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The management of primary mediastinal B-cell lymphoma with sclerosis
Annals of Oncology 5: 943-947, 1994. O 1994 Kluwer Academic Publishers. Primed in the Netherlands.
Clinical case The management of primary mediastinal B-cell lymphoma with sclerosis W. Brugger, R. Engelhardt, R. Mertelsmann & L. Kanz Albert-Ludwigs University Medical Center, Department of Hematology/Oncology, Freiburg, Germany
Key words: mediastinal large cell lymphoma, VACOP-B chemotherapy, high-dose chemotherapy
Introduction
Primary mediastinal large-cell lymphoma with sclerosis is a distinctive subtype of non-Hodgkin's lympoma with unique clinicopathologic aspects and aggressive behavior. The following case history illustrates the management of this disease, and discusses possible therapeutic options for patients with refractory disease or adverse prognostic factors.
Case history
A 22-year-old woman was admitted to an outside hospital, presenting with cough, chest pain and dyspnea. The physical examination showed findings of superior vena cava syndrome (SVCS) and a chest radiograph demonstrated a large mass of the anterior mediastinum with tracheobronchial compression (Fig. 1). Computer tomography (CT) revealed a bulky mediastinal mass of 14 x 20 x 9 cm with displacement and compression of the trachea and the large vessels. No pleural or pericardial effusion were present or infiltration of adjacent thoracic structures. An abdominal CT-scan and a bone marrow biopsy showed no signs of disease. Lactic dehydrogenase level (LDH) was elevated at 286 U/l. A biopsy was obtained by mediastinoscopy; the tumor displayed cytomorphologic features of a large cell lymphoma with massive sclerosis and a reactive infiltrate of lymphocytes, plasma cells, eosinophils and histiocytes. Immunohistochemistry showed a positive staining of the neoplastic cells with CD45, HLA-DR, as well as the pan-B cell marker CD20. No reactivity was found for CD3, CD15, CD30 and CD43 antigens and the tumor cells were negative for cytokeratins. Due to tracheobronchial compression, the patient required artificial ventilation following mediastinoscopy for 7 days. Immediate treatment was radiotherapy with a total dose of 20 Gy in 10 fractions. Her status improved rapidly, and she was referred to our hospital. At our institution, she was treated wih the VACOP-B chemotherapy regimen for aggressive lymphomas. Re-
L
Fig. 1. Chest radiograph (erect posterior-anterior view) at diagnosis.
staging after 7 weeks on treatment resulted in a partial remission (PR) with a residual tumor mass in the anterior mediastinum (Fig. 2). Treatment was changed to a second line regimen and the patient was considered for high-dose chemotherapy with autologous peripheral blood progenitor cell (PBPC) transplantation. She received VP16, ifosfamide, and cisplatin (VIP) and PBPCs were mobilized simultaneously using G-CSF administration and collected by leukapheresis. Further restaging of the mediastinal mass after VIP chemotherapy again revealed no significant difference in the size of the tumor. A second biopsy was obtained by minithoracotomy. The pathologic findings included massive tumor necrosis and sclerosis but no viable tumor cells expressing the original phenotype. Although the patient had shown a pathological com-
944 are young adults, predominantly women, with a median age of less than 30 years. They present with symptoms of a rapidly enlarging thoracic mass, often with superior venacaval compression and infiltration of adjacent structures such as lung, pleura, pericardium, and chest wall [1-4]. Due to its characteristic location in the anterior mediastinum, this lymphoma sometimes presents as an acute oncologic emergency, such as occurred in this patient. The presenting symptoms are cough, chest pain, dyspnea, or complaints from caval obstruction which occurs in 40%-50% of the patients. Few patients are asymptomatic. Fever or weight loss are present in 20% of the cases. Approximately 50% of the patients have pleura! effusions, and one third demonstrate supraclavicular disease [2]. The mediastinal mass is greater than 10 cm in diameter in more than 70% of the patients, however, it is not correlated with the presence of pleural or pericardial effusions [4]. Intrathoracic extension to adjacent organs can be demonstrated in half of the patients. Despite its invasive behavior, however, the disease is confined to the mediastinum and to Fig. 2. Chest radiograph seven weeks after initiation of VACOP-B contiguous nodal areas in about 80%. Only 20% of all patients are clinical stages III and IV with extranodal chemotherapy and 20 Gy emergency irradiation. spread being present in 10%. Bilateral renal infiltration is the most common extra-thoracic site. Other unusual plete response she was considered to be at increased sites of spread are the ovaries, the breast and the risk of subsequent relapse due to bulky disease (> 10 adrenal cortex [5]. Bone marrow involvement is excm) and elevated LDH levels at diagnosis. She was tremely rare. therefore considered to be a candidate for intensive consolidation therapy with stem cell transplantation. Diagnostic features The patient was treated with high-dose BCNU, VP16, Ara-C and Melphalan (BEAM) chemotherapy with The primary mediastinal large-cell lymphoma with PBPC transplantation. After reinfusion of PBPCs, the sclerosis is a distinct subtype of non-Hodgkin's lympatient