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© 2003 American Society for Clinical Oncology Lymphocyte-Predominant Hodgkin’s Lymphoma in Children: Therapeutic Abstention After Initial Lymph Node Resection—A Study of the French Society of Pediatric Oncology
From the Departments of Pediatric Hematology/Oncology of Hôpital Armand Trousseau, Hôpital Saint Louis, AP-HP; and Institut Curie, Paris; Institut G. Roussy, Villejuif; Hôpital Debrousse, Centre Léon Berard, Lyon; Hôpital Pellegrin, Bordeaux; Hôpital Americain, Reims; Hôpital Sud, Rennes; Hôpital d’Enfants, Nancy; Hôpital A. Michalon, Limoges; Hôpital C. Nicolle, Rouen; Hôpital J. de Flandre, Lille; Hôpital d’Enfants, Dijon; Hôpital Hautepierre, Strasbourg; Hôpital La Timone, Marseille; Hôtel Dieu, Clermont Ferrand; and Pathology Departments of Hôpital Purpan, Toulouse; and Institut Gustave Roussy, Villejuif, France. Address reprint requests to Judith Landman-Parker, MD, Service d’Hématologie et d’Oncologie Pédiatrique, Hôpital d’Enfants Armand Trousseau; 26 ave Arnold Netter, Paris 75012, France; email: judith.landman-parker{at}trs.ap-hop-paris.fr.
Purpose: To clarify treatment strategy for lymphocyte-predominant Hodgkin’s lymphoma (LPHL), the French Society of Pediatric Oncology initiated a prospective, nonrandomized study in 1988. Patients received either standard treatment for Hodgkin’s lymphoma or were not treated beyond initial adenectomy. Patients and Methods: From 1988 to 1998, 27 patients were available for study. Twenty-four patients were male, and median age was 10 years (range, 4 to 16 years). Twenty-two, two, and three patients had stage I, II, and III disease, respectively. Thirteen patients (stage I, n = 11; stage III, n = 2) received no further treatment after initial surgical adenectomy (SA). Fourteen patients received combined treatment (CT; n = 10), involved-field radiotherapy alone (n = 1), or chemotherapy alone (n = 3). The two groups were comparable for clinical status, treatment, and follow-up. Results: Twenty-three of 27 patients achieved complete remission (CR). With a median follow-up time of 70 months (range, 32 to 214 months), overall survival to date is 100%, and overall event-free survival (EFS) is 69% ± 10% (SA, 42% ± 16%; CT, 90% ± 8.6%; P < .04). If we considered only the patients in CR after initial surgery (n = 12), EFS was no longer significantly different between the two groups. Patients with residual mass after initial surgery (n = 15) had worse EFS if they did not receive complementary treatment (P < .05). Conclusion: Although based on a small number of patients, our study showed that (1) no further therapy is a valid therapeutic approach in LPHL patient in CR after initial lymph node resection, and (2) complementary treatment diminishes relapse frequency but has no impact on survival.
NODULAR LYMPHOCYTE-PREDOMINANT Hodgkin’s lymphoma (LPHL), or Poppema-Lennert paragranuloma, previously included in type 1 of the Rye classification, has been viewed individually in recent years on the basis of its pathologic and clinical characteristics.1 This form, which is rare in children (1% to 4% of all pediatric cases of Hodgkin’s disease),2,3 is considered a distinct entity in the new classification proposed by the International Lymphoma Study Group in 1994 and the World Health Organization.4,5 Histologically, LPHL is characterized by the presence of atypical (lymphocytic and histiocytic [L&H]) cells with polylobular nuclei, within nodules composed of small mature B lymphocytes. Reed-Sternberg cells are few or absent. Almost all these L&H cells express antigenic markers of the B-cell lineage (CD20, CD79a, and CD75) and leukocytes (CD45), as well as epithelial membrane antigen. Antigens usually expressed by Reed-Sternberg cells (CD15 and CD30) are absent or weakly positive.5 Nevertheless, in some cases, diagnostic difficulties persist between LPHL and nodular lymphocyte-rich classical Hodgkin’s lymphoma, as reported by Stein et al.6 In the last decade, treatment of LPHL has been controversial. Studies in children2,3 and in adults7–10 have shown an excellent spontaneous prognosis, and because most deaths are treatment-related,2,8,11,12 some authors have suggested a wait-and-see approach,8,13,14 whereas others in recent years have treated such cases in a fashion similar to that of favorable stages of Hodgkin’s lymphoma.8,15–17 Between 1982 and 1998, the French Society of Pediatric Oncology (SFOP) conducted two trials in pediatric Hodgkin’s disease (MDH 82 and MDH 90). Since 1988, all French children with LPHL have been systematically enrolled. After initial lymph node resection to establish the diagnosis, patients were treated according to the MDH 90 or MDH 82 protocol or received no treatment after diagnostic biopsy excision, in a nonrandom manner, according to physician discretion. To clarify a risk-adapted strategy in children, we report the experience of the SFOP in this study, comparing the outcome of patients who did and did not receive further treatment after initial lymph node resection.
