The diagnosis of DLBCL-CI is heavily dependent on patient history, presence of a tumor with the appropriate histology, and evidence indicating EBV infection. The patient should have a history of long-term chronic<unk>  in a site that is known or thought to be sequestered from the immune system such as the pleural space, skin ulcer, or foreign body. The lesions, which generally are tumorous rather than infiltrative, should consist of large cells that resemble centroblasts, immunoblasts, or, less commonly, anaplastic, i.e. poorly differentiated, cells that are arranged in a diffuse pattern. Most of these large cells should be B-cells as identified by their expression of B-cell marker proteins (e.g. CD20, CD79a, PAX5, and IRF4) by immunostaining methods. These cells often show mutations in the P53 gene, overexpression of the Myc protein, and deletion of the TNFAIP3 gene and in all cases must show evidence of EBV infection as determined most commonly be detecting the expression of this virus's microRNA product, EBER-1 by polymerase chain reaction analysis. Typically, the neoplastic cells are identified as ABC rather than GBC or unclassifiable cells by gene expression profiling. In addition to the neoplastic B-cells, these lesions often contain non-neoplastic white blood cells such as T-cell lymphocytes, plasmacytes, and/or plasmavyte-like cells. The tissue background in these lesions usually shows fibrous thickening. Differential diagnosis DLBCL-CI must be differentiated from Fibrin-associated diffuse large B cell lymphoma (FA-DLBCL) and Epstein–Barr virus-positive diffuse large B-cell lymphoma, not otherwise specified (EBV+ DLBCL, NOS). * Similar to DLBCL-CI, FA-DLBCL is an activated B-cell- (i.e. ABC)-type B-cell lymphoma driven by EBV infection (latency stage III) that develops in spaces known or thought to be sequestered from the immune system. Unlike DLBCL-CI, FA-DLB usually is not associated with local symptoms (e.g. pain) or systemic symptoms (e.g. fever) and is often discovered as an incidental infiltrate rather than a mass that develops: in pseudocysts of the spleen, adrenal gland, or retroperitoneum; in hydroceles or cysts of the testes or other organs; in or around hematomas of the subdural space, testes, or foreign bodies; in thrombi (i.e. blood clots) of large arteries; in myxomas (i.e. connective tissue tumors) of the heart's left atrium; and around artificial heart valves; or breast implants. Histologically, these infiltrates, similar to DLBCL-CI, consist of large B cells. Unlike DLBCL-CI, these lesions develop in, on, or around long-standing hamartomas, pseudocysts, cardiac myxommas, prosthetic heart valves, thrombus-laden endovascular grafts, hematomas, hydroceles, and prosthetic implants of the hip. The infiltrations consist of sheets, ribbons, or clusters of proliferating large B cells within avascular tissue that are often coated with or contain abundant fibrin and a paucity or complete absence of other types of inflammatory cells. The infiltrates typically do not spread beyond their initial sites and there is no evidence of lymph node, spleen, or other tissue involvement: FA-DLBCL often appears to be a non-malignant proliferation of EBV+ large B cells that are unable to proliferate and survive long-term outside of the sequestered sites. While DLBCL-CI, particularly in its PAL form, is an aggressive lymphoma with a five-year overall survival rate of 20–35%, FA-DLBCL, usually has a highly favorable outcome except when it involves the heart (e.g. in myxomas or on prosthetic valves) or vasculature structures (e.g. on thrombus-laden vascular grafts), in which cases life-threatening cardiovascular complications, particularly strokes, may occur. * EBV+ DLBCL, NOS is distinguished from DLBCL-CI in that it: 1) occurs predominantly in East Asia and Mexico and less commonly in Europe and the USA; 2) most often develops in individuals who are immune-deficient due to HIV/AIDS or immunosuppressing anti-rejection drug therapy following solid organ transplantation or in rare cases known as the Richter transformation, is a progression of established chronic lymphocytic leukemia; 3) most often occurs in the middle-aged and elderly but has also been described in younger individuals; 4) commonly presents with systemic symptoms such as fever, night sweats, weight loss; 5) involves the infiltration of EBV-infected B-cells (stage III or stage II latency) in the upper gastrointestinal tract, lungs, upper airways, and/or other organs and 6) consists of variable histology with infiltrative lesions consisting of wither anaplastic cells and prominent Reed–Sternberg-like cells embedded in a background of histiocytes and lymphocytes;, immunoblasts, or centroblasts. These histological features are typically accompanied by the invasion and destruction (i.e. necrosis) of small blood vessels.
Diffuse large B-cell lymphoma associated with chronic inflammation
Large B-cell lymphoma arising in HHV8-associated multicentric Castleman's disease
Splenic lymphoma with villous lymphocytes
Germinal center B-cell like diffuse large B-cell lymphoma
Chronic multifocal Langerhans cell histiocytosis
Thymoma-associated multiorgan autoimmunity
Epstein–Barr virus positive diffuse large B-cell lymphoma, not otherwise specified
Lymphoid neoplasms with plasmablastic differentiation