received 300 \ig G-CSF daily by s.c. injection in phoma (NHL) which is composed of large polymororder to further accelerate hematopoietic recovery. phous cells that lack of follicular pattern [6]. Sclerosis is Both neutrophil and platelet reconstitution occurred marked in approximately 60% of the cases [3, 6, 7], rapidly and stable. No infectious or bleeding complica- which is rarely seen in other lymphomas of nodal tions occurred, and severe mucositis (WHO grade HI) origin, except for nodular sclerosing Hodgkin's disease. was the major non-hematological side effect. The pa- Immunohistochemistry reveals that it is a B-cell lymtient was discharged from the hospital 15 days from the phoma with a uniform expression of the pan-B cell start of chemotherapy. After high dose treatment fur- marker CD20 and the leukocyte-common antigen ther investigation showed a residual mass in the ante- CD45/LCA. Light chain-restricted surface and cytorior mediastinum. A positron-emission tomography plasmic immunoglobulins, however, are usually nega(PET) scan was performed in order to differentiate be- tive [5, 8, 9]. Moreover, the tumor does not express tween active residual tumor tissue and sclerosis. The CD3, CD5, CD10, CD15, CD30, CD45RO, and result showed no increased metabolism due to tumor, CD68. Epithelial membrane antigens (EMA) and pansuggesting that the residual mass consisted of inactive cytokeratins are also negative, allowing differentiation scar tissue or sclerosis. No further treatment has been from solid tumors. Previous studies suggested that this given. The patient is well at 18 months following high type of lymphoma may originate in the thymus from a dose chemotherapy and subsequent scans do not show specific thymic B-cell population [9]. any change in the residual mass. Differential diagnosis includes non-lymphoid tumors (thymoma, metastatic carcinoma, germ cell tumors) and other lymphoid malignancies, particularly nodular sclerosing Hodgkin's disease, T-lymphoblastic Discussion lymphomas as well as the Ki-1 + (CD30+) large-cell anaplastic lymphoma (Table 1). Although Hodgkin's disClinical features ease may express CD20, it can be excluded from a priPatients with large-cell lymphoma of the mediastinum mary B-cell lymphoma by staining for CD15, which is have some characteristic clinical features: most of them mostly co-expressed in Hodgkin's disease [10, 11] as
945 well as by a negative staining for CD45. Moreover, CD30 is uniformly negative in mediastinal B-cell lymphoma with sclerosis (Table 1). Another primary lymphoma of the mediastinum which arises in boys and adolescent males is the T-lymphoblastic lymphoma, which can easily be excluded by staining for the pan-T cell marker CD3.
proach, complete response (CR) rates vary between 75 and 90% with a 3-year disease-free survival rate of approximately 70% in patients with CR [3, 14, 15]. Almost all relapses occur within the first 15 months after treatment initiation [4, 14]. The patients who are free of disease after this time period are most likely to be cured. Non-responding patients, however, do not show long-term survival [3]. Those patients and paTable 1. Immunohistochemical characteristics of mediastinal lym- tients who relapse after having achieved an initial rephoma. mission, should be considered for treatment with a salvage regimen, followed by high-dose chemotherapy Mediastinal B-cell lymphoma CD20+, CD45+, CD3-, CD 15-, with bone marrow or peripheral blood stem cell transwith sclerosis CD30plantation (see below). Anaplastic large cell lymCD20 15%+,CD45+, The management for patients who present with phoma CD3 75%+, CD 15-, CD30+ bulky disease, pleural effusion or more than one extraHodgkin's disease CD20 20%+, CD45-, nodal site is somewhat different since these patients are CD3 40%+, CD 15+ CD30+ at highest risk in terms of treatment failure or early relapse [4, 14]. Many centers would therefore recommend to treat such patients with a third-generation Management of mediastinal B-cell lymphoma with regimen, such as VACOP-B [19] which is also used at sclerosis our own institution, but the CHOP regimen is a reasonable alternative even for less favorable tumors [2]. In Several studies described this lymphoma as an aggres- any case, patients with adverse prognostic factors sive disorder with a relatively poor prognosis [2, 3, 5, should be closely monitored radiologically (see below) 12-15]. Recent studies with CHOP therapy for third- in order to identify patients with suboptimal response generation regimens such as MACOP-B or VACOP-B, at a timepoint when additional therapeutic intervenhowever, reported that it is a curable disease with a tions may be most effective. We undertake the first re5-year failure-free survival between 40 and 60% [3-5, evaluation after 6-7 weeks of VACOP-B therapy. Pa14, 15]. Nevertheless, it requires prompt diagnosis and tients who achieve a complete radiological response immediate treatment since it can evolve into a medical (CR) at that time can be continued with full-dose emergency. VACOP-B for 12 weeks, followed by a 36-40 Gy inAt the present time, the patients are treated with volved-field mediastinal irradiation. In our department, chemotherapy regimens for aggressive NHLs, such as those patients who do not achieve a CR are started on CHOP or VACOP-B. Achievement of a complete re- second-line therapy with high-dose consolidation. Such mission after first-line chemotherapy is essential