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Primary Mediastinal Large B-Cell Lymphoma: A Clinicopathologic Study of 43 Patients From the Nebraska Lymphoma Study Group

From the Departments of Pathology and Microbiology, Internal Medicine, and Preventive and Societal Medicine, University of Nebraska Medical Center, Omaha, NE.

Address reprint requests to Dennis D. Weisenburger, MD, Department of Pathology and Microbiology, 983135 Nebraska Medical Center, Omaha, NE 68198-3135; email dweisenb{at}unmc.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To investigate whether primary mediastinal large B-cell lymphoma (PMLBL) is a distinct clinicopathologic entity with a more aggressive course than other diffuse large B-cell lymphomas (DLBL).

MATERIALS AND METHODS: All patients with CD20-positive DLBL who presented with a mediastinal mass measuring at least 5.0 cm and were treated with curative intent were identified. A control group of 352 patients with nonmediastinal DLBL was selected for comparison.

RESULTS: The 43 patients with PMLBL had a male to female ratio of 20:23 and a median age of 42 years. Stage I/II disease was present in 58% of the patients, with only 9% having bone marrow involvement. A complete remission was achieved in 63% of the patients, and the 5-year overall and failure-free survivals were 46% and 38%, respectively. Among the clinical variables, an elevated serum lactate dehydrogenase level, a low performance score, more than one extranodal site, and an intermediate or high International Prognostic Index score were predictive of poor survival. When compared with the DLBL group, a younger median age was the only clinical feature that was significantly different in the PMLBL group.

CONCLUSION: The clinical features of PMLBL do not appear to be significantly different from those of nonmediastinal DLBL. Although the younger age of onset, slight female predominance, mediastinal location, and size of the mass may justify the recognition of PMLBL as a clinical syndrome, additional evidence is needed to define it as a distinct disease entity.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
PRIMARY MEDIASTINAL large B-cell lymphoma (PMLBL) is thought by some to be a distinct disease entity, and it is reported to occur characteristically in young females with a bulky mediastinal mass and low-stage disease. Clinical features that are associated with PMLBL include pleural and pericardial effusions, superior vena cava syndrome, an elevated serum lactate dehydrogenase level, and a tendency to relapse in unusual sites.^1-4 The histologic features that have been associated with PMLBL include (1) a diffuse proliferation of medium-sized to large transformed B-cells, which are often devoid of surface immunoglobulin; (2) abundant clear cytoplasm; and (3) areas of sclerosis.^2,5 However, the various reported series indicate that these histologic features are inconsistent and that PMLBL actually consists of a group of lymphomas with rather heterogeneous morphology, including diffuse mixed-cell, diffuse large-cell, and immunoblastic types.^1,2,6-11 Currently, there are limited data on the molecular features of PMLBL. A recent study reported amplification of the rel oncogene in PMLBL, but only in a minority (7.7%) of the cases.¹² Other studies have identified a few cases with c-myc mutations or rearrangements, or p53 mutations, and have reported the infrequency of bcl-6 rearrangements.^13,14 However, in a recent study,¹⁵ we found no characteristic chromosomal abnormalities in a subset of this series of PMLBL in which adequate tissue was available for competitive genomic hybridization studies.

Controversy also exists regarding the response to therapy and prognosis of patients with PMLBL. Whereas some early studies indicated that patients with PMLBL have an aggressive clinical course with a low median survival,^5,16,17 more recent studies have reported a relatively good response rate and survival.^3,8,18-23 The purpose of this study is to report our clinical experience with PMLBL. For the study, we identified and characterized a group of patients with PMLBL, as defined by previously described clinical and pathologic criteria,^3,10,11 who were treated with curative intent. The clinical features and behavior of this group, including response to therapy and survival, were then compared with those of a similar group of patients with nonmediastinal diffuse large B-cell lymphomas (DLBL).

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Population
The database of the Nebraska Lymphoma Study Group Registry was searched for all patients with a diagnosis of PMLBL. The eligibility criteria were as follows: (1) a mediastinal mass of at least 5.0 cm in maximum dimensions, with no extramediastinal mass larger than that in the mediastinum; (2) a diagnosis of diffuse mixed-cell, diffuse large-cell, or immunoblastic lymphoma; (3) a B-cell phenotype as determined by CD20 positivity and negative staining for CD3 and a variety of other T-cell–specific markers; and (4) treatment with a chemotherapeutic protocol having curative potential. We identified 43 cases of PMLBL meeting these criteria. A second (control) group of 352 similarly treated patients (see Therapy) with nonmediastinal DLBL of the same histologic types and a mass of at least 5.0 cm was identified from the registry for comparison.

