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Lee, J.C.; Logan, A.C. Diagnosis of Malignancy-Associated Hemophagocytic Lymphohistiocytosis. Encyclopedia. Available online: https://encyclopedia.pub/entry/42665 (accessed on 21 June 2024).
Lee JC, Logan AC. Diagnosis of Malignancy-Associated Hemophagocytic Lymphohistiocytosis. Encyclopedia. Available at: https://encyclopedia.pub/entry/42665. Accessed June 21, 2024.
Lee, Jerry C., Aaron C. Logan. "Diagnosis of Malignancy-Associated Hemophagocytic Lymphohistiocytosis" Encyclopedia, https://encyclopedia.pub/entry/42665 (accessed June 21, 2024).
Lee, J.C., & Logan, A.C. (2023, March 30). Diagnosis of Malignancy-Associated Hemophagocytic Lymphohistiocytosis. In Encyclopedia. https://encyclopedia.pub/entry/42665
Lee, Jerry C. and Aaron C. Logan. "Diagnosis of Malignancy-Associated Hemophagocytic Lymphohistiocytosis." Encyclopedia. Web. 30 March, 2023.
Diagnosis of Malignancy-Associated Hemophagocytic Lymphohistiocytosis
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Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of severe, dysregulated inflammation driven by the inability of T cells to clear an antigenic target. When associated with malignancy (mHLH), the HLH syndrome is typically associated with extremely poor survival. Since HLH represents a spectrum of hyperinflammatory disorders with heterogeneous inciting conditions, often with both genetic and environmental components, diagnosis can be challenging.

hemophagocytic lymphohistiocytosis hemophagocytosis HLH

1. Introduction

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome of excessive, dysregulated inflammation in response to a provoking trigger [1][2]. Defective termination of this immune response, driven by dysregulated positive feedback loops between CD8+ T lymphocytes and macrophages, results in hypercytokinemia that leads to cytolysis, tissue infiltration of immune cells, and end-organ injury. Frequently, HLH can cause death due to hemodynamic collapse and end-organ dysfunction.
The current understanding of HLH pathogenesis is derived from murine models and primary patient samples. In these studies, CD8+ T cells have been shown to be activated in response to an immunologic trigger, leading to the production of type 2 interferon (IFN), which primes macrophages to secrete additional proinflammatory cytokines [3][4][5][6][7]. Deficiencies in this cytolytic pathway result in an inability to proceed with normal activation-induced cell death, generating uncontrolled accumulation and activation of CD8+ T cells, natural killer (NK) cells, macrophages, and proinflammatory cytokines [8]. When HLH occurs as the result of congenital deficiencies of key cytolytic pathway proteins, this is called primary HLH (pHLH), which mainly occurs in children [9][10]. In adults, HLH is usually driven by a highly immunogenic trigger (i.e., secondary HLH, sHLH) rather than primary cytotoxicity defects [11], though in some cases, a relevant, often hypomorphic genetic mutation affecting cell-mediated immunity may be identified [12][13][14][15].
Triggers for sHLH vary greatly by geographic location. Common triggers are diseases associated with immune activation, such as autoimmune disorders, infections, and malignancies (Table 1). In North America and Europe, around 50% of adult HLH is due to an underlying malignancy, with the remaining 50% associated with rheumatologic diseases (also known as macrophage activation syndrome, or MAS, in this setting), infections (especially chronic viral infections, such as Epstein–Barr virus (EBV), cytomegalovirus (CMV), varicella zoster virus (VZV), herpes simplex virus (HSV), or human immunodeficiency virus (HIV), and under less frequent circumstances, infections with other non-viral pathogens), or treatment, usually from cell therapy (hematopoietic cell transplantation (HCT) or chimeric antigen receptor (CAR) T cells) [16][17][18][19]. A minority of adult HLH cases are late presentations of primary HLH or are idiopathic, in which no discernable cause is found.
Table 1. Representative Etiologies of Adult sHLH [16].
Based on retrospective data, outcomes in adults with sHLH differ widely between those in whom the syndrome is non-malignant (nmHLH) or malignancy-associated (mHLH). Long-term survival for adult nmHLH is comparable to pediatric HLH, whereas mHLH outcomes are particularly poor, with <20% survival at one year (median survival ~2 months) based on retrospective studies from the Mayo Clinic, MD Anderson Cancer Center, and the Harvard-affiliated hospitals [20][21][22]. mHLH therefore represents an area of much-needed investigation since many studies (for adult and pediatric HLH) exclude mHLH. Current management practices advise treating acute hypercytokinemia, followed by cancer-directed therapy [23][24][25][26]. It is unknown, however, whether treatment of mHLH confers a survival benefit over treatment of the underlying malignancy. It is also unknown whether the diagnostic criteria for mHLH should be the same as with nmHLH. This review provides an updated summary of the existing literature on the diagnosis and management of adult malignancy-associated HLH, especially in the setting of emerging research on effective treatment strategies in the age of engineered cellular and immunotherapies.

