Next-generation sequencing of idiopathic multicentric and unicentric Castleman disease and follicular dendritic cell sarcomas

Abstract

Castleman disease (CD) is a rare lymphoproliferative disorder subclassified as unicentric CD (UCD) or multicentric CD (MCD) based on clinical features and the distribution of enlarged lymph nodes with characteristic histopathology. MCD can be further subtyped based on human herpes virus 8 (HHV8) infection into HHV8-associated MCD, HHV8/idiopathic MCD (iMCD), and polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin change (POEMS)-associated MCD. In a subset of cases of UCD, an associated follicular dendritic cell sarcoma (FDCS) may be seen. Although numerous reports of the clinical and histologic features of UCD, MCD, and FDCS exist, an understanding of the genetic and epigenetic landscape of these rare diseases is lacking. Given this paucity of knowledge, we analyzed 15 cases of UCD and 3 cases of iMCD by targeted next-generation sequencing (NGS; 405 genes) and 3 cases of FDCS associated with UCD hyaline vascular variant (UCD-HVV) by whole-exome sequencing. Common amplifications of ,, and were seen in 1 iMCD and 1 UCD case; the iMCD case also had a somatic L295Q mutation. This iMCD patient also showed clinicopathologic features consistent with a specific subtype known as Castleman-Kojima disease (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly [TAFRO] clinical subtype). Additionally, 1 case of UCD-HVV showed amplification of the cluster of histone genes on chromosome 6p. FDCS associated with UCD-HVV showed mutations and copy number changes in known oncogenes, tumor suppressors, and chromatin structural-remodeling proteins.

Potential application of genomic profiling for the diagnosis and treatment of patients with sarcoma

“…To date, histological examination remains the primary method of sarcoma diagnosis ( 36 ). The histological and molecular heterogeneity of sarcoma make it particularly difficult to diagnose, though with the rapid development of NGS technology, increasing numbers of sarcoma genome sequencing studies have emerged ( 37 – 40 ). In the present study, the most commonly mutated genes were identified in 199 patients with sarcoma, and included TP53, CDKN2A, CDKN2B, KIT, ATRX and RB1 .…”

Intra-abdominal inflammatory pseudotumor-like follicular dendritic cell sarcoma associated with paraneoplastic pemphigus: A case report and review of the literature

“…Some researchers assumed that FDC sarcoma arose from hyaline vascular Castleman disease, possibly through a mechanism involving epidermal growth factor receptors[ 37 ]. A recent genetic study has suggested that FDC sarcomas associated with unicentric hyaline-vascular Castleman disease show mutations and copy number changes in known oncogenes, tumor suppressors, and chromatin remodeling genes[ 38 ]. In addition, histologically, indolent T-lymphoblastic proliferation is frequently found in FDC sarcomas and shows an association with paraneoplastic autoimmune multiorgan syndrome; this association suggests that neoplastic follicular dendritic cells can recruit or foster the proliferation of immature T cells, which may lead to the occurrence of PNP[ 4 , 22 ].…”

Genetic basis for iMCD-TAFRO

“…The data above identify pathogenic genetic variants in two out of three subjects studied with iMCD-TAFRO. Although, a DNMT3A mutation was previously reported in an iMCD-TAFRO patient [ 11 ], the causative relationship of this mutation to iMCD-TAFRO is uncertain as DNMT3A is frequently mutated in clonal hematopoiesis [ 12 , 13 ]. Another study reported a germline FASL mutation in a family with unicentric Castleman disease and iMCD [ 14 ].…”