for approaches are also currently being recommended by long-term survival, whereas primarily resistant and several centers [2-4, 16, 18]. Our approach in such relapsed patients are extremely refractory to salvage patients is to apply a salvage regimen using etoposide therapy [13]. Moreover, the presence of bulky tumor (VP16), ifosfamide and cisplatin (VIP; [20]). This regi(>10 cm), pleural effusion or extranodal spread gen- men yields encouraging results in aggressive NHLs erally compromises survival [4, 14]. Such patients as [21], and, moreover, the VIP regimen simultaneously well as patients who do not respond satisfactorily to mobilizes PBPCs using hematopoietic growth factors induction chemotherapy or who relapse are poor-prog- [22, 23]. Patients will then be treated with high-dose nosis patients and should be considered immediately chemotherapy and autologous bone marrow or PBPC for more intensive or investigational treatment includ- support. The reason for using PBPCs instead of autoing high-dose chemotherapy with stem cell transplanta- logous bone marrow is based on the finding that tion [2,4]. PBPCs induce a more rapid restoration of hematoPatients with localized disease without adverse prog- poiesis [24] and the fact that there might be a reduced nostic factors (e.g. LDH, bulky disease, performance risk of tumor cell contamination in PBPC preparations status, extranodal sites) [16], and no pleura! effusion [25-27]. Since the mortality rate after high-dose should be treated with either CHOP, or one of the chemotherapy and PBPC transplantation is very low in third-generation regimens, such as VACOP-B [2,4,14]. recent series, this treatment option does not result in an However, there is at present no clear benefit of newer increased rate of treatment-related mortality than any chemotherapy regimens over CHOP in large cell lym- other third-generation regimen for aggressive NHLs phomas at all sites [17, 18] suggesting that CHOP [17]. Therefore, high-dose chemotherapy with PBPC should still be considered the standard regimen for the transplantation should be considered in patients pretreatment of large cell lymphoma. The role of adjuvant senting with bulky disease, pleural effusion or more radiation after completion of chemotherapy remains than one extranodal site as part of the front-line treatunproven at present [2], although most centers irradiate ment. patients after chemotherapy [14]. Using such an apThe rationale for high-dose chemotherapy in high-
946 risk aggressive NHL patients in general is based on previous non-randomized trials which have indicated that this treatment option might produce superior results to conventional chemotherapy [28]. However, interim analyses of recently performed randomized trials have not yet demonstrated a significantly better survival as compared to conventional therapy [29, 30]. Until the final results of these studies are available, high-dose chemotherapy in all poor-prognosis aggressive NHL patients including this subtype of lymphoma remains to be determined. Management of residual tumor after treatment in mediastinal B-cell lymphoma with sclerosis Patients with bulky disease in the mediastinum frequently have residual abnormalities of uncertain significance on regular X-ray films, CT or magnetic resonance scans, independent of the subtype of the lymphoma. This situation is similar to that which can be found in nodular sclerosing Hodgkin's disease where residual masses are also frequently observed. In Hodgkin's disease, however, residual mediastinal abnormalities do not by themselves indicate persistent active disease or an increased risk of relapse [31, 32], whereas in B-cell lymphoma with sclerosis, several studies suggested that any residual tumor after treatment is associated with an increased risk of relapse [2, 4]. Therefore, a technique is needed to differentiate between active tumor tissue and fibrosis within residual radiographic masses. Gallium-67 citrate imaging has been used and shown to be a both sensitive and specific indicator of active lymphoma [33]. An alternative method to again differentiate between residual rumor and sclerosis is the positron-emission tomography (PET). This method as well as Ga-67 imaging might be particularly helpful in patients with positive-scans prior to treatment which revert to normal following completion of therapy. Persistent Ga-67 uptake after the end of treatment predicts for a poor outcome in this lymphoma [4]. At present, there are no general recommendations for the management of these patients. In addition, the role of consolidation radiotherapy in patients with residua] radiographic masses after high-dose chemotherapy remains to be determined.
6. 7.
8.
9. 10. 11. 12.
13. 14.
15. 16.
17.
18. 19. 20.
21. 22.
References 1. Levitt LJ, Aisenberg AC, Harris NL et al. Primary nonHodgkin's lymphoma of the mediastinum. Cancer 1982; 50: 2486-92. 2. Aisenberg AC. Primary large-cell lymphoma of the mediastinum. J Clin Oncol 1993; 11: 2291-4. 3. Lazzarino M, Orland E, Paulli M et al. Primary mediastintal B-cell lymphoma with sclerosis: An aggressive tumor with distinctive clinical and pathological features. J Clin Oncol 1993; 11:2306-13. 4. Kirn D, Mauch P, Shaffer K et al. Large-cell and immunoblastic lymphoma of the mediastinum: Prognostic and pathologic features in 57 patients. J Clin Oncol 1993; 11:1336-43. 5. Todeschini G, Ambrosetti A, Meneghini V et al. Mediastinal
23.
24.
