Germline HAVCR2 mutations and their relation to the clinical spectrum of subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis: results from a multicenter study and meta-analysis

Haematologica. 2023 Oct 1;108(10):2743-2752. doi: 10.3324/haematol.2022.282419.


Germline HAVCR2 mutations are frequently detected in subcutaneous panniculitis-like T-cell lymphoma (SPTCL) patients with/without hemophagocytic lymphohistiocytosis (HLH) but factors associated with variable manifestations remain undetermined. To evaluate clinical variations and associated factors in SPTCL and/or HLH with/without HAVCR2 mutations, we performed direct sequencing of HAVCR2 exon 2 using DNA from patients with SPTCL or idiopathic HLH/HLH-like systemic illnesses, defined by HLH alone without secondary causes. The systematic review and individual patient data (IPD) level meta-analysis which included the present and previously published studies reporting HAVCR2 mutations in SPTCL with/without HLH populations was subsequently conducted using random-effects meta-analysis and multivariate logistic regression. Among 34 patients enrolled, ten of 28 SPTCL patients developed HLH/HLH-like systemic illnesses. Six cases with HAVCR2Y82C mutation manifested with HLH without panniculitis. Male sex (P=0.03) and age <18 years (P=0.04) were associated with HLH, corresponding to the inverse correlation between age and HLH-2004 score (r=-0.40; P=0.02). Homozygous HAVCR2Y82C mutation was more common in the presence of HLH compared with the absence (75.0% vs. 44.4%; P=0.02). Using IPD from the present and the other three eligible cohorts (N=127), male sex, heterozygous and homozygous/compound heterozygous HAVCR2 mutations were associated with HLH by the adjusted odds ratio of 2.93 (95% confidence interval [CI]: 1.22-7.06), 4.77 (95% CI: 1.05-21.63) and 8.48 (95% CI: 2.98-24.10), respectively. Patients with male sex and/or germline HAVCR2 mutations showed an increased risk of developing HLH. Younger patients tended to manifest with HLH, while older patients typically presented with SPTCL with less frequent HLH/HLH-like systemic illnesses.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Germ Cells / pathology
  • Germ-Line Mutation
  • Hepatitis A Virus Cellular Receptor 2 / genetics
  • Humans
  • Lymphohistiocytosis, Hemophagocytic* / diagnosis
  • Lymphohistiocytosis, Hemophagocytic* / genetics
  • Male
  • Multicenter Studies as Topic
  • Panniculitis* / complications
  • Panniculitis* / genetics
  • Panniculitis* / pathology


  • HAVCR2 protein, human
  • Hepatitis A Virus Cellular Receptor 2

Supplementary concepts

  • Subcutaneous panniculitis-like T-cell lymphoma

Grants and funding

Funding: This research was supported by grants from the Anandamahidol Foundation (to CP), the Center of Excellence in Translational Hematology, Faculty of Medicine, Chulalongkorn University (to CP), the Ratchadapiseksompotch Fund, Faculty of Medicine, Chulalongkorn University (RA64/004; to CP), and the Thailand Science Research and Innovation Fund, Chulalongkorn University (CU_FRB65_hea(24)_031_30_12; to CP).