Albert J. H. Suurmeijer

Thoracic fibrous dysplasia (FD) is a benign, osseous chest wall tumor. It originates from bone marrow and accounts for 30–50% of all benign osseous neoplasms in the chest wall. In FD, normal bone marrow is replaced by fibrous stroma and immature bone. We present a rare case in which massive intrathoracic polyostotic FD originating from the rib was diagnosed and treated. The extrathoracic part of the tumor appeared stable and unalarming for decades; however, in hindsight, the intrathoracic part significantly progressed, eventually leading to symptoms. The tumor was removed through a hemi-clamshell approach, which allowed adequate visualization and control of mediastinal structures. After establishing the diagnosis of FD, regular follow-up imaging is crucial for timing of a surgical intervention to prevent symptoms, impairment of quality of life, and unnecessarily complex resections.

Mesenchymal spindle cell tumors with kinase fusions, often presenting in superficial or deep soft tissue locations, may rarely occur in bone. Herein, we describe the clinicopathologic and molecular data of eight bone tumors characterized by various kinase fusions from our files and incorporate the findings with the previously reported seven cases, mainly as single case reports. In the current series all but one of the patients were young children or teenagers, with an age range from newborn to 59 years (mean 19 years). Most tumors (n = 5) presented in the head and neck area (skull base, mastoid, maxilla, and mandible), and remaining three in the tibia, pelvic bone, and chest wall. The fusions included NTRK1 (n = 3), RET (n = 2), NTRK3 (n = 2), and BRAF (n = 1). In the combined series (n = 15), most tumors (73%) occurred in children and young adults (NTRK3 (n = 6), NTRK1 (n = 4), RET (n = 2), BRAF (n = 2), and RAF1 (n = 1). All fusions confirmed by targeted RNA sequencing were in‐frame and retained the kinase domain within the fusion oncoprotein. Similar to the soft tissue counterparts, most NTRK3‐positive bone tumors in this series showed high‐grade morphology (5/6), whereas the majority of NTRK1 tumors were low‐grade (3/4). Notably, all four tumors presenting in the elderly were high‐grade spindle cell sarcomas, with adult fibrosarcoma (FS)‐like, malignant peripheral nerve sheath tumor (MPNST)‐like and MPNST phenotypes. Overall, 10 tumors had high‐grade morphology, ranging from infantile and adult‐types FS, MPNST‐like, and MPNST, whereas five showed benign/low‐grade histology (MPNST‐like and myxoma‐like). Immunohistochemically (IHC), S100 and CD34 positivity was noted in 57% and 50%, respectively, while co‐expression of S100 and CD34 in 43% of cases. One‐third of tumors (4 high grade and the myxoma‐like) were negative for both S100 and CD34. IHC for Pan‐TRK was positive in all eight NTRK‐fusion positive tumors tested and negative in two tumors with other kinase fusions. Clinical follow‐up was too limited to allow general conclusions.

The classification of many soft tissue tumors remains subjective due their rarity, significant overlap in microscopic features and often a non‐specific immunohistochemical (IHC) profile. The application of molecular genetic tools, which leverage the underlying molecular pathogenesis of these neoplasms, have considerably improved the diagnostic abilities of pathologists and refined classification based on objective molecular markers. In this study, we describe the results of an international collaboration conducted over a 3‐year period, assessing the added diagnostic value of applying molecular genetics to sarcoma expert pathologic review in a selected series of 84 uncommon, mostly unclassifiable mesenchymal tumors, 74 of which originated in soft tissues and 10 in bone. The case mix (71% historical, 29% contemporary) included mostly unusual and challenging soft tissue tumors, which remained unclassified even with the benefit of expert review and routine ancillary methods, including broad IHC panels and a limited number of commercially available fluorescence in situ hybridization (FISH) probes. All cases were further tested by FISH using a wide range of custom bacterial artificial chromosome probes covering most of known fusions in sarcomas, whereas targeted RNA sequencing was performed in 13 cases negative by FISH, for potential discovery of novel fusion genes. Tumor‐defining molecular alterations were found in 48/84 tumors (57%). In 27 (32%) cases the tumor diagnosis was refined or revised by the additional molecular work‐up, including five cases (6%), in which the updated diagnosis had clinical implications. Sarcoma classification is rapidly evolving due to an increased molecular characterization of these neoplasms, so unsurprisingly 17% of the tumors in this series harbored abnormalities only very recently described as defining novel molecularly defined soft tissue tumor subsets.

Cisplatin sensitivity in TC cells and RTK validation on western blot

MTORC1/2 downstream pathway evaluation in Tera cells

MTOR knock down in combination with cisplatin in resistant TC cells