Pathologic Assessment
The slides were reviewed by two of the authors (A.A.A.-E., D.D.W.), and the tumors were classified using the Working Formulation.²⁴ Each case was also evaluated with regard to the presence or absence of sclerosis, clear cytoplasm, zonal necrosis, and single-cell necrosis (apoptosis), and the mitotic rate per 10 random high-power fields was determined.

Immunohistochemistry
Archival paraffin-embedded tissue or, when available, frozen tissue was used to phenotype the cases with a battery of B-cell antibodies, which included CD20, CD79a, immunoglobulin (Ig) heavy chains, kappa, and lambda, and a battery of T-cell antibodies, which included CD3, CD45RO, and CD43 (Dako, Carpinteria, CA). The immunohistochemical stains were performed on 5-µm sections using an avidin-biotin complex technique, as previously described.²⁵ The primary antibodies were applied for 30 minutes and developed with 3,3'-diaminobenzidine tetrahydrochloride, and the slides were counterstained with hematoxylin.

Clinical Assessment
All patients underwent uniform staging that included a physical examination, blood cell counts, routine blood chemistries, computed tomography of the chest, abdomen, and pelvis, and bone marrow aspiration and core biopsy. Clinical features, including the age, sex, stage, presence of B symptoms, mediastinal mass size (< or 10 cm), serum lactate dehydrogenase level, extent of extranodal disease, bone marrow involvement, Eastern Cooperative Oncology Group performance score, and International Prognostic Index (IPI) score,²⁶ were recorded. Sites of extranodal involvement at the time of presentation and relapse were tabulated in both groups and compared.

Therapy
All patients with PMLBL and DLBL were entered into one of four sequential curative treatment protocols used by the Nebraska Lymphoma Study Group. The four treatment protocols were as follows: (1) cyclophosphamide 650 mg/m² intravenously (IV) day 1, doxorubicin 50 mg/m² IV day 1, procarbazine 100 mg/m²/d orally days 1 through 7, bleomycin 10 mg/m² IV day 15, vincristine 1.4 mg/m² IV day 15 (maximum, 2.0 mg), and prednisone 100 mg orally days 15 through 21; (2) cyclophosphamide 350 mg/m² IV day 1, doxorubicin 35 mg/m² IV day 1, procarbazine 100 mg/m²/d orally days 1 through 5, bleomycin 4 mg/m²/d IV continuous infusion days 1 through 2, vincristine 1 mg/m²/d IV continuous infusion days 1 through 4, dexamethasone 10 mg/m²/d; (3) cyclophosphamide 650 mg/m² IV day 1, mitoxantrone 12 mg/m² IV day 1, procarbazine 100 mg/m²/d orally days 1 through 7, bleomycin 10 mg/m² IV day 15, vincristine 1.4 mg/m² IV day 15, prednisone 100 mg/d orally days 15 through 21; or (4) cyclophosphamide 750 mg/m² IV day 1, mitoxantrone 12 mg/m² IV day 1, vincristine 1.4 mg/m² IV day 1, prednisone 100 mg orally days 1 through 5.²⁷ All patients received two cycles past complete remission (CR), or a maximum of eight cycles.

A CR was defined as normalization of the physical examination, laboratory values, and radiologic abnormalities for a minimum of 4 weeks. Overall survival (OAS) was measured from the beginning of treatment to the date of death from any cause or to the date of the last follow-up evaluation. Failure-free survival (FFS) was defined as the time from the beginning of treatment to disease progression, relapse, or death from any cause.