25.
large-B-cell with sclerosis: A clinical study of 21 patients. J Clin Oncol 1990; 8: 804-8. Lennert K, Feller AC. Histopathology of non-Hodgkin's Lymphomas. New York: Springer-Verlag 1992; 157-61. Miller JB, Variakojis D, Bitran JD et al. Diffuse histiocytic lymphoma with sclerosis: A clinicopathologica] entity frequently causing superior venacaval obstruction. Cancer 1981; 47: 748-56. Al-Sharabati M, Chittal S, Duga-Neulet I et al. Primary anterior mediastinal B-cell lymphoma; A clinicopathological and immunohistochemical study of 16 cases. Cancer 1991; 67: 2579-87. Moller P, Moldenhauer G, Momberg F et al. Mediastinal clear cell lymphoma of clear cell type is a tumor corresponding to terminal steps of B-cell differentation. Blood 1987; 69:1087-95. Stein H, Uchanska-Ziegler B, Gerdes J et al. Hodgkin and Sternberg-Reed cells contain antigens specific to late cells of granulopoiesis. Int J Cancer 1982; 29: 283-90. Zukeberg LR, Collins AB, Ferry JA et al. Coexpression of CD15 and CD20 by Reed-Sternberg cells in Hodgkin's disease. Am J Pathol 1991; 139:475-83. 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 1982; 50: 277-82. Haioun C, Gaulard P, Roudot-Thoraval F et al. Mediastinal diffuse large-cell lymphoma with sclerosis: A condition with a poor prognosis. Am J Clin Oncol 1989; 12:425-9. Jacobson JO, Aisenberg AC, Lamarre L et al. Mediastinal large-cell lymphoma: An uncommon subset of adult lymphoma curable with combined modality therapy. Cancer 1988; 62: 1893-8. Bertini M, Orsucci L, Vitolo U et al. Stage II large B-cell lymphoma with sclerosis treated with MACOP-B. Ann Oncol 1991; 2: 733-7. Shipp MA, Harrington DP. The international non-Hodgkin's lymphoma prognostic factors project: A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med 1993; 329: 987-4 Fisher RI, Gaynor ER, Dahlberg S et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med 1993; 328: 1002-6. Armitage JO. Treatment of non-Hodgkin's lymphoma. N Engl J Med 1993; 328:1023-30. O'Reilly SE, Hoskins P, Klimo P et al. MACOP-B and VACOP-B in diffuse large-cell lymphomas and MOPP/ABV in Hodgkin's disease. Ann Oncol 1991; 2:17-23. Brugger W, Frisch J, Schulz G et al. Sequential administration of IL-3 and GM-CSF following standard-dose combination chemotherapy wtih etoposide, ifosfamide and cisplatin. J Clin Oncol 1992; 10:1452-9. Hickish T, Roldan A, Cunningham D et al. EPIC: An effective low toxicity regimen for relapsing lymphoma. Br J Cancer 1993; 3: 599-604. Brugger W, Bross KH, Frisch J et al. Mobilization of peripheral blood progenitor cells by sequential administration of IL-3 and GM-CSF following polychemotherpay with etoposide, ifosfamide, and cisplatin. Blood 1992; 79: 1193-200. Brugger W, Birken R, Bertz H et al. Peripheral blood progenitor cells mobilized by chemotherapy + G-CSF accelerate both neutrophil and platelet recovery after high-dose VP16, ifosfamide and cisplatin. Br J Haematol 1993; 84: 402-8. Sheridan WP, Begley CG, Juttner C et al. Effect of peripheralblood progenitor cells mobilised by filgrastim (G-CSF) on platelet recovery after high-dose chemotherapy. Lancet 1992; i: 640. Ross AA, Cooper BW, Lazarus HM et al. Detection and viability of tumor cells in peripheral blood stem cell collections from breast cancer patients using immunocytochemical and clonogenic assay techniques. Blood 1993; 82: 2605.
947 26. Brugger W, Bross KJ, Glatt M et al. Mobilization of tumor cells and hematopoietic progenitor cells into peripheral blood of patients with solid tumors. Blood 1994; 83:636-40. 27. Shpall EJ, Jones RB. Release of tumor cells from bone marrow. Blood 1994; 83: 623-5. 28. Gulati SC, Shank B, Black P et al. Autologous bone marrow transplantation for patients with poor prognosis lymphoma. J Clin Oncol 1988; 6:1303-13. 29. Haioun C, Lepage E, Gisselbrecht C et al. Autologous bone marrow transplantation versus sequential chemotherapy in first complete remission aggressive non-Hodgkin's lymphoma: 1st Interim analysis on 370 patients (LNH87 protocol). Proc Am Soc Clin Oncol 1992; 11: 316a. 30. Gianni AG, Bregni M, Siena S et al. 5-Year update of the Milan Cancer Institute randomized trial of high-dose sequential vs. MACOP-B therapy for diffuse large-cell lymphomas. Proc Am Soc Clin Oncol 1994; 13: 373a (# 1263). 31. Jochelson MS, Mauch P, Balikian J et al. The significance of the
residual mediastinal mass in the treated Hodgkin's disease. J Clin Oncol 1985; 3:637-41. 32. Canellos GP. Residual mass in lymphoma may not be residual disease. J Clin Oncol 1988; 6: 931-3. 33. Kaplan WD, Jochelson MS, Herman TS et al. Gallium-67 imaging: A predictor of residual tumor viability and clinical outcome in patients with diffuse large-cell lymphoma. J Clin Oncol 1990; 8:1966-73. Received 20 September 1994; accepted 21 September 1994. Correspondence to: Wolfram Brugger, MX). Albert-Ludwigs University Medical Center I Dept. of Hematology/Oncology Hugstetter Str. 55 79106 Freiburg Germany
Clinical case The management of primary mediastinal B-cell lymphoma with sclerosis W. Brugger, R. Engelhardt, R. Mertelsmann & L. Kanz Albert-Ludwigs University Medical Center, Department of Hematology/Oncology, Freiburg, Germany
Key words: mediastinal large cell lymphoma, VACOP-B chemotherapy, high-dose chemotherapy
Introduction
Primary mediastinal large-cell lymphoma with sclerosis is a distinctive subtype of non-Hodgkin's lympoma with unique clinicopathologic aspects and aggressive behavior. The following case history illustrates the management of this disease, and discusses possible therapeutic options for patients with refractory disease or adverse prognostic factors.