Patients Of 610 patients reported to the Hodgkin’s disease committee during two successive SFOP protocols (MDH 82 and MDH 90) between February 1982 and December 1998, 36 (6%) had a pathologic diagnosis of LPHL. All patients were classified according to the Ann Arbor system. The number and location of initial disease sites were obtained in each case during a full physical examination and a paraclinical work-up that routinely included chest radiography, thoracoabdominal computed tomography, and abdominal sonography. Seventeen patients also had lymphography and bone marrow biopsies (n = 9). None of the patients underwent exploratory laparotomy. All the patients gave informed consent according to local ethical committee guidelines.
Histology
Statistical Analysis
Patient Characteristics Clinical characteristics of the 27 patients are listed in Table 1  . Patient age at diagnosis ranged from 4 to 16 years (median, 10 years). Most patients were male (24 boys and three girls). One to three node territories were involved at diagnosis. The sites were mainly supradiaphragmatic — in particular, the cervical region (left cervical, n = 8; right cervical, n = 8; bilateral, n = 3) — or axillary (n = 4), and, more rarely, subdiaphragmatic (inguinal, n = 4; spleen, n = 2) or abdominal (liver hilar node, n = 1). No mediastinal involvement was found. None of the patients had clinical or biologic systemic symptoms. After the initial work-up, the patients were therefore classified as follows: stage I, n = 22; stage II, n = 2; and stage III, n = 3.
Treatment For analysis, patients were divided into two groups according to the treatment received after initial adenectomy. The surgery alone (SA) group consisted of 13 patients who received no treatment after initial adenectomy, and the complementary treatment (CT) group consisted of 14 patients who received SFOP Hodgkin’s protocols.18,19 Patients with stages I and II disease received four courses of vinblastine, bleomycin, etoposide, and prednisone (VBVP), and those with stage III disease received two cycles of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), and doxorubicin, bleomycin, vinblastine, and prednisone, combined with 20 Gy of radiation therapy to initially involved fields. Characteristics of patients in SA and CT groups are listed in Table 2 . Overall, 10 of 27 patients (nine patients with stage I disease and one patient with stage II disease) received combined treatment (VBVP x 4 plus 20 Gy of radiation therapy), three patients received chemotherapy alone (MOPP x 1, n = 1; VBVP x 2, n = 1; and VBVP x 4, n = 1), and one patient received radiotherapy alone after surgery (20 Gy) according to the decision of the treating physician. There was no significant difference between the two groups in terms of age, stage, disease site, sex, or mean follow-up.
Outcome Complete remission (CR) was defined as complete disappearance of superficial adenopathy after either surgical initial adenectomy or CT or response greater than 90% by radiologic evaluation (computed tomography) in case of subdiaphragmatic involvement. Follow-up ranged from 28 to 214 months after initial diagnosis (median, 4.5 years for SA and 5 years 10 months for CT). The OS rate was 100%. Twenty-three (85%) of the 27 patients achieved CR either after initial surgery (n = 12) or CT (n = 11).
Relapses Multiples relapses at initial site occurred in three patients. One of them developed a diffuse large B-cell lymphoma 10 years after initial diagnosis. For seven of nine patients, treatment of relapse was based on classical Hodgkin’s disease stage-adapted strategies (two to six cycles followed by low-dose radiation therapy). In two patients, adenectomy was treatment for the first relapse. At the median follow-up of 33 months, all patients were well in CR.
