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Evolution of ISFN to aggressive B-cell lymphoma
Scientific). Variant validation was performed using either a bidi- rectional single amplicon resequencing approach or, for ISFN samples, a second targeted NGS analysis after microdissection of affected GC. For a detailed description of library preparation, sequencing, data analyses and validation, including a primer list, see the Online Supplementary Appendix and the Online Supplementary Table S2.
Results
Clinical features
Ten cases of aggressive BCL and paired ISFN were included (Table 1). In six cases, the aggressive lymphoma was considered de novo, whereas four cases also had an associated FL. In two of the four latter cases, the FL com- ponent was only detected during the screening of lym- phoid tissues originally interpreted as reactive, while the two others had a history of FL. None of the six de novo cases developed or relapsed as FL during follow-up, which ranged from 7 to 54 months. In seven of ten cases, the ISFN lesions were present simultaneously in seeming- ly non-involved lymph nodes (LN) adjacent to the aggres-
sive component. In cases 4, 5, and 7, the ISFN was iden- tified retrospectively in LN resected for other reasons sev- eral years prior to the DLBCL diagnosis.
Histological and immunohistochemical findings
The ISFN samples exhibited the typical features with overall preserved LN architecture and involved GC show- ing strong staining for BCL2 and CD10 and a very low proliferation rate (Figure 1A and B). All aggressive BCL, including eight DLBCL (one case with two samples) and three DH/TH HGBL, were classified as GCB subtype according to the Hans algorithm and expressed BCL2 (Table 2; Figure 1D). The aggressive tumors of cases 1 and 3 exhibited strong and homogenous P53 expression, whereas the DLBCL of case 2 was completely negative. All of these samples showed TP53 mutations (Figure 2; Online Supplementary Table S4). All FL were grade 1/2 and expressed BCL2. A summary of immunohistochemical findings is included in the Online Supplementary Table S3.
Chromosomal translocations
FISH analysis with a BCL2 break-apart probe confirmed a break in BCL2 for all samples of nine cases, indicative of
Table 1. Clinical data of patients with in situ follicular neoplasia and aggressive B-cell lymphoma.
Patient Age* Sex Diagnosis (years)
De novo aggressive B-cell lymphoma
Follow-up (Treatment)
CR–7months(Sx+CT) N/A
DOD (CT+ RT)
CR – 54 months (CT)
CR – 38 months (CT) N/A
CR – 54 months (CT)
CR–90months(Sx+CT)
CR – 133 months (Sx + CT)
CR – 158 months (Sx + CT)
1 59
2 61
3 64
4 76
5 67
6 74
Transformed FL
7 54
8# 74
9 64
10 54
Site
M ISFN
HGBL-TH Mesenterial LN
Stage Additional information
Synchronous with HGBL Synchronous with DLBCL Synchronous with primary DLBCL
F ISFN
DLBCL Mesenterial LN
Mesenterial LN
IVA/IE N/A
Mesenterial LN
M ISFN
DLBCL Axillary LN
Axillary LN DLBCL Cervical LN
IIIA Primary DLBCL
7 months after primary DLBCL
Resected during surgery for colorectal cancer 159 months prior to DLBCL diagnosis
Resected during surgery for bowel obstruction 42 months prior to DLBCL diagnosis
Synchronous with DLBCL
Sentinel node for melanoma
116 months prior to DLBCL diagnosis Synchronous with DLBCL, Grade 1/2
Synchronous with HGBL Synchronous with HGBL, Grade 1/2
Synchronous with HGBL Synchronous with HGBL, Grade 1/2
Synchronous with DLBCL Synchronous with DLBCL, Grade 1/2
F ISFN
DLBCL Paravertebral
Mesenterial LN
M ISFN
DLBCL Paraaortic LN
IIA
IIIA N/A
IIIS
IIA
IVB
IIA
F ISFN
DLBCL Small intestine
Mesenterial LN
Mesenterial LN
F ISFN
Axillary LN
FL Cervical LN DLBCL Cervical LN
F ISFN
FL Mesenterial LN
Mesenterial LN HGBL-DH Small intestine
M ISFN
FL Mesenterial LN
Mesenterial LN HGBL-DH Large intestine
M ISFN
FL Mesenterial LN
Mesenterial LN DLBCL Mesenterial LN
CR:complete remission;CT:chemotherapy;DOD:dead of disease;F:female;M:male;N/A:information not available;RT:radiotherapy;Sx:surgery;ISFN:in situ follicular neoplasia ; FL: follicular lymphoma; HGBL-TH: high-grade B-cell lymphoma triple-hit; HGBL-DH: HGBL double-hit; DLBCL: diffuse large B-cell lymphoma; LN: lymph node. *Age at diagnosis of aggressive B-cell lymphoma. #FL not available for analysis.
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