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Large-Cell Lymphoma Arising in the Mediastinum in Children and Adolescents Is Associated With an Excellent Outcome: A Children’s Cancer Group Report

From the Pathology Department, Children’s Hospital of Orange County/St. Joseph Hospital, Orange; Department of Preventive Medicine, University of Southern California School of Medicine, Los Angeles; and Operations Center, Children’s Cancer Group, Arcadia, CA; Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, UT; Department of Pathology, Beth Israel Deaconess Hospital and Harvard Medical School, Boston, MA; and Division of Pediatric Oncology, Babies and Children’s Hospital of New York, Columbia University, New York, NY.

Address reprint requests to Mark A. Lones, MD, Children’s Cancer Group, PO Box 60012, Arcadia, CA 91066-6012.

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION APPENDIX Participating Principal... REFERENCES

 
PURPOSE: Large-cell lymphoma (LCL) arising in the mediastinum (LCL-M) is a heterogeneous group of non-Hodgkin’s lymphoma (NHL) that includes B-cell lymphomas as well as T-cell lymphomas, including anaplastic LCL. LCL-M is well recognized in young adults but is less well characterized and infrequent in children and adolescents.

METHODS: A retrospective review of Children’s Cancer Group therapeutic studies for nonlymphoblastic lymphomas (CCG-551, CCG-503, CCG-552, and CCG-5911) identified 20 patients with LCL-M, representing 7.2% of all LCLs classified by central pathology review.

RESULTS: The patients ranged in age from 4 to 19 years (median, 12.5 years; mean, 12 years); 55% of the patients were male. Although a variety of chemotherapy regimens were used, response was excellent, with all 20 patients (100%) achieving a complete response. Four patients (20%) experienced relapse locally or in distant sites including brain and kidney. One patient died of sepsis during therapy. For the 20 patients with LCL-M, the product-limit estimated 5-year event-free survival (EFS) and 5-year overall survival (OS) rates are 75% ± 10% and 85% ± 8%, respectively. For disseminated LCLs (192 cases), the EFS and OS rates were 50% ± 4% and 63% ± 4%, respectively, which differ significantly from the those of the LCL-M cases (EFS, P = .025; OS, P = .034). The 5-year EFS and OS rates for patients with localized LCL (67 cases) were 92 ± 3% and 97 ± 2%, respectively.

CONCLUSION: LCL-M is a heterogeneous group of NHLs that makes up approximately 7.2% of LCL in children and adolescents. Response to therapy and OS in this young age group seems excellent and superior to that of disseminated LCLs but inferior to that of other localized LCL. Future studies of LCL-M will evaluate short intense chemotherapy administered without radiation therapy.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION APPENDIX Participating Principal... REFERENCES

 
LARGE-CELL LYMPHOMA (LCL) is well recognized in pediatric and adolescent patients and comprises approximately 30% of non-Hodgkin’s lymphoma (NHL) in this age group.¹ The morphologic and clinical spectrum of LCL is quite diverse in these young patients as well as in adults. Advances in biologic immunophenotyping and molecular genetic techniques have led to greater understanding of LCLs and their B-cell or T-cell lineage origins. These advances have allowed recognition of unique subtypes of LCL on the basis of clinical, morphologic, and biologic features as described in the revised European-American lymphoma classification.²

One distinctive type of LCL that was initially described in adults is LCL arising in the mediastinum (LCL-M), which has a unique location and frequent association with sclerosis.^3-5 Clinical studies originally described LCL-M in young adults, with a predilection for young females in their fourth decade.^6,7 The pathologic features of LCL-M indicate a heterogeneous group of LCLs with most cases reported to be of B-cell origin along with some cases of T-cell origin, such as anaplastic large-cell Ki-1 (CD30⁺) lymphoma.^8,9 The tumor presents as a mediastinal mass, with some cases having direct extension into adjacent tissues. The tumor seems to have a propensity for invasion into the vena cava and adjacent organs. Airway obstruction or superior vena cava syndrome is frequent at clinical presentation for this tumor.^3,4 The tumor is limited most often to the mediastinum at initial diagnosis, but relapse or recurrent disease may be seen in distant, often extranodal sites, outside of the thoracic cavity.