Statistical Analysis
This study assessed outcome according to treatment in children with LPHL. Advances in immunophenotyping and molecular biology have led to a more precise definition of the lymphohistiocytic cells characteristic of LPHL and led to a separation from the other subtypes of Hodgkin’s disease by the Revised European-American Lymphoma and World Health Organization classifications.20–22 Nevertheless, pathologic difficulties persist, mainly between LPHL and a variant of classical Hodgkin’s disease described as nodular lymphocyte-rich classical Hodgkin’s disease, as clearly reported in a previous study6 as well as in our study (six cases). Therefore, we believe that central review by hematopathologists is highly recommended to minimize misdiagnosis (12% of our cases). Our results are comparable to those previously published in adult and children and confirm excellent prognosis of LPHL, with 100% OS with a median follow-up of 6 years and the absence of benefit of combined radiochemotherapy in terms of survival. With a relatively limited follow-up considering the LPHL propensity for late recurrence, our findings demonstrate a statistical advantage for CT in terms of frequency of relapse. Although our study as an open study may suffer from bias, we noticed that 11 of 20 children treated after 1992 did not receive radiotherapy or chemotherapy after initial adenectomy. This latter fact is mainly explained by a better knowledge and definition of the disease, particularly from the pathologic point of view. However, our series included all children treated for LPHL during this period in the SFOP centers available for central panel review, and the two groups were comparable in number, stage, age, and follow-up. One of the most common clinical presentations of LPHL is a single lymph node involvement that leads to adenectomy and therefore complete CR. In theses cases (12 of 27), our study did not demonstrate statistical advantage of CT to reach higher disease-free survival. Although with limited median follow-up, treatment of relapse was based on classical Hodgkin’s disease risk-adapted treatment and allowed sustained remission in all the patients except three who subsequently experienced relapse. Therefore, a standard delayed therapy was applicable in the majority of the patients in the SA group. Because most deaths reported in LPHL seem to be related to treatment rather than progression of initial disease, it seems that suspending further treatment and waiting for a possible relapse may minimize well-known late effects of chemotherapy or radiation treatment, especially in young patients.23 In our study, we demonstrated an advantage for CT in the case of residual mass after initial lymph node resection, although in a low number of patients. Most relapses in LPHL occurred at initial site of disease presentation,7,8 suggesting that a local therapy with low-dose radiation may be sufficient to control disease in these cases. In patients with stage II and III disease, response-adapted strategy used for children in classical Hodgkin’s disease may be considered, as well as treatment with monoclonal anti-CD20, as reported with success in patients experiencing relapse.24 An international study of treatment by rituximab in patients experiencing relapse is currently underway.25 The timing of these therapeutic interventions remains debated. One of our patients developed a diffuse large B-cell lymphoma. Non-Hodgkin’s lymphoma after LPHL is reported in 3% of patients and is probably part of the natural history of the disease rather than a consequence of therapy.8,13 Although follow-up for patients was limited, the fact that there were no severe treatment complications (eg, leukemias and secondary cancers) suggests that using treatment strategies for children with Hodgkin’s disease is a good alternative choice for treating patients with LPHL. In conclusion, lymph node resection of the initial site of LPHL is a sufficient strategy for obtaining persistent CR in patients with stage I disease with a unique lymph node localization. To limit therapeutic complications, we propose a new current management strategy for pediatric LPHL that involves a wait-and-see approach for patients in CR after initial surgery and requires a careful postoperative staging based on computed tomography and fluorodeoxyglucose positron emission tomography scan. For other patients, the choice of CT is currently under discussion.
We thank Prof Diebold for pathology review in three cases, J. Donadieu for statistical analysis, and David Young for editing the manuscript.
Preliminary results of this study were reported at the Annual Meeting of the American Society of Hematology, December 3–7, 1999, New Orleans, LA (abstract 2366).
