Faculty Bibliography

BACKGROUND:Histologic grading using the Fédération Nationale des Centres de Lutte Contre Le Cancer (FNCLCC) system is not universally accepted as applicable to malignant peripheral nerve sheath tumor (MPNST), as its prognostic value is not well established. METHODS:We retrospectively evaluated 99 cases of MPNST to investigate any association between the outcomes overall survival (OS) and progression-free survival (PFS), and predictor variables FNCLCC grade, clinical setting, tumor location, and tumor size at diagnosis using multivariable Cox proportional hazard analysis. RESULTS:Univariable and multivariable analysis demonstrate a statistically significant association between FNCLCC grade and both OS and PFS when comparing tumors by histologic grade. Of note, no deaths were observed in patients with grade 1 MPNST. Other variables associated with unfavorable outcomes include fragmented resection and primary site, with tumors in the extremities having favorable OS, but not PFS, when compared with those in truncal locations. Tumors in the head and neck had favorable PFS, but not OS, compared with those in the trunk. No statistically significant differences in OS or PFS were observed when comparing patient age and sex, tumor size at diagnosis, clinical setting (primary vs. type-1 neurofibromatosis vs. radiation associated) or history of neoadjuvant therapy. Interobserver agreement for FNCLCC grading of these tumors was considered good (S*=0.77, 95% confidence interval: 0.71-0.84). CONCLUSIONS:Association between FNCLCC grading and survival outcomes in MPNST suggests potential value to routinely grading these neoplasms. However, the subjectivity of the grading system, particularly when assigning a tumor differentiation score, may pose a challenge, especially in low and intermediate grade lesions.

BACKGROUND:inhibitors, little is known about the immune microenvironment in relation to patient prognosis. METHODS:We performed a retrospective study of 61 patients with DDLPS. We completed deep sequencing of the T-cell receptor (TCR) β-chain and RNA sequencing for predictive modeling, evaluating both immune markers and tumor escape genes. Hierarchical clustering and recursive partitioning were employed to elucidate relationships of cellular infiltrates within the tumor microenvironment, while an immune score for single markers was created as a predictive tool. RESULTS:(p=0.02). In a composite immune score, CD4+ T cells had the strongest positive predictive value, while CD14+ monocytes and M2 macrophages had the strongest negative predictive values. CONCLUSIONS:Immune cell infiltration predicts clinical outcome in DDLPS, with CD4+ cells associated with better outcomes; CD14+ cells and M2 macrophages are associated with worse outcomes. Future checkpoint inhibitor studies in DDLPS should incorporate immunosequencing and gene expression profiling techniques that can generate immune landscape profiles.

Translocations involving FN1 have been described in a variety of neoplasms that share the presence of a cartilage matrix and may also contain a variable extent of calcification. Fusions of FN1 to FGFR1 or FGFR2 have been reported in nine soft tissue chondromas, mostly demonstrated indirectly by FISH analysis. Delineation of FN1 fusions with various partner genes will facilitate our understanding of the pathogenesis and diagnostic classification of these neoplasms. In this study, we present molecular, clinical, and pathologic features of 12 cartilaginous soft tissue neoplasms showing a predilection for the TMJ region and the distal extremities. We analyzed for gene fusions with precise breakpoints using targeted RNA-seq with a 115-gene panel. We detected gene fusions in ten cases, including three novel fusions, FN1-MERTK, FN1-NTRK1, and FN1-TEK, each in one case, recurrent FN1-FGFR2 fusion in five cases, FN1-FGFR1 in one case, and FGFR1-PLAG1 in one case. The breakpoints in the 5' partner gene FN1 ranged from exons 11-48, retaining the domains of a signal peptide, FN1, FN2, and/or FN3, while the 3' partner genes retained the transmembrane domain, tyrosine kinase (TK) domains, and/or Ig domain. The tumors are generally characterized by nodular/lobular growth of polygonal to stellate cells within a chondroid matrix, often accompanied by various patterns of calcification, resembling those described for the chondroblastoma-like variant of soft tissue chondroma. Additional histologic findings include extensive calcium pyrophosphate dihydrate deposition in two cases and features resembling tenosynovial giant cell tumor (TGCT). Overall, while the tumors from our series show significant morphologic overlap with chondroblastoma-like soft tissue chondroma, we describe findings that expand the morphologic spectrum of these neoplasms and therefore refer to them as "calcified chondroid mesenchymal neoplasms." These neoplasms represent a spectrum of chondroid/cartilage matrix-forming tumors harboring FN1-receptor TK fusions that include those classified as soft tissue chondroma as well as chondroid TGCT.

In this article, we describe a spindle cell neoplasm harboring an EML4-ALK gene fusion presenting as an intraosseous vertebral mass with extension into the adjacent soft tissue in a 65-year-old man. Histologically, the lesion was characterized by the presence of monotonous, cytologically bland spindle cells with loose myxoedematous stroma and interspersed areas of amianthoid-like collagen fiber deposition. Immunohistochemistry demonstrated strong diffuse staining for CD34 and S100, with absent immunoreactivity for SOX10. At 1 year of follow-up after resection, there is no evidence of local recurrence or metastatic disease. This case adds to the clinical and pathologic spectrum of the recently described group of kinase fusion-positive spindle cell neoplasms and represents the first reported intra-osseous example. The presence of ALK rearrangement in this lesion represents a potential therapeutic target, if clinically indicated.