Abstract
Follicular dendritic cell (FDC) sarcomas are rare mesenchymal tumors with variable clinical, morphologic, and phenotypic characteristics. Transcriptome analysis was performed on multiple FDC sarcomas and compared with other mesenchymal tumors, microdissected Castleman FDCs, and normal fibroblasts. Using unsupervised analysis, FDC sarcomas clustered with microdissected FDCs, distinct from other mesenchymal tumors and fibroblasts. The specific endowment of FDC-related gene expression programs in FDC sarcomas emerged by applying a gene signature of differentially expressed genes (n = 1,289) between microdissected FDCs and fibroblasts. Supervised analysis comparing FDC sarcomas with microdissected FDCs and other mesenchymal tumors identified 370 and 2,927 differentially expressed transcripts, respectively, and on the basis of pathway enrichment analysis ascribed to signal transduction, chromatin organization, and extracellular matrix organization programs. As the transcriptome of FDC sarcomas retained similarity with FDCs, the immune landscape of FDC sarcoma was investigated by applying the CIBERSORT algorithm to FDC sarcomas and non-FDC mesenchymal tumors and demonstrated that FDC sarcomas were enriched in T follicular helper (TFH) and T regulatory (TREG) cell populations, as confirmed in situ by immunohistochemistry. The enrichment in specific T-cell subsets prompted investigating the mRNA expression of the inhibitory immune receptor PD-1 and its ligands PD-L1 and PD-L2, which were found to be significantly upregulated in FDC sarcomas as compared with other mesenchymal tumors, a finding also confirmed in situ Here, it is demonstrated for the first time the transcriptional relationship of FDC sarcomas with nonmalignant FDCs and their distinction from other mesenchymal tumors.Implications: The current study provides evidence of a peculiar immune microenvironment associated with FDC sarcomas that may have clinical utility. Mol Cancer Res; 15(5); 541-52. ©2017 AACR.
Highlights
Follicular dendritic cell (FDC) sarcomas are rare malignancies first described by Monda and colleagues [1], characterized by a rather variable clinical presentation and a high degree of morphologic and immunophenotypical heterogeneity [2]
We first adopted an unsupervised hierarchical clustering approach to determine whether the transcriptional profile of the 29 FDC sarcomas had significant overlap with that of other mesenchymal tumors, which encompassed 3 cases of desmoid-type fibromatosis, 8 cases of dermatofibrosarcoma protuberans, 3 low-grade fibromyxoid sarcomas, 6 inflammatory myofibroblastic tumors (4 ALKþ, 2 ALKÀ), and 12 solitary fibrous tumors
Tumor cell–enriched cores from FDC sarcomas showed conspicuous reactivity for PD-L1 in more than 60% of cases whereas cores from other mesenchymal tumors displayed detectable PD-L1 in only 4% of cases (Fig. 5E; Supplementary table S9). These results indicate that FDC sarcomas have a peculiar immunological microenvironment that is contributed by functionally specialized T-cell populations, namely T follicular helper (TFH) and T regulatory (TREG), and that can fall under the influence of the PD-1 and PD-L1/2 axis
Summary
Follicular dendritic cell (FDC) sarcomas are rare malignancies first described by Monda and colleagues [1], characterized by a rather variable clinical presentation and a high degree of morphologic and immunophenotypical heterogeneity [2]. FDC sarcoma presents with lymph node disease in 31% of cases, extranodal disease in 58%, and both nodal and extranodal disease in 10% [3]. Cervical nodes are most often affected in nodal presentation. A wide variety of extranodal sites can be affected, most commonly tonsil, gastrointestinal tract, soft tissue, mediastinum, retroperitoneum, omentum, skin, and lung [4]. The clinical behavior is generally indolent with nearly 10% of patients dying.
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