Spindle Cell Rhabdomyosarcoma Research Articles

Spindle cell rhabdomyosarcoma: A study of demographics and socioeconomic factors using NCDB.

e23539 Background: Spindle cell rhabdomyosarcoma (SC-RMS) is a rare malignancy characterized by elongated spindle cells displaying eosinophilic and fibrillar cytoplasm, resembling smooth muscle fibers. SC-RMS is primarily diagnosed in children with particular involvement of the nasopharynx, parotid gland, nasal cavity, and paratesticular regions. Though surgical resection and chemotherapy are the current recommendations, definitive treatment guidelines remain unestablished. Because SC-RMS is a novel cancer type, evaluating the diagnostic trend of the disease has the potential to provide valuable insights into its epidemiology. An analysis of the National Cancer Database (NCDB) was conducted to identify the demographic factors associated with patients who have been diagnosed with SC-RMS. Methods: A retrospective cohort analysis of the 2004–2020 NCDB, using ICD-O-3 code 8912/3, included patients with a histologically-confirmed diagnosis of SC-RMS (N = 132). Demographic factors (age, sex, race, Hispanic status, educational attainment, insurance status, facility type, distance from facility, and Charles/Deyo score) were analyzed by descriptive statistics and incidence trends were interpreted in regression analysis. Results: A total of 132 patients with a confirmed diagnosis of SC-RMS were identified, with a declining incidence of diagnoses per year (R² = 0.4507). The average age of diagnosis was 33.9 years (SD = 27.2, Range = 1-90). SC-RMS was more commonly observed among males (63%), with a majority of patients being non-Hispanic (87%) and White (74.2%). The top primary site was the testis (20%). Most patients (83%) had a Charlson/Deyo comorbidity score of 0. The majority (69%) of patients received surgery as their primary treatment. Most patients were privately insured (49%) and resided in metropolitan areas with a population greater than 1 million (48%). More (29%) patients were in the highest quartile of income earners of $74,063 or greater. Patients were treated most often at an academic/research program (19%) or comprehensive community care program (12%). Patients lived an average of 68.2 miles (SD = 267.9, Range = 0.6 - 2403.1) from the treatment facility. Conclusions: To the best of our knowledge, this is the first NCDB analysis on SC-RMS. Our analysis revealed that the majority of SC-RMS patients were young males with primary involvement of the testis, supporting previous studies. Analysis of the socioeconomic factors of SC-RMS patients revealed that more patients were privately insured, resided in densely populated metropolitan areas, and were part of the top quartile of income earners. Further research is supported to better understand the impact of socioeconomic factors on diagnosis, treatment options, and overall mortality rates associated with SC-RMS.

Low-grade undifferentiated sarcoma with MEIS1::NCOA2-rearrangement primary to the lung: a case report

BackgroundMEIS1::NCOA2 is a rare fusion gene that has been recently described in a subset of spindle cell rhabdomyosarcomas and multiple low-grade undifferentiated spindle cell sarcomas predominantly arising in the genitourinary and gynecologic tracts with no specific line of differentiation. We present the first documented case of this neoplasm arising as a lung primary tumor.Case PresentationA 74-year-old woman with a 40-year smoking history presented with a 2.1 × 1.7 cm lung nodule discovered on computed tomography (CT) scan. A biopsy and subsequent lobe resection were performed, as well as an extensive metastatic work up, which revealed no additional masses. No specific line of differentiation was found by immunohistochemical staining, and an RNA-based fusion panel revealed a MEIS1::NCOA2 fusion, at which point a diagnosis of Low-Grade Undifferentiated Sarcoma with MEIS1::NCOA2-Rearrangement was rendered.ConclusionsThis report represents the first diagnosis of this tumor primary to the lung, and provides additional insight into the origin and localization of these rare tumors.

FGFR1 fusions as a novel molecular driver in rhabdomyosarcoma.

