High-grade Spindle Cell Sarcoma Research Articles

Incidental Finding of Spindle Cell Sarcoma on 68Ga-PSMA-11 PET/CT.

A 78-year-old man underwent 68Ga-prostate-specific membrane antigen-11 (PSMA-11) PET/CT for biochemical recurrence of prostate adenocarcinoma following a simple prostatectomy. The scan showed PSMA-avid local recurrence within the prostatectomy bed and a suspicious right internal iliac nodal metastasis. In addition, there was a mildly avid subcutaneous lesion in the right flank, which revealed high-grade spindle cell sarcoma at histopathology. This case represents a potential pitfall for PSMA-11 PET imaging. The presentation of mildly avid, atypical soft tissue lesions should warrant a biopsy to allow for proper diagnosis and treatment management.

Malignant peripheral nerve sheath tumor (MPNST) and MPNST-like entities are defined by a specific DNA methylation profile in pediatric and juvenile population

BackgroundMalignant peripheral nerve sheath tumors (MPNSTs) account for 3–10% of pediatric sarcomas, 50% of which occur in neurofibromatosis type 1 (NF1). Sporadic MPNSTs diagnosis may be challenging due to the absence of specific markers, apart from immunohistochemical H3K27me3 loss. DNA methylation (DNAm) profiling is a useful tool for brain and mesenchymal neoplasms categorization, and MPNSTs exhibit a specific DNAm signature. An MPNST-like group has recently been recognized, including pediatric tumors with retained H3K27me3 mark and clinical/histological features not yet well explored. This study aims to characterize the DNAm profile of pediatric/juvenile MPNSTs/MPNST-like entities and its diagnostic/prognostic relevance.ResultsWe studied 42 tumors from two groups. Group 1 included 32 tumors histologically diagnosed as atypical neurofibroma (ANF) (N = 5) or MPNST (N = 27); group 2 comprised 10 tumors classified as MPNST-like according to Heidelberg sarcoma classifier. We performed further immunohistochemical and molecular tests to reach an integrated diagnosis. In group 1, DNAm profiling was inconclusive for ANF; while, it confirmed the original diagnosis in 12/27 MPNSTs, all occurring in NF1 patients. Five/27 MPNSTs were classified as MPNST-like: Integrated diagnosis confirmed MPNST identity for 3 cases; while, the immunophenotype supported the change to high-grade undifferentiated spindle cell sarcoma in 2 samples. The remaining 10/27 MPNSTs variably classified as schwannoma, osteosarcoma, BCOR-altered sarcoma, rhabdomyosarcoma (RMS)-MYOD1 mutant, RMS-like, and embryonal RMS or did not match with any defined entity. Molecular analysis and histologic review confirmed the diagnoses of BCOR, RMS-MYOD1 mutant, DICER1-syndrome and ERMS. Group 2 samples included 5 high-grade undifferentiated sarcomas/MPNSTs and 5 low-grade mesenchymal neoplasms. Two high-grade and 4 low-grade lesions harbored tyrosine kinase (TRK) gene fusions.By HDBSCAN clustering analysis of the whole cohort we identified two clusters mainly distinguished by H3K27me3 epigenetic signature. Exploring the copy number variation, high-grade tumors showed frequent chromosomal aberrations and CDKN2A/B loss significantly impacted on survival in the MPNSTs cohort.ConclusionDNAm profiling is a useful tool in diagnostic work-up of MPNSTs. Its application in a retrospective series collected during pre-molecular era contributed to classify morphologic mimics. The methylation group MPNST-like is a ‘hybrid’ category in pediatrics including high-grade and low-grade tumors mainly characterized by TRK alterations.

Primary Cardiac Tumours: A Series of Four Cases

Primary cardiac tumours are uncommon, and approximately 90% of them, in both children and adults, are benign. Primary tumours are less prevalent than secondary malignancies that spread to the heart. The subtle and non specific nature of the clinical signs could cause a delay in diagnosis, as well as surgical treatment. Although epidemiology and multimodality imaging approaches are helpful, the definitive diagnosis often necessitates histologic evaluation, and histological characterisation continues to be the gold standard in diagnostics. Herein the authors described four (two males and two females) cases of intriguing primary cardiac tumours. All the cases were diagnosed to have a cardiac mass/clot by Echocardiography (Echo), and the cases underwent tumour excision. Histopathological analysis revealed three benign cases diagnosed as atrial myomas, and one malignant case diagnosed as high-grade spindle cell sarcoma, specifically rhabdomyosarcoma. Immunohistochemistry (IHC) was required for the definitive diagnosis of the malignant patient. All the patients were followed-up for a period of one year. All benign cases were symptom- free, while the patient who had rhabdomyosarcoma expired. The aim of the present case series was to highlight the importance of histopathological examination, as well as the prognosis of cardiac tumours.