Case history
A 22-year-old woman was admitted to an outside hospital, presenting with cough, chest pain and dyspnea. The physical examination showed findings of superior vena cava syndrome (SVCS) and a chest radiograph demonstrated a large mass of the anterior mediastinum with tracheobronchial compression (Fig. 1). Computer tomography (CT) revealed a bulky mediastinal mass of 14 x 20 x 9 cm with displacement and compression of the trachea and the large vessels. No pleural or pericardial effusion were present or infiltration of adjacent thoracic structures. An abdominal CT-scan and a bone marrow biopsy showed no signs of disease. Lactic dehydrogenase level (LDH) was elevated at 286 U/l. A biopsy was obtained by mediastinoscopy; the tumor displayed cytomorphologic features of a large cell lymphoma with massive sclerosis and a reactive infiltrate of lymphocytes, plasma cells, eosinophils and histiocytes. Immunohistochemistry showed a positive staining of the neoplastic cells with CD45, HLA-DR, as well as the pan-B cell marker CD20. No reactivity was found for CD3, CD15, CD30 and CD43 antigens and the tumor cells were negative for cytokeratins. Due to tracheobronchial compression, the patient required artificial ventilation following mediastinoscopy for 7 days. Immediate treatment was radiotherapy with a total dose of 20 Gy in 10 fractions. Her status improved rapidly, and she was referred to our hospital. At our institution, she was treated wih the VACOP-B chemotherapy regimen for aggressive lymphomas. Re-
L
Fig. 1. Chest radiograph (erect posterior-anterior view) at diagnosis.
staging after 7 weeks on treatment resulted in a partial remission (PR) with a residual tumor mass in the anterior mediastinum (Fig. 2). Treatment was changed to a second line regimen and the patient was considered for high-dose chemotherapy with autologous peripheral blood progenitor cell (PBPC) transplantation. She received VP16, ifosfamide, and cisplatin (VIP) and PBPCs were mobilized simultaneously using G-CSF administration and collected by leukapheresis. Further restaging of the mediastinal mass after VIP chemotherapy again revealed no significant difference in the size of the tumor. A second biopsy was obtained by minithoracotomy. The pathologic findings included massive tumor necrosis and sclerosis but no viable tumor cells expressing the original phenotype. Although the patient had shown a pathological com-
944 are young adults, predominantly women, with a median age of less than 30 years. They present with symptoms of a rapidly enlarging thoracic mass, often with superior venacaval compression and infiltration of adjacent structures such as lung, pleura, pericardium, and chest wall [1-4]. Due to its characteristic location in the anterior mediastinum, this lymphoma sometimes presents as an acute oncologic emergency, such as occurred in this patient. The presenting symptoms are cough, chest pain, dyspnea, or complaints from caval obstruction which occurs in 40%-50% of the patients. Few patients are asymptomatic. Fever or weight loss are present in 20% of the cases. Approximately 50% of the patients have pleura! effusions, and one third demonstrate supraclavicular disease [2]. The mediastinal mass is greater than 10 cm in diameter in more than 70% of the patients, however, it is not correlated with the presence of pleural or pericardial effusions [4]. Intrathoracic extension to adjacent organs can be demonstrated in half of the patients. Despite its invasive behavior, however, the disease is confined to the mediastinum and to Fig. 2. Chest radiograph seven weeks after initiation of VACOP-B contiguous nodal areas in about 80%. Only 20% of all patients are clinical stages III and IV with extranodal chemotherapy and 20 Gy emergency irradiation. spread being present in 10%. Bilateral renal infiltration is the most common extra-thoracic site. Other unusual plete response she was considered to be at increased sites of spread are the ovaries, the breast and the risk of subsequent relapse due to bulky disease (> 10 adrenal cortex [5]. Bone marrow involvement is excm) and elevated LDH levels at diagnosis. She was tremely rare. therefore considered to be a candidate for intensive consolidation therapy with stem cell transplantation. Diagnostic features The patient was treated with high-dose BCNU, VP16, Ara-C and Melphalan (BEAM) chemotherapy with The primary mediastinal large-cell lymphoma with PBPC transplantation. After reinfusion of PBPCs, the sclerosis is a distinct subtype of non-Hodgkin's lympatient received 300 \ig G-CSF daily by s.c. injection in phoma (NHL) which is composed of large polymororder to further accelerate hematopoietic recovery. phous cells that lack of follicular pattern [6]. Sclerosis is Both neutrophil and platelet reconstitution occurred marked in approximately 60% of the cases [3, 6, 7], rapidly and stable. No infectious or bleeding complica- which is rarely seen in other lymphomas of nodal tions occurred, and severe mucositis (WHO grade HI) origin, except for nodular sclerosing Hodgkin's disease. was the major non-hematological side effect. The pa- Immunohistochemistry reveals that it is