The wide application of RNA sequencing in clinical practice has allowed the discovery of novel fusion genes, which have contributed to a refined molecular classification of rhabdomyosarcoma (RMS). Most fusions in RMS result in aberrant transcription factors, such as PAX3/7::FOXO1 in alveolar RMS (ARMS) and fusions involving VGLL2 or NCOA2 in infantile spindle cell RMS. However, recurrent fusions driving oncogenic kinase activation have not been reported in RMS. Triggered by an index case of an unclassified RMS (overlapping features between ARMS and sclerosing RMS) with a novel FGFR1::ANK1 fusion, we reviewed our molecular files for cases harboring FGFR1-related fusions. One additional case with an FGFR1::TACC1 fusion was identified in a tumor resembling embryonal RMS (ERMS) with anaplasia, but with no pathogenic variants in TP53 or DICER1 on germline testing. Both cases occurred in males, aged 7 and 24, and in the pelvis. The 2nd case also harbored additional alterations, including somatic TP53 and TET2 mutations. Two additional RMS cases (one unclassified, one ERMS) with FGFR1 overexpression but lacking FGFR1 fusions were identified by RNA sequencing. These two cases and the FGFR1::TACC1-positive case clustered together with the ERMS group by RNAseq. This is the first report of RMS harboring recurrent FGFR1 fusions. However, it remains unclear if FGFR1 fusions define a novel subset of RMS or alternatively, whether this alteration can sporadically drive the pathogenesis of known RMS subtypes, such as ERMS. Additional larger series with integrated genomic and epigenetic datasets are needed for better subclassification, as the resulting oncogenic kinase activation underscores the potential for targeted therapy.

Congenital chest wall spindle cell rhabdomyosarcoma in a one-month-old patient

This article presents a rare clinical case of an infant with congenital spindle-cell rhabdomyosarcoma, demonstrates a combined approach to the patient's therapy, describes in detail the performed reconstructive plastic surgery, analyzes the short-term and long-term results of the treatment with an emphasis on late orthopedic complications, provides a detailed literary review on the topic of the publication. The patient's parents gave consent to the use of their child's data, including photographs, for research purposes and in publications.

Spindle cell rhabdomyosarcomas: With TFCP2 rearrangements, and novel EWSR1::ZBTB41 and PLOD2::RBM6 gene fusions. A study of five cases and review of theliterature.

Spindle-cell/sclerosing rhabdomyosarcomas (SS-RMS) are clinically and genetically heterogeneous. They include three well-defined molecular subtypes, of which those with EWSR1/FUS::TFCP2 rearrangements were described only recently. This study aimed to evaluate five new cases of SS-RMS and to perform a clinicopathological and statistical analysis of all TFCP2-rearranged SS-RMS described in the English literature to more comprehensively characterize this rare tumour type. Cases were retrospectively selected and studied by immunohistochemistry, fluorescence in situ hybridization with EWSR1/FUS and TFCP2 break-apart probes, next-generation sequencing (Archer FusionPlex Sarcoma kit and TruSight RNA Pan-Cancer Panel). The PubMed database was searched for relevant peer-reviewed English reports. Five cases of SS-RMS were found. Three cases were TFCP2 rearranged SS-RMS, having FUSex6::TFCP2ex2 gene fusion in two cases and triple gene fusion EWSR1ex5::TFCP2ex2, VAX2ex2::ALKex2 and VAX2intron2::ALKex2 in one case. Two cases showed rhabdomyoblastic differentiation and spindle-round cell/sclerosing morphology, but were characterized by novel genetic fusions including EWSR1ex8::ZBTB41ex7 and PLOD2ex8::RBM6ex7, respectively. In the statistical analysis of all published cases, CDKN2A or ALK alterations, the use of standard chemotherapy and age at presentation in the range of 18-24 years were negatively correlated to overall survival. EWSR1/FUS::TFCP2-rearranged SS-RMS is a rare rhabdomyosarcoma subtype, affecting predominantly young adults with average age at presentation 34 years (median 29.5 years; age range 7-86 years), with a predilection for craniofacial bones, rapid clinical course with frequent bone and lung metastases, and poor prognosis (3-year overall survival rate 28%).

Comparison of 18F-FDG PET/CT and 68Ga-FAPI in Spindle Cell Rhabdomyosarcoma.

We report a rare case of spindle cell rhabdomyosarcoma. Sarcomas generally exhibit an abnormal increased FDG uptake on 18F-FDG PET/CT imaging, while spindle cell rhabdosarcomas exhibits a significantly increased lesion uptake on 68Ga FAPI PET/CT imaging compared to 18F-FDG. This case suggests that 68Ga-FAPI PET/CT has potential value in evaluating spindle cell rhabdomyosarcoma.