Statistical Analysis
The pathologic and clinical variables were evaluated for their prognostic value. The influence of these variables on the response to treatment was determined by logistic regression using Wald's test.²⁸ Fisher's exact test and the ² test were used to compare the clinical variables in the two groups.²⁹ Survival curves were plotted according to the method of Kaplan and Meier.³⁰ Comparisons of time to event distributions were made using the log-rank test.³¹

	RESULTS

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Pathologic Features of PMLBL
The 43 cases were distributed in the following histologic categories: diffuse mixed-cell type (four cases), diffuse large-cell type (25 cases), and immunoblastic type (14 cases). All cases were CD20 positive, and 84% of the cases (26 of 31) stained for CD79a were positive. Seven of 13 cases (54%) had clonal surface Ig (sIg) by frozen-section immunohistochemistry (three IgG, one IgA, two IgM, one IgD), whereas seven of 34 cases (21%) had clonal cytoplasmic Ig (cIg) by paraffin immunohistochemistry (four IgG, one IgA, one IgM, one IgD). Of the six cases that were negative for sIg, five were positive for CD79a and three were positive for cIg. Clear-cell cytology and sclerosis were present in 44% and 63% of the cases, respectively. Interestingly, 85% of the biopsies with sclerosis were mediastinal in location. Zonal necrosis was noted in 68% of the cases and was the only histologic feature that correlated with poor survival. However, the presence of zonal necrosis also correlated with large ( 10 cm) mediastinal tumors (P = .038). Sclerosis, clear-cell cytology, single-cell necrosis (apoptosis), and the mitotic rate did not correlate with survival.

Presenting Clinical Features of PMLBL
The clinical features of the 43 patients are given in Table 1. There was a slight female predominance in the PMLBL group, with 23 females (54%) and 20 males (46%). The median age of the group was 42 years, with a range of 15 to 92 years. There was no significant difference in the median age between the two sexes (data not shown; P = .49). The majority of the cases had stage I/II disease (58%), with an equal male:female ratio (12:13) in this group. A similar sex ratio was observed in the stage III/IV patients (8:10). Bulky disease ( 10 cm) was present in 53% of the patients, and B symptoms were noted in 38%. Bone marrow involvement was found in only 9% of the patients, whereas extranodal involvement of two or more sites was seen in 21%.

Comparison of the Clinical Features of PMLBL and DLBL
Table 1 also compares the frequency of various clinical features in PMLBL and nonmediastinal DLBL presenting with a mass of 5 cm. The younger median age of the PMLBL group was the only significantly different variable identified (P < .0001). The extranodal sites at presentation in both groups were also compared. PMLBL involved one or more extranodal sites in nine (21%) of 43 patients, with the lung and pleura representing 46% of all extranodal locations. The other sites included the gastrointestinal tract (one case), skin (one case), bone marrow (four cases), kidney (two cases), soft tissue (four cases), orbital bone (one case), and miscellaneous other sites (two cases). These sites of extranodal involvement did not differ significantly from those of DLBL except for the lung (P = .002), which was due to direct extension from the PMLBL, and the gastrointestinal tract, which is a common primary site of DLBL (P = .01). The sites of relapse of PMLBL also were not distinctly unusual. Lymph nodes (32 cases), lung (three cases), and bone marrow (eight cases) represented the common sites of relapse or progression (75%), with the remainder including the gastrointestinal tract (one case), skin (one case), liver (two cases), CNS (two cases), and soft tissue (one case).

Comparison of Survival in PMLBL and DLBL
Both groups of patients were similarly distributed among the different therapeutic protocols. In PMLBL, 27 (63%) of the 43 patients achieved a CR, whereas 204 (58%) of 352 patients with DLBL achieved a CR (P = .62). The 5-year OAS and FFS were 46% and 38%, respectively, for the PMLBL group, and 39% and 29%, respectively, for the DLBL group (Table 1 and Fig 1). Twenty-two patients with PMLBL (51%) received salvage therapy. Twelve (54%) of these 22 patients received chemotherapy, radiotherapy, or both, whereas 10 patients (46%) underwent bone marrow transplantation. Of the 22 patients who received salvage therapy, only four (17.4%) are still alive. All four living patients underwent bone marrow transplantation.

View larger version (19K): [in this window] [in a new window]   Fig 1. Survival comparisons of PMLBL and DLBL.

In Table 2, the prognostic importance of the various clinical features with regard to OAS and FFS is compared. There were no real differences in the predictive value of the clinical features in the PMLBL and DLBL groups, although stage and B symptoms were not statistically significant predictors of survival in PMLBL, owing to the small number of patients. The same can be said for disease bulk in PMLBL. The IPI scores were similarly predictive of survival in both groups (Fig 2). However, there were no significant differences (P .05) in survival when comparing the same clinical subgroups listed in Table 2 or shown in Fig 2 for PMLBL versus DLBL.