a B-cell lymtient was discharged from the hospital 15 days from the phoma with a uniform expression of the pan-B cell start of chemotherapy. After high dose treatment fur- marker CD20 and the leukocyte-common antigen ther investigation showed a residual mass in the ante- CD45/LCA. Light chain-restricted surface and cytorior mediastinum. A positron-emission tomography plasmic immunoglobulins, however, are usually nega(PET) scan was performed in order to differentiate be- tive [5, 8, 9]. Moreover, the tumor does not express tween active residual tumor tissue and sclerosis. The CD3, CD5, CD10, CD15, CD30, CD45RO, and result showed no increased metabolism due to tumor, CD68. Epithelial membrane antigens (EMA) and pansuggesting that the residual mass consisted of inactive cytokeratins are also negative, allowing differentiation scar tissue or sclerosis. No further treatment has been from solid tumors. Previous studies suggested that this given. The patient is well at 18 months following high type of lymphoma may originate in the thymus from a dose chemotherapy and subsequent scans do not show specific thymic B-cell population [9]. any change in the residual mass. Differential diagnosis includes non-lymphoid tumors (thymoma, metastatic carcinoma, germ cell tumors) and other lymphoid malignancies, particularly nodular sclerosing Hodgkin's disease, T-lymphoblastic Discussion lymphomas as well as the Ki-1 + (CD30+) large-cell anaplastic lymphoma (Table 1). Although Hodgkin's disClinical features ease may express CD20, it can be excluded from a priPatients with large-cell lymphoma of the mediastinum mary B-cell lymphoma by staining for CD15, which is have some characteristic clinical features: most of them mostly co-expressed in Hodgkin's disease [10, 11] as
945 well as by a negative staining for CD45. Moreover, CD30 is uniformly negative in mediastinal B-cell lymphoma with sclerosis (Table 1). Another primary lymphoma of the mediastinum which arises in boys and adolescent males is the T-lymphoblastic lymphoma, which can easily be excluded by staining for the pan-T cell marker CD3.
proach, complete response (CR) rates vary between 75 and 90% with a 3-year disease-free survival rate of approximately 70% in patients with CR [3, 14, 15]. Almost all relapses occur within the first 15 months after treatment initiation [4, 14]. The patients who are free of disease after this time period are most likely to be cured. Non-responding patients, however, do not show long-term survival [3]. Those patients and paTable 1. Immunohistochemical characteristics of mediastinal lym- tients who relapse after having achieved an initial rephoma. mission, should be considered for treatment with a salvage regimen, followed by high-dose chemotherapy Mediastinal B-cell lymphoma CD20+, CD45+, CD3-, CD 15-, with bone marrow or peripheral blood stem cell transwith sclerosis CD30plantation (see below). Anaplastic large cell lymCD20 15%+,CD45+, The management for patients who present with phoma CD3 75%+, CD 15-, CD30+ bulky disease, pleural effusion or more than one extraHodgkin's disease CD20 20%+, CD45-, nodal site is somewhat different since these patients are CD3 40%+, CD 15+ CD30+ at highest risk in terms of treatment failure or early relapse [4, 14]. Many centers would therefore recommend to treat such patients with a third-generation Management of mediastinal B-cell lymphoma with regimen, such as VACOP-B [19] which is also used at sclerosis our own institution, but the CHOP regimen is a reasonable alternative even for less favorable tumors [2]. In Several studies described this lymphoma as an aggres- any case, patients with adverse prognostic factors sive disorder with a relatively poor prognosis [2, 3, 5, should be closely monitored radiologically (see below) 12-15]. Recent studies with CHOP therapy for third- in order to identify patients with suboptimal response generation regimens such as MACOP-B or VACOP-B, at a timepoint when additional therapeutic intervenhowever, reported that it is a curable disease with a tions may be most effective. We undertake the first re5-year failure-free survival between 40 and 60% [3-5, evaluation after 6-7 weeks of VACOP-B therapy. Pa14, 15]. Nevertheless, it requires prompt diagnosis and tients who achieve a complete radiological response immediate treatment since it can evolve into a medical (CR) at that time can be continued with full-dose emergency. VACOP-B for 12 weeks, followed by a 36-40 Gy inAt the present time, the patients are treated with volved-field mediastinal irradiation. In our department, chemotherapy regimens for aggressive NHLs, such as those patients who do not achieve a CR are started on CHOP or VACOP-B. Achievement of a complete re- second-line therapy with high-dose consolidation. Such mission after first-line chemotherapy is essential for approaches are also currently being recommended by long-term survival, whereas primarily resistant and several centers [2-4, 16, 18]. Our approach in such relapsed patients are extremely refractory to salvage patients is to apply a salvage regimen using etoposide therapy [13]. Moreover, the presence of bulky tumor (VP16), ifosfamide