Intraosseous Spindle Cell Rhabdomyosarcoma with MEIS1::NCOA2 Fusion – Case Report with Substantial Clinical Follow-up and Review of the Literature

Spindle cell/sclerosing rhabdomyosarcoma (SSRMS) is a clinicopathologically and molecularly heterogeneous disease. Gene fusions have been identified in intraosseous SSRMS, consisting predominantly of EWSR1/FUS::TFCP2 and MEIS1::NCOA2. The former often follow an aggressive clinical course; there is limited clinical follow-up available for the latter. We report here a new case of the very rare intraosseous SSRMS with MEIS1::NCOA2 gene fusion and include the detailed treatment course and 52 months of clinical follow-up. SSRMS with MEIS1::NCOA2 gene fusion appears biologically distinct from other intraosseous SSRMS, following a course characterized by local recurrence with rare reports of metastasis to date.

Fusion-driven Spindle Cell Rhabdomyosarcomas of Bone and Soft Tissue: A Clinicopathologic and Molecular Genetic Study of 25 Cases

The evolving classification of rhabdomyosarcoma (RMS) now includes spindle cell RMS (SRMS). Bone/soft tissue SRMS often harbor TFCP2, or less often MEIS1 rearrangements. We studied 25 fusion-driven SRMS involving bone (n = 19) and soft tissue (n = 6).Osseous SRMS occurred in 13 women and 6 men (median age: 41 years) and involved the pelvis (5), sacrum (2), spine (4), maxilla (4), mandible (1), skull (1), and femur (2). Follow-up (median: 5 months) demonstrated local recurrence in 2/16 and distant metastases in 8/17 patients (median time to metastasis: 1 month). Eight patients died of disease; 9 were alive with disease. Soft tissue SRMS occurred in 4 men and 2 women (median: 50 years). Follow-up (median: 10 months) revealed distant metastasis at diagnosis (1), alive with unresected tumor (1), and no evidence of disease (4). Next-generation sequencing demonstrated FUS::TFCP2 (12), EWSR1::TFCP2 (3) and MEIS1::NCOA2 (2); FISH identified EWSR1 (2) rearrangements. Most TFCP2-rearranged SRMS (13/17) showed spindled/epithelioid morphology, rarely with rhabdomyoblasts. The bone tumors were diffusely desmin and MyoD1 positive with limited myogenin; 10/13 were ALK -positive and 6/15 were keratin positive. Soft tissue SRMS harbored EWSR1::TFCP2, MEIS1::NCOA2, ZFP64::NCOA2, MEIS1::FOXO1, TCF12::VGLL3 and DCTN1::ALK, and displayed spindled/epithelioid, leiomyomatous, and myxofibrosarcoma-like morphologies. Immunohistochemistry (IHC) was positive for MyoD1 (6/6), focal desmin (5/6), myogenin (3/6), and keratin (1/6).We conclude that TFCP2-rearranged SRMS of bone and soft tissue show consistent morphologic and IHC features, likely representing a distinct subset of RMS. Non-TFCP2 fusion-positive SRMS could represent a single RMS subset, multiple subtypes of RMS, or “fusion-defined” sarcomas with rhabdomyoblastic differentiation.

Complete mimicry: Rhabdomyosarcoma with FUS::TFCP2 fusion masquerading as carcinoma-diagnostic challenge and report of two cases.

Rhabdomyosarcomas (RMS) are malignant mesenchymal tumors with skeletal muscle differentiation which are classified into alveolar, embryonal, pleomorphic, and spindle cell/sclerosing RMS. Within the spindle cell/sclerosing RMS tumor type there is a recently recognized sub-type categorized as intraosseous spindle cell RMS with TFCP2/NCOA2 gene fusion. This rare tumor is highly aggressive with predominant involvement of the craniofacial and pelvic bones with approximately 30 cases reported to date. Histopathologic features include spindle cell and epithelioid morphology with a characteristic co-expression of epithelial markers, myogenic markers, and ALK1 expression. We report two cases of gnathic spindle cell/sclerosing RMS with FUS::TFCP2 gene fusion that were initially interpreted as carcinomas by referring institutions and later reclassified when encountered in our practice after additional work-up and molecular characterization.