View this table: [in this window] [in a new window]   Table 2. Comparison of 5-Year Survivals According to Clinical Features in PMLBL and DLBL With a Mass 5 cm

View larger version (41K): [in this window] [in a new window]   Fig 2. Survival comparisons of PMLBL (left) and DLBL (right), according to IPI scores. The numbers of patients in each group are as follows: PMLBL 0/1 = 19, 2/3 = 19, 4/5 = 4; DLBL 0/1 = 83, 2/3 = 145, 4/5 = 46.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
PMLBL has been considered by some to be a distinct entity since it was first described in 1980,¹⁶ and characteristic clinical and histologic features have been ascribed to this group of lymphomas.^1-5 However, no common definition of PMLBL is currently accepted, and therefore the criteria for patient selection have varied considerably among the various studies. Some studies have restricted cases a priori to include only tumors with sclerosis and clear-cell morphology,^4,32,33 or only those with low-stage disease, with the exclusion of cases having extrathoracic involvement,^7,9,23,25,34 or only cases with evidence of involved thymic tissue.³⁵ Others have been overly inclusive, including even cases of follicular lymphoma.^6,22 Rodriguez et al¹⁰ have defined PMLBL as "a diffuse large B-cell lymphoma that either presents with disease limited to the mediastinal field or more advanced presentations with the dominant site of the disease in the mediastinum." Using this definition, cases of disseminated extramediastinal lymphoma with secondary mediastinal involvement are unlikely to be included. Therefore, in our study, any DLBL that presented with a mediastinal mass measuring 5 cm or more was included. However, any such case that also had an associated extramediastinal mass larger than that in the mediastinum was excluded, thus minimizing the inclusion of extramediastinal lymphomas with spread to the mediastinum. Other investigators have used similar criteria in their studies.^3,8,11,14,36 In the following discussion, we will present a comparison of our findings in patients with PMLBL and nonmediastinal DLBL and will compare our experience with the reported literature in an attempt to determine whether PMLBL is a distinct disease entity.

Although slightly more than one half of the cases of PMLBL in our study were females (54%), this was not significantly different from our finding in DLBL (49%). Our results are similar to those of a number of studies of PMLBL^{1,5,6,8,9,22,34,37} but differ from others reporting a more clear female predominance.^{2,3,7,11,32,33,38} A few studies have even reported a male predominance in PMLBL.^8,12,21 We could not confirm an exceptionally young age of the female patients in our series of PMLBL, since the median age of the females did not differ significantly from that of the males (P = .49). What was evident, however, was the remarkably young median age of those with PMLBL when compared with the DLBL group (42 v 68 years, respectively; P < .0001). Although of interest, we can offer no speculation regarding the significance of this finding.

Eighteen (42%) of our 43 patients with PMLBL presented with stage III or IV disease, which is different from some reports that had few or no patients with advanced-stage disease.^3,8,33,34,38 However, other studies have specifically excluded cases with advanced-stage disease as part of their selection criteria.^7,9,23,25 Several other studies, however, have included advanced-stage patients, which ranged from 32% to 43% of those studied.^{11,16,22,32,39} In our study, only eight (19%) of the 43 patients presented with stage I disease (ie, disease confined to the mediastinum), whereas 17 patients (39%) presented with stage II disease. Our findings, along with the results of several other studies,^{11,22,23,32,39} confirm that PMLBL can present in an advanced stage, just like other large-cell lymphomas. In fact, there was no difference in stage when we compared PMLBL with DLBL. Bone marrow involvement was identified in only four (9%) of 43 patients with PMLBL, but this, too, was not different from the frequency of bone marrow involvement in DLBL (P = .49). A popular notion is that PMLBL may commonly present or relapse at unusual anatomic sites that are different from those of DLBL. Lazzarino et al⁵ stated that PMLBL exhibits renal tropism, especially at relapse; this observation was also reported by two other groups.^4,37 The frequency of kidney involvement at presentation was 7% in one study,⁵ whereas the rate of kidney involvement at relapse in these reports varied from 7% to 50%.^4,5,37 In our study, kidney involvement at presentation was found in only two PMLBL cases (5%), which was not different from the DLBL group. Furthermore, the kidney was not a reported site of relapse in our study. Involvement of unusual extranodal sites was not characteristic of PMLBL in our study, and several other studies show very similar distributions of extranodal involvement to those in our study.^4,11,22,23 Other clinical features that have been reported to be associated with PMLBL include pleural and pericardial effusions and the superior vena cava syndrome, which are due to the unique site of the mass. However, none of these features is unique or specific for PMLBL.

