tgf beta receptor 1 Upon diagnosis the patient s lymphoma an
Upon diagnosis, the patient׳s lymphoma and HLH represented a therapeutic dilemma. Effective early therapy reduces mortality of HLH from 95% to 30–35% . The HLH-2004 treatment protocol consists of T-cell targeted immunosupression with dexamethasone and cyclosporine, macrophage targeted etoposide with intrathecal methotrexate, if indicated, and monthly IV immunoglobulin . In addition, patients with THRLBCL should be treated similarly to DLBCL with anthracycline-based chemotherapy and an anti-CD20 monoclonal antibody. Complicating this scenario was the patient׳s multiorgan failure with severe hepatitis and high total bilirubin levels, which represent contraindications to many chemotherapy agents. As etoposide has significantly impacted survival outcome in HLH and induced sustained remissions of HLH, a full dose was administered per HLH-2004 despite being contraindicated in liver failure . Three weeks later, when the patient׳s HLH had responded (ferritin decreased from 14,298 to 3056ng/mL), a treatment with dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) with rituximab was started. This regimen was selected as it contains etoposide, and doses for subsequent cycles can be adjusted based on cytopenias, avoiding the use of G-CSF which can be catastrophic in HLH .
Discussion Recent studies of genetic HLH have shed light on the pathophysiology of the disease. Defects in cytotoxic pathways of T tgf beta receptor 1 and NK cells are thought to lead to an inability to clear antigenic stimuli, resulting in a “cytokine storm” and perpetuation of the inflammatory response . Unchecked macrophage activation, hemophagocytosis, and tissue infiltration ensue. Acquired HLH is most often associated with infections (49%), of which EBV is the most common, followed by malignancies (27%), rheumatologic disorders (7%) and immune deficiency syndromes (6%) . Still׳s disease, also known as systemic-onset juvenile idiopathic arthritis, is a form of juvenile rheumatoid arthritis that carries an overall risk of HLH of 10% . In our particular case, the relationship between the patient׳s hematologic malignancy and underlying autoimmune disorder, diagnosed as adult-onset Still׳s disease, is unclear. When HLH is associated with malignancy, T- and NK-cell leukemias/lymphomas predominate, although HLH has also been seen with anaplastic large cell lymphoma, other leukemias, and solid tumors. HLH association with non-Hodgkin B-cell lymphoma is relatively rare, involving predominantly older patients (>60 years), with sparing of the bone marrow, as compared with T- or NK-cell lymphomas . T-cell/histiocyte-rich large B cell lymphoma accounts for 1–3% of DLBCL, presents more commonly in males with a median age of 30 years, and typically pursues an aggressive clinical course. Diagnosis is based on the identification of <10% large neoplastic B cells in a background of cytotoxic T cells and histiocytes . Immunohistochemistry can assist with differentiation from nodular lymphocyte-predominant Hodgkin lymphoma and lymphocyte-rich classical Hodgkin lymphoma by demonstrating expression of pan-B cell markers and absence of CD15 and CD30 in large cells, along with a cytotoxic phenotype of the background lymphocytes. Molecular analysis for [email protected]/[email protected] gene rearrangements can assist in demonstrating clonality; however, the paucity of neoplastic cells in THRLBCL can diminish the sensitivity of this PCR based assay leading to false-negative results . From a pathophysiologic standpoint, it is of interest that HLH arose in the setting of THRLBCL in this patient. Although THRLBCL is a B-cell malignancy, it is unique in that the predominant cell population consists of cytotoxic T cells and histiocytes. Recent gene expression profiling studies have suggested that the tumor microenvironment of THRLBCL in fact favors a tolerogenic host immune response despite the abundance of apparently ineffective cytotoxic T cells . In addition, both the tumor cells as well as the infiltrating histiocytes have been shown to express the immune suppressive molecule PD-L1, presumably as a mechanism for tumor immune evasion, representing a potential target for therapy . Interestingly, in 1999, Mitterer, et al. , reported one other case of HLH-associated THRLBCL, which was associated with reactivated EBV infection, again raising the possibility that the overall host immune environment contributes to disease manifestation. Further studies examining the interplay between systemic immune hyperactivation, tumor-mediated immune suppression, and autoimmunity in cases of malignancy-associated HLH are warranted to uncover novel and directed therapeutic approaches.