Limitations of HLH‐2004 criteria in distinguishing malignancy‐associated hemophagocytic lymphohistiocytosis

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is characterized by dysregulated immune activation. Primary HLH involves hereditary deficits in cytotoxic lymphocytes while secondary HLH is triggered by extrinsic factors. The HLH‐2004 criteria are widely used for clinical diagnosis, yet their specificity for HLH or their ability to differentiate primary from secondary disease is unclear, potentially leading to inappropriate treatment. We describe several cases where fulfillment of HLH‐2004 criteria obscured the diagnoses of underlying malignancies and delayed curative management. These issues are remedied without waiting for genetic testing results through an alternative diagnostic approach using flow cytometry–based immunologic assays and a thorough investigation for malignancy.

Challenges in the diagnosis of hemophagocytic lymphohistiocytosis: Recommendations from the North American Consortium for Histiocytosis (NACHO)

“…Lymphoma deserves special mention as it is the most common malignancy associated with HLH at its initial presentation. Because of the difficulty of distinguishing lymphoma from F‐HLH or R‐HLH, thorough imaging and aggressive biopsy, often guided by PET‐CT, should be pursued or at least considered before starting corticosteroids and other therapies that may obscure diagnosis . Malignancy may present with HLH at all ages (including infancy), but is increasingly likely at older ages, and is associated with perhaps a majority of cases in adults .…”

STX11‐deficient familial hemophagocytic lymphohistiocytosis type 4 is associated with self‐resolving flares and a milder clinical course

“…1,2 HLH is a syndromic diagnosis made by meeting at least five of eight of the HLH-2004 diagnostic criteria, although this is not 100% specific. 3 Syntaxin 11 (STX11) is crucial for cytotoxic granule exocytosis. Mutations in the STX11 gene lead to failure of cytotoxic lymphocyte degranulation and are classified as FHL type 4 (FHL4).…”

“…4-6 FHL4 often presents later (postinfancy) than other types of FHL; however, additional phenotypic features of this supposed milder disease have otherwise not been described. [7][8][9][10][11] A previously healthy 18-month-old male child with no relevant family history presented with 10 days of fever and diarrhea, and was found to have pancytopenia (WBC: 4500 cells per mm 3 ; ANC: 270 per mm 3 ; hemoglobin: 6.8 g/dL; platelets: 19 000 per mm 3 Two weeks later, the patient developed recurrent pancytopenia, febrile neutropenia, and enlarging splenomegaly compared to discharge. He was readmitted with a presumed ALPS flare and given steroids and mycophenolate mofetil (MMF).…”

“…To the Editor: Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome characterized by aberrant activation of lymphocytes and macrophages, which results in hypercytokinemia . HLH is a syndromic diagnosis made by meeting at least five of eight of the HLH‐2004 diagnostic criteria, although this is not 100% specific . Syntaxin 11 (STX11) is crucial for cytotoxic granule exocytosis.…”

Reevaluating the role of ferritin in the diagnosis of adult secondary hemophagocytic lymphohistiocytosis

“…Recently, data have been emerging which call into question the specificity and relevance of several of the HLH-2004 criteria among adults with suspected secondary HLH. 5,6 Much of these data have focused on the criterion of serum ferritin, a non-specific marker of inflammation which, when markedly abnormal, is often a primary driver of HLH workups among hospitalized patients. 7,8 Studies examining serum ferritin thresholds >3000 ng/mL, 4000 ng/mL, 10 000 ng/mL, and 50 000 ng/mL have demonstrated that hyperferritinemia lacks specificity for HLH.…”