Intraoral Endoscopic Approach to Excision of an Infratemporal Fossa Tumour

Introduction: The infratemporal fossa is an inverted pyramid shaped structure that lies at the skull base, posterior to the maxillary sinus. It has a complex anatomy due to its relationship to various important vascular and neural channels. Surgical approaches to this region, via the lateral skull base and access mandibulotomies, have high morbidity. By our minimally invasive intra-oral endoscopic technique, an external incision, bony osteotomies and cranial nerve palsies were avoided with an expedited road to recovery and shorter hospital stay. Case Report: A middle aged lady who presented with left sided facial swelling and numbness was evaluated for the same with a Diagnostic nasal endoscopy and imaging. MRI of the maxilla with contrast revealed a well-defined left infra-temporal fossa soft tissue signal intensity mass, which was subsequently planned for intra-oral endoscopic removal. The surgery was performed via a transvestibular-paramandibular incision through which the endoscope was passed, structures delineated and tumour removed piece meal. Immunohistochemical analysis confirmed that it was a Spindle cell Rhabdomyosarcoma. Hence, she was given post operative chemoradiotherapy and is currently one year post surgery, with good outcomes. Discussion The infratemporal fossa has a varied and complex anatomy, due to its interior location and multiple important neurovascular structures within it. This intra-oral endoscopic approach, although challenging for the novice surgeon, avoided an external scar, providing better cosmesis and also had lesser patient morbidity related to wound gaping and dehiscence. It also allowed a direct and magnified visualization of the neuro-vascular structures in that region, aiding in tumour removal.

Diagnostic utility of FOXO1 immunohistochemistry for rhabdomyosarcoma classification.

Rhabdomyosarcomas currently are classified into one of four subtypes (alveolar, embryonal, spindle cell/sclerosing, or pleomorphic) according to their morphological, immunohistochemical, and molecular genetic features. The alveolar subtype is characterised by a recurrent translocation involving PAX3 or PAX7 and FOXO1; identification of this translocation is important for appropriate classification and prognostication. In this study, we aimed to explore the diagnostic utility of FOXO1 immunohistochemistry for rhabdomyosarcoma classification. A monoclonal antibody targeting a FOXO1 epitope retained in the fusion oncoprotein was used to study 105 rhabdomyosarcomas. FOXO1 was positive for expression by immunohistochemistry in all 25 alveolar rhabdomyosarcomas, with 84% showing diffuse expression in greater than 90% of neoplastic cells; the remainder of alveolar rhabdomyosarcomas displayed at least moderate staining in a minimum of 60% of lesional cells. Apart from three spindle cell rhabdomyosarcomas showing heterogeneous nuclear immunoreactivity in 40-80% of tumour cells, the 80 cases of embryonal, pleomorphic, and spindle cell/sclerosing rhabdomyosarcoma were negative for FOXO1 expression (96.3% specific) when using a threshold of nuclear staining in 20% of neoplastic cells to determine positivity. Variable cytoplasmic staining was present in a fraction of all rhabdomyosarcoma subtypes. Nonneoplastic lymphocytes, endothelial cells, and Schwann cells also showed variably intense nuclear anti-FOXO1 immunoreactivity. Taken together, our findings suggest that FOXO1 immunohistochemistry is a highly sensitive and relatively specific surrogate marker of the PAX3/7::FOXO1 fusion oncoprotein in rhabdomyosarcoma. Cytoplasmic immunoreactivity, expression in nonneoplastic tissues, and limited nuclear staining of nonalveolar rhabdomyosarcomas represent potential pitfalls in interpretation.

Rhabdomyosarcoma Arising in Inflammatory Rhabdomyoblastic Tumor: A Genetically Distinctive Subtype of Rhabdomyosarcoma