Treatment of LCL-M has usually consisted of standard LCL chemotherapy regimens with or without additional radiotherapy.⁶ Responses to therapy have been variable, perhaps reflecting the diversity of treatment approaches, with survival rates ranging between 50% and 70% in predominantly limited-stage disease from larger reported series in adults.^7,9-12

Limited data are available regarding the clinical presentation and prognosis of LCL-M in children and adolescents.^13-15 To better define LCL-M in pediatric and adolescent age groups, a retrospective study was undertaken of LCL cases from four previous Children’s Cancer Group (CCG) trials for treatment of children and adolescents with nonlymphoblastic NHL (CCG-551, CCG-503, CCG-552, and CCG-5911). These trials compared several different chemotherapy regimens. Mediastinal NHL was considered a poor prognostic variable from earlier CCG trial data and was subsequently treated identically to disseminated disease. From this analysis, 212 cases of LCL were identified, of which 20 were restricted to the mediastinum with or without direct extension into adjacent tissues or organs; these were classified as LCL-M. These 20 patients were further analyzed for clinical features, response to therapy, and survival and were compared with the 192 cases of disseminated LCL treated identically but not classified as LCL-M.

	METHODS

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Patient Selection
A retrospective review of CCG NHL studies was undertaken to identify cases of LCL-M. These prior studies covered a time period from 1977 to 1993 and included the following protocols: CCG-551 Non-Hodgkin’s Lymphoma (1977 to 1982)^16,17; CCG-503 Non-Lymphoblastic Non-Hodgkin’s Lymphoma, Disseminated (1983 to 1990)¹⁸; CCG-552 Disseminated Non-Lymphoblastic Lymphoma of Childhood (1986 to 1989)¹⁹; CCG-5911 A Pilot Study in the Treatment of Childhood Non-Localized Non-Lymphoblastic Non-Hodgkin’s Lymphoma (1991 to 1993).²⁰ Cases of LCL from these protocols were confirmed by central pathology review.²¹ This study included those cases restricted to disease involvement of the mediastinum, including cases exhibiting direct extension into adjacent tissues or organs. These were compared with disseminated LCL cases not restricted to the mediastinum. Cases of LCL involving the mediastinum and separate sites were excluded because of the difficulty of distinction between mediastinal origin versus secondary involvement of the mediastinum in this retrospective analysis.

Staging Evaluation
The extent of disease was determined by clinical staging methods, which varied among the four protocols. Radiology studies included chest x-ray, computed tomography (CT) scan, bone scan, liver/spleen scan, gallium scan, intravenous pyelogram, and abdominal/pelvic ultrasound. Pathology evaluations included CSF examination and bone marrow examination (bone marrow aspirate only or aspirate with biopsy). All patients with a mediastinal mass on CCG-503, CCG-552, and CCG-5911 protocols were treated in a manner identical to that of patients with disseminated disease based on initial prognostic observations in CCG-551 and pediatric NHL staging schemes by the CCG¹⁶ or the Murphy Stage.²²

Pathology Evaluation
Biopsy tissue was processed and evaluated at the primary institution. Central pathology review during each respective CCG study consisted of light microscopy morphologic evaluation only, with details for some studies presented previously.²³ Classification was performed according to the Rappaport classification²⁴ and/or National Cancer Institute Working Formulation.^25,26 After all of these studies had closed, 10 cases with available paraffin-embedded tissue were retrieved for immunophenotyping studies performed by paraffin immunohistochemical methods that have been described previously.¹⁵

Therapy
The therapeutic regimens for disseminated LCL varied among the different protocols, and for LCL-M included the following: cyclophosphamide, vincristine, methotrexate, and prednisone (COMP) with radiation (CCG-551)^16,17; modified LSA2-L2 (COMP with daunomycin, cytarabine, thioguanine, asparaginase, carmustine, and hydroxyurea) with radiation (CCG-551)^16,17; COMP (CCG-503)¹⁸; COMP plus daunomycin (CCG-503)¹⁹; cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus additional drugs (methotrexate, cytarabine, thioguanine, and etoposide; CCG-552); and Orange-CHOP, with etoposide, ifosfamide, methotrexate, cytarabine, dexamethasone, L-asparaginase, and cisplatin (CCG-5911).²⁰

