Primary mediastinal B-cell lymphoma is a distinct clinicopathologic entity that has a predilection for young women. It is clinically and molecularly different from other subtypes of diffuse large B-cell lymphoma and has a unique paradigm of management. While the cure rate for patients with primary mediastinal B-cell lymphoma is high, approaches have historically included mediastinal radiation; in moving therapeutics forward, strategies that obviate the need for radiation while maintaining high cure rates are critical. Mediastinal gray zone lymphoma is a closely related disease that is exceedingly rare and more common in men. Over recent years, there has been much progress in elucidating the biology of these lymphomas, and this has paved the way for novel therapies that are currently under investigation in clinical trials.
Introduction
Primary mediastinal B-cell lymphoma represents approximately 10% of all diffuse large B-cell lymphomas (DLBCL) and, importantly, has demographic, clinical, and biological characteristics that distinguish it from the other subtypes of DLBCL (germinal center B-cell–like and activated B-cell–like). Molecular studies have, in fact, shown that primary mediastinal B-cell lymphoma shares a third of its genes with nodular sclerosing Hodgkin lymphoma, and that both diseases harbor common driver mutations.[1,2] Mediastinal gray zone lymphoma is a very rare disease entity with histologic features intermediate between those of primary mediastinal B-cell lymphoma and nodular sclerosing Hodgkin lymphoma; the few studies that have looked at its biological features suggest that it is a unique molecular entity.[3] The optimal management of primary mediastinal B-cell lymphoma is controversial, owing to its rarity and the paucity of prospective studies. While rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy followed by mediastinal radiation has been a de facto standard of care, increased–dose intensity approaches that obviate the need for radiation have excellent outcomes and challenge this. The identification of novel targets in mediastinal lymphomas has paved the way for small-molecule inhibitor and new immunotherapy approaches in these diseases.
KEY POINTS
- Although primary mediastinal B-cell lymphoma is a subtype of diffuse large B-cell lymphoma (DLBCL), clinically and molecularly it closely resembles nodular sclerosing Hodgkin lymphoma, and this is important to consider when making decisions about its management.
- The management of primary mediastinal B-cell lymphoma and mediastinal gray zone lymphoma should be distinct from that of other subtypes of DLBCL; strategies that obviate the need for radiation therapy, such as the dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin, plus rituximab (DA-EPOCH-R) regimen, are favored.
- For relapsed and refractory cases in which disease is confined to the mediastinum and which are radiation-naive, mediastinal radiation is the most promising curative therapy.
Initial Workup
The same routine tests performed for any other patient with DLBCL should be ordered. Frequently, the diagnosis is made on the basis of a small tissue biopsy; because distinguishing between primary mediastinal B-cell lymphoma and nodular sclerosing Hodgkin lymphoma may be challenging, tissue evaluation by a pathologist expert in the diagnosis of lymphoma is particularly critical. A thorough history and physical examination; complete evaluation of laboratory parameters; CT of the chest, abdomen, and pelvis; and bone marrow aspiration and biopsy should be performed. A fluorodeoxyglucose (FDG)–positron emission tomography (PET) scan may be helpful, particularly to assess extranodal disease outside the mediastinum. Central nervous system (CNS) involvement is very rare at diagnosis and should only be checked for if clinical characteristics associated with a high risk of CNS spread are present. Pleural and pericardial effusions can be present at diagnosis, so a baseline echocardiogram may be helpful. Because primary mediastinal B-cell lymphoma and mediastinal gray zone lymphoma have young age distributions and are confined to the mediastinum, the International Prognostic Index is of limited utility.[4]
Treatment and Regimen Choice
Because these diseases are rare and have been described only relatively recently, there are few studies and no randomized comparisons of strategies to guide initial therapy selection.[5] Early trials in primary mediastinal B-cell lymphoma suggested that consolidation mediastinal radiation was critical for cure, and as a result, radiation is still frequently administered. This is problematic, however, given that most patients with primary mediastinal B-cell lymphoma are young women with a significant long-term risk of secondary malignancies and ischemic heart disease secondary to mediastinal radiation.[6] Although this risk may be reduced with more focused radiation fields and lower doses than were historically administered, whether these measures actually do reduce risk will only be known with time and longer follow-up.
