Diffuse Large B-cell Lymphoma Associated With Chronic Inflammation Research Articles

Fibrin-Associated Large B-Cell Lymphoma in a Young Patient in the Setting of Pleural Effusion

Abstract Introduction/Objective Fibrin-associated large B-cell lymphoma (FA-LBCL) is a proliferation of EBV-positive large B- cells in association with fibrinous debris, typically in the context of prostheses, hematomas, pseudocysts and myxomas. It is a newly described entity and is extremely rare, with no deaths reported as a direct result. It is indolent and not visible on imaging, instead being found incidentally on microscopy. It is mainly a diagnosis of exclusion and is characterized by sheets of neoplastic lymphocytes contained within a fibrin background. The median age of presentation is 55, with 75% of cases being reported among elderly patients. The prognosis is excellent and surgery is considered curative. It needs to be distinguished from malignant lymphomas, mainly diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI), which is also EBV-positive but occurs in elderly patients with a longstanding history of inflammation. The two have identical immunohistochemical profiles but vastly different clinical presentations and outcomes. Methods/Case Report A 35-year-old male with end-stage renal disease and a history of recurrent pleural effusions presented with dyspnea. CT showed a large loculated right-sided pleural effusion with no lymphadenopathy. Pleural fluid cytology was negative for any malignant cells. He underwent decortication to relieve pleural rind constriction. Microscopy revealed small layers of fibrin with an infiltrate of atypical, EBV-positive B-cells with a Ki-67 index of 60%. As the morphological findings and clinical presentation did not fit other known lymphomas, the case was signed out as FA-LBCL. The patient has followed up with oncology and PET scans have been negative for any malignancy. He is currently on the waiting list for a renal transplant. Results (if a Case Study enter NA) NA Conclusion FA-LBCL is a rare benign neoplasm, identified incidentally and cured by surgical resection. It is mainly diagnosed in the elderly, but the number of cases is limited and the age distribution may be skewed. This case involved a much younger patient and is the first known diagnosis in the pleural setting. It is important to differentiate this entity from DLBCL-CI, which is aggressive and requires intense oncological treatment. In addition, patients with FA-LBCL can undergo immediate solid organ transplantation, whereas those with DLBCL-CI need to be in remission for at least three years before receiving a transplant.

EBV-positive pyothorax-associated lymphoma expresses CXCL9 and CXCL10 chemokines that attract cytotoxic lymphocytes via CXCR3.

Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI) develops in the setting of long-standing inflammation. This type of lymphoma may have specific expression profiles of chemokines involved in the pathogenesis of DLBCL-CI. EBV-positive pyothorax-associated lymphoma (PAL) is a prototype of DLBCL-CI and represents a valuable model for the study of this disease category. Using a panel of PAL cell lines, we found that PAL cells expressed and secreted C-X-C motif chemokine ligands 9 and 10 (CXCL9 and CXCL10), the ligands of CXCR3, in contrast to EBV-negative DLBCL cell lines, which did not. Culture supernatants from PAL cell lines attracted CXCR3-expressing CD4+ T cells, CD8+ T cells, and CD56+ natural killer cells from human peripheral blood mononuclear cells. PAL cells injected into mice also attracted CXCR3-positive cytotoxic lymphocytes that expressed interferon-γ. The expression of CXCL9 and CXCL10 was detected in PAL tumor biopsy samples from patients, and CXCR3-positive lymphocytes were abundant in the tissue samples. Collectively, these findings suggest that CXCL9 and CXCL10 are produced by PAL cells and can elicit cytotoxic responses via CXCR3. This chemokine system is also likely to contribute to tissue necrosis, which is a signature histological feature of DLBCL-CI. Further studies are warranted to determine whether the CXCL9-CXCL10/CXCR3 axis exerts antitumor effects in DLBCL-CI.

Primary central nervous system lymphomas associated with chronic inflammation: diagnostic pitfalls of central nervous system lymphomas.

