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Case Report
tional Tier III variants including APC p.G53R, FAT1 p.L761W, and NOTCH3 p.R2109Q. The sequential CNS LBCL in case #2 harbored pathogenic (Tier I/II) TP53 p.C238R and FBXW7 p.R465H missense variants.
In this report, we detailed the clinicopathologic and molecular features of two adolescent patients with sequential GZL involving the CNS. Notably, this is the first report describing CNS involvement as a manifesta- tion of sequential GZL, a finding which expands the clin- icopathologic spectrum of this rare pediatric disease. Consistent with previous reports, both patients present- ed with mediastinal NS-cHL and advanced extranodal disease with similar histopathologic and immunopheno- typic findings, and developed GZL in a similar chronolog- ic fashion.4,8 The sequential CNS lesions showed differing morphologic and immunohistochemical profiles with strong and diffuse expression of several B-cell markers and CD30, the latter arguing against an extramediastinal primary mediastinal B-cell lymphoma (PMBCL) diagno- sis, and the NS-cHL diagnosis preceded the diagnosis of LBCL temporally establishing the sequential GZL diagno- sis. Additionally, the findings of synchronous GZL with subsequent development of sequential GZL in the first patient is also exceptional. Furthermore, unlike previous reports, an early evolution (e.g., second lymphoma diag- nosis within 1 year) may not necessarily portend a poor clinical outcome4 given the favorable clinical responses in our two patients and a relatively long term follow-up in the first.
Recent molecular characterization of GZL supports the classification of two distinct subtypes of GZL: a "thymic" subtype that occurs in the anterior mediastinum and resembles Epstein-Barr virus (EBV)-negative cHL and PMBCL, and a “non-thymic” subtype which occurs out- side the thymus and harbors TP53 mutations in a subset of cases.9,10 In our two patients, the CNS location and mutations in TP53 (case #2) and other associated genes (e.g., CREBBP, RELN, and KMT2D) support a “non- thymic” GZL classification. The presence of complex genomic profiles is also consistent with dysregulated TP53 signaling, and both CNS LBCL harbored complex cytogenomic arrays with copy number abnormalities pre- viously reported in GZL11-13 and frequently reported in cHL and PMBCL.14,15 We acknowledge that a thorough investigation of enriched Reed-Sternberg cells from the cHL lesions and specific subsets of lesional cells may yield valuable molecular insights but this was beyond the scope of the current study.
In summary, we present the first report of sequential GZL with CNS involvement in two adolescent patients, and the first clinical genomic profiling of such paired lesions. These lesions showed chromosome aberrations identified in GZLs and NGS mutations associated with non-thymic GZL. These findings expand the clinico- pathologic and genomic spectrum of this rare pediatric disease.
Cagla Yasa-Benkli,1 Andrea N. Marcogliese,1,2 Jennifer E. Agrusa,2 Adekunle M. Adesina,1,2 Howard L. Weiner,3 Kevin E. Fisher1#
and Choladda V. Curry1#
#KEF and CVC contributed equally as co-senior authors.
1Department of Pathology & Immunology, Baylor College of Medicine and Texas Children’s Hospital; 2Department of Pediatrics, Baylor College of Medicine and Texas Children's Cancer Center and
3Division of Pediatric Neurosurgery, Department of Surgery, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA
Correspondence: CHOLADDA V. CURRY - ccurry@bcm.edu doi:10.3324/haematol.2021.278936
Received: April 8, 2021.
Accepted: June 16, 2021.
Pre-published: June 24, 2021.
Disclosures: no conflicts of interest to disclose.
Contributions: CYB researched the literature, wrote the manuscript, and constructed the tables/figures; ANM, JEA, AMA, and HLW assisted with reviewing medical and pathological records of patients involved, as well as manuscript editing; KEF and CVC conceived the study, interpreted the data, provided feedback and supervision. All authors contributed to patient care, manuscript editing, and evaluation.
References
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