Primary mediastinal large B-cell lymphoma.
Primary mediastinal large B-cell lymphoma (PMLBCL) is a distinct disease entity that has a relatively short history. The prognosis and therapy of patients with PMLBCL is still controversial. We summarize our experience with PMLBCL at the Medical University of South Carolina between 1997 and 2000.
THE PRINCIPAL PRIMARY NEOPLASMS of the anterior mediastinum are non-Hodgkin's lymphomas (primary mediastinal large B-cell lymphoma [PMLBCL] and lymphoblastic lymphoma), Hodgkin's disease, thyrnoma, and dysgerminoma. Primary mediastinal large B-cell lymphoma has a relatively short history. The first description appeared in the 1980s, and it was included in the Revised European-American Lymphoma (REAL) classification as PMLBCL in 1994. (1) Primary mediastinal large B-cell lymphoma is usually seen in young adults (median age, 30-35) as a rapidly enlarging anterior mediastinal mass, frequently with superior vena cava compression. It is more prevalent in females, with a male-to-female ratio of 1:2. The tumor invades thoracic structures, such as lung and pleura; it also invades or relapses in unusual sites, such as the breast, gastrointestinal tract, kidney, adrenal gland, pericardium, and chest wall. (2-4) Primary mediastinal large Bcell lymphoma is an uncommon, but not rare, condition. It constituted 2.4% of 1403 cases reviewed for the Non-Hodgkin's Lymphoma Classification Project. (5)
The response to therapy and prognosis of patients with PMLBCL is still controversial. Some early studies showed that patients with PMLBCL have an aggressive clinical course with a low median survival time, (3,6,7) but more recent studies have reported relatively good response and survival rates. (2,4,8,9) In this report, we summarize our experience with 6 PMLBCL patients treated at the Medical University of South Carolina between 1997 and 2000.
Case 1. In April 1997, when she was 6 months pregnant, a 28-year-old woman was diagnosed with stage IIB PML BCL. She had a mediastinal mass measuring 10 cm and pericardial effusion with tamponade that required a pericardial window. She received 6 cycles of chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), with a residual 2.7-cm mediastinal mass. After the first cycle of CHOP chemotherapy, she gave birth to a healthy baby boy. Within 1 month, the mass increased to 5.2 cm in size and she received mediastinal radiotherapy (XRT) of 36 Gray total dose given in 20 fractions (36 Gy TD/20 fx). The residual mass measured 2.5 cm. Consolidative therapy consisted of an autologous peripheral-blood stem-cell transplant (auto PBSCT) with a preparative regimen of cyclophosphamide, carmustine (BCNU), and etoposide (CBV). The mediastinal mass resolved, and she had a normal computed tomography (CT) scan in January 2001. She has remained disease-free without any further treatment for 3 years.
Case 2. A 52-year-old woman presented in August 1997 with stage IIIA PMLBCL, involving a 12-cm mediastinal mass, pericardial effusion, and bilateral pleural effusions. After 4 cycles of CHOP chemotherapy, the mass measured 11 cm. Salvage mediastinal XRT of 45 Gy TD/25 fx further reduced the mass to 7.6 cm. She received consolidative auto PBSCT with a preparative regimen of CBV in April 1998. She developed BCNU/radiation pneumonitis that responded to treatment with corticosteroids. One year after XRT, she developed transverse myelitis at the level of T5, which responded to corticosteroid therapy. Two subsequent relapses of transverse myelitis also responded to treatment with corticosteroids. She has been disease-free for 3 years without any additional treatment, but residual radiologic abnormalities remained on the August 2001 CT scan.
Case 3. In August 1999, a 29-year-old man was diagnosed. with stage IIA PMLBCL, with a gallium-positive mediastinal mass measuring 13 x 11 cm. After 6 cycles of CHOP chemotherapy, the mass measured 6.7 cm and was gallium-negative. He received an auto PBSCT with CBV therapy, but by day 100 had disease progression in the pericardium and paraaortic nodes. He received mediastinal XRT of 18 Gy TD/25 fx. He died 1.8 years after salvage therapy from sudden death. Autopsy was refused.
