Lastly it is equally important to mention that the microenvi
Lastly, it is equally important to mention that the microenvironment and genetic background of the host with a previous history of two independent malignancies may have further facilitated the selective proliferation of a clone with trisomy 11 [9,10], while normal carboxypeptidase b suffered proliferative stress resulting in senescence or apoptosis.
We, therefore, propose that the sequence of genetic and epigenetic events leading to leukemogenesis of donor cells with trisomy 11 includes telomere shortening in normal donor derived hematopoietic stem cells due to excessive stress to reconstitute host hematopoietic compartment, results in selective proliferation of a clone with MLL amplification, which in turn activated genes such as HOX, known to be deregulated in MDS and AML .
Introduction Hemophagocytic lymphohistiocytosis (HLH) is an uncommon, hyperinflammatory syndrome that is often fatal when treatment is delayed . Diagnosis may be difficult due to the wide range of symptoms associated with HLH and lack of specific diagnostic tests. Genetic causes of familial HLH relate to defects in cytotoxic granule exocytosis or function, whereas the acquired or secondary form is often associated with infection, malignancy, or autoimmune/immunodeficiency conditions. Defects in cytotoxic T cells and natural killer (NK) cells are seen in nearly all cases of HLH . Hematologic neoplasms account for the majority of malignancy-associated HLH, and T-cell malignancies predominate. HLH associated with underlying B-cell lymphoma is rare, and seems to occur in older patients with a low incidence of marrow involvement by lymphoma . Here, we describe a case of HLH arising in a young patient with diffuse marrow involvement by T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL), a subtype representing 1–3% of diffuse large B-cell lymphomas (DLBCL) with a characteristic background of cytotoxic T cells and histiocytes.
Clinical presentation A 30-year-old male with a past medical history of adult-onset Still׳s disease diagnosed 1.5 years ago was transferred from an outside hospital with fever, jaundice, weight loss, and impending respiratory failure. On physical exam, there was splenomegaly and imaging demonstrated retroperitoneal lymphadenopathy and pulmonary infiltrates. Lab findings revealed pancytopenia and liver function tests were suggestive of severe hepatitis. Significant laboratory findings included total bilirubin 10.2mg/dL (reference range 0.3–1.2mg/dL), alkaline phosphatase 410IU/L (30–115IU/L), AST 320IU/L (10–41IU/L), ALT 476IU/L (10–40IU/L), LDH 749IU/L (110–240IU/L), ferritin 14,298ng/mL (23–336ng/mL), WBC 2100/µL (4300–10,300/µL), hemoglobin 7.5g/dL (14.0–18.0g/dL), and platelet count 68,000/μL (140,000–440,000/μL). An extensive infectious disease workup did not reveal an etiology. Concern for hemophagocytic lymphohistiocytosis was raised and a bone marrow biopsy was performed.
Pathologic findings Bone marrow aspirate smears were hemodilute but notable for frequent macrophages exhibiting erythro- and leukophagocytosis (Fig. 1A). Bone biopsy demonstrated absent normal hematopoiesis and diffuse infiltration by lymphocytes and histiocytes (Fig. 1B). CD20 highlighted scattered, large atypical cells (Fig. 1C) that were negative for CD15 and CD30. The background infiltrate was composed predominantly of T cells with a cytotoxic phenotype (CD3+, CD5+, CD7+, CD8+, and TIA-1+ [Fig. 2]), with admixed CD68+-histiocytes (Fig. 2D). Flow cytometry analysis did not show evidence of an abnormal B- or T-cell population. Polymerase chain reaction studies did not detect clonal [email protected], [email protected] or TCR gene rearrangements, although neoplastic cells were scant. in situ hybridization for Epstein Barr virus (EBV)-encoded RNA was negative.
Clinical management Diagnostic criteria for HLH were updated in 2004 and rely on a combination of clinical, laboratory, pathologic, and genetic results (Table 1) [3,4]. Further laboratory workup for the patient revealed hypertriglyceridemia (1040mg/dL; reference range <150mg/dL), hypofibrinogenemia (113mg/dL; 150–400mg/dL), and elevated soluble IL-2 receptor (7469U/mL; 45–1105U/mL). NK cell function was within normal limits. Thus, this patient fulfilled 7 out of 8 criteria for the diagnosis of HLH. Primary HLH was considered unlikely given the patient׳s age, and studies on peripheral blood did not show abnormalities in expression of perforin, granzyme B, SLAM-associated protein, or X-linked inhibitor of apoptosis [3,4]. The patient did show a very low titer of EBV DNA (278IU/mL) of uncertain significance, which was undetectable 3 weeks into treatment.