Primary Carcinosarcoma of the Pancreas with Focal Cartilaginous Differentiation

Abstract Introduction/Objective Carcinosarcoma is a neoplasm reported in multiple sites with a biphasic pattern sharing both sarcomatous and epithelial morphology. Each component should constitute 30% of the neoplasm to qualify as carcinosarcoma, according to the World Health Organization (WHO) classification. This subtype of malignancy is most frequently found in the uterus but carcinosarcoma of the pancreas is extremely rare. It is a very aggressive tumor with a low survival rate. Methods/Case Report A 76-year-old Caucasian man with a history of hypertension was admitted to the emergency department with new-onset atrial fibrillation and ischemic stroke 5 months ago. Initial workup showed "moth-eaten" lesions in the skull base and clivus bone, suggesting malignancy. The further evaluation led to chest/abdomen and pelvis CT scans, revealing a subtle attenuation in the pancreatic tail. MRI of the abdomen showed a pancreatic tail mass concerning pancreatic cancer. CA19-9 and CEA were elevated (133 U/ mL, and 10 ng/ mL, respectively). Endoscopic ultrasound was performed and showed a 2 cm mass in the tail of the pancreas and fine needle aspiration (FNA) confirmed malignancy with a diagnosis of adenocarcinoma. The patient received neoadjuvant chemotherapy with gemcitabine and paclitaxel and underwent distal pancreatectomy, splenectomy, and left adrenalectomy. Histopathologic examination revealed a biphasic neoplasm with moderately differentiated adenocarcinoma and abruptly transitioning spindle cell malignancy with focal cartilaginous differentiation. Due to the presence of focal cartilaginous differentiation, no immunohistochemistry (IHC) was required and a final diagnosis of carcinosarcoma of the pancreas with multiple lymph node involvement (ypT2, pN2) was made. Results (if a Case Study enter NA) NA Conclusion Carcinosarcoma is a neoplasm of mixed epithelial and mesenchymal-like tumor cells on pathologic examination. IHC is often very helpful for correct diagnosis, especially Cytokeratin and CEA. In this case, due to the presence of high-grade spindle cell sarcoma and cartilaginous differentiation, no IHC is required. Surgical resection is the definitive treatment for operable patients and is recommended when possible. In this case, only the adenocarcinoma component was identified preoperatively on FNA, and standard pancreatic adenocarcinoma neoadjuvant chemotherapy was also utilized in treatment.

Abstract 14216: Acute Heart Failure and Mitral Stenosis in a Patient With Spindle Cell Sarcoma of the Mitral Valve

A 27-year-old male with no past medical history presented with a productive cough, intermittent hemoptysis, dyspnea, orthopnea, and lower extremity edema. He underwent an echocardiogram that was significant for a large 6.2 cm x 3.5 cm left atrial mass moving into the left ventricle across the mitral valve concerning for a myxoma. Other pertinent findings were an ejection fraction of 50-55%, severe mitral stenosis with a mean mitral valve gradient of 23, severely reduced right heart function, and severe tricuspid regurgitation. Cardiovascular surgery was consulted for evaluation of atrial mass. He underwent left atrial mass resection. The left atrial mass was attached to the mitral valve, so the mitral valve was repaired with Onyx mechanical valve. After the surgery, there was a significant improvement in right heart function, mitral valve gradient, and velocities were within the expected range. Pathology from atrial mass back with high-grade spindle cell sarcoma so Oncology was consulted. Further studies were negative for metastatic spread. He was started on adjuvant chemotherapy and currently, he is undergoing his fourth cycle. Follow-up TEE six months later noted a left atrial mass located in or where the left atrial appendage should be approximately that was 2.5cm x 1.5cm concerning for recurrence of his sarcoma. This case demonstrates a rare primary cardiac tumor, spindle cell sarcoma, which is generally aggressive and therefore has a poor prognosis. The clinical symptoms are more related to the location of the sarcoma than the histopathology. Depending on location, cardiac sarcomas generally present with heart failure as in this patient. About 25% of cardiac tumors are malignant with the majority of those being sarcomas. Initial evaluation of primary cardiac sarcomas should include echocardiography. The primary treatment is surgical resection of the mass with adjuvant chemotherapy, however, there is a high rate of recurrence and metastatic spread.

Synovial Sarcoma of Cheek: A Rare Case Report with Review of Literature.

Synovial sarcomas are a rare entity in the head and neck region. We present a rare case of a 50year old female presenting with a painless mass over right cheek since one year which gradually increased in size since past two months. Imaging was done which revealed a mass lesion in soft tissue of right cheek deep to the masseter muscle with no obvious involvement of the adjacent part of maxilla and mandible. Local wide excision of tumor was done. Histopathological examination revealed a malignant mesenchymal tumour. Further the specimen was subjected to immunohistochemical marker studies and diagnosis of high grade spindle cell sarcoma possibly synovial sarcoma was given. Patient then received Image guided radiation therapy and along with platinum based chemotherapy. Patient tolerated the treatment well. Patient was followed up for one year after completion of treatment and no recurrence was observed.