“Inflammatory rhabdomyoblastic tumor” (IRMT) is a recently coined name for a distinctive soft tissue neoplasm characterized by slow growth, a dense histiocytic infiltrate, scattered, bizarre-appearing tumor cells with morphologic and immunohistochemical evidence of skeletal muscle differentiation, a near-haploid karyotype with retained biparental disomy of chromosomes 5 and 22, and usually indolent behavior. There are 2 reports of rhabdomyosarcoma (RMS) arising in IRMT. We studied the clinicopathologic and cytogenomic features of 6 cases of IRMT with progression to RMS.Tumors occurred in the extremities of 5 men and 1 woman (median patient age, 50 years; median tumor size, 6.5 cm). Clinical follow-up (6 patients: median, 11 months; range 4-163 months) documented local recurrence and distant metastases in 1 and 5 of 6 patients, respectively. Therapy included complete surgical resection (4 patients) and adjuvant/neoadjuvant chemo/radiotherapy (6 patients). One patient died of disease, 4 were alive with metastatic disease, and one was without evidence of disease.All primary tumors contained conventional IRMT. Progression to RMS appeared as follows: (1) overgrowth of monomorphic rhabdomyoblasts with diminished histiocytes, (2) monomorphic spindle cell morphology with variably pleomorphic rhabdomyoblasts and low mitotic activity, or (3) morphologically undifferentiated spindle cell and epithelioid sarcoma. All but one were diffusely desmin-positive, with more limited MyoD1/myogenin expression. All RMS arising in IRMT, either primary or metastatic, demonstrated widespread loss of heterozygosity with retained heterozygosity of chromosomes 5 and 20, and all but one displayed additional gains and losses involving loci containing oncogenes/ tumor suppressor genes, most often CDKN2A and CDKN2B.RMS arising in IRMT have unique clinicopathologic and cytogenomic features, warranting classification as a distinct, potentially aggressive RMS subtype. It should be distinguished from other RMSs, particularly fusion-driven spindle cell RMS and pleomorphic RMS.

A congenital spindle cell auricular rhabdomyosarcoma in a newborn

Rhabdomyosarcomas make up 5% of all pediatric malignant tumors. They are extremely rare in neonates. Furthermore, the external ear as a primary tumor site is very uncommon. In this paper, a neonate with a congenital auricular rhabdomyosarcoma is presented. At birth, a newborn male was noted to have a right posterior auricular mass. He is admitted to a children's hospital where he has diagnostic imaging, undergoes a biopsy, and then surgical resection of the auricular mass. Pathology confirms an infantile spindle cell rhabdomyosarcoma. He completes 22 weeks of chemotherapy without incident. At one year of age, there is no evidence of metastasis or recurrence of the auricular tumor. A rare case of a neonate with a congenital auricular rhabdomyosarcoma is presented. The prognosis of congenital auricular rhabdomyosarcomas tends to be favorable.

Expanding the Spectrum of Perioral Myogenic Tumors in Pediatric Patients: An SRF::NCOA2 Fused Perivascular Tumor of the Philtrum.

Perivascular tumors, which include myopericytoma and myofibroma, are rare benign soft tissue neoplasms composed of perivascular smooth muscle cells. Most demonstrate characteristic morphology and are readily diagnosed. However, a recently identified hypercellular subset shows atypical histologic features and harbor unique SRF gene fusions. These cellular perivascular tumors can mimic other more common sarcomas with myogenic differentiation. Clinical, radiological, morphological, immunohistochemical, and molecular findings were reviewed. A slow-growing, fluctuant mass was noted within the philtrum at 16 months. Ultrasonography revealed a well-circumscribed cystic hypoechoic lesion. A small (1.0 cm), tan, well-circumscribed soft-tissue mass was excised after continued growth. Histologically, the encapsulated tumor was hypercellular and composed of spindle cells with predominantly-storiform architecture, focal perivascular condensation, dilated branching thin-walled vessels, increased mitoses, and a smooth muscle immunophenotype. An SRF::NCOA2 fusion was identified. We report the first case of an SRF-rearranged cellular myopericytoma in the perioral region in a young child. This case expands the differential diagnosis of perioral soft tissue tumors with myogenic differentiation. We highlight key clinical, pathological, and molecular features. As we illustrate, these rare tumors pose a considerable diagnostic challenge, and risk misdiagnosis as sarcoma, most notably spindle cell rhabdomyosarcoma.

Clinicopathological features of rhabdomyosarcoma with novel FET::TFCP2 and TIMP3::ALK fusion: report of two cases and literature review.

