Clinical Presentation and Natural History
PMBLs are uncommon, comprising slightly less than 3% of (non-Hodgkin) lymphoma and 6% to 10% of DLBCL cases.[6,14] PMBL presents as a bulky tumor (often >10 cm) in the anterior mediastinum of young adults, with peak incidence ranging between 30 and 39 years of age, and a female predominance,[3,15] although analysis of a Surveillance, Epidemiology, and End Results program database found no significant gender bias among the Black population of patients.[16,17] Patients experience local compressive effects attributable to the mass, including superior vena cava syndrome, shortness of breath, and cough. Pleural and pericardial effusions can develop related to the physiology of pressure and local tumor extension. Occasionally, symptoms may include breast or upper extremity edema, chest pain, or hoarseness of the voice caused by phrenic or laryngeal nerve palsy.[4,18,19]
Patients may experience B symptoms in addition to the features mentioned above. The serum LDH level is typically elevated.[20,21] PMBL has an aggressive presentation because of local mass effects, which results in early detection for the majority of patients, usually at a low Ann Arbor stage (I/II). In addition to a mediastinal mass, the tumor can spread to involve regional supraclavicular and cervical lymph nodes.[6,20] Tumors outside the thoracic cavity are less common, but extranodal sites may be involved (kidneys, adrenal glands, liver, ovaries), particularly at the time of relapse. Bone marrow is not typically involved at the time of presentation.[15,18,21] There is no established genetic susceptibility to or environmental cause for the development of PMBL, and it shows no geographic tendency.
A diagnostic tissue sample can be obtained by mediastinoscopy, by a directed needle biopsy through the chest wall or supraclavicular fossa (depending on growth characteristics), or by anterior mediastinotomy or minithoracotomy. Fine-needle aspiration specimens alone are not optimal but, when combined with a core needle biopsy, may be necessary to avoid airway-related complications. Larger biopsy specimens may be requested when significant fibrosis or crush artifacts are present or when variable histologic features may suggest another entity in the differential diagnosis that may require architectural assessment. Following a diagnosis of PMBL, staging evaluation follows along in much the same manner as for other types of nodal and extranodal lymphomas, with physical examination and fluorodeoxyglucose PET or CT scans of the chest, abdomen, and pelvis and bone marrow biopsy.
The optimal therapeutic regimen for PMBL varies across centers, with guiding principles that include aggressive first-line therapy because options for relapse and salvage therapy are limited and that seek to minimize long-term toxicity. In particular, because patients with PMBL are younger and have a longer life expectancy, consolidative radiation therapy is less often used to avoid future cardiovascular disease and reduce breast cancer risk. In the post-rituximab era for the adult/young adult population, many centers in the United States use dose-adjusted R-EPOC (DA-R-EPOCH), while in Europe a similar high-intensity regimen with rituximab, doxorubicin, cyclophosphamide, prednisone, vincristine, and bleomycin, and either etoposide (R-VACOP-B) or methotrexate with leucovorin rescue (R-MACOP-B) is often used. Large prospective studies have shown an event-free survival rate of 93% at 5 years with DA-R-EPOCH and a progression-free survival rate of 86% at 5 years with R-MACOP-B/R-VACOP-B.[24,25] Currently, the role of specialized therapies, such as pembrolizumab, which targets the interaction of programmed cell death 1 protein (PD-1) and PD-2 ligands; checkpoint inhibitors, which target B-cell receptor signaling; ruxolitinib, which targets JAK/STAT signaling; and anti-CD19 chimeric antigen therapy are being evaluated in the setting of relapsed/refractory disease.
Many studies have shown that PMBL has a more favorable prognosis than diffuse large B-cell lymphoma NOS.[15,26] Independent clinical predictors of prognosis are serum LDH level, age over 40 years, performance status of 2 or higher, and number of extranodal sites.[5,27] A large series from the International Extranodal Lymphoma Study Group identified male sex, advanced-stage disease, and poor performance status as negative predictors of outcome. The utility of the International Prognostic Index has been called into question for this disease because patients characteristically present with low-stage disease and encompass a younger demographic. Despite low stage, bulky disease was shown to predict persistent mediastinal abnormalities and risk of relapse. Treatment response and end-of-treatment PET results have been strongly correlated with survival outcome.
Am J Clin Pathol. 2021;156(4):497-512. © 2021 American Society for Clinical Pathology