Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Aaron C Logan
 -- 1766 2023-03-30 17:57:05 |
2 format correct
Conner Chen
 Meta information modification 1766 2023-04-03 07:18:46 |

Video Upload Options

Do you have a full video?
Send video materials Upload full video

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Lee, J.C.; Logan, A.C. Diagnosis of Malignancy-Associated Hemophagocytic Lymphohistiocytosis. Encyclopedia. Available online: https://encyclopedia.pub/entry/42665 (accessed on 27 July 2024).
Lee JC, Logan AC. Diagnosis of Malignancy-Associated Hemophagocytic Lymphohistiocytosis. Encyclopedia. Available at: https://encyclopedia.pub/entry/42665. Accessed July 27, 2024.
Lee, Jerry C., Aaron C. Logan. "Diagnosis of Malignancy-Associated Hemophagocytic Lymphohistiocytosis" Encyclopedia, https://encyclopedia.pub/entry/42665 (accessed July 27, 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
Edit
This entry is adapted from the peer-reviewed paper 10.3390/cancers15061839

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].
Category Specific Causes
Infection  
Viral Human Herpesviridae (e.g., EBV, HSV, CMV, VZV), HIV, viral hepatitis, influenza, parvovirus B19, dengue
Bacterial Mycobacterium tuberculosis, Staphylococcus aureus, Rickettsia, Mycoplasma
Parasitic Leishmania, Plasmodium, Toxoplasma
Fungal Histoplasma, Candida, Cryptococcus, Aspergillus
Malignancy  
Hematologic T/NK-cell lymphomas, aggressive B-cell lymphomas, leukemia, Hodgkin lymphoma, Castleman disease
Solid Metastatic carcinomas, sarcomas
Autoimmune Systemic lupus erythematosus, adult-onset Still’s disease, rheumatoid arthritis, vasculitis, inflammatory bowel disease
Treatment-Related  
Transplantation Allogeneic hematopoietic cell transplantation, solid organ transplantation
T Cell Therapy CAR T cell therapy, bispecific T cell engagers
Other Therapy Immune checkpoint inhibitors, chemotherapy-induced, drug-induced hypersensitivity, surgery, vaccination, hemodialysis
Other Pregnancy, trauma, idiopathic, unknown, multifactorial
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].
Either:
-
A molecular diagnosis consistent with HLH, or
-
Five of the following eight criteria:
  • Fever *
2.
Splenomegaly
3.
Cytopenias affecting at least two lineages: neutrophils < 1.0 × 109/L; hemoglobin < 10 g/dL *; platelets < 100 × 109/L
4.
Fasting triglycerides ≥ 3.0 mmol/L (265 mg/dL) or fibrinogen ≤ 1.5 g/L (150 mg/dL)
5.
Hemophagocytosis in bone marrow, spleen, or lymph nodes *
6.
Low or absent NK cell activity
7.
Ferritin ≥ 500 ng/mL (reported by some labs in μg/L)
8.
Soluble IL2 receptor (sIL2R, aka sCD25) ≥ 2400 U/mL *
Supporting evidence: liver biopsy showing chronic/persistent hepatitis; spinal fluid pleocytosis (mononuclear cells) and/or elevated spinal fluid protein; cerebromeningeal symptoms; liver enzyme abnormalities; lymphadenopathy; hypoproteinemia; hyponatremia; high VLDL; low HDL; skin rash; edema. * Subsequent proposed modifications/specifications to the diagnostic guidelines include fever ≥ 38.5 °C; hemoglobin < 9 g/dL except in infants; hemophagocytosis in the marrow, spleen, lymph nodes, or liver; and elevated sIL2R > 2 standard deviations from the laboratory age-adjusted mean [30].
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.

References

  1. Janka, G.E. Familial and Acquired Hemophagocytic Lymphohistiocytosis. Eur. J. Pediatr. 2007, 166, 95–109.
  2. Al-Samkari, H.; Berliner, N. Hemophagocytic Lymphohistiocytosis. Annu. Rev. Pathol. 2018, 13, 27–49.
  3. Jordan, M.B.; Hildeman, D.; Kappler, J.; Marrack, P. An Animal Model of Hemophagocytic Lymphohistiocytosis (HLH): CD8+ T Cells and Interferon Gamma Are Essential for The. Blood 2004, 104, 735–743.
  4. Akashi, K.; Hayashi, S.; Gondo, H.; Mizuno, S.; Harada, M.; Tamura, K.; Yamasaki, K.; Shibuya, T.; Uike, N.; Okamura, T. Involvement of Interferon-Gamma and Macrophage Colony-Stimulating in Pathogenesis of Haemophagocytic Lymphohistiocytosis in adults. Br. J. Haematol. 1994, 87, 243–250.