In recent years, the features of lymphomas associated with chronic inflammation, referred to as diffuse large B-cell lymphoma (DLBCL) associated with chronic inflammation (DLBCL-CI), have been elucidated. DLBCL-CI is an aggressive lymphoma occurring in the context of long-standing chronic inflammation and showing an association with Epstein-Barr virus. Fibrin-associated diffuse large B-cell lymphoma (F-DLBCL) was suggested as a new and unusual form of DLBCL-CI in the most recent version of the World Health Organization classification. From the perspective of genetics, DLBCL-CI was associated with frequent TP53 mutation, MYC amplification and complex karyotypes, but cases of F-DLBCL behaved indolently and showed a relatively lower genetic complexity. In the central nervous system (CNS), several examples of DLBCL-CI and F-DLBCL have been reported. As with DLBCL-CI outside the CNS, DLBCL-CI in the CNS is an aggressive lymphoma. However, the clinical outcome of F-DLBCL in the CNS is good. Immunohistochemistry for p53 and c-Myc in DLBCL-CI and F-DLBCL in the CNS showed similar findings of those outside the CNS. However, one aggressive case showed transitional genetics and morphology between F-DLBCL and DLBCL-CI. These findings suggest that some cases of F-DLBCL in the CNS might have the potential to progress to DLBCL-CI.

Fibrin-Associated Diffuse Large B-Cell Lymphoma Occurring as a Pararenal Pseudocyst

Abstract A 60-year-old male underwent nephrectomy for a tumor on the posterior aspect of the right kidney. Grossly, a completely encapsulated 8 × 8 × 6.8-cm nodule was found in the perinephric fat adjacent to the renal capsule and indenting the renal surface. The renal parenchyma was microscopically unremarkable. The capsule of the lesion was composed of dense fibrous tissue with chronic inflammation, remote hemorrhage, and prominent calcifications. The nodule/pseudocyst contained predominantly amorphous, eosinophilic material with cholesterol clefts and calcifications. Within the pseudocyst, clusters of large cells were identified. These cells showed abundant amphophilic cytoplasm and large pleomorphic nuclei with dispersed chromatin, prominent nucleoli, and occasional mitotic figures. Immunohistochemical (IHC) staining showed that these cells were positive for CD20, CD79a, IRF4, BCL2 (>90%), C-MYC (70-80%), and EBV-ISH; variably positive for CD30 and PAX5; and negative for CD3, CD10, CD68, CD138, ALK1, and BCL6. MYC FISH break-apart probe demonstrated no rearrangements or copy number changes. Based on the overall features, the diagnosis of fibrin-associated diffuse large B-cell lymphoma (FA-DLBCL) was rendered. This entity has been recently recognized under a larger category of diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI). Unlike DLBCL-CI, which is considered clinically aggressive, FA-DLBCL typically demonstrates a favorable outcome with surgical resection alone. FA-DLBCL is usually incidentally found at unusual sites (cardiac myxomas, prosthetic cardiac valves, thrombi, hematomas, and pseudocysts including intracranial, splenic, retroperitoneal, paratesticular, adrenal, and renal). To our knowledge, this is the first report of a FA-DLBCL arising in a pararenal location. In addition, our case demonstrates unusually high MYC IHC positivity. Although rare, this entity should be kept in mind, especially in an appropriate clinical setting, and should not be misclassified into a more aggressive category, such as “double expressor” DLBCL or DLBCL-CI.

Diffuse large B cell lymphoma associated with chronic inflammation arising within atrial myxoma: aggressive histological features but indolent clinical behaviour.