S2408 A Case of Advanced Esophageal Carcinosarcoma

Introduction: The majority of esophageal cancers are classified histologically as squamous cell carcinomas or adenocarcinomas. We present a case of a 69-year-old man, presented with progressive dysphagia, found to have an esophageal carcinosarcoma, a rare etiology of esophageal cancer. Case Description/Methods: A 69-year-old man, an everyday smoker with a history of ongoing alcohol use, presented for the evaluation of unintentional weight loss and progressive dysphagia of 2 months duration. Upper endoscopy revealed a large, 6 cm in diameter, partially obstructing ulcerating mass in the mid esophagus. PET/CT revealed intense FDG uptake in the esophageal mass, mediastinal lymph nodes, T6 and T10 ribs suggestive of metastatic disease. Surgical pathology of the tumor was consistent with a high grade squamous cell carcinoma mixed with a high grade spindle cell sarcoma (carcinosarcoma). The patient was started on chemoradiation including Paclitaxel, Carboplatin. Improvement of symptoms and CT findings was documented with treatment (Figure). Discussion: Esophageal cancer ranks seventh in incidence and sixth in cancer-related mortality. The majority of esophageal cancers are classified histologically as squamous cell carcinomas or adenocarcinomas. When 2 distinct malignant components, both carcinomatous and sarcomatous are present histologically, the tumor is classified as esophageal carcinosarcoma (ECS). The pathogenesis is debatable, with some arguing that it is an initial carcinoma, facilitating a simultaneous secondary development of sarcoma, while others hypothesize a single cell origin. Carcinosarcomas were documented in tumors of the uterus, breast, thyroid, lung and gastrointestinal tract. ECSs have a rare incidence, accounting for approximately 1.5% of all esophageal tumors. It has been noted that ECS tumors have different clinical behaviors when compared to squamous cell carcinomas or adenocarcinomas. ECS tumors were noted to have a calculated doubling time of 2.2 months, with predominantly exogenous polypoid growth, perhaps explaining the earlier symptom of dysphagia, earlier diagnosis and more favorable 5 year survival rate. Given their rarity, no standard protocol has been developed to treat ECS tumors. Resection, regional lymph node dissection, radiotherapy and chemotherapy have all been utilized. Our case presentation further enriches the literature regarding rare, advanced esophageal adenocarcinoma tumors responding to systemic therapy.Figure 1.: A, B - Endoscopic findings. A large protruding, 6 cm in diameter partially obstructing ulcerating mass in the mid esophagus. C - Intense FDG uptake by the esophageal tumor in the esophagus (green arrow) and intense FDG uptake in the posterior/lateral aspect of the right T6 rib (yellow circle). D - Intensely avid subcarinal lymph node (yellow circle).

Secondary Malignancy in Giant Cell Tumor: A Single-Center Study.

Giant cell tumor of bone (GCTB) undergoes a sarcomatous transformation. Secondary malignancy in giant cell tumor (MGCT) is associated with radiotherapy and has a dismal prognosis. We reviewed medical records to investigate the clinicopathological characteristics and prognosis of MGCT patients. The enrollment criterion was high-grade spindle-cell sarcoma, which developed at the site of prior GCTB treatment. Twelve patients were analyzed: six females and six males. The median age was 42.5 years. Benign recurrence occurred in five GCTB patients not treated with radiotherapy. No pulmonary implants were observed. The median latency to the malignant transformation was 63 months. Nine patients were AJCC stage IIB, and three were stage IVA. The median follow-up period after malignant transformation was 62.5 months. Five patients developed local recurrence, and six had distant metastasis. Five-year overall recurrence and metastasis-free survival rates were 61.9%, 66.7%, and 58.3%, respectively. Initial metastasis was a predictive factor for overall survival. Benign local recurrence of GCTB was also a negative factor for metastasis-free survival of MGCT patients. Differences in overall survival according to benign recurrence also showed a tendency toward significance. In our series, secondary MGCT did not occur after radiotherapy. The prognosis was better than previous findings. Benign recurrence of GCTB could reflect the prognosis of MGCT.

Neuregulin 1 (NRG1) fusion-positive high-grade spindle cell sarcoma: A distinct group of soft tissue tumors with metastatic potential.

Neuregulin 1 (NRG1) is an epidermal growth factor (EGF)-like ligand that activates receptor tyrosine kinases of the ErbB family of receptors. NRG1 gene fusions, which are rare (<1%) but recurrent events in solid tumors, are an emerging oncogenic driver that is potentially actionable using ErbB-targeted tyrosine kinase inhibitors. Largely characterized only in carcinomas, we describe three cases of NRG1-rearranged sarcomas. The patients were all female, aged 32-47 years old. Two cases were deep-seated tumors in the lower extremities (right thigh and calf); one case presented as a uterine mass. The tumors measured 9-11.5 cm in the greatest dimensions. Histologically, all three tumors were high-grade spindle cell sarcomas composed of monomorphic spindle cells arranged in interlacing fascicles. The tumor cells were set in the loose collagenous stroma with branching, curvilinear thin-walled vasculature in the background. Cytologically, the neoplastic cells displayed ovoid to fusiform nuclei with finely stippled chromatin, inconspicuous nucleoli, scant to moderate clear to eosinophilic cytoplasm, occasional cytoplasmic vacuoles, and elongated cytoplasmic processes. Mitotic activity was elevated (> 20/10 high power fields) and tumor necrosis was present. None of the tumors expressed lineage-specific immunophenotypical markers. Targeted RNA-sequencing uncovered gene fusions involving NRG1 and the 5' untranslated regions of PPHLN1, HMBOX1, or MTUS1. In all cases, the C-terminal EGF-like domain of NRG1 was preserved in the predicted chimeric protein product. All three patients developed metastatic disease within 2 years from initial presentation and were alive with disease at last follow-up (mean follow-up period=19 months). In conclusion, we present the first case series of NRG1-rearranged sarcomas characterized by high-grade fascicular spindle cell morphology, non-specific immunoprofile, and aggressive clinical behavior. Further studies are needed to determine whether this distinct subgroup of spindle cell sarcomas are amenable to targeted therapies.