  5. Terrell, C.E.; Jordan, M.B. Perforin Deficiency Impairs a Critical Immunoregulatory Loop Murine CD8(+) T Cells and Dendritic Cells. Blood 2013, 121, 5184–5191.
  6. Lykens, J.E.; Terrell, C.E.; Zoller Erin, E.; Risma, K.; Jordan, M.B. Perforin Is a Critical Physiologic Regulator of T-Cell. Blood 2011, 118, 618–626.
  7. Stepp, S.E.; Dufourcq-Lagelouse, R.; le Deist, F.; Bhawan, S.; Certain, S.; Mathew, P.A.; Henter, J.I.; Bennett, M.; Fischer, A.; de Saint Basile, G.; et al. Perforin Gene Defects in Familial Hemophagocytic. Science (1979) 1999, 286, 1957–1959.
  8. Sumegi, J.; Barnes, M.G.; Nestheide, S.v.; Molleran-Lee, S.; Villanueva, J.; Zhang, K.; Risma, K.A.; Grom, A.A.; Filipovich, A.H. Gene Expression Profiling of Peripheral Blood Mononuclear Cells from Children with Active Hemophagocytic Lymphohistiocytosis. Blood 2011, 117, e151–e160.
  9. Canna, S.W.; Marsh, R.A. Pediatric Hemophagocytic Lymphohistiocytosis. Blood 2020, 135, 1332–1343.
  10. Janka, G.E.; Lehmberg, K. Hemophagocytic Syndromes—An Update. Blood Rev. 2014, 28, 135–142.
  11. Carvelli, J.; Piperoglou, C.; Farnarier, C.; Vely, F.; Mazodier, K.; Audonnet, S.; Nitschke, P.; Bole-Feysot, C.; Boucekine, M.; Cambon, A.; et al. Functional and Genetic Testing in Adults with HLH Reveals an Inflammatory Profile Rather than a Cytotoxicity Defect. Blood 2020, 136, 542–552.
  12. Schulert, G.S.; Cron, R.Q. The Genetics of Macrophage Activation Syndrome. Genes. Immun. 2020, 21, 169–181.
  13. Zhang, K.; Jordan, M.B.; Marsh, R.A.; Johnson, J.A.; Kissell, D.; Meller, J.; Villanueva, J.; Risma, K.A.; Wei, Q.; Klein, P.S.; et al. Hypomorphic Mutations in PRF1, MUNC13-4, and STXBP2 Are Associated with Adult-Onset Familial HLH. Blood 2011, 118, 5794–5798.
  14. Chinn, I.K.; Eckstein, O.S.; Peckham-Gregory Erin, C.; Goldberg, B.R.; Forbes, L.R.; Nicholas Sarah, K.; Mace, E.M.; Vogel, T.P.; Abhyankar Harshal, A.; Diaz, M.I.; et al. Genetic and Mechanistic Diversity in Pediatric Hemophagocytic. Blood 2018, 132, 89–100.
  15. Wang, Y.; Wang, Z.; Zhang, J.; Wei, Q.; Tang, R.; Qi, J.; Li, L.; Ye, L.; Wang, J.; Ye, L. Genetic Features of Late Onset Primary Hemophagocytic Lymphohistiocytosis in Adolescence or Adulthood. PLoS ONE 2014, 9, e107386.
  16. Ramos-Casals, M.; Brito-Zerón, P.; López-Guillermo, A.; Khamashta, M.A.; Bosch, X. Adult Haemophagocytic Syndrome. Lancet 2014, 383, 1503–1516.
  17. Ishii, E.; Ohga, S.; Imashuku, S.; Yasukawa, M.; Tsuda, H.; Miura, I.; Yamamoto, K.; Horiuchi, H.; Takada, K.; Ohshima, K.; et al. Nationwide Survey of Hemophagocytic Lymphohistiocytosis in Japan. Int. J. Hematol. 2007, 86, 58–65.
  18. Abdelkefi, A.; ben Jamil, W.; Torjman, L.; Ladeb, S.; Ksouri, H.; Lakhal, A.; ben Hassen, A.; ben Abdeladhim, A.; Othman, T. ben Hemophagocytic Syndrome after Hematopoietic Stem Cell: A Prospective Observational Study. Int. J. Hematol. 2009, 89, 368–373.