Response Evaluation
Response to therapy was assessed at each institution after two general phases of therapy (Table 1) as follows: Response 1 was assessed usually after induction therapy, and response 2 was assessed usually after consolidation or maintenance therapy. The responses were classified in the protocols as follows: complete response (CR), disappearance of all disease; partial response (PR), decrease of 50% or more of all measurable lesions; no response, all lesions remain within 50% of initial size.

where, i denotes the group of LCL cases, either LCL-M or disseminated LCL (excluding LCL-M) patients; S_i(t) is the survival function; _i is the long-term EFS or survival rate; and F(t) is a log normal distribution function.²⁹ Estimates and SEs for long-term EFS and OS rates were obtained using maximum likelihood methods, and significance tests were based on the likelihood ratio criterion.³⁰

	RESULTS

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Case Selection
A total of 279 cases of LCL were identified from previous CCG studies.²¹ Twenty cases (7.2%) were classified by clinical and pathologic features as LCL-M, restricted to the mediastinal region. There were 192 cases of disseminated LCL without restriction to the mediastinal region. The remaining 67 cases represented localized LCL.

Clinical Presentation
The clinical features at presentation of the patients with LCL-M are listed in Table 2. Eleven patients were male (55%). The median age was 12.5 years (range, 4 to 19 years; mean, 12 years). For male patients, the median age was 11.5 years (mean, 11 years; range, 4 to 14 years). The female patients had a median age of 16 years (mean, 15 years; range, 8 to 19 years). Ten patients (50%) were children (< 13 years old), whereas 10 (50%) were adolescents ( 13 years old). These patients were classified for racial groups as follows: 16 patients were white, two were black, and two were Hispanic. Information on other clinical features at presentation was available in only limited numbers of cases and included "B" symptoms and superior vena cava syndrome, which were explicitly reported present in seven and four cases, respectively.

Pathology Evaluation
The biopsies in this series represented surgical biopsy specimens from thoracotomy or mediastinoscopy procedures (surgical, 18 patients; not available, two patients). There were no cases in which the diagnostic material represented fine-needle aspirate material or needle-core biopsies. All 20 cases of LCL-M underwent central pathology review and were confirmed as LCL during each of the respective CCG studies. The pathologic features of LCL-M are illustrated in Fig 1.

View larger version (72K): [in this window] [in a new window]   Fig 1. Pathologic features of LCL-M. (A) and (B) show LCL with associated sclerosis at diagnosis (patient no. 19). (A) Associated sclerosis (magnification x100); (B) malignant cytologic features of the LCL (magnification x1,000).

Therapeutic Response
All 20 patients with LCL-M achieved CR (Table 3), although at varied times during treatment. During the first phase of therapy (response 1), CR occurred in 12 (60%) of the assessable patients. Two patients achieved CR during the second phase of therapy (response 2). The remaining six patients achieved CR during a later phase of therapy. There was no modification in treatment for any of the six patients who failed to achieve CR during the first two phases of therapy. The overall response rate (CR or PR) in the assessable cases during the first phase of therapy was 89%, and after the second phase it was 100%.

Other Events
Patient no. 13 had a seizure during induction (day 20), but there was no radiologic evaluation of the brain. This patient had a relapse in the brain only at 13 months and died 3 months later. Patient no. 19 died at 1 month as a result of sepsis, and postmortem examination confirmed a CR demonstrating a mediastinal mass with extensive fibrosis but no viable lymphoma (Fig 2). There were no second malignancies in patients with LCL-M.

View larger version (63K): [in this window] [in a new window]   Fig 2. Pathologic features of LCL-M after therapy. (A) and (B) show the residual mediastinal mass at autopsy, after 1 month of chemotherapy, revealing no residual lymphoma (patient no. 19). (A) Extensive dense fibrosis and areas of granulation tissue (magnification x100); (B) benign stroma and vessels without residual lymphoma (magnification x400).

View larger version (13K): [in this window] [in a new window]   Fig 3. Product-limit estimated 5-year EFS and OS for 20 cases of LCL-M in children and adolescents.