and cisplatin (VIP; [20]). This regi(>10 cm), pleural effusion or extranodal spread gen- men yields encouraging results in aggressive NHLs erally compromises survival [4, 14]. Such patients as [21], and, moreover, the VIP regimen simultaneously well as patients who do not respond satisfactorily to mobilizes PBPCs using hematopoietic growth factors induction chemotherapy or who relapse are poor-prog- [22, 23]. Patients will then be treated with high-dose nosis patients and should be considered immediately chemotherapy and autologous bone marrow or PBPC for more intensive or investigational treatment includ- support. The reason for using PBPCs instead of autoing high-dose chemotherapy with stem cell transplanta- logous bone marrow is based on the finding that tion [2,4]. PBPCs induce a more rapid restoration of hematoPatients with localized disease without adverse prog- poiesis [24] and the fact that there might be a reduced nostic factors (e.g. LDH, bulky disease, performance risk of tumor cell contamination in PBPC preparations status, extranodal sites) [16], and no pleura! effusion [25-27]. Since the mortality rate after high-dose should be treated with either CHOP, or one of the chemotherapy and PBPC transplantation is very low in third-generation regimens, such as VACOP-B [2,4,14]. recent series, this treatment option does not result in an However, there is at present no clear benefit of newer increased rate of treatment-related mortality than any chemotherapy regimens over CHOP in large cell lym- other third-generation regimen for aggressive NHLs phomas at all sites [17, 18] suggesting that CHOP [17]. Therefore, high-dose chemotherapy with PBPC should still be considered the standard regimen for the transplantation should be considered in patients pretreatment of large cell lymphoma. The role of adjuvant senting with bulky disease, pleural effusion or more radiation after completion of chemotherapy remains than one extranodal site as part of the front-line treatunproven at present [2], although most centers irradiate ment. patients after chemotherapy [14]. Using such an apThe rationale for high-dose chemotherapy in high-
946 risk aggressive NHL patients in general is based on previous non-randomized trials which have indicated that this treatment option might produce superior results to conventional chemotherapy [28]. However, interim analyses of recently performed randomized trials have not yet demonstrated a significantly better survival as compared to conventional therapy [29, 30]. Until the final results of these studies are available, high-dose chemotherapy in all poor-prognosis aggressive NHL patients including this subtype of lymphoma remains to be determined. Management of residual tumor after treatment in mediastinal B-cell lymphoma with sclerosis Patients with bulky disease in the mediastinum frequently have residual abnormalities of uncertain significance on regular X-ray films, CT or magnetic resonance scans, independent of the subtype of the lymphoma. This situation is similar to that which can be found in nodular sclerosing Hodgkin's disease where residual masses are also frequently observed. In Hodgkin's disease, however, residual mediastinal abnormalities do not by themselves indicate persistent active disease or an increased risk of relapse [31, 32], whereas in B-cell lymphoma with sclerosis, several studies suggested that any residual tumor after treatment is associated with an increased risk of relapse [2, 4]. Therefore, a technique is needed to differentiate between active tumor tissue and fibrosis within residual radiographic masses. Gallium-67 citrate imaging has been used and shown to be a both sensitive and specific indicator of active lymphoma [33]. An alternative method to again differentiate between residual rumor and sclerosis is the positron-emission tomography (PET). This method as well as Ga-67 imaging might be particularly helpful in patients with positive-scans prior to treatment which revert to normal following completion of therapy. Persistent Ga-67 uptake after the end of treatment predicts for a poor outcome in this lymphoma [4]. At present, there are no general recommendations for the management of these patients. In addition, the role of consolidation radiotherapy in patients with residua] radiographic masses after high-dose chemotherapy remains to be determined.
6. 7.
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9. 10. 11. 12.
13. 14.
15. 16.
17.
18. 19. 20.
21. 22.
References 1. Levitt LJ, Aisenberg AC, Harris NL et al. Primary nonHodgkin's lymphoma of the mediastinum. Cancer 1982; 50: 2486-92. 2. Aisenberg AC. Primary large-cell lymphoma of the mediastinum. J Clin Oncol 1993; 11: 2291-4. 3. Lazzarino M, Orland E, Paulli M et al. Primary mediastintal B-cell lymphoma with sclerosis: An aggressive tumor with distinctive clinical and pathological features. J Clin Oncol 1993; 11:2306-13. 4. Kirn D, Mauch P, Shaffer K et al. Large-cell and immunoblastic lymphoma of the mediastinum: Prognostic and pathologic features in 57 patients. J Clin Oncol 1993; 11:1336-43. 5. Todeschini G, Ambrosetti A, Meneghini V et al. Mediastinal
23.
24.