  19. Yildiz, H.; Castanares-Zapatero, D.; d’Abadie, P.; Bailly, S.; Yombi, J.C. Hemophagocytic Lymphohistiocytosis in Adults: A Retrospective in a Belgian Teaching Hospital. Int. J. Gen. Med. 2022, 15, 8111–8120.
  20. Parikh, S.A.; Kapoor, P.; Letendre, L.; Kumar, S.; Wolanskyj, A.P. Prognostic Factors and Outcomes of Adults with Hemophagocytic. Mayo Clin. Proc. 2014, 89, 484–492.
  21. Tamamyan, G.N.; Kantarjian, H.M.; Ning, J.; Jain, P.; Sasaki, K.; McClain, K.L.; Allen, C.E.; Pierce, S.A.; Cortes, J.E.; Ravandi, F.; et al. Malignancy-Associated Hemophagocytic Lymphohistiocytosis in adults: Relation to Hemophagocytosis, Characteristics, and outcomes. Cancer 2016, 122, 2857–2866.
  22. Schram, A.M.; Comstock, P.; Campo, M.; Gorovets, D.; Mullally, A.; Bodio, K.; Arnason, J.; Berliner, N. Haemophagocytic Lymphohistiocytosis in Adults: A Multicentre Case Series over 7 Years. Br. J. Haematol. 2016, 172, 412–419.
  23. la Rosée, P.; Horne, A.; Hines, M.; von Bahr Greenwood, T.; Machowicz, R.; Berliner, N.; Birndt, S.; Gil-Herrera, J.; Girschikofsky, M.; Jordan, M.B.; et al. Recommendations for the Management of Hemophagocytic in Adults. Blood 2019, 133, 2465–2477.
  24. Lehmberg, K.; Nichols, K.E.; Henter, J.-I.; Girschikofsky, M.; Greenwood, T.; Jordan, M.; Kumar, A.; Minkov, M.; la Rosée, P.; Weitzman, S.; et al. Consensus Recommendations for the Diagnosis and Management of Hemophagocytic Lymphohistiocytosis Associated with Malignancies. Haematologica 2015, 100, 997–1004.
  25. Daver, N.; McClain, K.; Allen, C.E.; Parikh, S.A.; Otrock, Z.; Rojas-Hernandez, C.; Blechacz, B.; Wang, S.; Minkov, M.; Jordan, M.B.; et al. A Consensus Review on Malignancy-Associated Hemophagocytic Lymphohistiocytosis in Adults. Cancer 2017, 123, 3229–3240.
  26. Hines, M.R.; von Bahr Greenwood, T.; Beutel, G.; Beutel, K.; Hays, J.A.; Horne, A.; Janka, G.; Jordan, M.B.; van Laar, J.A.M.; Lachmann, G.; et al. Consensus-Based Guidelines for the Recognition, Diagnosis, and management of Hemophagocytic Lymphohistiocytosis in Critically Children and Adults. Crit. Care Med. 2022, 50, 860–872.
  27. Henter, J.-I.; Horne, A.; Aricó, M.; Egeler, R.M.; Filipovich, A.H.; Imashuku, S.; Ladisch, S.; McClain, K.; Webb, D.; Winiarski, J.; et al. HLH-2004: Diagnostic and Therapeutic Guidelines for hemophagocytic Lymphohistiocytosis. Pediatr. Blood Cancer 2007, 48, 124–131.
  28. Esumi, N.; Ikushima, S.; Todo, S.; Imashuku, S. Hyperferritinemia in Malignant Histiocytosis, Virus-Associated Hemophagocytic Syndrome and Familial Erythrophagocytic Lymphohistiocytosis. Acta Paediatr. 1989, 78, 268–270.
  29. Komp, D.M.; McNamara, J.; Buckley, P. Elevated Soluble Interleukin-2 Receptor in Childhood Hemophagocytic Histiocytic Syndromes. Blood 1989, 73, 2128–2132.
  30. Jordan, M.B.; Allen, C.E.; Weitzman, S.; Filipovich, A.H.; McClain, K.L. How I Treat Hemophagocytic Lymphohistiocytosis. Blood 2011, 118, 4041–4052.
  31. Allen, C.E.; McClain, K.L. Pathophysiology and Epidemiology of Hemophagocytic Lymphohistiocytosis. Hematology 2015, 2015, 177–182.
  32. Lehmberg, K.; Sprekels, B.; Nichols, K.E.; Woessmann, W.; Müller, I.; Suttorp, M.; Bernig, T.; Beutel, K.; Bode, S.F.N.; Kentouche, K.; et al. Malignancy-Associated Haemophagocytic Lymphohistiocytosis in Children and Adolescents. Br. J. Haematol. 2015, 170, 539–549.