Clinicopathological features of malignant mixed mesodermal tumor: analysis of 50 cases

Objective: To investigate the clinicpathological, immunohistochemical and molecular genetic features of malignant mixed mesodermal tumor (MMMT) in the female reproductive system. Methods: To analyze its histopathological characteristics, we performed a retrospective review of the MMMT cases diagnosed at PLA General Hospital, Beijing, China during 2005-2019 using its surgical and pathological databases. EnVision immunohistochemical staining was used to detect the expression of ER, PR, p16, p53 and MMR proteins. Results: Fifty cases were conformed to the diagnosis, including 29 cases originated in the uterus, 16 cases in ovary, 4 cases of synchronous occurrence in uterus and ovary, 1 case in cervix. The tumor was histologically composed of two components, namely carcinoma and sarcoma ones, with clear borderline or blend mutually. The proportion of cancer component in the whole tumor ranged from 5%-90%. The proportion of carcinoma was more than 50% in 76% of the cases, and less than 50% in 24% of cases, including 2 cases with<10% of carcinoma. In the cases of primary uterine MMMT, the main carcinoma type was high grade endometrioid carcinoma (55%, 16/29). In ovarian MMMT, the main carcinoma type was serous carcinoma (12/16), while that of cervical MMMT was squamous cell carcinoma. The others were clear cell carcinoma or the undifferentiated carcinoma. There was one carcinoma type in most cases, only 7 cases had two carcinoma types. Homologous sarcomas, including stromal sarcoma, leiomyosarcoma and high-grade spindle cell sarcomas, were more commonly found in uterine MMMT (72.4%, 21/29). While heterogenic sarcomas, including chondrosarcoma, osteosarcoma and rhabdomyosarcoma, were more commonly noted in ovarian MMMT (12/16) than MMMT of other sites. There were 10 cases that consisted of two types of sarcomas. The synchronous MMMT of uterus and ovary had similar morphology and the types of carcinoma and sarcoma. The tumor cells that spread or metastasized to lymph node, omentum, intestinal wall or skin were all carcinoma cells, and were morphologically consistent with the original tumors. Immunohistochemically, ER and PR were both negative (23/25 in uterine, 8/10 in ovarian tumors). p16 was strongly positive (11/11 in uterine tumors, and 6/6 in ovarian tumors), with similar expression patterns in the carcinoma and sarcoma components. p53 showed mutant-type staining (64%, 21/33) and expressed synchronously in carcinoma and sarcoma components. p53 mutation was found in 35% cases of endometrial carcinoma and 46.7% cases of non-endometrial carcinoma. p53 mutation was also found in only 31.8% cases of heterogenic sarcomas, but in 50% of non-heterogenic sarcomas. Twenty-eight cases (28/33, 85%) presented intact mismatch repair proteins, while 5 cases (5/33, 15%) presented deficient mismatch repair proteins. Conclusions: MMMT in female reproductive system is a rare high-grade biphasic tumor with complex and diverse morphology. The immunohistochemical features are characterized by negative ER/PR and strongly positive p16, mostly mutant p53 and proficient mismatch repair proteins. The patients with a high FIGO stage have worse prognosis.

Giant Myxoid Spindle Cell Neoplasm Presenting with Abdominal Swelling and Concurrent Weight Loss

Retroperitoneal sarcomas may grow extremely large before becoming clinically symptomatic, and curative resection often has high associated morbidity. An 83-year-old man presented with insidious-onset abdominal pain and weight loss owing to a 16.3× 13.1× 25.8-cm retroperitoneal high-grade myxoid spindle cell sarcoma. The patient was ultimately deemed to be unfit for surgery before rapidly succumbing to his disease. This case illustrates both the indolent growth seen in these lesions and the importance of proper patient selection. Older patients with large, high-grade lesions and multiple associated comorbidities are often poor surgical candidates, as the associated surgical morbidity outweighs the potential survival benefit. While the ultimate treatment plan relies on shared decision making by the patient and the healthcare provider, the decision to pursue surgical intervention should take into consideration the patient's broader clinical condition.

