Abstract
Background Hemophagocytic Lymphohystiocytosis (HLH) is a rare disorder, characterized by uncontrolled hyperinflammation, fever, cytopenias, hepatosplenomegaly and hemophagocytosis caused by genetic defects, e.g. perforin 1, causing impaired natural killer (NK) and cytotoxic T-cell function. A disease characterized by hyperactive phagocytosis similar to familial HLH can occasionally develop in adult patients (pts) and is called acquired hemophagocytic syndrome (AHS). The diagnosis of AHS is often overlooked because of its rarity and heterogeneous clinical presentation. It is usually associated with virus infection (VAHS), autoimmune disorders or malignancies. AHS has been described in Asian pts with lymphoma particularly of T-cell or intravascular large B cell phenotype but has been only occasionally reported in pts of Western origin.
Aims To evaluate the occurrence of AHS in adult lymphoma pts of Western origin, focusing on its biological and clinical features.
Methods From 2/03 through 02/08 the revised diagnostic criteria of the Histiocyte Society were applied to lymphoma pts presenting with persistent FUO, unexplained cytopenia or clinical signs of AHS. Work-up included detection of HHV-8, EBV, CMV, Parvovirus viral DNA, evaluation of NK activity of PBMCs by 4-hour51Cr-release assay with K562 cells, perforin expression on NK cells by flow cytometry, and by immunohystochemistry on bone marrow biopsy and analysis of perforin gene mutations by PCR and sequencing.
Results Fifteen pts fulfilling the criteria for HLH were identified. Their M/F ratio was 1,5 and median age was 66 (31–79). Lymphoma diagnoses clustered in three groups: 5 cases of indolent B cell lymphoma (4 SLL/CLL, 1 SMZL), 5 cases of diffuse large B cell lymphoma (DLBCL), two of which associated with Hodgkin lymphoma (HL),1 case of HL, and 4 cases of T cell lymphoma (1 anaplastic, 1 peripheral unspecified and 2 enteropathic). Among HLH diagnostic criteria, fever, cytopenia and high ferritin occurred in 100%, hypertriglyceridemia in 86%; hypofibrinogenemia and splenomegaly in 66%, and prominent bone marrow hemophagocytosis in 46% of cases. Median Hgb level was 9,1 g/L, ANC 0,7 × 109/L and platelets 23 × 109/L. Median trygliceride levels was 305 mg/dL, fibrinogen 122 mg/dL ferritin 6800 ng/mL. Moreover LDH was elevated in 13/15 cases (median 711 U/L). No significant differences were recorded between the different types of lymphoma except for a lower platelet count in pts with indolent B cell lymphoma (P=.008). No recurrent immunological abnormalities were identified except for direct antiglobulin test positivity in 5/8 pts with B cell lymphoma, without signs of overt hemolysis. Viral DNA was detected only in 3 pts (1 EBV, 1 CMV and 1 CMV+EBV). Biological investigations showed defective NK activity in 83% of pts. Among 9 evaluable pts, analysis of PRF1 gene identified G1070A mutation in 1 pt. and A91V heterozygous polymorphism in 2 pts showing defective PRF1 expression of NK cells by flow cytometry. Perforin expression on bone marrow biopsies was increased in 6 of 11 evaluable pts. Twelve pts died 1–120 days after diagnosis in spite of therapy with steroid, rituximab, high-dose IgG, antivirals and etoposide. Three are alive 22–34+ months after diagnosis. They had not distinctive clinicopathological features at presentation.
Conclusions AHS is not unusual in Western adults with lymphoma of T-cell but also of B cell phenotype, being overrepresented in SLL/CLL and in DLBCL, particularly when associated with HL. Genetic abnormalities of PRF1 are predisposing factors in some cases. However further mechanisms of defective NK function likely account for the development of this very severe condition and should be actively explored in order to ameliorate its dismal prognosis.
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