2. Diagnosis of Malignancy-Associated HLH

2.1. HLH-2004 Diagnostic Guidelines

Since HLH represents a spectrum of hyperinflammatory disorders with heterogeneous inciting conditions, often with both genetic and environmental components, diagnosis can be challenging. Traditionally, diagnosis is based on the HLH-2004 revised diagnostic guidelines from the Histiocyte Society, which do not distinguish between nmHLH and mHLH and rely on a combination of clinical, laboratory, and pathological data [27]. In patients without an HLH-predisposing genetic variant, five of eight diagnostic criteria are required (Table 2), some of which denote macrophage activation such as ferritin elevation and hemophagocytosis, and some of which denote T cell proliferation such as soluble IL2 receptor (sIL2R) [28][29].
Table 2. HLH-2004 Diagnostic Guidelines for Hemophagocytic Lymphohistiocytosis [27].
These diagnostic guidelines were based on data from pediatric HLH, and differences between pediatric and adult HLH raise questions about their utility in adults. For instance, malignancy accounts for nearly 50% of adult triggers, as opposed to 8% in children [31][32]. There is a higher prevalence of hepatomegaly (95%) and neurological symptoms (33%) in pediatric cases compared with adults (18–67% and 9–25%, respectively) [33]. A ferritin of >2000 achieves a sensitivity of 70% and specificity of 68% in children [34], which rises to 90% sensitivity with 96% specificity if the ferritin is >10,000 ng/mL [35]. In adults, on the other hand, higher ferritin cutoffs have poorer test characteristics (at 3000 ng/mL, ~67% sensitivity/specificity [36]; at 10,000 ng/mL, 43% sensitivity [20]; at 50,000 ng/mL, <20% sensitivity/specificity [37]). This is due to a more heterogeneous range of conditions associated with hyperferritinemia in older individuals.

2.2. Alternatives to HLH-2004 Diagnostic Guidelines

Several attempts have been made to improve the HLH-2004 diagnostic guidelines. In addition to modifying ferritin cutoffs (or mandating hyperferritinemia as a required criterion due to its high negative predictive value), other suggestions have been made to redefine HLH around clinicopathologic features. In this view, the diagnosis of HLH is made based on parameters fulfilling categories representing predisposing immunodeficiency, significant immune activation, and/or abnormal immunopathology—an approach that may better reflect the current understanding of HLH pathophysiology [30]. A modified HLH-2004 strategy has been proposed to assist with earlier diagnosis, which requires three of four clinical findings (fever, splenomegaly, cytopenias, and hepatitis), plus at least one of four immunologic test abnormalities (hyperferritinemia, elevated serum soluble IL-2Rα (sIL2R), absent/markedly decreased natural killer (NK) cell function, or the presence of hemophagocytosis) [38]. In a 2012 survey of HLH experts, an iterative questionnaire was utilized to determine the clinical features thought most important in adult HLH, which were the presence of a predisposing disease, fever, organomegaly, cytopenias, elevated ferritin, elevated LDH, and hemophagocytosis [39]. A scoring system (“HScore”) was developed to define and predict the likelihood of adult HLH based on HLH-2004 weighted parameters, for which the optimal cutoff HScore value was 169 (sensitivity 93%, specificity 86%) [40]; notably, the study cohort included 137 cancer patients out of a total of 312 adults. A subsequent study compared the accuracy of HScore against HLH-2004 and found that although the HScore achieved a sensitivity and specificity of 90% and 79% for adults at initial presentation, performance dropped to 73% sensitivity and specificity (similar to HLH-2004) when clinical status worsened [41].
The additional diagnostic challenges posed by mHLH are the many alternative explanations for abnormal laboratory parameters. Most mHLH is driven by hematologic malignancies, particularly lymphoma [42], where marrow and/or spleen neoplastic infiltration can explain cytopenias and splenomegaly; fever often occurs from concomitant infections in immunocompromised hosts or from tumor fever; hypofibrinogenemia can be secondary to malignancy-related disseminated intravascular coagulation (DIC); and hyperferritinemia can result from tumor-related inflammation or transfusional iron overload. As such, there has been no accepted definition for mHLH, and consensus recommendations have advocated for using HLH-2004 as a diagnostic tool in conjunction with physician judgement as to whether the clinical phenotype observed is out of proportion to the malignancy alone [24][26]. A high sIL2R/ferritin ratio has been proposed as a marker for lymphoma-associated HLH (LAHS). In a retrospective analysis of 21 patients comparing nmHLH and LAHS, the mean sIL2R/ferritin ratio was 0.66 amongst nmHLH patients and 8.56 in LAHS, hypothesized to reflect excessive T cell activation out of proportion to macrophage stimulation [43]. LAHS also have comparatively higher mean levels of microRNA-133 [44], IFN-inducible protein 10 (IP-10)/CXCL10, and monokine-induced by IFNγ (MIG)/CXCL9 [45], which have been proposed but not yet validated as diagnostic biomarkers.
In another retrospective analysis performed using the MD Anderson Cancer Center database, only 21% of patients with suspected HLH met HLH-2004 diagnostic criteria [21]. As such, the authors suggested expanding the diagnostic criteria to 18 variables, for which any five would be diagnostic. In this schema, 35 of 61 patients with pathologic hemophagocytosis or lymphohistiocytosis were thought to have true mHLH, with no differences in outcomes compared to those who met the standard HLH-2004 criteria, but with inferior outcomes compared to the remaining 26 patients with pathologic hemophagocytosis or lymphohistiocytosis but who did not meet the extended criteria.
Finally, a recent multicenter retrospective study using a cohort of 225 patients with hematologic malignancies for which sIL2R was available identified an optimal cutoff of sIL2R > 3601 U/mL and ferritin > 920 ng/mL, achieving a sensitivity of 88% and specificity of 76% for identifying the presence of HLH [46]. Comparatively, the cutoffs used in HLH-2004 (sIL2R > 2400 U/mL and ferritin > 500 ng/mL) demonstrate a sensitivity of 92% and a specificity of 72%. The authors suggest that the optimized HLH inflammatory (OHI) index, using sIL2R > 3900 U/mL and ferritin > 1000 ng/mL for simplicity, provides both diagnostic and prognostic value in hematologic malignancies with HLH.
These diagnostic modifications were proposed to enhance the expediency, simplicity, and generalizability to community practices. However, whether they are intended to raise suspicion index, increase accuracy, or reflect biological pathogenesis, any formal definition of adult mHLH will ultimately require prospective validation and international consensus.

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