Mesenchymal tumors of the gastrointestinal tract with NTRK rearrangements: a clinicopathological, immunophenotypic, and molecular study of eight cases, emphasizing their distinction from gastrointestinal stromal tumor (GIST)

Mesenchymal tumors driven by NTRK fusions are clinically and morphologically heterogeneous. With an increasing number of clinicopathological entities being associated with NTRK fusions, the diagnostic and predictive value of the identification of NTRK fusions is uncertain. Recently, mesenchymal tumors in the gastrointestinal tract with NTRK fusions were described as gastrointestinal stromal tumors (GIST), but the nosology of such neoplasms remains controversial. We report eight mesenchymal tumors involving the gastrointestinal tract with NTRK1 or NTRK3 rearrangements. The tumors occurred in six children and two adults, five males and three females (age range 2 months–55 years; median 3.5 years), and involved the small intestine (n = 4), stomach (n = 2), rectum (n = 1), and mesentery (n = 1). Clinical outcomes were variable, ranging from relatively indolent (n = 2) to aggressive diseases (n = 2). Morphologically, the tumors were heterogeneous and could be classified in the following three groups: (1) infantile fibrosarcoma involving the gastrointestinal tract (n = 4), enriched for NTRK3 fusions; (2) low-grade CD34-positive, S100 protein-positive spindle-cell tumors, associated with NTRK1 fusions (n = 2); and (3) unclassified high-grade spindle-cell sarcomas, with NTRK1 fusions (n = 2). By immunohistochemistry, the tumors demonstrated diffuse pan-TRK expression, of variable intensity, and lacked a specific line of differentiation. Four cases expressed CD34, which was coexpressed with S100 protein in three cases. Expression of SOX10, KIT, and DOG1 was consistently absent. Molecular genetic testing identified TPM3–NTRK1 (n = 3), TPR–NTRK1, LMNA–NTRK1, and ETV6–NTRK3 (n = 2), and SPECC1L–NTRK3 in-frame gene fusions. We conclude that the evaluation of mesenchymal spindle-cell neoplasms of the gastrointestinal tract without a definitive line of differentiation should include interrogation of NTRK alterations, particularly in pediatric patients. Mesenchymal tumors of the gastrointestinal tract with NTRK rearrangements are clinically and morphologically heterogeneous, and few, if any, seem related to GIST.

RARE-38. CLINICAL PRESENTATION OF MGA-NUTM1 FUSION TRANSCRIPT SARCOMA

BACKGROUNDMGA-NUTM1 fusion gene tumor are recently described as new subtype of NUTM1-rearranged tumors. Regarding its rarity, standard treatment has not been reported. Here we described clinical presentation, radiologic finding, immunohistological profile, and treatment of a boy with MGA-NUTM1 fusion gene tumor. CASE REPORT: A 13-year-old boy with 2-month history of progressive right hemiparesis and headache. Magnetic resonance imaging (MRI) revealed 7.8 x10.6 x 8.0 cm well defined heterogeneous enhancing mass at left fronto-parietal lobe. CT chest and abdomen, bone scan, MRI spine, and CSF studies were unremarkable. He underwent craniotomy with total tumor removal. Pathology demonstrated high grade spindle cell sarcoma. The immunohistological profile was positive for BCOR, NUT1, and TEL1, but negative for CD34, STAT6, desmin, SMA, actin sarcomeric, EMA, PR, S100, SOX10, BCL 6, and SABT2. The INI-1 showed nuclear expression and Ki-67 was positive in 50% of tumor nuclei. Molecular test for MGA-NUTM1 fusion transcript was positive, while SYT-SSX1, SYT-SSX2, and SYT-SSX4 fusion transcripts were negative. Four months after operation, MRI showed newly-seen two small enhancing foci at lateral and inferior aspects of the surgical cavity. He underwent re-surgery. Then focal radiation (54Gy and boost up to 60Gy at recurrent area) to the resection cavity was decided. Post-radiation chemotherapy including ifosfamide 3 g/m2 and etoposide 150 mg/m2 on Day 1–2, and carboplatin 500 mg/m2 on Day 3, every 21–28 days was started. He has completed the first course of chemotherapy without any complication.CONCLUSIONMGA-NUTM1 fusion CNS sarcoma is rare. Treatment may require surgery, radiation and chemotherapy.

Identification of a Novel MAN1A1-ROS1 Fusion Gene Through mRNA-based Screening for Tyrosine Kinase Gene Aberrations in a Patient with Leiomyosarcoma.

