Diffuse Large B-Cell Lymphoma (DLBCL) represents an aggressive form of non-Hodgkin lymphoma, originating from B-lymphocytes. It is characterized by the rapid growth of abnormal B cells, often presenting as quickly enlarging lymph nodes or masses. When DLBCL is suspected, healthcare providers undertake a comprehensive differential diagnosis. This systematic approach distinguishes DLBCL from other conditions with similar clinical signs, symptoms, or laboratory findings. An accurate differential diagnosis is fundamental for proper disease identification.
The Diagnostic Evaluation Process
When DLBCL is suspected, patients often report rapidly growing lumps in the neck, armpit, or groin, alongside systemic indicators like unexplained fever, drenching night sweats, and significant unintentional weight loss. These “B symptoms” frequently prompt a medical visit. The initial clinical assessment involves a detailed physical examination to locate enlarged lymph nodes or other suspicious masses.
Blood tests are usually conducted to evaluate general health and organ function, though these rarely provide a definitive diagnosis. Imaging studies, such as computed tomography (CT) scans of the chest, abdomen, and pelvis, or positron emission tomography (PET)/CT scans, are then performed. These scans help identify the extent of disease throughout the body and pinpoint areas for further investigation.
While these initial evaluations suggest lymphoma, they cannot confirm the specific subtype. A definitive diagnosis of DLBCL requires tissue acquisition from the suspected tumor. This is typically achieved through an excisional biopsy, removing an entire lymph node, or a core needle biopsy, extracting a piece of the tumor. The collected tissue is sent to a pathology laboratory for detailed examination.
Pathology and Molecular Testing Methods
Upon arrival in the laboratory, the biopsy sample undergoes specialized analyses to characterize abnormal cells. Histological examination, where pathologists view thin sections of tissue under a microscope, is the first step. They observe the large size and abnormal shapes of lymphocytes, noting their diffuse growth pattern, meaning the cells are spread throughout the tissue rather than clustered in organized structures. This initial microscopic assessment indicates a large B-cell lymphoma.
Immunohistochemistry (IHC) is then performed, a technique that uses antibodies to detect specific proteins (antigens) on the surface or inside the cancer cells. This method confirms the B-cell origin of the lymphoma, with nearly all DLBCL cases showing positivity for B-cell markers like CD20 and CD19. Additional IHC markers, such as BCL6, BCL2, and MYC, are assessed to help classify the molecular subtype of DLBCL, which can influence prognosis. Flow cytometry may also be used, particularly on fresh tissue or bone marrow samples, to analyze cell surface markers and determine cell lineage and clonality.
Further characterization involves molecular and genetic testing to identify DNA alterations within lymphoma cells. Fluorescence In Situ Hybridization (FISH) detects rearrangements (translocations) in specific genes. For DLBCL, FISH often looks for translocations involving MYC, BCL2, and BCL6 genes. The presence of these gene rearrangements is important for distinguishing DLBCL from other aggressive B-cell lymphomas and identifying high-risk subtypes.
Distinguishing DLBCL from Similar Lymphomas
Advanced testing methods help differentiate DLBCL from other lymphomas that appear similar under initial microscopic examination. High-Grade B-cell Lymphoma (HGBL) includes lymphomas often referred to as “double-hit” or “triple-hit” due to specific gene rearrangements. HGBL is distinguished from DLBCL by MYC rearrangements along with BCL2 and/or BCL6 genes, identified through FISH. These genetic alterations indicate a more aggressive disease course.
Burkitt Lymphoma is another aggressive B-cell lymphoma that can resemble DLBCL. It is characterized by a distinctive MYC gene rearrangement, typically without concomitant BCL2 or BCL6 rearrangements. Burkitt Lymphoma also exhibits a high proliferation rate, indicated by a Ki-67 staining score approaching 100%, which helps differentiate it. Primary Mediastinal Large B-cell Lymphoma (PMBCL) is a DLBCL subtype typically arising in the mediastinum (the area between the lungs), often affecting young adults. It has a distinct clinical presentation and unique molecular signature, often showing genetic alterations like gains in chromosome 9p and PD-L1 expression.
The blastoid variant of Mantle Cell Lymphoma can mimic DLBCL. This aggressive subtype is distinguished by Cyclin D1 protein overexpression, identified by IHC, usually from the t(11;14) chromosomal translocation. Follicular Lymphoma, Grade 3B, composed entirely of large cells, can resemble DLBCL. It originates from a different cell type within the germinal center and may retain some features of follicular architecture not seen in classic DLBCL.
Considering Other Malignant and Benign Mimics
Beyond other B-cell lymphomas, a range of malignant and benign conditions can initially suggest DLBCL. Anaplastic Large Cell Lymphoma (ALCL) is a T-cell lymphoma, not a B-cell lymphoma. It is distinguished by positivity for T-cell markers like CD30 and, in some cases, the Anaplastic Lymphoma Kinase (ALK) protein, identified through IHC. These markers clearly separate ALCL from B-cell lymphomas.
Poorly differentiated carcinomas or melanomas that have metastasized (spread) to lymph nodes can also be mistaken for DLBCL. These metastatic cancers can appear as sheets of large, undifferentiated cells under the microscope. Pathologists use a panel of IHC stains, such as cytokeratin for carcinomas or S100 and SOX10 for melanoma, to pinpoint the true lineage of these malignant cells. This allows for accurate identification.
Certain non-cancerous conditions, known as reactive processes, can cause lymph node enlargement with features resembling lymphoma. Severe infections, such as infectious mononucleosis caused by the Epstein-Barr virus, can lead to swollen lymph nodes containing large, activated lymphocytes. Pathological review, including specific viral studies and the absence of clonal B-cell populations, helps differentiate these benign inflammatory responses from true lymphoma.