In contrast, for the group of 192 patients with disseminated LCL, the product-limit estimated 5-year EFS is 50% ± 4%, whereas the estimated 5-year OS is 63% ± 4% (Fig 4). For patients not experiencing events, the median follow-up interval is 6.7 years (95% > 3 years, 85% > 5 years). The likelihood ratio test of the difference in EFS and OS between the disseminated LCL and the LCL-M groups yielded ²(1df) = 5.0, P = .025 (EFS), and ²(1df) = 4.5, P = .034 (OS), respectively. These results are not changed after adjusting for patients with bone marrow or CNS involvement at diagnosis or for those who received LSA2-L2 therapy in CCG-551, which was less effective than COMP therapy for subjects with disseminated nonlymphoblastic lymphoma, including disseminated LCL.^16,17,23

View larger version (15K): [in this window] [in a new window]   Fig 4. Product-limit estimated 5-year EFS and OS for 192 cases of disseminated LCL in children and adolescents (excluding LCL-M).

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION APPENDIX Participating Principal... REFERENCES

 
Although LCL-M has been described predominantly as occurring in young adults, more often in females,^6,7 it also occurs in children and adolescents. Reports of therapeutic response and survival in adults have been variable, with OS rates ranging from approximately 50% to 70% in larger studies of patients with predominantly limited-stage disease.^7,9-12 LCL-M is a heterogeneous group of LCLs of B-cell or T-cell origin, and most cases seem to represent primary mediastinal (thymic) large B-cell lymphoma that is recognized as a unique clinicopathologic entity in the revised European-American lymphoma classification.² In children and adolescents, there have been a few reports with only small numbers of cases of LCL-M and limited documentation of B-cell phenotype.^13-15 These studies in young patients, which contain some heterogeneous types of LCL, have reported variable survival rates (Table 3).

The first study of children by Bunin et al¹³ included 25 mediastinal nonlymphoblastic lymphomas composed mostly of LCLs that occurred predominantly in females. Phenotype was evaluated in only three cases (two were B-cell lymphomas; one was T-cell lymphoma). This report included a mixture of patients with different Ann Arbor stages; disease seemed to be restricted to the mediastinal area in 13 patients (stages I and IIE). For the 25 cases Bunin et al reported, most were treated with CHOP and radiation or variations of CHOP-based regimens with radiation. Relapse occurred in 32% of all 25 cases in this report. Relapse occurred in three (23%) of the 13 cases among the mediastinal-localized disease group (Ann Arbor stage I or IIE). However, the EFS in this study may have been overestimated, because the follow-up interval was very short and product-limit estimates of survival could not be determined from this report.

Another report by Carr et al¹⁴ included four cases of LCL-M in children and adolescents without other sites of disease, occurring mostly in males. All four cases were of B-cell phenotype, confirming these as primary mediastinal (thymic) large B-cell lymphomas. Outcome was poor with CHOP or variants of CHOP-based chemotherapy regimens, including radiation therapy in two cases. Two patients were reported as having a poor clinical response. One exhibited progressive disease, including brain involvement and death at 7 months, whereas the other died of bronchopneumonia with postmortem examination demonstrating the mediastinal mass to have extensive fibrosis and necrosis with no lymphoma. This study is limited by the small number of cases reported.

The current study of 20 patients with LCL-M includes six previously reported by Piira et al.¹⁵ The 20 patients contain an equal distribution of children and adolescent groups. Unlike previous studies in adults or the study of Bunin et al,¹³ there is a predominance of males in the current study. Information on other clinical and pathologic features at presentation was limited in this retrospective analysis. Also, the Rappaport classification and the Working Formulation did not include separate categories based on phenotype or a category for anaplastic large-cell Ki-1 (CD30⁺) lymphoma. The phenotype was evaluated in only nine cases, demonstrating eight cases of B-cell lymphoma and one case of T-cell lymphoma. This indicates that these 20 cases of LCL-M are likely comprised of predominantly primary mediastinal (thymic) large B-cell lymphoma, but there is some heterogeneity, including primary mediastinal T-cell anaplastic large-cell Ki-1 (CD30⁺) lymphoma.