Primary cardiac lymphoma (PCL) is a rare neoplasm. PCL is fatal, unless it is diagnosed and treated early. Recently, a small number of cases of diffuse large B cell lymphoma (DLBCL) arising within atrial myxoma have been reported in immunocompetent patients and showed aggressive histological features but an indolent clinical behaviour. We present four unusual cases of Epstein-Barr virus (EBV)-positive DLBCL arising within atrial myxoma with detailed clinical, histological, immunophenotypical and genotypical features in immunocompetent patients, and review the literature for 11 similar cases. All the patients appeared to have morphological features of DLBCL, B lineage immunophenotype, high proliferative index and latency type III of EBV infection. They achieved complete tumour resection without chemotherapy orradiotherapy after surgery and were healthy at 3- and 7-month and 7- and 10-year follow-ups, respectively. We suggest that this lymphoma should be regarded as a unique DLBCL associated with chronic inflammation (DLBCL-CI) because of an indolent clinical behaviour to avoid excessive or unnecessary treatments. In addition, early accurate diagnosis and complete resection of this tumour are crucial for optimal patient outcome.

Fibrin-associated EBV-positive Large B-Cell Lymphoma: An Indolent Neoplasm With Features Distinct From Diffuse Large B-Cell Lymphoma Associated With Chronic Inflammation.

Incidental cases of localized fibrin-associated Epstein-Barr virus (EBV)+ large B-cell proliferations have been described at unusual anatomic sites and have been included in the category of diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI) in the WHO Classification. We describe 12 cases and review the literature to define their clinicopathologic spectrum and compare features with typical cases of DLBCL-CI. Median age was 55.5 years with a M:F ratio of 3. In all 12 cases, the lymphoma was an incidental microscopic finding involving atrial myxomas (n=3), thrombi associated with endovascular grafts (n=3), chronic hematomas (n=2), and pseudocysts (n=4). All cases tested were nongerminal center B-cell origin, type III EBV latency, and were negative for MYC rearrangements and alternative lengthening of telomeres by FISH. Most showed high CD30, Ki67, and PD-L1, and low to moderate MYC and p53 expression. Among 11 patients with detailed follow-up, 6 were treated surgically, 3 with cardiac or vascular lesions had persistent/recurrent disease at intravascular sites, and 4 died of causes not directly attributable to lymphoma. Reports of previously published fibrin-associated cases showed similar features, whereas traditional DLBCL-CI cases with a mass lesion had significantly higher lymphoma-associated mortality. Fibrin-associated EBV+ large B-cell lymphoma is clinicopathologically distinct from DLBCL-CI, warranting separate classification. Most cases, particularly those associated with pseudocysts, behave indolently with the potential for cure by surgery alone and may represent a form of EBV+ lymphoproliferative disease rather than lymphoma. However, primary cardiac or vascular disease may have a higher risk of recurrence despite systemic chemotherapy.

Microscopic Diffuse Large B-Cell Lymphoma (DLBCL) Occurring in Pseudocysts

We report 2 cases of localized, microscopic diffuse large B-cell lymphoma (DLBCL) that were detected incidentally within pseudocysts. In case 1, the neoplasm was identified within a 26-cm, 860-g adrenal gland pseudocyst. In case 2, the neoplasm was detected within a 9-cm, 90-g paratesticular pseudocyst. In both cases, the neoplastic cells were large, had a nongerminal center B-cell immunophenotype, and were positive for Epstein-Barr virus (EBV)-encoded RNA detected by in situ hybridization. The most appropriate classification of these tumors using current World Health Organization classification is uncertain. The best fit seems to be DLBCL associated with chronic inflammation (DLBCL-CI), defined as DLBCL arising in the context of long-standing chronic inflammation and associated with EBV infection, with the prototype for this category being pyothorax-associated lymphoma. This term has been used by others in the literature for tumors similar to the cases reported here. However, in the 2 cases we report chronic inflammation was not a prominent feature, and the inflammatory cells that were present showed little relationship to the lymphoma cells. The findings in these cases have led us to question the role of chronic inflammation in pathogenesis. Perhaps the closed space of the pseudocyst, by preventing a cytolytic response to EBV-infected cells, results in local immunodeficiency that may be most important for pathogenesis. We also have concerns about using the term DLBCL-CI for these tumors. Perhaps the cases we report and the few other similar cases reported previously deserve their own category in a future version of the World Health Organization classification.