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5. Harris NL, Jaffe ES, Diebold J, et al: World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: Report of the clinical advisory committee meeting, Airlie House, Virginia, November 1997. J Clin Oncol 17:3835–3849, 1999 6. Anagnostopoulos I, Hansmann ML, Franssila, et al: European Task Force on Lymphoma Project on lymphocyte predominance Hodgkin disease: Histologic and immunohistologic analysis of submitted cases reveals 2 types of Hodgkin disease with a nodular growth pattern and abundant lymphocytes. Blood 96:1889–1899, 2001 7. Orlandi E, Lazzarino M, Brusamolino E, et al: Nodular lymphocyte predominance Hodgkin’s disease: Long-term observation reveals a continuous pattern of recurrence. Leuk Lymphoma 26:359–368, 1997[Medline]
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9. Pappa VI, Norton AJ, Gupta RK, et al: Nodular type of lymphocyte predominant Hodgkin’s disease, a clinical study of 50 cases. Ann Oncol 6:559–565, 1995 10. Russell KJ, Hoppe RT, Burns BF, et al: Lymphocyte predominant Hodgkin’s disease: Clinical presentation and result of treatment. Radiother Oncol 1:197–205, 1989[CrossRef] 11. Regula DP, Hoppe RT, Weiss LM: Nodular and diffuse types of lymphocyte Hodgkin’s disease. N Engl J Med 318:214–219, 1988[Abstract] 12. Trudel MA, Krikorian JG, Neimann RS: Lymphocyte predominant Hodgkin’s disease: A clinicopathologic reassessment. Cancer 59:99–106, 1987[CrossRef][Medline] 13. Miettinen M, Franssila KO, Saxen E: Hodgkin’s disease, lymphocytic predominance nodular: Increased risk for subsequent non-Hodgkin’s lymphomas. Cancer 54:2293–2300, 1983 14. Meignin V, Briere J, Brice P, et al: Maladie de Hodgkin à predominance lymphocytaire nodulaire de type I (paragranulome de Poppema-Lennert) : une entité anatomo-clinique. Ann Pathol 20:19–24, 2000[Medline] 15. Ha CS, Kavadi V, Dimopoulos MA, et al: Hodgkin’s disease with lymphocyte predominance: Long-term results based on current histopathologic criteria. Int J Radiat Oncol Biol Phys 43:329–334, 1999[CrossRef][Medline] 16. Divine M, Brice P, Bastion Y, et al: Indolent relapsing pattern in nodular lymphocyte-predominance Hodgkin’s disease: The GELA experience in a series of 69 patients—6th International Conference on Malignant Lymphoma, Lugano 1996. Ann Oncol 7:S1–S230, 1996 (suppl 3) 17. Mason D, Banks P, Chan J, et al: Nodular lymphocyte predominant Hodgkin’s disease: A distinct clinicopathologic entity. Am J Surg Pathol 18:526–530, 1994[Medline]
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19. Landman-Parker J, Leblanc T, Pacquement H, et al: Localized childhood Hodgkin’s disease: Response-adapted treatment by chemotherapy regimen with etoposide, bleomycin, vinblastine, and prednisone before low dose radiation therapy—Results of the study by the French Society of Pediatric Oncology. J Clin Oncol 18:1500–1507, 2000 20. Timens W, Visser L, Poppema S: Nodular lymphocyte predominance type of Hodgkin’s disease is a germinal center lymphoma. Lab Invest 54:457–461, 1986[Medline] 21. Chittal S, Alard C, Rossi JF: Further phenotypic evidence that nodular lymphocyte predominant Hodgkin’s disease is a large B cell lymphoma in evolution. Am J Surg Pathol 14:1024–1035, 1990[Medline] 22. Marafioti T, Hummel M, Anagnostopoulos I, et al: Origin of nodular lymphocyte predominant Hodgkin’s disease from a clonal expansion of highly mutated germinal-center B cells. N Engl J Med 33:453–458, 1997
23. Green DM, Maurice AH, Barcos P, et al: Second malignant neoplasms after treatment for Hodgkin’s disease in childhood and adolescence. J Clin Oncol 18:1492–1499, 2000 24. Keilholz U, Szelenyi H, Siehl J, et al: Rapid regression of chemotherapy refractory lymphocyte predominant Hodgkin’s disease after administration of rituximab (anti CD20 monoclonal antibody) and interleukin 2. Leuk Lymphoma 35:641–642, 1999[Medline] 25. Schulz H, Rehwald U, Reiser M et al : The monoclonal antibody rituximab is well tolerated and extremely effective in the treatment of relapsed CD20-positive Hodgkin’s lymphoma: An update—8th International Conference on Malignant Lymphoma, Lugano 2002. Ann Oncol 13:63, 2002 (suppl 2, abstr 210) Submitted January 14, 2003; accepted May 14, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
