When HLH is associated with malignancy

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 [2]. 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 5 alpha reductase inhibitor in a background of cytotoxic T cells and histiocytes [7]. 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 IGH@/IGK@ 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 [8]. 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 [9]. 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 [10]. Interestingly, in 1999, Mitterer, et al. [11], 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.
Introduction Aplastic anemia (AA) is a rare disease characterized by pancytopenia and a hypocellular bone marrow. Specific cytogenetic abnormalities, monosomy 7 and trisomy 8, are frequently associated with clonal evolution [1]. Clonal cytogenetic abnormalities also may be present with hypocellular bone marrow morphology: some experts have used them to differentiate AA from hypoplastic myelodysplastic syndrome (MDS) [2], while others accept certain aberrations as consistent with AA [3]. Although cryptic RUNX1/AML1 lesions have been reported in patients with Fanconi anemia and MDS [4], the (8;21) translocation is not observed by standard cytogenetic methods in bone marrow failure diseases.
Case report A 23-year-old Ecuadorian homemaker, resident in the United States, presented to medical attention with a peritonsillar abscess. Laboratory studies at presentation showed white blood cells 1.38k/μL, absolute neutrophil count 0k/μL, hemoglobin 7.4g/dL, absolute reticulocyte count 5k/μL, and platelets 38k/μL. Initial bone marrow biopsy revealed 5% cellularity with minimal trilineage hematopoiesis. Cytogenetics showed normal female karyotype 46,XX in all 20 analyzed metaphases. She was referred to the National Institutes of Health (NIH) for evaluation and consideration for immunosuppressive therapy (IST) and eltrombopag on a clinical trial (NCT01623167). There was no evidence of an inherited bone marrow failure disorder on physical examination or from a detailed family history. Tests for Fanconi anemia (diepoxybutane stress) and telomere disorders (leukocyte telomere length) were normal. Flow cytometric evaluation for paroxysmal nocturnal hemoglobinuria (PNH) was negative. Repeat bone marrow analysis performed immediately prior to IST (as required by protocol) demonstrated 10% cellularity, no dysplasia, nor increased number of blasts. Less than 1% of cells were CD34 positive. Severity of neutropenia (ANC<200/μL) prompted immediate treatment on protocol, beginning with equine antithymocyte globulin (ATG) and cyclosporine, standard for severe AA. However, two days after completion of IST, standard cytogenetic analysis returned t(8;21)(q22;q22) in 3 out of 20 metaphases, with confirmation by FISH (Fig. 1A). The patient was placed “off protocol” and did not receive the study drug, eltrombopag. This significant cytogenetic abnormality was unexpected and was inconsistent with the marrow morphology. Three months after initial presentation at NIH, confirmatory bone marrow evaluation showed 2/2 metaphases with t(8;21) abnormality. Focally increased CD34+ cells were observed by IHC (Fig. 1B, C) but not by flow cytometry. Her clinical status was unchanged after receiving IST: she remained severely pancytopenic and transfusion-dependent. Chemotherapy for AML was withheld due to the severe pancytopenia, hypocellularity, and absence of increased blasts. Progression to frank leukemia with circulating blasts did not occur until eight months following initial presentation. She underwent allogeneic stem cell transplantation from a matched sibling donor. She had minimal grade chronic GVHD of the skin, that was successfully treated with steroids. Eight months after successful bone marrow transplant, the patient is in remission.