Hematopathology Case 02
Final Diagnosis & Discussions:
FINAL DIAGNOSIS: DIFFUSE LARGE B-CELL LYMPHOMA, NOT OTHERWISE SPECIFIED, ANAPLASTIC MORPHOLOGY VARIANT.
The primary differential diagnostic considerations include diffuse large B-cell lymphoma (DLBCL), classical Hodgkin lymphoma, and anaplastic large cell lymphoma (ALCL).
The scattered very large mono- and bi-nucleate forms with prominent nucleoli suggest a diagnosis of Hodgkin lymphoma. However, the background of numerous atypical large cells in sheets rather than the typical inflammatory milieu of Hodgkin lymphoma, along with the CD45 positivity, the uniform strong staining for pan B-cell markers (CD20, and CD79a), and the strong reactivity with B-cell transcription factors (BOB.1, PAX-5 and OCT-2) argues against Hodgkin lymphoma and are consistent with DLBCL. The weak focal staining for CD30 in some but not all of the large Reed-Sternberg (RS) like cells is compatible with DLBCL and is particularly associated with an anaplastic morphology (5). Although it is very unusual for DLBCL to show CD15 expression, the focal weak expression of CD15 has been reported in a recent study (9).
Distinguishing classical Hodgkin lymphoma from DLBCL can be challenging either when Hodgkin lymphoma lacks CD15 expression or when DLBCL is CD15+/CD30+, which, although rare, does occur (2,7, 8, 9). However, the neoplastic cells of classical Hodgkin lymphoma show a near global shutdown of B-cell antigen expression, with weak to absent expression of most B-cell antigens, a phenomenon that has been termed the Hodgkin lymphoma signature (3, 11). Thus, strong uniform expression of multiple B-cells markers such as CD20, PAX-5, BOB1 and OCT-2 argues strongly in favor of large B-cell non-Hodgkin lymphoma (NHL) and essentially excludes classical Hodgkin lymphoma (3, 10, 11). In some instances a definitive distinction cannot be made, and such cases may be classified as in gray zone category that overlaps both classical Hodgkin lymphoma and DLBCL: B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma (3, 10).
ALCL is also considered in the differential due to the large, pleomorphic cells. However, the CD30 reactivity in this case was weak and variable in contrast to the strong, diffuse reactivity characteristic of ALCL. In addition, the B-lineage staining pattern (CD20, CD79a and/or PAX5 expression) supports the diagnosis of anaplastic variant of DLBCL and excludes ALCL, which is characterized by a T-cell or null cell phenotype. Other characteristic features of ALCL include; a tendency to grow cohesively with predilection for invading lymph node sinuses, ALK staining by immunohistochemistry and clonal T-cell receptor (TCR) gene rearrangements.
DLBCL, not otherwise specified (NOS), is the most common type of adult NHL (1). It constitutes 25-30% of adult NHL in western countries and a higher percentage in developing countries. It is more common in the elderly (median age 70), but it may also occur in children and young adults. Bone marrow involvement varies from 11% to 27% when routine microscopy alone is used for detection of disease (4).
Histologically, the pattern of involvement in the lymph node and in extra nodal tissue is diffuse. Lymph nodes are usually entirely effaced, and the perinodal tissue is frequently infiltrated. Less frequently the lymph node involvement is partial being interfollicular or sinusoidal (5). The morphology of the malignant cells is quite variable and multiple morphological variants are described. The most common include centroblastic, immunoblastic, and anaplastic. The anaplastic variant is characterized by very large cells with bizarre pleomorphic nuclei that may in part resemble tumor cells of ALCL or the RS cells of classical Hodgkin lymphoma.
RS cells are bona fide B-cells with immunoglobulin heavy chain rearrangement, but they are crippled in the production of immunoglobulin as a result of aberrant expression of transcription regulators (6). They are characteristically weakly PAX5 positive, and occasionally express weak, variable CD20. The B-cell transcription factors OCT-2 and BOB.1 may be weakly expressed, but often one or both is negative. They are usually CD15+ (80%) and always CD30+, and are negative for CD45, CD3 and Cd79a. They are usually associated with a background of reactive lymphocytes, plasma cells, eosinophils, and hyalinized fibrosis (6).
Overlapping features between subtypes of malignant lymphomas can occur and present diagnostic challenges. Distinguishing DLBCL and Hodgkin lymphoma can be challenging either when Hodgkin lymphoma cells lack CD15 expression or when DLBCL is CD15+/CD30+. Workup of such cases should include extended panel of immunohistochemical stains including the B-cell transcription factors PAX-5, OCT-2 and BOB.1. In the present case, strong, uniform expression of multiple B-cell markers (CD20, PAX-5, BOB.1 and OCT-2) allowed diagnosis of DLBCL and exclusion of Hodgkin lymphoma despite the expression of some CD15. The diagnosis of a gray zone lymphoma should be reserved for only those rare cases that defy specific classification despite an extensive work-up.
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