Soft tissue sarcomas are a heterogeneous group of rare malignant tumors. Advanced soft tissue sarcomas have a poor prognosis, and effective systemic therapies have not been established. Tyrosine kinases are increasingly being used as therapeutic targets for a variety of cancers and soft tissue sarcomas. Although complex karyotype sarcomas typically tend to carry more potentially actionable genetic alterations than do translocation-associated sarcomas (fusion gene sarcomas), based on our database review, we found that leiomyosarcoma and malignant peripheral nerve sheath tumors have lower frequencies of potential targets than other nontranslocation soft tissue sarcomas. We theorized that both leiomyosarcoma and malignant peripheral nerve sheath tumors might be included in any unique translocations. Furthermore, if tyrosine kinase imbalances, especially fusion genes, occur in patients with leiomyosarcomas and malignant peripheral nerve sheath tumors, tyrosine kinase inhibitors might be a drug development target for this sarcoma. In this study, we used a tyrosine kinase screening system that could detect an imbalance in mRNA between 5'- and 3'-sides in tyrosine kinase genes to identify potential novel therapeutic tyrosine kinase targets for soft tissue sarcomas. (1) Are there novel therapeutic tyrosine kinase targets in tumors from patients with soft tissue sarcomas that are detectable using mRNA screening focusing on imbalance expressions between the 5' and 3' end of the kinase domain? (2) Can potential targets be verified by RNA sequencing and reverse transcription PCR (RT-PCR)? (3) Will potential fusion gene(s) transform cells in in vitro assays? (4) Will tumors in mice that have an identified fusion gene respond to treatment with a therapeutic drug directed at that target? We used mRNA screening to look for novel tyrosine kinase targets that might be of therapeutic potential. Using functional assays, we verified whether the identified fusion genes would be good therapeutic candidates for soft tissue sarcomas. Additionally, using in vivo assays, we assessed whether suppressing the fusion's kinase activity has therapeutic potential. Study eligibility was based on a patient having high-grade spindle cell and nontranslocation sarcomas, including leiomyosarcoma, malignant peripheral nerve sheath tumor, and high-grade myxofibrosarcoma. Between 2015 and 2019, of the 172 patients with soft tissue sarcomas treated with surgical resection at Juntendo University Hospital, 72 patients had high-grade nontranslocation sarcomas. The analysis was primarily for leiomyosarcoma and malignant peripheral nerve sheath tumors, and there was a limitation of analysis size (reagent limitations) totaling 24 samples at the start of the study. We collected additional samples from a sample bank at the Tokyo Medical and Dental University to increase the number of sarcomas to study. Therefore, in this study, a total of 15 leiomyosarcoma samples, five malignant peripheral nerve sheath tumors samples, and four high-grade myxofibrosarcoma samples were collected to achieve the sample size of 24 patients. To identify tyrosine kinase fusion genes, we designed a NanoString-based assay (NanoString Technologies Inc, Seattle, WA, USA) to query the expression balances regarding transcripts of 90 tyrosine kinases at two points: the 5' end of the kinase domain and within the kinase domain or 3' end of the kinase domain. The tumor's RNA was hybridized to the NanoString probes and analyzed for the expression ratios of outliers from the 3' to 5' end of the kinase domain. Presumed novel fusion events in these positive tumors that were defined by NanoString-based assays were confirmed tyrosine kinase fusion genes by RNA sequencing and confirmatory RT-PCR. Functional analyses consisting of in vitro and in vivo assays were also performed to elucidate whether the identified tyrosine kinase gene fusions were associated with oncogenic abilities and drug responses. We identified aberrant expression ratios regarding the 3' to 5' end of the kinase domain ratios in ROS1 transcripts in a leiomyosarcoma in a 90-year-old woman. A novel MAN1A1-ROS1 fusion gene was identified from her thigh tumor through RNA sequencing, which was confirmed with real-time PCR. In functional assays, MAN1A1-ROS1 rearrangement revealed strong transforming potential in 3T3 cells. Moreover, in an in vivo assay, crizotinib, a ROS1 inhibitor, markedly inhibited the growth of MAN1A1-ROS1 rearrangement-induced transformed cells in a dose-dependent manner. We conducted tyrosine kinase screening to identify new therapeutic targets in soft tissue sarcomas. We found a novel MAN1A1-ROS1 fusion gene that may be a therapeutic target in patients with leiomyosarcoma. This study demonstrates that the mRNA screening system may aid in the development of useful therapeutic options for soft tissue sarcomas. If novel tyrosine fusions such as MAN1A1-ROS1 fusion can be found in sarcomas from other patients, they could offer avenues for new molecular target therapies for sarcomas that currently do not have effective chemotherapeutic options. Therefore, the establishment of a screening system that includes both genomic and transcript analyses in the clinical setting is needed to verify our discoveries and take the developmental process of treatment to the next step.

How Are Indeterminate Pulmonary Nodules at Diagnosis Associated with Survival in Patients with High-Grade Osteosarcoma?

How Are Indeterminate Pulmonary Nodules at Diagnosis Associated with Survival in Patients with High-Grade Osteosarcoma?

Paratesticular Liposarcoma Mimicking Inguinal Hernia: a Case Report

Paratesticular tumors account for approximately 5% of intrascrotal mass, and mostly they arise from the spermatic cord (75%). Here, we report a paratesticular mass having a misleading presentation of irreducible inguinal hernia. A 54-year-male patient presented with complaint of right inguino-scrotal swelling for 5 years. Serum tumor markers were within normal limits. Ultrasound of scrotum reveals inguino-scrotal hernia with omental fat and bowel loop herniating out. Patient underwent right inguinal exploration with high inguinal orchidectomy. Histopathology revealed paratesticular high-grade spindle cell sarcoma, and immunohistochemistry was suggestive of paratesticular liposarcoma.

