June 2019 Case

Primary mediastinal large B-cell lymphoma (PMBL) is an uncommon subtype of large B-cell lymphoma accounting for 2-3% of non-Hodgkin lymphomas. It is thought to be derived from thymic medullary B-cells and arise primarily in the mediastinum. It predominantly affects young adults with median age of approximately 35 years. There is a female predominance, with male-to-female ratio of 1:2.

PMBL often presents as a large bulky mass confined to anterior-superior mediastinum, often with invasion of local structures, and may involve regional lymph nodes. The disease may involve extra-thoracic and extra-nodal site as it progresses or relapses. However, bone marrow involvement is extremely rare, and can be used to distinguish PMBL from systemic diffuse large B-cell lymphoma (DLBCL) with secondary mediastinal involvement. Clinical symptoms are often related to direct local invasion or mass effect, including dyspnea, cough, dysphasia, hoarseness and pain. Patients often have superior vena cava syndrome. Pleural and pericardial effusion occurs in approximately 1/3 of cases.

There is a wide range of histological morphology. The growth pattern is often diffuse. So-called "alveolar fibrosis" surrounding groups of tumor cells is usually present, leading to compartmentalization. The tumor cells are intermediate to large, often with abundant pale cytoplasm. The nuclear contour is usually round to oval; however, it can be irregular, pleomorphic or multilobulated in some cases, and may resemble Reed-Sternberg cells or lacunar cells in classic Hodgkin lymphoma (CHL).

By immunohistochemistry, the tumor cells express B-cells markers including CD19, CD20, CD22 and CD79a, but often do no express surface immunoglobulin light chains. Other often expressed markers include MUM1 (75%), BCL2 (55-80%), BCL6 (45-100%) and CD23 (70%). CD10 expression is variable and less common (8-32%). 70% of cases also express MAL, PD-L1 and PD-L2. Of note, CD30 is positive in up to 80% of cases, but the staining is often weak and heterogeneous. CD15 is typically negative. MYC stain may be positive, independent of MYC gene aberrancies. Majority of cases lack surface immunoglobulin.

PMBL has distinct gene expression profile different from DLBCL, but similar to CHL. Upregulation of JAK/STAT and NF-kappa B pathway is common. It is also common to see copy number gains involving REL and JAK2 genes. BCL2, BCL6 and MYC rearrangement is very rare. EBV is almost always negative.

The differential diagnosis includes the following:

1. Classic Hodgkin lymphoma, in which the tumor cells are often negative for B-cell markers including CD20 and CD79a, weakly positive for PAX5, and show strong and uniform CD30 expression.
2. Mediastinal grey-zone lymphoma (GZL), which is now classified under high-grade B-cell lymphoma unclassifiable, with features intermediate between DLBCL and CHL. GZL has a male predominance. The tumor cells are often large, bearing more resemblance to DLBCL, and are positive for CD20 and CD79a. However; CD30 and CD15 are often strongly expressed at the same time.
3. DLBCL with secondary mediastinal involvement, which often involves distant lymph nodes and bone marrow.
4. Anaplastic large cell lymphoma, which has uniform strong CD30 expression.
5. Lymphoblastic lymphoma, which has small to mediate-sized lymphoblasts expressing TdT, variable CD34 and T-cell markers.

In general, PMBL is associated with more favorable outcome than DLBCL and mediastinal GZL. Due to the rarity of the disease, there is no single standard treatment. With the newly developed treatment protocols, there is a high cure rate in adult and pediatric patients, with complete remission rate ranging from 40-80%.