In situ follicular neoplasia in a young post‐liver transplant patient

To the Editor, T(14:18)(q32;q21), causing IGH::BCL2, occurs as a result of erroneous genomic rearrangements during VDJ recombination at the pre‐B stage of B‐cell development in the bone marrow. The translocation can be detected in peripheral blood lymphocytes in healthy individuals by polymerase chain reaction (PCR) and its prevalence depends on age, ranging from 0% in individuals <10 years old to 60% in those >40 years age. These circulating translocation positive cells are thought to correspond to those of in situ follicular neoplasia (ISFN) (in situ follicular B‐cell neoplasm according to the 5th edition of the World Health Organization classification of haematolymphoid tumours) in lymph nodes (LN), which are incidentally identified by their strong BCL2 expression by immunohistochemistry. Besides the translocation, several pathogenic mutations have also been described in ISFN, albeit exclusively from patients >40 year olds to date. It is unclear when such mutations occur during the clonal expansion of IGH::BCL2 positive B‐cells, whether the mutations occur in young patients? Herein, we report genetic analyses of ISFN in a young patient. The patient is a 24 year old male with a history of Crohn's disease and autoimmune hepatitis. He received two liver allografts at age 14 and 21 years, and was evaluated for a third transplant due to liver graft failure. Non‐bulky periportal, mesenteric lymphadenopathy, and splenomegaly were identified on computed tomograph (CT) scan in 2017. Core needle biopsies from a prehepatic LN showed reactive hyperplasia with no evidence of lymphoma. Hematological review demonstrated no disease progression. Subsequently, a mild generalized lymphadenopathy was identified on positron emission tomography (PET) CT with a whole right groin LN excised in January 2021. The groin LN showed preservation of the follicular and sinus architecture. There was an increase in germinal centers with interfollicular and perifollicular reactive polytypic plasmacytosis. Many (~40%) of the follicles showed a monotonous population of centrocytes with few centroblasts and absence of tingible body macrophages, and displayed both strong CD10 and BCL2 staining (Figure 1a). The morphology and immunophenotype suggested ISFN and there was no evidence of an overt lymphoma or PTLD (posttransplant lymphoproliferative disorder) though presence of occasional EBV‐positive cells in the interfollicular areas was noted by EBER‐in situ hybridization. Analysis of whole tissue section of the LN by BIOMED‐2 clonality assays showed no evidence of clonal IG gene rearrangements. Flow cytometry analysis of peripheral blood samples showed no evidence of clonal B‐cells. Bone marrow aspirate and trephine examination was negative for malignancy. PCR analysis of the peripheral blood mononuclear cells for EBV was positive, and follow‐up analyses showed decline of EBV load. Six months later, a follow‐up positron emission tomography computed tomograph revealed avid right axillary LN, which was excised and shown to be histologically reactive, without any evidence of ISFN by BCL2 immunohistochemistry. The patient underwent an orthotropic liver transplant in November 2021, and was well apart from wound dehiscence and mild pancytopenia following the transplant surgery. The ISFN lesions in the right groin LN were microdissected for DNA extraction and was subjected to mutation analysis by targeted sequencing of 191 genes (frequently mutated in follicular lymphoma and diffuse large B‐cell lymphoma) using the TWIST target enrichment kit (Supporting Information: Materials and methods). This revealed a single pathogenic mutation, TNF Receptor Superfamily Member 14 (TNFRSF14 c.G136T), p.E46* (Figure 1b). Targeted sequencing analysis of the right axillary LN, which showed no evidence of ISFN, did not identify any pathogenic mutations. We also performed PCR analyses of BCL2‐IGHJ genomic fusion using the BIOMED‐2 assays, followed by Sanger sequencing (Supporting Information: Figure 1). This identified a BCL2‐IGHJ fusion in the right inguinal LN, but not the subsequent right axillary