Soft tissue sarcomas: Evaluation by immunohistochemistry

Soft tissue sarcomas represent a histologically heterogenous group of malignant tumors arising from the soft tissue compartments, i.e smooth muscles, skeletal muscles, adipose tissue, blood vessels, connective tissue mesenchyme, neural tissue and other tumors of uncertain histogenesis(1). Soft tissue sarcomas are relatively rare tumors, represent less than 1% of adult malignancies based on data report from American Cancer Society (2). The crude incidence rate in Iraq for soft tissue sarcomas was 219/ 100,000 population during 2014 with male: female ratio of 1.3:1, and highest peak age between 30-34 years (3). The histological subtype and microscopic criteria are two parameters that influence the tumor grade which is the best predictor for aggressiveness. ( 2)&#x0D; Objectives:&#x0D; A retrospective evaluation of soft tissue sarcomas, using immunohistochemical study of Myosin, Desmin, Smooth muscle Actin (SMA) and Vimentin, aiming to re-evaluate the primary diagnosis and whether IHC assessment in soft tissue sarcoma is mandatory to reach a final interpretation.&#x0D; Material and Patients: &#x0D; A total of 50 cases soft tissue sarcomas were reviewed retrospectively from case archives of histopathology department/ Central Public Health Laboratory, for the period (2011-2018). The data for these cases were collected including the age, gender, site of the tumor and the preliminary biopsy report findings. Hematoxylin&amp; Eosin (H&amp;E) stain and IHC staining of unstained sections from formalin-fixed, paraffin-embedded tissue were performed using SMA, Vimentin, Desmin and Myosin.&#x0D; Methods: Age and gender distribution of the 50 cases was correlated. The IHC staining performed on 5 microns paraffin sections, applying peroxidase-Antiperoxidase technique and both positive and negative control slides were included for Smooth muscle actin (SMA), clone 1A4, Desmin (clone D33), Myosin (clone 2F12.A9) and Vimentin (Clone V9). The monoclonal antibodies used were from DAKO manufacturer as ready to use monoclonal antibodies while freeze-dried antibodies used for myosin with 1:20 dilution. Negative and positive control slides were used simultaneously. The staining intensity was assessed based on the percentage of positive cells expression of the four IHC monoclonal antibodies. Negative staining reported when no stain seen. Positive (+) means up to 30% of tumor cells with antigen expression. Positive (++) interpretation given when 31-60% of tumor cells show staining reaction, while Positive (+++) interpretation reported when over 60% of tumor cells showing staining reaction.&#x0D; Results:&#x0D; The staining interpretation of the four monoclonal antibodies were confirmatory for the original diagnosis in 40% of cases, while 60% of the final diagnoses were against the original interpretation. SMA was positive in 38/50 cases (76%). Desmin was positive in 8/50 cases (20%) Vimentin was positive in 42/50 of cases (84%), Myosin was positive in 30/50 of cases (71.4%).&#x0D; The current study focus on histological re-evaluation of different types of soft tissue sarcomas (including RMS-with its subtypes), MFH-storiform, pleomorphic and myxoid subtypes), fibrosarcoma, leiomyosarcoma, alveolar soft part sarcoma and synovial sarcoma depending on immunohistochemical study. The original diagnosis have been changed after the immunohistochemistry stain from fibrosarcoma to rhabdomyosarcoma and leiomyosarcoma , Malignant fibrous histiocytoma to rhabdomyosarcoma, alveolar rhabdomyosarcoma to Malignant fibrous histiocytoma, soft tissue sarcoma to rhabdomyosarcoma , pleomorphic MFH to pleomorphic rhabdomyosarcoma. Embryonal and alveolar rhabdomyosarcoma were confirmed by IHC as so. Leiomyosarcoma was confirmed as the same in one case. Embryonal Rhabdomyosarcoma changed to leiomyosarcoma by IHC positivity for desmin. Six cases of MFH were confirmed as malignant fibrous histiocytoma after IHC. Two cases of synovial sarcoma were re-evaluated as rhabdomyosarcoma. Vimentin revealed 100% positivity in 10 cases and regarded as a sensitive marker for mesenchymal tissue but it is not specific for certain types of sarcomas. The presence of desmin diffusely throughout a tumor is an indication of myoid differentiation and the presence of either SMA or desmin focally should not necessarily be equated with myoid lineage but rather with myofibroblastic lineage, which go in the same direction with Hirofumi N. et al. (1998).(4)&#x0D; Conclusions: The co-expression of SMA and Desmin helped in the diagnosis of leiomyosarcoma (LMS). Myosin expression was helpful in the diagnosis of rhabdomyosarcoma (RMS) and alveolar soft part sarcoma (ASPS). Smooth muscle actin (SMA) and vimentin were not specific for the diagnosis of malignant fibrous histiocytoma (MFH). High grade spindle cell sarcoma express SMA only without myosin or desmin can be categorized as pleomorphic myogenic sarcoma. By applying immunohistochemical markers, 60% of soft tissue sarcomas were different from the preliminary diagnosis while 40% of cases were supportive of the original H&amp;E diagnosis.