Case 4. A 25-year-old woman developed superior vena cava syndrome in March 1999. Medical history revealed breast augmentation. She was diagnosed with stage IIB PMLBCL, with a gallium-positive mediastinal mass measuring 13 x 15 cm and a small pericardial effusion. She was treated with 6 cycles of CHOP chemotherapy and mediastinal XRT of 30 GyTD/15 fx. The residual mass was 3 cm in diameter and gallium-negative, but in 3 months the disease progressed in the gastric mucosa, bilateral kidneys, and spleen. Salvage chemotherapy with 3 cycles of etoposide, methylprednisolone, cytarabine, and cisplatin (ESHAP) produced a partial response. Autologous peripheral-blood stem-cell transplant with a preparative regimen of CBV was unsuccessful, with progressive disease at the relapse sites by day 48. Rituximab therapy was ineffective; the patient died within 1 year of diagnosis.
Case 5. A 42-year-old woman presented in December 1999 with stage IIA PMLBCL, with a mediastinal mass measuring 12 x 12 cm. After 6 cycles of CHOP chemotherapy, the mass was reduced to 5 cm in diameter, and mediastinal XRT of 18 Gy TD/23 fx was given. Three months later, she relapsed in the mediastinum, bilateral kidneys, and peripancreatic, retroperitoneal, and mesenteric lymph nodes. Neither 3 cycles of chemotherapy with ifosfamide, carboplatin, and etoposide (ICE) nor rituximab treatment were effective. The patient died within 1 year of diagnosis.
Case 6. A 44-year-old woman was diagnosed with stage IIB PMLBCL in March 2000, with a mediastinal mass measuring 12 x 13 cm and pericardial effusion. The mass was gallium-positive. Medical history revealed breast augmentation. She received 6 cycles of CHOP chemotherapy. Restaging after chemotherapy showed a reduction in the mediastinal mass to 5.3 cm, but disease progression had occurred in both kidneys, with multiple 0.5 to 1 cm lesions. The disease quickly progressed, and she developed gastric and pancreatic masses and abdominal adenopathy. She received treatment with paclitaxol, topotecan, and nituximab as part of an investigational study, but had disease progression after 2 cycles. She also failed one cycle of ICE chemotherapy at 50% dose reduction (dose reduction due to her poor performance status). She died almost a year after diagnosis.
The current cases suggest a distinctive clinical behavior of PMLBCL. This malignancy is characterized by rapid growth, large bulk, and early local and extranodal extension in the absence of generalized adenopathy. Most patients demonstrate symptoms, often present for only several days, from a rapidly enlarging mediastinal mass. Superior vena cava syndrome is common, as is involvement of the pericardium. It is predominantly a disease of young adults, particularly women. The clinico-pathologic risk factors and treatment guidelines remain controversial, however.
One of the earliest studies, by Jacobson et [a1.sup.2] from Massachusetts General Hospital, was published in 1988. They studied 30 patients with PMLBCL treated from 1976 to 1985. Twenty-two patients were given CHOP chemotherapy; 14 of 22 received consolidation XRT, and 3 of 22 received salvage XRT. Eight patients were treated with different chemotherapy regimens. The patients who were treated with CHOP therapy and consolidation XRT had art 80% complete response (CR) rate, with a 59% 5-year survival rate. They concluded that the size of the mediastinal mass adversely affected the failure-free survival rate (89% in patients with a small mass vs 40% in patients with a large mass), and that patients with bulky disease should be treated with more intensive regimens.