In the current series, the response to therapy seems good, with all 20 patients achieving CR. The low proportion of CR during the initial phase of therapy, as determined by reduced size of the mediastinal mass, suggested a poor response to induction therapy and likelihood for poor outcome. However, high rates of OS in this group of children and adolescents indicate that a slow reduction in size of the mediastinal mass does not predict poor outcome. In cases with residual mediastinal mass in which additional pathologic examination has been performed early during therapy, there is extensive necrosis of the lymphoma with residual fibrosis, as seen in the postmortem examinations from the current study and one previous study.¹⁴ It is this extensive fibrosis, often associated with LCL-M, which may account for the frequent clinical observation of persistent mediastinal mass during or after therapy, even when there is no pathologic evidence of viable lymphoma.

The survival data in this group of LCL-M seem better than that of previous reports in children and adolescents or in adults. Earlier reports in children and adolescents were limited by smaller numbers of patients and very short follow-up intervals. The EFS and OS of LCL-M are significantly better than for disseminated LCLs treated on identical LCL protocols in earlier CCG studies.²¹ The survival in the LCL-M seems inferior to that achieved in localized LCL in young patients treated with similar or shorter-duration regimens^21,31 and other regimens.^32-34 These excellent results suggest that treating LCL restricted to the mediastinal area as a disseminated lymphoma or stage III in lymphoma staging systems for these young patients is not associated with such a poor outcome as previously believed.

Recent changes in treatment for all children and adolescents with LCL have suggested that short intense chemotherapy (6 months) without radiation therapy results in improved long-term disease-free survival.²¹ The recent study by Zinzani et al³⁵ in adults with primary mediastinal large B-cell lymphoma with sclerosis treated with methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin and 36 Gy of mediastinal radiotherapy suggests the need for postchemotherapy radiotherapy for this disease. The last 12 patients in our retrospective review study did not receive therapeutic doses of mediastinal radiotherapy and still had an 83% OS rate. Mediastinal radiotherapy is associated with both short-term and long-term effects in children and adolescents. Although the numbers of patients are small, our current study suggests that chemotherapy alone may be adequate for this disease and adverse effects of radiation can be avoided. Patients with disseminated LCL treated on CCG-5911 (short intense chemotherapy) have improved survival over patients in earlier CCG studies.²¹ This suggests that young patients with LCL-M may also benefit from short intense chemotherapy and do not need radiation therapy to the mediastinum. However, the number of LCL-M patients from the CCG-5911 study is too small to allow a comparison with other disseminated LCLs for a difference in survival. Other recent studies of B-cell NHL in children and adolescents^36,37 have also reported successful outcomes with chemotherapy alone, providing support for elimination of radiation therapy. The strategy of short intensive chemotherapy and elimination of radiation therapy for LCL-M should be further evaluated in a larger cohort in future studies.

In conclusion, LCL-M occurs in children and adolescents in low frequency, representing 7.2% of all LCLs from CCG studies. Survival is excellent and superior to that of patients with disseminated LCL but seems inferior to that achieved in patients with localized LCL. LCL-M may require only short intense chemotherapy without radiation therapy and seems to have an improved prognosis in children and adolescents compared with adults. Future studies should focus on short intense chemotherapy in the clinicopathologic entity of primary mediastinal (thymic) large B-cell lymphoma² in children and adolescents and should separate this entity from other types of LCL-M. Because of the low frequency of this entity, future studies may best be achieved with an international cooperative protocol. Currently, young patients with primary mediastinal (thymic) large B-cell lymphomas are enrolled in CCG treatment protocol CCG-5961,³⁸ in which short intensive chemotherapy without radiation therapy is used. Clinical response and survival data from this study will become available in the next few years along with data on other diffuse large B-cell lymphomas.

	APPENDIX Participating Principal CCG Investigators

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION APPENDIX Participating Principal... REFERENCES

 

	ACKNOWLEDGMENTS

 
Supported by the Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD. Contributing Children’s Cancer Group investigators, institutions, and grant numbers are listed in the Appendix.

We thank Lucia Noll of the Children’s Cancer Group Publications Office for assistance with this manuscript.

	NOTES

 
Presented in part at the Forty-First Annual Meeting of the American Society of Hematology, December 3-8, 1999, New Orleans, LA.

	REFERENCES

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION APPENDIX Participating Principal... REFERENCES

 
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Submitted December 20, 1999; accepted June 16, 2000.

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