64. Characterization of BCOR ITD in pediatric solid tumors using targeted NGS panel and whole transcriptome sequencing

BCL6 corepressor (BCOR) functions with B-cell CLL/lymphoma 6 (BCL6) as a transcriptional silencer. BCOR internal tandem duplications (ITD), which occur in-frame in the last exon of BCOR, have been described in clear cell sarcoma of kidney (CCSK), primitive mesenchymal myxoid tumor of infancy (PMMTI), undifferentiated round cell sarcomas (URCS), and CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR). We studied BCOR ITDs identified through routine tumor sequencing using a custom-designed Comprehensive Solid Tumor Panel interrogating 238 cancer genes and fusions associated with 110 cancer genes. BCOR ITDs were detected in seven of the 1,286 solid tumor cases tested, including three CCSK, two CNS HGNET-BCOR, one PMMTI, and one high-grade spindle cell sarcoma of bone, a tumor type recently associated with BCOR ITD. No fusion genes were detected. In four of the seven cases, the identification of a BCOR ITD confirmed the histological diagnosis, while in three cases, the presence of a BCOR ITD changed the original diagnosis. The shortest duplication identified contained 23 amino acids and the longest 38. The minimal overlapping duplicated region of all cases spans residues 1725-1738, consistent with previously reported ITDs. Whole-transcriptome analyses (RNA-seq) revealed a distinct gene expression pattern with increased expression of BCOR, PDGFRA, and CCND1 in all cases.

Sarcoma metastasis to the pancreas: experience at a single institution.

BackgroundReports of metastatic sarcoma to the pancreas are limited. We reviewed the clinicopathologic characteristics of such cases.MethodsWe reviewed 124 cases of metastatic tumors to the pancreas diagnosed at Asan Medical Center between 2000 and 2017.ResultsMetastatic tumors to the pancreas consisted of 111 carcinomas (89.5%), 12 sarcomas (9.6%), and one melanoma (0.8%). Primary sarcoma sites were bone (n=4); brain, lung, and soft tissue (n=2 for each); and the uterus and pulmonary vein (n=1 for each). Pathologically, the 12 sarcomas comprised 2 World Health Organization grade III solitary fibrous tumors/hemangiopericytomas, and one case each of synovial sarcoma, malignant solitary fibrous tumor, undifferentiated pleomorphic sarcoma, osteosarcoma, mesenchymal chondrosarcoma, intimal sarcoma, myxofibrosarcoma, myxoid liposarcoma, rhabdomyosarcoma, subtype uncertain, and high-grade spindle-cell sarcoma of uncertain type. The median interval between primary cancer diagnosis and pancreatic metastasis was 28.5 months. One case manifested as a solitary pancreatic osteosarcoma metastasis 15 months prior to detection of osteosarcoma in the femur and was initially misdiagnosed as sarcomatoid carcinoma of the pancreas.ConclusionsThe metastatic sarcoma should remain a differential diagnosis when spindle-cell malignancy is found in the pancreas, even for solitary lesions or in patients without prior history.

The incidence of skip metastases on whole bone MRI in high-grade bone sarcomas.

Skip metastases have been described with osteosarcoma, Ewing sarcoma and rarely chondrosarcoma. The aim of this study was to determine the incidence of skip metastases on whole bone MRI in all primary high-grade sarcomas of the major long bones. Retrospective review of patients from April 2007 to April 2019 with high-grade primary bone sarcomas of the humerus, radius, ulna, femur, tibia or fibula who had whole bone MRI at initial staging. Data collected included age, sex, tumour type, presence and location of skip metastases based on whole bone MRI and presence of distant metastases (the skeleton and lung). The study included 216 males and 171 females with mean age 30.6years (range 4-92years). Tumour types were as follows: High-grade osteosarcoma n = 202, Ewing sarcoma n = 68, high-grade chondrosarcoma n = 44, dedifferentiated chondrosarcoma n = 37, high-grade spindle cell sarcoma n = 29 and angiosarcoma n = 7. Skip lesions were identified in 63 (16.3%). However, after taking into account the presence of distant skeletal (n = 11) and pulmonary (n = 33) metastases, the overall incidence of skip metastases was 6.5%, occurring in 15 (7.5%) high-grade osteosarcomas, 3 (4.5%) Ewing sarcoma, 1 (2.8%) high-grade chondrosarcoma, 4 (10.8%) dedifferentiated chondrosarcomas, and 2 (6.9%) high-grade spindle cell sarcomas. A false positive MRI diagnosis of skip metastasis was made in 4 cases, 3 enchondromata and one focal nodular marrow hyperplasia. The current study has documented the incidence of skip metastases in common types of high-grade primary bone sarcoma. The possibility of false positive skip metastases has also been highlighted.