case_images: PMC10937737_01
case_images: Transformation of a follicular lymphoma (A-F) into a DLBCL with high PD-L1 expression (G-L). (A-F) Follicular lymphoma diagnosed on a retroperitoneal lymph node biopsy. H&E sections (A, B) showing a vaguely nodular lymphoid proliferation composed mainly of centrocytes with rare centroblasts (grade I). The nodular architecture is better highlighted in immunohistochemistry with a T-cell marker (CD5, D). The tumor cells are diffusely reactive to CD10 (C) and Bcl2 (E) with a very low proliferation index (5%, F). (G-L) Transformation into a DLBCL with PD-L1 expression in a bone marrow core biopsy. H&E sections (G, H) showing a replacement of the hematopoietic lineages by a diffuse lymphoid proliferation consisting of large-size and atypical cells. The tumor cells retain a CD20 positivity (I) with half of them showing a PD-L1 expression (K). Proliferation index is high (70%, J). FISH analysis confirms a BCL2 rearrangement (L). BCL-2, B-cell lymphoma 2; DLBCL, diffuse large B-cell lymphoma; FISH, fluorescence in situ hybridization; H&E, hematoxylin and eosin; PD-L1, programmed death-ligand 1.
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case_images: PMC10937737_01_fonc-14-1308492-g001.jpg
case_images: f1
case_images: At the time of this diagnosis, his FLIPI score was 3/5, meeting criteria based on age, stage, and involvement of more than four nodal areas (refer to  Figures 1 ,  2  for the initial radiological and pathological assessments). Cell Signaling) ( Figure 1 ). Complementary molecular analysis using a 400-gene next-generation sequencing (NGS) panel ( Supplementary Figure S1 ) unveiled classical mutations commonly associated with transformed FL, including CREBBP, KMT2D, BCL2, EP300, and TNFSRF14 genes; however, these mutations were not actionable.
case_images: List of somatic mutations retained with a 400-gene NGS panel in the bone marrow sample. Bone marrow sample of patient was sequenced in 2020. The panel used for the sequencing was the NGS400v2, the custom capture panel based on Agilent SureSelect XT HS technology and covering all exons of 420 genes and the TERT promoter region. Sequencing was done on an Illumina NextSeq 500 System. The data were analyzed using HUG internal software (Soap 2.1.1):Oncobench v4. with hg19 as a reference. The variant calling software detected 26 somatic mutations. The germline variants were detected by sequencing of blood or non-tumor tissue samples. Of the 26 somatic variants detected, only 16 had a potential impact on the protein, and of these 16 variants, two had an allelic frequency below 5% and were filtered out. Pathogenicity was assessed for the remaining 14 variants presented. The tumor mutation burden was 6.75 mut/Mb. Reference:ENSEMBL transcript ID, pathogenicity is classified as follows: 1, benign/2, probably benign/3, uncertain/4, probably pathogenic/5, pathogenic. HGVS, Human Genome Variation Society; HGVS.c, DNA variant, HGVS.p, protein variant; HUG, Hopitaux Universitaires de Geneve; VAF, variant allele frequency.
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case_images: PMC10937737_01_fonc-14-1308492-g002.jpg
case_images: f2
case_images: At the time of this diagnosis, his FLIPI score was 3/5, meeting criteria based on age, stage, and involvement of more than four nodal areas (refer to  Figures 1 ,  2  for the initial radiological and pathological assessments). Furthermore, the analysis revealed a moderate tumor mutational burden (TMB) of 6.75 mutations per megabase (mut/Mb) ( Figure 2 ). Furthermore, we conducted Oncoscan Affymetrix analysis, which unveiled gains in 17q, 18q, and 18p, along with loss of heterozygosity (LOH) in Xq and Xp.
case_images: PET-CT response assessment of transformed FL on PD-1 ICB. (A) Intense bone marrow diffuse metabolism and mild lymph nodes, at diagnosis of transformation; (B) 3-month response assessment; (C) 9-month response assessment. FL, follicular lymphoma; ICB, immune checkpoint blockade; PD-1, programmed death-1; PET-CT, positron emission tomography and computed tomography; SUV max, maximum standardized uptake value.
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case_images: PMC10937737_01_fonc-14-1308492-g003.jpg
case_images: f3
case_images: Astonishingly, the patient's overall condition improved dramatically, culminating in a complete metabolic response at the 3-month mark ( Figure 3 ).