  33. Nikiforow, S.; Berliner, N. The Unique Aspects of Presentation and Diagnosis of Hemophagocytic Lymphohistiocytosis in Adults. Hematology 2015, 2015, 183–189.
  34. Lehmberg, K.; McClain, K.L.; Janka, G.E.; Allen, C.E. Determination of an Appropriate Cut-off Value for Ferritin in the Diagnosis of Hemophagocytic Lymphohistiocytosis. Pediatr. Blood Cancer 2014, 61, 2101–2103.
  35. Allen, C.E.; Yu, X.; Kozinetz, C.A.; McClain, K.L. Highly Elevated Ferritin Levels and the Diagnosis of Hemophagocytic Lymphohistiocytosis. Pediatr. Blood Cancer 2008, 50, 1227–1235.
  36. Tabata, C.; Tabata, R. Possible Prediction of Underlying Lymphoma by High SIL-2R/Ferritin Ratio in Hemophagocytic Syndrome. Ann. Hematol. 2012, 91, 63–71.
  37. Schram, A.M.; Campigotto, F.; Mullally, A.; Fogerty, A.; Massarotti, E.; Neuberg, D.; Berliner, N. Marked Hyperferritinemia Does Not Predict for HLH in the Adult Population. Blood 2015, 125, 1548–1552.
  38. Filipovich, A.H. Hemophagocytic Lymphohistiocytosis (HLH) and Related Disorders. Hematology 2009, 2009, 127–131.
  39. Hejblum, G.; Lambotte, O.; Galicier, L.; Coppo, P.; Marzac, C.; Aumont, C.; Fardet, L. A Web-Based Delphi Study for Eliciting Helpful Criteria in the Positive Diagnosis of Hemophagocytic Syndrome in Adult Patients. PLoS ONE 2014, 9, e94024.
  40. Fardet, L.; Galicier, L.; Lambotte, O.; Marzac, C.; Aumont, C.; Chahwan, D.; Coppo, P.; Hejblum, G. Development and Validation of the HScore, a Score for the Diagnosis of Reactive Hemophagocytic Syndrome. Arthritis Rheumatol. 2014, 66, 2613–2620.
  41. Debaugnies, F.; Mahadeb, B.; Ferster, A.; Meuleman, N.; Rozen, L.; Demulder, A.; Corazza, F. Performances of the H-Score for Diagnosis of Hemophagocytic Lymphohistiocytosis in Adult and Pediatric Patients. Am. J. Clin. Pathol. 2016, 145, 862–870.
  42. Rivière, S.; Galicier, L.; Coppo, P.; Marzac, C.; Aumont, C.; Lambotte, O.; Fardet, L. Reactive Hemophagocytic Syndrome in Adults: A Retrospective Analysis of 162 Patients. Am. J. Med. 2014, 127, 1118–1125.
  43. Tsuji, T.; Hirano, T.; Yamasaki, H.; Tsuji, M.; Tsuda, H. A High SIL-2R/Ferritin Ratio Is a Useful Marker for the Diagnosis of Lymphoma-Associated Hemophagocytic Syndrome. Ann. Hematol. 2014, 93, 821–826.
  44. Li, W.; Zhong, Y.; Shuang, Y.; Huang, H.; Huang, Y.; Yu, L.; Huang, X. High Concentration of MiR-133 Is a Useful Marker for the Diagnosis of Lymphoma- Associated Hemophagocytic Syndrome. Cancer Biomark. 2017, 20, 159–164.
  45. Maruoka, H.; Inoue, D.; Takiuchi, Y.; Nagano, S.; Arima, H.; Tabata, S.; Matsushita, A.; Ishikawa, T.; Oita, T.; Takahashi, T. IP-10/CXCL10 and MIG/CXCL9 as Novel Markers for the Diagnosis of Lymphoma-Associated Hemophagocytic Syndrome. Ann. Hematol. 2014, 93, 393–401.
  46. Zoref-Lorenz, A.; Murakami, J.; Hofstetter, L.; Iyer, S.; Alotaibi, A.S.; Mohamed, S.F.; Miller, P.G.; Guber, E.; Weinstein, S.; Yacobovich, J.; et al. An Improved Index for Diagnosis and Mortality Prediction in Malignancy-Associated Hemophagocytic Lymphohistiocytosis. Blood 2022, 139, 1098–1110.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Hematology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Jerry C. Lee
,
Aaron C. Logan
View Times: 369
Revisions: 2 times (View History)
Update Date: 03 Apr 2023
Table of Contents
    1000/1000
    Hot Most Recent
    Video Production Service
    Feedback