In 1993, Lazzorino and colleagues (3) studied 29 patients with PMLBCL. Sixteen of 29 patients achieved CR: 5 of 14 treated with CHOP chemotherapy, and 11 of 15 treated with methotrexate plus leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B), or etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (VACOP-B). Following chemotherapy, 14 of 16 patients received mediastinal XRT. The actual survival rate at 3 years was 38% for all cases and 72% for remitters. None of the 13 patients who failed to achieve CR responded to salvage treatment,
The same group later reported a new study that included 106 patients with PMLBCL. (10) Ninety-nine patients received doxorubicin-containing chemotherapy; 36 received CHOP chemotherapy, and the remainder received 1 of 5 intensified CHOP regimens. Thirty-five patients were resistant to chemotherapy. Of the 64 responders, 23 had complete responses and 41 had residual mediastinal abnormalities. Mediastinal XRT was given to 77% of the responders. Of the responders, 71% were relapse-free at 3 years. The researchers concluded that patients with pericardial effusions and poor performance status have poor outcomes, and that bulky disease confers an increased risk of relapse.
Interestingly, Abou-Elella et al (11) could not confirm that the clinical course of PMLBCL was distinct from diffuse large B-cell lymphoma (DLBCL). They studied 43 patients with PMLBCL, 53% of whom presented with bulky disease. Chemotherapy consisted of 1 of 4 regimens similar to CHOP, plus procarbazine and bleomycin. The CR rate was 63%, and the 5-year overall and failure-free survival rates were 46% and 38%, respectively. They concluded that the clinical features of PMLBCL, including stage and sites of relapse (especially renal relapse) were not significantly different from those of nonmediastinal DLBCL. There were no differences in overall and failure-free survival rates. The poor prognostic factors were predicted by the international prognostic index and not by the bulk of the mediastinal disease.
Although PMLBCL is a distinct clinical entity in the REAL classification, Abou-Elella et al (11) question the legitimacy of this distinction from DLBCL. Also in dispute are the poor prognostic features of PMLBCL, including bulky disease. The therapeutic implications are significant, since many PMLBCL patients are treated with regimens for DLBCL such as CHOP (or similar), with or without XRT. Our experience with CHOP resulted in clear progression or no response in 3 of 6 patients. Despite initial responses in the other 3 patients treated with CHOP with or without XRT, early relapse occurred with the failure of salvage chemotherapy, including auto PBSCT. Only 2 of our patients remained alive 3 years after diagnosis. Although our experience is limited, PMLBCL appears to be a distinct clinical entity with unusual sites of relapse in the kidneys, gastric mucosa, and pancreas. Failure to respond to treatment with CHOP or rapid progression after CHOP therapy occurred in all patients, so alternative chemotherapy regi mens are needed for initial therapy. This would allow patients to be considered for consolidative XRT and/or auto PBSCT prior to relapse.
In our experience, PMLBCL is a distinct disease entity and its response to the CHOP regimen is poor. Adding rituximab to CHOP chemotherapy may be beneficial and deserves further investigation. Until more conclusive studies are available, we believe primary treatment of PMLBCL should consist of aggressive chemotherapy and radiotherapy, followed by consideration of autologous stem-cell transplantation.
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(3.) 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 1993; 11:2306-2313
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(6.) Lichtenstein AK, Levine A, Taylor CR, et al: Primary mediastinal lymphoma in adults. Am J Med 1980; 68:509-514
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RELATED ARTICLE: KEY POINTS
* Primary mediastinal large B-cell lymphoma is different than other diffuse large B-cell lymphomas.
* Prognosis and treatment of patients with primary mediastinal large B-cell lymphoma is still controversial.
* Until more conclusive studies are available, primary treatment of primary mediastinal large B-cell lymphoma should consist of aggressive chemotherapy and radiotherapy, followed by consideration of autologous stem-cell transplantation.
From the Department of Medicine, Medical University of South Carolina, Charleston.
Reprint requests to Sitki M. Ergul, MD, 3541 Granite Way, Martinez, GA 30907.