the largest proportion reported to date. Testicular involvement always was associated clinically with another site of disease, with the exception of one case (patient no. 18), testicular involvement was always associated with another site of disease. The diagnosis could always be established without orchidectomy.

Only two studies have been published, and they reported small numbers of children and different NHL histology. The appropriate treatment was not clearly established and the need for local treatment was controversial. In one study, local therapy was important for disease-free survival, whereas in the other, local treatment seemed pointless with intensive combination chemotherapy.

In the NCI study,³ nine patients with NHL involving the testis received additional local therapy (radiotherapy in three and orchidectomy in six). Among eight assessable cases, five patients died, with a mean survival of 4.4 months, and three experienced a long-term remission, with a mean survival of 68.3 months. These three survivors had stage III Burkitt’s lymphoma. Two of them had undergone early orchidectomy, and the third also underwent orchidectomy after a testicular relapse during the third cycle of treatment. That patient achieved a second long-term complete remission after local radiotherapy associated with continued systemic chemotherapy. Of the five patients who died, two had never undergone orchidectomy and had never achieved a complete remission, and three had undergone orchidectomy, one of whom also had received local radiotherapy. On the basis of the observation that three long-term survivors had undergone orchidectomy, the authors concluded that local treatment was efficient and necessary.³

In contrast, Kellie et al⁴ reported six cases of childhood NHL of all histologic subtypes with testicular involvement at diagnosis and three cases with testicular involvement at relapse. Four of the six boys are disease free 3 to 8 years after intensive chemotherapy without irradiation of the testes, but one patient underwent orchidectomy. Two patients died of disease. The first, who had T-cell NHL, developed a recurrence in the testis, CNS, BM, and soft tissue. The other, who had B-NHL, developed disseminated recurrent disease during therapy.

In our study, intrascrotal involvement was not the main clinical symptom except in one case (patient no. 18). As for other disease sites, histologic confirmation of testis involvement was not mandatory when histologic diagnosis of B-cell lymphoma was made elsewhere. Twenty-eight boys achieved a complete remission, including clinical remission of testis involvement, 26 experienced a long-term remission, and four patients died of progressive disease elsewhere. One of the patients whose treatment failed developed grade 4 renal toxicity and neurotoxicity attributed to high-dose methotrexate chemotherapy, and this patient received further treatment without high-dose methotrexate.

None of our patients received local radiotherapy to the testes. No recurrence occurred in the testis. In five cases, however, initial orchidectomy was performed at diagnosis. This mutilation was justified in only one case.

There was no difference in outcome between children who underwent orchidectomy and those who did not. The event-free survival of these 30 patients with testicular involvement is 87 ± 10%, with a plateau at 10 months. This result seems similar to those obtained in the other patients treated on the LMB program (Table 2), although this was not tested statistically.

In our study, all boys (except patient no. 7, who died) received several courses with high-dose methotrexate (3 or 8 g/m² per cycle) and elevated doses of cyclophosphamide (1.5 g/m² and 3 g/m² in the first and second induction courses, respectively). Our study demonstrates that with intensive combination chemotherapy, the testis does not remain a sanctuary site for malignant cells.

Local radiotherapy at curative doses ( 2 Gy) affects both testicular endocrine and germinal functions.^17-18 It is too early to assert that intensive LMB cyclophosphamide-containing chemotherapy preserves testicular endocrine function in all cases. Patients achieved puberty at a normal age, and the follicle-stimulating hormone and luteinizing hormone levels measured in most of them were normal. The patient whose spermogram revealed azoospermia had an ectopic testis at presentation. The percentage of patients with altered germinal function increased with the total dose of cyclophosphamide received. Germinal function is likely to be preserved when the total dose of cyclophosphamide is less than 9 g/m².^19-20

In conclusion, an intensive combined chemotherapy regimen based on high-dose methotrexate, cyclophosphamide, and cytarabine in continuous infusion is similarly efficient for the treatment of testicular involvement in B-NHL and B-ALL as for other disease sites.

Testicular involvement at diagnosis does not seem to be an adverse prognostic factor. Local therapy (surgery and/or radiotherapy) is needless and should be avoided. Endocrine gonadal function is more likely to be preserved after conventional chemotherapy than when radiotherapy is used. Radiotherapy always destroys germinal and endocrine testicular function. In addition, testis conservation is extremely important psychologically for these boys, who already are strongly shaken by illness and treatments. This psychological aspect should not be underestimated.