Nor is the pathology of PMLBL unique or specific. The cytology of PMLBL is quite varied, including mixed-cell and a variety of large-cell types ranging from large-cleaved to noncleaved to immunoblastic in appearance. This variation in cytology has been consistently reported in almost every study of PMLBL, with the large-noncleaved cell type being the most frequently reported.^{1,3-11,17,21,23,36} Sclerosis also does not appear to be a constant or specific feature of PMLBL. In this study, we identified some degree of sclerosis in 63% of the cases, but the sclerosis occurred primarily in the mediastinal biopsies. Others^6-8,18,38 have found sclerosis in various proportions, including Yousem et al,⁶ who found sclerosis in less than half of the cases studied, and Levitt et al,¹⁸ who reported only slight sclerosis in 67% of their cases. Various authors^6,7,18 have stated that it is difficult to assess sclerosis in many cases because of the small size of the biopsies and the extensive crush artifact. The variation in the extent of sclerosis has also been attributed to sampling of the tumor. Furthermore, sclerosis is a common tissue response in other lymphoid and nonlymphoid tumors involving the mediastinum,^39,40 as is seen in other soft tissue sites such as the retroperitoneum. Thus, the sclerosis found in PMLBL is most likely a result of its mediastinal location and not an integral part of the tumor biology.⁴ Likewise, clear-cell cytology was identified in only 44% of our cases, and prominent clear-cell cytology was found in only five cases (12%). None of the cases in the study of Al-Sharabati et al⁸ had clear-cell cytology, whereas other studies have reported variable percentages of cases with this feature.^8-10 However, clear-cell cytology has been a defining feature of some studies,^{2,4,11,14,22,23,38} whereas others do not even comment on this feature.^1,3,6,7,36 These findings highlight the lack of consistency of the histologic features of PMLBL, and, thus, they cannot be used as diagnostic criteria.

The clinical parameters which predicted both the OAS and FFS of the PMLBL group in our study were the serum lactate dehydrogenase level, performance score, number of extranodal sites, and IPI score. Interestingly, bulky disease ( 10 cm) was not a significant predictor of survival in our study, most probably owing to the small number of cases, although there was a suggestion of poorer survival in those with large mediastinal masses (Table 2). Other studies are divided as to the influence of bulky disease on survival in PMLBL. Whereas Cazals-Hatem et al¹¹ and Kirn et al²¹ found that bulky disease did not predict survival, Lazzarino et al²³ concluded that bulky disease resulted in a residual mediastinal mass and a greater probability of relapse. Jacobson et al³ also found that the size of the mass was predictive of FFS, with a similar trend for OAS. There were no statistical differences in survival between our PMLBL group and the control group of DLBL (Figs 1 and 2), including stratified comparisons according to IPI scores. Cazals-Hatem et al¹¹ also found no differences in survival between PMLBL and a similar control group of DLBL. Rodriguez et al¹⁰ recently reviewed the literature on PMLBL and stated that, although some studies report a poor prognosis for PMLBL, most recent studies have found that the prognosis is probably no different from that of other DLBL when patients are given curative chemotherapeutic regimens.^3,8,18-23 Two recent studies^41,42 have also reported that high-dose therapy and autologous hematopoietic stem-cell transplantation are effective as salvage treatment for those with persistent or relapsed PMLBL. Our findings also support these conclusions.

In summary, in the absence of consistent pathologic or molecular features that can be used as defining criteria, as in other distinct non-Hodgkin's lymphomas, we believe that PMLBL should, at this time, be considered a clinical syndrome. It appears from our study that the clinical and pathologic features of PMLBL are very similar to those of DLBL. The only clinical features that are different are a slight female predominance and a younger median age. Although these findings are of interest, additional evidence is needed to define PMLBL as a distinct disease entity.