25.
large-B-cell with sclerosis: A clinical study of 21 patients. J Clin Oncol 1990; 8: 804-8. Lennert K, Feller AC. Histopathology of non-Hodgkin's Lymphomas. New York: Springer-Verlag 1992; 157-61. Miller JB, Variakojis D, Bitran JD et al. Diffuse histiocytic lymphoma with sclerosis: A clinicopathologica] entity frequently causing superior venacaval obstruction. Cancer 1981; 47: 748-56. Al-Sharabati M, Chittal S, Duga-Neulet I et al. Primary anterior mediastinal B-cell lymphoma; A clinicopathological and immunohistochemical study of 16 cases. Cancer 1991; 67: 2579-87. Moller P, Moldenhauer G, Momberg F et al. Mediastinal clear cell lymphoma of clear cell type is a tumor corresponding to terminal steps of B-cell differentation. Blood 1987; 69:1087-95. Stein H, Uchanska-Ziegler B, Gerdes J et al. Hodgkin and Sternberg-Reed cells contain antigens specific to late cells of granulopoiesis. Int J Cancer 1982; 29: 283-90. Zukeberg LR, Collins AB, Ferry JA et al. Coexpression of CD15 and CD20 by Reed-Sternberg cells in Hodgkin's disease. Am J Pathol 1991; 139:475-83. 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 1982; 50: 277-82. Haioun C, Gaulard P, Roudot-Thoraval F et al. Mediastinal diffuse large-cell lymphoma with sclerosis: A condition with a poor prognosis. Am J Clin Oncol 1989; 12:425-9. Jacobson JO, Aisenberg AC, Lamarre L et al. Mediastinal large-cell lymphoma: An uncommon subset of adult lymphoma curable with combined modality therapy. Cancer 1988; 62: 1893-8. Bertini M, Orsucci L, Vitolo U et al. Stage II large B-cell lymphoma with sclerosis treated with MACOP-B. Ann Oncol 1991; 2: 733-7. Shipp MA, Harrington DP. The international non-Hodgkin's lymphoma prognostic factors project: A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med 1993; 329: 987-4 Fisher RI, Gaynor ER, Dahlberg S et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med 1993; 328: 1002-6. Armitage JO. Treatment of non-Hodgkin's lymphoma. N Engl J Med 1993; 328:1023-30. O'Reilly SE, Hoskins P, Klimo P et al. MACOP-B and VACOP-B in diffuse large-cell lymphomas and MOPP/ABV in Hodgkin's disease. Ann Oncol 1991; 2:17-23. Brugger W, Frisch J, Schulz G et al. Sequential administration of IL-3 and GM-CSF following standard-dose combination chemotherapy wtih etoposide, ifosfamide and cisplatin. J Clin Oncol 1992; 10:1452-9. Hickish T, Roldan A, Cunningham D et al. EPIC: An effective low toxicity regimen for relapsing lymphoma. Br J Cancer 1993; 3: 599-604. Brugger W, Bross KH, Frisch J et al. Mobilization of peripheral blood progenitor cells by sequential administration of IL-3 and GM-CSF following polychemotherpay with etoposide, ifosfamide, and cisplatin. Blood 1992; 79: 1193-200. Brugger W, Birken R, Bertz H et al. Peripheral blood progenitor cells mobilized by chemotherapy + G-CSF accelerate both neutrophil and platelet recovery after high-dose VP16, ifosfamide and cisplatin. Br J Haematol 1993; 84: 402-8. Sheridan WP, Begley CG, Juttner C et al. Effect of peripheralblood progenitor cells mobilised by filgrastim (G-CSF) on platelet recovery after high-dose chemotherapy. Lancet 1992; i: 640. Ross AA, Cooper BW, Lazarus HM et al. Detection and viability of tumor cells in peripheral blood stem cell collections from breast cancer patients using immunocytochemical and clonogenic assay techniques. Blood 1993; 82: 2605.
947 26. Brugger W, Bross KJ, Glatt M et al. Mobilization of tumor cells and hematopoietic progenitor cells into peripheral blood of patients with solid tumors. Blood 1994; 83:636-40. 27. Shpall EJ, Jones RB. Release of tumor cells from bone marrow. Blood 1994; 83: 623-5. 28. Gulati SC, Shank B, Black P et al. Autologous bone marrow transplantation for patients with poor prognosis lymphoma. J Clin Oncol 1988; 6:1303-13. 29. Haioun C, Lepage E, Gisselbrecht C et al. Autologous bone marrow transplantation versus sequential chemotherapy in first complete remission aggressive non-Hodgkin's lymphoma: 1st Interim analysis on 370 patients (LNH87 protocol). Proc Am Soc Clin Oncol 1992; 11: 316a. 30. Gianni AG, Bregni M, Siena S et al. 5-Year update of the Milan Cancer Institute randomized trial of high-dose sequential vs. MACOP-B therapy for diffuse large-cell lymphomas. Proc Am Soc Clin Oncol 1994; 13: 373a (# 1263). 31. Jochelson MS, Mauch P, Balikian J et al. The significance of the
residual mediastinal mass in the treated Hodgkin's disease. J Clin Oncol 1985; 3:637-41. 32. Canellos GP. Residual mass in lymphoma may not be residual disease. J Clin Oncol 1988; 6: 931-3. 33. Kaplan WD, Jochelson MS, Herman TS et al. Gallium-67 imaging: A predictor of residual tumor viability and clinical outcome in patients with diffuse large-cell lymphoma. J Clin Oncol 1990; 8:1966-73. Received 20 September 1994; accepted 21 September 1994. Correspondence to: Wolfram Brugger, MX). Albert-Ludwigs University Medical Center I Dept. of Hematology/Oncology Hugstetter Str. 55 79106 Freiburg Germany