	ACKNOWLEDGMENTS

 
We thank Lorna Saint Ange and Sue Martin for editing the manuscript and Hazem Mahmoud for helpful advice.

	NOTES

 
Presented in part at the Thirty-First Annual Meeting of The American Society of Clinical Oncology, Los Angeles, CA, May 21-23, 1995.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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2. Murphy SB: Management of pediatric lymphomas. Curr Opin Oncol 1: 42-46, 1989[Medline]

3. Haddy TB, Sandlund JT, Magrath IT: Testicular involvement in young patients with non-Hodgkin’s lymphoma. Am J Pediatr Hematol Oncol 10: 224-229, 1988[Medline]

4. Kellie SJ, Pui CH, Murphy SB: Childhood non-Hodgkin’s lymphoma involving the testis: Clinical features and treatment outcome. J Clin Oncol 7: 1066-1070, 1989[Abstract]

5. Leonard MP, Schlegel PN, Crovatta A, et al: Burkitt’s lymphoma of the testis: An unusual scrotal mass in childhood. J Urol 143: 104-106, 1990[Medline]

6. Patte C, Philip T, Rodary C, et al: Improved survival rate in children with stage III and IV B cell non-Hodgkin’s lymphoma and leukemia using multi-agent chemotherapy: Results of a study of 114 children from the French Pediatric Oncology Society. J Clin Oncol 4: 1219-1226, 1986[Abstract/Free Full Text]

7. Patte C, Philip T, Rodary C, et al: High survival rate in advanced-stage B-cell lymphomas and leukemias without CNS involvement with short intensive polychemotherapy: Results from the French Pediatric Oncology Society of a randomized trial of 216 children. J Clin Oncol 9: 123-32, 1991[Abstract/Free Full Text]

8. Patte C, Leverger G, Perel Y, et al: Updated results of the LMB 86 protocol of the French Pediatric Oncology Society (SFOP) for B-cell non-Hodgkin’s lymphoma (B-NHL) with CNS involvement (CNS+) and B-ALL. Med Ped Oncol 18: 387, 1990

9. Patte C, Michon J, Leverger G, et al: High survival rate of childhood B-cell lymphoma and leukemia (ALL) as result of the LMB 89 protocol of the SFOP (French Pediatric Oncology Society). Med Ped Oncol 21: 531, 1993[Medline]

10. Murphy S: Classification, staging and end results of treatment of childhood non-Hodgkin’s lymphoma: Dissimilarities from lymphomas in adults. Semin Oncol 7: 332-339, 1980[Medline]

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

12. Riccardi R, Vigersky RA, Barnes S, et al: Methotrexate levels in the interstitial space and seminiferous tubule of rat testis. Cancer Res 42: 1617-1619, 1982[Abstract/Free Full Text]

13. Van Eys M, Sullivan MP: Testicular leukaemia and temperature. Lancet 2: 256-257, 1976 (letter)

14. Bleyer WA, Poplack D: Prophylaxis and treatment of leukaemia in the central nervous system and other sanctuaries. Semin Oncol 12: 131-148, 1985[Medline]

15. Bowman WP, Aur RJA, Hustu HO, et al: Isolated testicular relapse in acute lymphocytic leukemia of childhood: Categories and influence on survival. J Clin Oncol 2: 924-929, 1984[Abstract]

16. Tiedemann K, Chessels JM, Sandland RM: Isolated testicular relapse in boys with acute lymphoblastic leukaemia: Treatment and outcome. BMJ 285: 1614-1616, 1992

17. Leiper AD, Grant DB, Chessells JM: Gonadal function after testicular radiation for acute lymphoblastic leukaemia. Arch Dis Child 61: 53-56, 1986[Abstract/Free Full Text]

18. Castillo LA, Craft AW, Kernahan J, et al: Gonadal function after 12-Gy testicular irradiation in childhood acute lymphoblastic leukaemia. Med Pediatr Oncol 18: 185-189, 1990[Medline]

19. Aubier F, Flamant F, Brauner R, et al: Male gonadal function after chemotherapy for solid tumors in childhood. J Clin Oncol 7: 304-309, 1987[Abstract]

20. Aubier F, Oberlin O, De Vathaire F, et al: A study of 175 patients with solid tumor treated at the Institut Gustave Roussy between 1963 and 1988. Med Ped Oncol 23: 177-80, 1994

Submitted August 10, 1998; accepted February 5, 2001.

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