The aim of this study was to evaluate the clinicopathological features, immunophenotype, differential diagnosis, molecular genetic features and prognosis of spindle cell rhabdomyosarcoma with TFCP2 rearrangement. Two cases of spindle cell rhabdomyosarcoma with FET::TFCP2 gene fusion were included in this study. Samples were collected and evaluated through histological observation, immunohistochemistry, fluorescence in-situ hybridisation and high-throughput gene sequencing and previous findings. The tumour tissues mainly comprised spindle cells and epithelioid cells, which expressed striated muscle markers, and exhibited high expression levels of CK and ALK protein markers. Molecular detection showed that the FET::TFCP2 gene was fused. A rare case with TIMP3::ALK and FUS::TFCP2 double-fusion was observed in this study. A case with double fusion of ALK and TFCP2 was reported in rhabdomyosarcoma for the first time in this study, which provides information on the molecular characteristic of the tumour. Spindle cell rhabdomyosarcoma with FET::TFCP2 fusion is characterised by histological, immunohistochemical and genetic changes. The tumour is aggressive, with poor prognosis and poor response to radiotherapy and chemotherapy. The efficacy of targeted therapy for ALK should be explored through more clinical studies.

Recurrent VGLL3 fusions define a distinctive subset of spindle cell rhabdomyosarcoma with an indolent clinical course and striking predilection for the head and neck.

The mammalian Vestigial-like (VGLL) transcriptional cofactor family of proteins VGLL1-4 has recently emerged as an important player in the tumorigenesis of diverse neoplasms. The role of VGLL3 in soft tissue tumors is exemplified by its amplification in myxoinflammatory fibroblastic sarcoma and its rearrangement (fused to CHD7, CHD9, or MAMLD1) in hybrid schwannoma-perineurioma. This study characterizes a distinctive low-grade myogenic neoplasm with a striking predilection for the head and neck, characterized by VGLL3 fusions. The study includes five males and one female patient, aged 30-71 years (median, 56). Three tumors originated in the tongue, with one case each in the nasopharynx, oral cavity, and oropharynx. The VGLL3 fusion partners included TCF12 (n= 3), EP300 (n= 2), and PPARGC1A (n= 1). The tumor size range was 0.8-1.6cm (all, but one, was <1cm). Histologically, all tumors displayed bland spindle to ovoid cells arranged into vague fascicular and diffuse patterns. Mitotic activity ranged from 1 to 7 per 10 HPFs. Five tumors were muscle-centered and infiltrative, and one was centered beneath nasopharyngeal mucosa. Immunohistochemistry revealed consistent expression of desmin (diffuse in four and patchy in two cases) associated with patchy smooth muscle actin expression (4/6), and focal reactivity for myogenin (5/6) and myoD1 (1/3). All patients were managed surgically; one patient each received adjuvant radio- or chemotherapy. Three patients with follow-up were without disease at 8, 19, and 60 months and one was alive with unknown disease status at 24 months. All VGLL3 fusions were in-frame and involved exon 2, fused with either TCF12 exon 16, EP300 exon 31, or PPARGC1A exon 5, respectively. This series characterizes a distinctive subset of spindle cell rhabdomyosarcoma (RMS) with a predilection for the head and neck in adults, defined by VGLL3 fusions, likely indolent behavior and limited rhabdomyoblastic differentiation. Further delineation of this entity and differentiation from more aggressive molecular subtypes of spindle cell RMS is mandatory to define the most appropriate therapeutic strategy and avoid overtreatment.

EWSR1-TFCP2 in an adolescent represents an extremely rare and aggressive form of intraosseous spindle cell rhabdomyosarcomas.

The World Health Organization (WHO) Classification of Tumors of Soft Tissue and Bone subdivides rhabdomyosarcomas (RMSs) into alveolar, embryonal, pleomorphic, and spindle cell RMSs. Advances in molecular genetic diagnostics have made it possible to identify new RMS subgroups within traditional morphological entities. One of these subgroups comprises rare tumors characterized by epithelioid and spindle cell morphology, a highly aggressive clinical course with pronounced tendency to intraosseous growth, and the presence of pathognomonic recurring genetic aberrations—chimeric genes/transcripts EWSR1::TFCP2, FUS::TFCP2, or MEIS1::NCOA2. Starting from 2018, only 26 reported cases of RMS have been assigned to this subgroup. The rarity of such tumors hampers their correct diagnostics for both anatomic pathologists and molecular oncologists. Here, we describe a clinical case of intraosseous spindle cell RMSs expressing the EWSR1::TFCP2 fusion gene, encountered for the first time in our practice, in a 16-yr-old female patient presenting with mandibular lesion. The diagnostic process took considerable time and involved RNA sequencing—a high-throughput method of molecular genetic research. The tumor was extremely aggressive, showing resistance to polychemotherapy, radiation therapy, and crizotinib-targeted therapy, with the fatal outcome.

