Head and Neck Mesenchymal Tumors with Kinase Fusions:A Report of 15 Cases with Emphasis on Wide Anatomic Distribution and Diverse Histologic Appearance

Mesenchymal tumors harboring various kinase fusions were recently recognized as emerging entities mainly in the soft tissues. We herein investigate the clinicopathologic and molecular characteristics of head and neck mesenchymal tumors harboring kinase fusions. The study cohort included 15 patients with a median age of 13 years (ranging from congenital to 63 y). The kinase genes involved in descending order were NTRK1 (n=6), NTRK3 (n=5), BRAF (n=2), and 1 each with MET, and RET. The anatomic locations were broad involving all tissue planes, including skin (n=4), intraosseous (n=4), major salivary glands (n=2), sinonasal tract (n=2), soft tissue of face or neck (n=2), and oral cavity (n=1). The histologic spectrum ranged from benign to high grade, in descending order including tumors resembling malignant peripheral nerve sheath tumor (MPNST)-like, fibrosarcoma (infantile or adult-type), lipofibromatosis-like neural tumor (LPFNT), inflammatory myofibroblastic tumor-like, and a novel phenotype resembling myxoma. Perivascular hyalinization/stromal keloid-like collagen bands and staghorn vasculature were common features in MPNST-like and LPFNT-like tumors. Two tumors (1 each with NTRK1 or BRAF rearrangement) were classified as high grade. By immunohistochemistry, S100 and CD34 positivity was noted in 71% and 60%, frequently in MPNST-like and LPFNT-like phenotypes. Pan-TRK was a sensitive marker for NTRK-translocated tumors but was negative in tumor with other kinase fusions. One patient with a high-grade tumor developed distant metastasis. Molecular testing for various kinase fusions should be considered for S100+/CD34+ spindle cell neoplasms with perivascular hyalinization and staghorn vessels, as pan-TRK positivity is seen only in NTRK fusions.</p

Diagnostic yield of NanoString nCounter FusionPlex profiling in soft tissue tumors

Diagnostic histopathology of soft tissue tumors can be troublesome as many entities are quite rare and have overlapping morphologic features. Many soft tissue tumors harbor tumor-defining gene translocations, which may provide an important ancillary tool for tumor diagnosis. The NanoString nCounter platform enables multiplex detection of pre-defined gene fusion transcripts in formalin-fixed and paraffin-embedded tissue. A cohort of 104 soft tissue tumors representing 20 different histological types was analyzed for the expression of 174 unique gene fusion transcripts. A tumor-defining gene fusion transcript was detected in 60 cases (58%). Sensitivity and specificity of the NanoString assay calculated against the result of an alternative molecular method were 85% and 100%, respectively. Highest diagnostic coverage was obtained for Ewing sarcoma, synovial sarcoma, myxoid liposarcoma, alveolar rhabdomyosarcoma, and desmoplastic small round cell tumor. For these tumor types, the NanoString assay is a rapid, cost-effective, sensitive, and specific ancillary screening tool for molecular diagnosis. For other sarcomas, additional molecular testing may be required when a translocation transcript is not identified with the current 174 gene fusion panel

Head and neck rhabdomyosarcoma with TFCP2 fusions and ALK overexpression:a clinicopathological and molecular analysis of 11 cases

Aims Primary intraosseous rhabdomyosarcoma (RMS) is a rare entity defined by EWSR1/FUS-TFCP2 or, less commonly, MEIS1-NCOA2 fusions. The lesions often show a hybrid spindle and epithelioid phenotype, frequently coexpress myogenic markers, ALK, and cytokeratin, and show a striking propensity for the pelvic and craniofacial bones. The aim of this study was to investigate the clinicopathological and molecular features of 11 head and neck RMSs (HNRMSs) characterised by the genetic alterations described in intraosseous RMS. Methods and results The molecular abnormalities were analysed with fluorescence in-situ hybridisation and/or targeted RNA/DNA sequencing. Seven cases had FUS-TFCP2 fusions, four had EWSR1-TFCP2 fusions, and none had MEIS1-NCOA2 fusions. All except one case were intraosseous, affecting the mandible (n = 4), maxilla (n = 3), and skull (n = 3). One case occurred in the superficial soft tissue of the neck. The median age was 29 years (range, 16-74 years), with an equal sex distribution. All tumours showed mixed epithelioid and spindle morphology. Immunohistochemical coexpression of desmin, myogenin, MyoD1, ALK, and cytokeratin was seen in most cases. An intragenic ALK deletion was seen in 43% of cases. Regional and distant spread were seen in three and four patients, respectively. Two patients died of their disease. Conclusions We herein present the largest series of HNRMSs with TFCP2 fusions to date. The findings show a strong predilection for the skeleton in young adults, although we also report an extraosseous case. The tumours are characterised by a distinctive spindle and epithelioid phenotype and a peculiar immunoprofile, with coexpression of myogenic markers, epithelial markers, and ALK. They are associated with a poor prognosis, including regional or distant spread and disease-related death

Variant WWTR1 gene fusions in epithelioid hemangioendothelioma-A genetic subset associated with cardiac involvement