	REFERENCES

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Addis BJ, Isaacson PG: Large cell lymphoma of the mediastinum: A B-cell tumor of probable thymic origin. Histopathology 10:379-390, 1986[Medline]

2. Möller P, Lämmler B, Eberlein-Gonska M, et al: Primary mediastinal clear cell lymphoma of B-cell type. Virchows Arch A Pathol Pathol Anat 409:79-92, 1986

3. Jacobson JO, Aisenberg AC, Lamarre L, et al: Mediastinal large cell lymphoma: An uncommon subset of adult lymphoma curable with combined modality therapy. Cancer 62:1893-1898, 1988[Medline]

4. Perrone T, Frizzera G, Rosai J: Mediastinal diffuse large-cell lymphoma with sclerosis: A clinicopathologic study of 60 cases. Am J Surg Pathol 103:176-191, 1986

5. Lazzarino M, Orlandi E, Paulli M, et al: Primary mediastinal B-cell lymphoma with sclerosis: An aggressive tumor with distinctive clinical and pathologic features. J Clin Oncol 11:2306-2313, 1993[Abstract/Free Full Text]

6. Yousem SA, Weiss LM, Warnke RA: Primary mediastinal non-Hodgkin's lymphomas: A morphologic and immunologic study of 19 cases. Am J Clin Pathol 83:676-680, 1985[Medline]

7. Lamarre L, Jacobson JO, Aisenberg AC, et al: Primary large cell lymphoma of the mediastinum: A histologic and immunophenotypic study of 29 cases. Am J Surg Pathol 13:730-739, 1989[Medline]

8. Al-Sharabati M, Chittal S, Duga-Neulat I, et al: Primary anterior mediastinal B-cell lymphoma: A clinicopathologic and immunohistochemical study of 16 cases. Cancer 67:2579-2587, 1991[Medline]

9. Lavabre-Bertrand T, Donadio D, Fegueux N, et al: A study of 15 cases of primary mediastinal lymphoma of B-cell type. Cancer 69:2561-2566, 1992[Medline]

10. Rodriguez J, Pugh WC, Romaguera JE, et al: Primary mediastinal large cell lymphoma. Hematol Oncol 12:175-184, 1994[Medline]

11. Cazals-Hatem D, Lepage E, Brice P, et al: Primary mediastinal large B-cell lymphoma: A clinicopathologic study of 141 cases compared with 916 nonmediastinal large B-cell lymphomas—A GELA ("Groupe d'Etude des Lymphomes de l'Adulte") study. Am J Surg Pathol 20:877-888, 1996[Medline]

12. Joos S, Otaño-Joos MI, Ziegler S, et al: Primary mediastinal (thymic) B-cell lymphoma is characterized by gains of chromosomal material including 9p and amplification of the REL gene. Blood 87:1571-1578, 1996[Abstract/Free Full Text]

13. Scarpa A, Borgato L, Chilosi M, et al: Evidence of c-myc gene abnormalities in mediastinal large B-cell lymphoma of young adult age. Blood 78:780-788, 1991[Abstract/Free Full Text]

14. Tsang P, Cesarman E, Chadburn A, et al: Molecular characterization of primary mediastinal B cell lymphoma. Am J Pathol 148:2017-2025, 1996[Abstract]

15. Palanisamy N, Rao P, Abou-Elella A, et al: Comparison of primary mediastinal large B-cell and diffuse large cell lymphomas: Genetic anomalies defined by CGH. Blood 90:78a, 1997 (suppl 1, abstr 337)

16. Lichtenstein AK, Levine A, Taylor CR, et al: Primary mediastinal lymphoma in adults. Am J Med 68:509-514, 1980[Medline]

17. Trump DL, Mann RB: Diffuse large cell and undifferentiated lymphomas with prominent mediastinal involvement: A poor prognostic subset of patients with non-Hodgkin's lymphoma. Cancer 50:277-282, 1982[Medline]

18. Levitt LJ, Aisenberg AC, Harris NL, et al: Primary non-Hodgkin's lymphoma of the mediastinum. Cancer 50:2486-2492, 1982[Medline]

19. Bunin NJ, Hvizdala E, Link M, et al: Mediastinal nonlymphoblastic lymphomas in children: A clinicopathologic study. J Clin Oncol 4:154-159, 1986[Abstract]

20. Bertini M, Orsucci L, Vitolo U, et al: Stage II large B-cell lymphomas with sclerosis treated with MACOP-B. Ann Oncol 2:733-737, 1991[Abstract/Free Full Text]