Compared with other subtypes of DLBCL, the experience with R-CHOP in primary mediastinal B-cell lymphoma is limited to retrospective studies and retrospective evaluations of prospective studies in which most patients received radiation.[7,8] At this point, it is not established that R-CHOP without radiation is a curative strategy in primary mediastinal B-cell lymphoma. If one goes back and looks at early studies in primary mediastinal B-cell lymphoma, dose intensity was important, suggesting that this disease should be approached with a more intensive regimen than R-CHOP. Dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin, plus rituximab (DA-EPOCH-R) was studied in primary mediastinal B-cell lymphoma for this reason, and event-free survival and overall survival rates-importantly, without radiation-were both greater than 90% with long-term follow-up.[9] So, with the understanding that no randomized comparison of treatments in primary mediastinal B-cell lymphoma exists (for the aforementioned reasons), DA-EPOCH-R, because of its high efficacy without radiation, is an excellent strategy. Patients should receive 6 cycles of therapy. Because dose adjustment is a critical component of the treatment, twice-weekly complete blood cell counts are mandatory for guiding therapy. Most patients with this disease achieve dose level 3 or 4. Repeat CT imaging should be performed after 4 cycles; at this time, there are no data to support interim PET imaging. The indeterminate pathobiology of mediastinal gray zone lymphoma has led to uncertainty about its treatment, but based on one study, in CD20-positive mediastinal gray zone lymphoma, DA-EPOCH-R is a reasonable regimen in this disease.[10]
End-of-Therapy FDG-PET
End-of-treatment response assessment is very challenging in primary mediastinal B-cell lymphoma, since in most cases there is a residual mediastinal mass on CT imaging following completion of curative therapy.[11] FDG-PET may be helpful in further assessing such cases. Following DA-EPOCH-R, the negative predictive value of FDG-PET approaches 100%; however, it is nonspecific if positive. If the FDG-PET scan is negative, no further FDG-PET imaging is typically needed in routine follow-up. A high proportion of cases with a Deauville score of 5 are positive for disease, so in this setting, there should be a low threshold for considering performing a biopsy.[12] Other positive cases (Deauville score of 4) should be monitored closely with a repeat FDG-PET scan performed soon after the positive end-of-therapy PET scan, and if standardized uptake values are increasing, a biopsy should be considered.
The experience with FDG-PET assessment in mediastinal gray zone lymphoma is much more limited due to the rarity of this entity, but a similar paradigm can be used. While there is controversy about the utility and frequency of CT imaging in follow-up, in patients who have not received mediastinal radiation, it makes sense to perform CT scans every 3 or 4 months for the first 12 to 18 months following treatment to check for mediastinal recurrences.
Refractory/Relapsed Disease and Novel Approaches
For both (radiation-naive) refractory and relapsed cases with disease confined to the mediastinum, radiation should usually be considered as the principal curative strategy. Radiation boosts may occasionally be helpful in cases where disease has recurred at a site that was previously irradiated. For advanced-stage refractory/relapsed disease, there is no standard approach, but transplantation-based treatments or novel strategies/agents should be considered. Recently, several new targets have been recognized in these diseases, and this has paved the way for testing novel agents. The close clinical and biological relationship of these lymphomas to Hodgkin lymphoma is important to consider, since new agents that are effective in Hodgkin lymphoma may also have good activity in primary mediastinal B-cell lymphoma and mediastinal gray zone lymphoma. Because CD30 is variably expressed in primary mediastinal B-cell lymphoma and mediastinal gray zone lymphoma, brentuximab may be helpful.[13] Immune checkpoint inhibitors, given their activity in Hodgkin lymphoma, represent an interesting and promising class of agents for primary mediastinal B-cell lymphoma and mediastinal gray zone lymphoma, and an ongoing study of pembrolizumab in primary mediastinal B-cell lymphoma has so far shown promising activity.[14] Recently, a study using autologous T cells expressing an anti-CD19 chimeric antigen receptor reported responses in DLBCL and in particular in primary mediastinal B-cell lymphoma.[15]
Conclusions
Primary mediastinal B-cell lymphoma is a distinct clinicopathologic entity, and its molecular biology more closely resembles that of nodular sclerosing Hodgkin lymphoma than other subtypes of DLBCL. There is a paucity of clinical trials in this disease to guide upfront therapy selection, but retrospective experience suggests that dose intensity is important. DA-EPOCH-R is a regimen of intermediate intensity that is highly effective in primary mediastinal B-cell lymphoma without the use of radiation, and although randomized data are not available, it should be strongly considered a standard for upfront therapy in patients with primary mediastinal B-cell lymphoma. One of the challenges in managing these diseases is assessing whether residual disease is present; while FDG-PET is very helpful if the scan is negative, positive results need to be interpreted carefully. Many novel agents are under investigation; in particular, immune checkpoint inhibitors have demonstrated promising activity thus far.
Financial Disclosure:The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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