ZFP64::NCOA3 gene fusion defines a novel subset of spindle cell rhabdomyosarcoma.

Spindle cell rhabdomyosarcoma represents a rare neoplasm characterized by monomorphic spindle cells with a fascicular architecture and variable skeletal muscle differentiation. Following incidental identification of a ZFP64::NCOA3 gene fusion in an unclassified spindle cell sarcoma resembling adult-type fibrosarcoma, we performed a retrospective archival review and identified four additional cases with a similar histology and identical gene fusion. All tumors arose in adult males (28-71 years). The neoplasms were found in the deep soft tissues, two were gluteal, and one each arosein the thigh, abdominal wall, and chest wall. Morphologically, the tumors were characterized by spindle cells with a distinctive herringbone pattern and variable collagenous to myxoid stroma. The nuclei were relatively monomorphic with variable mitotic activity. Three tumors had immunoreactivity for MyoD1, and four contained variable expression of desmin and smooth muscle actin. All cases tested for myogenin, CD34, S100, pankeratin, and epithelial membrane antigen were negative. Targeted RNA sequencing revealed a ZFP64::NCOA3 fusion product in all five tumors. Three patients developed distant metastases, and two ultimately succumbed to their disease within 2 years of initial diagnosis. This study suggests ZFP64::NCOA3 fusions define a novel subtype of rhabdomyosarcoma with a spindle cell morphology and aggressive clinical behavior. The potential for morphologic and immunohistochemical overlap with several other sarcoma types underscores the value of molecular testing as a diagnostic adjunct to ensure accurate classification and management of these neoplasms.

Congenital spindle cell rhabdomyosarcoma: An international cooperative analysis

BackgroundSpindle cell rhabdomyosarcoma (RMS) is a rare variant of RMS accounting for up to 10% of cases in infants. In older children and adults, spindle cell RMS is associated with MYOD1 mutations and a poor prognosis. In infants, it is associated with recurring fusions involving NCOA2 and VGLL2. Reports in the literature suggest a favorable prognosis for this subset, however, little is known about treatment and outcome data of infants with spindle cell RMS. MethodsCharacteristics, treatment, and outcome of an international cohort of 40 patients aged ≤ 12 months with spindle cell RMS treated from 1997 to 2018 were evaluated. ResultsLocalized disease (LD) was diagnosed in 39 patients. The median age at diagnosis was 2.5 months (range 0–12 months). Expert pathologic review confirmed the diagnosis of spindle cell RMS in all patients. Among 26 tumors that had molecular evaluation, 13 had rearrangements of NCOA and/or VGLL. Multimodal treatment of infants with LD included conventional (age adjusted) chemotherapy (n = 37), resection (n = 31) and radiotherapy (RT) (n = 5, brachytherapy in 3). Complete remission was achieved in 37/39 patients. Progressive disease occurred in two infants, relapsed disease in three. Microscopically complete surgical resection was associated with five-year event-free survival (EFS) and overall survival (OS) of 100%. Two patients with tumors ≤ 5 cm were treated with microscopically complete resection only and were alive 1 and 4.2 years after diagnosis. The 5-year EFS and OS for infants with LD were 86% (±11; CI 95%) and 91% (±9; CI 95%), respectively. One patient had metastatic disease (NCOA fusion positive) with primary tumor in head and neck and brain metastases. This patient died despite chemotherapy and delayed resection of the primary tumor due to respiratory failure secondary to cytomegalovirus infection 1.2 years after diagnosis. ConclusionInfants with spindle cell RMS have an excellent prognosis. Multimodal treatment including microscopically complete resection of the tumor is strongly recommended.

Corrigendum: Functional impact and targetability of PI3KCA, GNAS, and PTEN mutations in a spindle cell rhabdomyosarcoma with MYOD1 L122R mutation.

Corrigendum: Functional impact and targetability of PI3KCA, GNAS, and PTEN mutations in a spindle cell rhabdomyosarcoma with MYOD1 L122R mutation.