21. Kirn D, Mauch P, Shaffer K, et al: Large-cell and immunoblastic lymphoma of the mediastinum: Prognostic features and treatment outcome in 57 patients. J Clin Oncol 11:1336-1343, 1993[Abstract/Free Full Text]

22. Rohatiner AZS, Whelan JS, Ganjoo RK, et al: Mediastinal large-cell lymphoma with sclerosis (MLCLS). Br J Cancer 69:601-604, 1994[Medline]

23. Lazzarino M, Orlandi E, Paulli M, et al: Treatment outcome and prognostic factors for primary mediastinal (thymic) B-cell lymphoma: A multicenter study of 106 patients. J Clin Oncol 15:1646-1653, 1997[Abstract]

24. The Non-Hodgkin's Lymphoma Pathologic Classification Project: National Cancer Institute sponsored study of classification of non-Hodgkin's lymphomas: Summary and description of a Working Formulation for clinical usage. Cancer 49:2112-2135, 1982[Medline]

25. Hsu SM, Raine L, Fanger H: Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: A comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem 29:577-580, 1981[Abstract]

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

27. Vose JM, Anderson JR, Bierman PJ, et al: Comparison of front-line chemotherapy for aggressive non-Hodgkin's lymphoma using the CAP-BOP regimens. Semin Hematol 31:4-8, 1994 (suppl 3) [Medline]

28. Kalbfleisch JD, Prentice RL: The Statistical Analysis of Failure Time Data. New York, NY, John Wiley and Sons, 1980

29. Snedecor GW, Cochran WG: Statistical Methods (ed 8). Ames, IA, Iowa State University Press, 1989

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

31. Cox DR: Regression models and life-tables. J R Stat Soc 34:187-220, 1972

32. Todeschini G, Ambrosetti A, Meneghini V, et al: Mediastinal large-B-cell lymphoma with sclerosis: A clinical study of 21 patients. J Clin Oncol 8:804-808, 1990[Abstract]

33. Zinzani PL, Bendandi M, Frezza G, et al: Primary mediastinal B-cell lymphoma with sclerosis: Clinical and therapeutic evaluation of 22 patients. Leuk Lymphoma 21:311-316, 1996[Medline]

34. Chim CS, Liang R, Chan ACL, et al: Primary B cell lymphoma of the mediastinum. Hematol Oncol 14:173-179, 1996[Medline]

35. Davis RE, Dorfman RF, Warnke RA: Primary large-cell lymphoma of the thymus: A diffuse B-cell neoplasm presenting as primary mediastinal lymphoma. Hum Pathol 21:1262-1268, 1990[Medline]

36. Haioun C, Gaulard P, Roudot-Thoraval F, et al: Mediastinal diffuse large-cell lymphoma with sclerosis: A condition with poor prognosis. Am J Clin Oncol 12:425-429, 1989[Medline]

37. Menestrina F, Chilosi M, Bonetti F, et al: Mediastinal large-cell lymphoma of B-type, with sclerosis: Histopathological and immunohistochemical study of eight cases. Histopathology 10:589-600, 1986[Medline]

38. Falini B, Venturi S, Martelli M, et al: Mediastinal large B-cell lymphoma: Clinical and immunohistological findings in 18 patients treated with different third-generation regimens. Br J Haematol 89:780-789, 1995[Medline]

39. Waldron JA, Newcomer LN, Katz ME, et al: Sclerosing variants of follicular center cell lymphomas presenting in the retroperitoneum. Cancer 52:712-720, 1983[Medline]

40. Witkin GB, Rosai J: Solitary fibrous tumor of the mediastinum: a report of 14 cases. Am J Surg Pathol 13:547-557, 1989[Medline]

41. Popat U, Przepiork D, Champlin R, et al: High-dose chemotherapy for relapsed and refractory diffuse large B-cell lymphoma: Mediastinal localization predicts for a favorable outcome. J Clin Oncol 16:63-69, 1998[Abstract/Free Full Text]

42. Sehn LH, Antin JH, Shulman LN, et al: Primary diffuse large B-cell lymphoma of the mediastinum: Outcome following high-dose chemotherapy and autologous hematopoietic cell transplantation. Blood 91:717-723, 1998[Abstract/Free Full Text]

Submitted June 17, 1998; accepted November 5, 1998.

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