The genetic hallmark of epithelioid hemangioendothelioma (EHE) is a recurrent WWTR1-CAMTA1 fusion, which is present in most cases bearing a conventional histology. A subset of cases is characterized by a distinct morphology and harbors instead a YAP1-TFE3 fusion. Nevertheless, isolated cases lack these canonical fusions and remain difficult to classify. Triggered by an index case of a left atrial mass in a 76-year-old female with morphologic features typical of EHE, but which showed an WWTR1-MAML2 fusion by targeted RNA sequencing, we searched our files for similar cases displaying alternative WWTR1 fusions. A total of 6 EHE cases were identified with variant WWTR1 fusions, four of them presenting within the heart. There were 3 females and 3 males, with a wide age range at diagnosis (21–76 years, mean 62, median 69). The 4 cardiac cases occurred in older adults (mean age of 72, equal gender distribution), three involved the left atrium and one the right ventricle. One case presented in the vertebral bone and one in pelvic soft tissue. Microscopically, all tumors had morphologic features within the spectrum of classic EHE; two of the cases appeared overtly malignant. All cases were tested by FISH and 4 were investigated by targeted RNA sequencing. Two tumors harbored WWTR1-MAML2 fusions, one WWTR1-ACTL6A, and in 3 cases no WWTR1 partner was identified. Of the 4 patients with follow-up, 2 died of disease, one was alive with lung metastases, and the only patient free of disease was s/p resection of a T11 vertebral mass. Our findings report on additional genetic variants involving WWTR1 rearrangements, with WWTR1-MAML2 being a recurrent event, in a small subset of EHE, which appears to have predilection for heart

Epithelioid hemangioma of bone harboring FOS and FOSB gene rearrangements:A clinicopathologic and molecular study

The diagnosis of epithelioid hemangioma (EH) remains challenging due to its rarity, worrisome histologic features and locally aggressive clinical and radiographic presentation. Especially in the bone, EH can be misdiagnosed as a malignant vascular neoplasm due its lytic, often destructive or multifocal growth, as well as atypical morphology. The discovery of recurrent FOS and FOSB gene fusions in the pathogenesis of most EH has strengthened its stand-alone classification, distinct from other malignant epithelioid vascular lesions, such as epithelioid hemangioendothelioma or angiosarcoma. In this study we investigate a group of molecularly confirmed skeletal EH by the presence of FOS or FOSB gene rearrangements to better define its clinical and pathologic characteristics within a homogenous molecular subset. The cohort included 38 patients (25 males, 13 females), with a mean age at diagnosis of 38 years (range, 4–75). Regional, multifocal presentation was noted in 10 cases. Only six cases were correctly recognized as EH by the referring institutions, while most were misdiagnosed as other vascular tumors. Of the 17 patients with follow-up data available, 5 patients (29%) developed local recurrence after marginal en bloc excision (n = 3) or curettage (n = 2). Local recurrence-free survival rates were 84% at 3 years and 38% at 5 years. No metastasis or disease-related death was identified. Imaging studies exhibited no specific features, showing cortical bone destruction and soft-tissue extension in 14 (38%) cases. FOS gene rearrangements were detected in 28 (74%) of cases, while FOSB rearrangements in 10 (26%) cases. Our results highlight the significant challenges encountered in establishing a correct diagnosis exclusive of the molecular testing, mainly due to its overlap to other malignant epithelioid vascular tumors. Skeletal EH emerges as a genetically defined locally aggressive vascular neoplasm, with a high rate of local recurrence, but lacking the propensity for distant spread

MRI after Whoops procedure:diagnostic value for residual sarcoma and predictive value for an incomplete second resection

OBJECTIVE: To determine the value of MRI for the detection and assessment of the anatomic extent of residual sarcoma after a Whoops procedure (unplanned sarcoma resection) and its utility for the prediction of an incomplete second resection. MATERIALS AND METHODS: This study included consecutive patients who underwent a Whoops procedure, successively followed by gadolinium chelate-enhanced MRI and second surgery at a tertiary care sarcoma center. RESULTS: Twenty-six patients were included, of whom 19 with residual tumor at the second surgery and 8 with an incomplete second resection (R1: n = 6 and R2: n = 2). Interobserver agreement for residual tumor at MRI after a Whoops procedure was perfect (κ value: 1.000). MRI achieved a sensitivity of 47.4% (9/19), a specificity of 100% (7/7), a positive predictive value of 100% (9/9), and a negative predictive value of 70.0% (7/17) for the detection of residual tumor. MRI correctly classified 2 of 19 residual sarcomas as deep-seated (i.e., extending beyond the superficial muscle fascia) but failed to correctly classify 3 of 19 residual sarcomas as deep-seated. There were no significant associations between MRI findings (presence of residual tumor, maximum tumor diameter, anatomic tumor extent, tumor margins, tumor spiculae, and tumor tail on the superficial fascia) with an incomplete (R1 or R2) second resection. CONCLUSION: Gadolinium chelate-enhanced MRI is a reproducible method to rule in residual sarcoma, but it is insufficiently accurate to rule out and assess the anatomic extent or residual sarcoma after a Whoops procedure. Furthermore, MRI has no utility in predicting an incomplete second resection

Hip fracture after radiofrequency ablation therapy for bone tumors: two case reports

Radiofrequency ablation (RFA) has become a valuable therapeutic modality in cancer treatment over the last decade. In orthopedic surgery, RFA is used for the treatment of benign bone tumors and bone metastases. Complications are rare and, to our knowledge, bone fracture as a complication due solely to RFA has not been reported to date. In this report we describe two patients with a fracture in the calcar region of the femur as a complication of RFA treatment for bone malignancies. Since RFA is applied increasingly often, it is important to report this risk of fracture as a complication of treatment of lesions in the femoral calcar