Cellular myofibromas with SRF fusions: clinicopathological and molecular study of 3 cases of a rare entity and a potential mimic of sarcoma.

Cellular myofibromas/myopericytomas harboring recurring SRF fusions are recently characterized as rare and diagnostically challenging entities, which can mimic myogenic sarcomas. These tumors belong to the pericytic/perivascular myoid tumor family, which comprises a group of genetically heterogenous and sometimes morphologically overlapping entities. In this series, we describe 3 cases of SRF-rearranged cellular myofibromas/perivascular myoid tumors with a smooth muscle-like phenotype in children. The children ranged from 7 to 16 years of age, and all presented with a painless mass in the extremities, 2 of which were deep-seated. Histologically, the tumors demonstrated a smooth muscle-like morphology and immunophenotype with mild atypia and low-level mitotic activity. Prominent dense collagen deposition and coarse calcification was observed in 2 tumors. RNA sequencing revealed SRF fusions in all cases, with each tumor showing a different 3' partner gene, RELA, NFKBIE, and NCOA3. Of these, NCOA3 has not been reported previously, and this expands the molecular spectrum by identifying a novel fusion partner for SRF. Given that histological features can be worrisome for a myogenic sarcoma, wider awareness of this emerging tumor is valuable to avoid potential misclassification.

PDGFRB and NOTCH3 Mutations are Detectable in a Wider Range of Pericytic Tumors, Including Myopericytomas, Angioleiomyomas, Glomus Tumors, and Their Combined Tumors.

Pericytic tumors are subclassified as myopericytomas, myofibromas, angioleiomyomas, and glomus tumors according to the current World Health Organization classification. These pericytic tumors form a continuous morphologic spectrum, including those with combined morphology. However, to our knowledge, no widely accepted criteria for classifying tumors with combined morphology are available. Recent studies have identified platelet-derived growth factor receptor-beta (PDGFRB) gene mutations in a subset of myofibromas, myopericytomas, and myopericytomatoses but not in angioleiomyomas. NOTCH receptor 3 (NOTCH3) mutations have been reported in a subset of infantile myofibromatosis. To assess their potential role in classifying pericytic tumors, we investigated PDGFRB and NOTCH3 mutations in 41 pericytic tumors of variable morphology, including some combined forms. Our results show these mutations to be present in a variety of pericytic tumors, such as myopericytomas (PDGFRB, 3/11; NOTCH3, 4/11), myopericytomatoses (1/2; 1/2), myofibromas (3/6; 0/6), angioleiomyomas (2/13; 3/13), and glomus tumors (5/9; 1/9). Point mutations were identified in 3 tumors in PDGFRB exon 12 (Y562C, S574F, and G576S), 12 tumors in PDGFRB exon 14 (M655I, H657L, and N666K), and 9 tumors in NOTCH3 exon 25 (A1480S/T, D1481N, G1482S, T1490A, E1491K, G1494S, and V1512A). All PDGFRB mutations and NOTCH3 G1482S, T1490A, and G1494S mutations were classified as "deleterious/damaging" by ≥4 of 6 pathogenicity prediction tools in silico. Five-mutation-positive tumors, including 1 myopericytoma-angioleiomyoma, 2 myopericytomatoses-myofibroma, 1 myofibroma-myopericytoma and 1 angioleiomyoma-myopericytoma, were of combined morphology. Therefore, we found PDGFRB and NOTCH3 mutations to be detectable in a much wider variety of pericytic tumors than previously reported and confirmed myopericytomas, myofibromas, angioleiomyomas, and glomus tumors as members harboring PDGFRB or NOTCH3 mutations. Our results thus suggest that PDGFRB or NOTCH3 mutations are not useful for subclassifying members of the pericytic tumor family.

Identification and functional characterization of transcriptional activators in human cells.

Transcription is orchestrated by thousands of transcription factors (TFs) and chromatin-associated proteins, but how these are causally connected to transcriptional activation is poorly understood. Here, we conduct an unbiased proteome-scale screen to systematically uncover human proteins that activate transcription in a natural chromatin context. By combining interaction proteomics and chemical inhibitors, we delineate the preference of these transcriptional activators for specific co-activators, highlighting how even closely related TFs can function via distinct cofactors. We also identify potent transactivation domains among the hits and use AlphaFold2 to predict and experimentally validate interaction interfaces of two activation domains with BRD4. Finally, we show that many novel activators are partners in fusion events in tumors and functionally characterize a myofibroma-associated fusion between SRF and C3orf62, a potent p300-dependent activator. Our work provides a functional catalog of potent transactivators in the human proteome and a platform for discovering transcriptional regulators at genome scale.

Fibroma of tendon sheath is defined by a USP6 gene fusion-morphologic and molecular reappraisal of the entity.

Fibroma of tendon sheath (FTS) is an uncommon benign myofibroblastic neoplasm that arises in association with tenosynovial tissue. Fusions of the USP6 gene have been recently documented in a proportion of so-called "cellular FTS" but not in "classic FTS". It remains unknown whether FTS can be defined by a USP6 fusion, regardless of cellularity, and what are USP6 fusion-negative "cellular FTS". Furthermore, FTS with low cellularity seems to be frequently confused with desmoplastic fibroblastoma. We performed a comprehensive analysis, including targeted RNA sequencing, of 58 consecutive cases originally diagnosed as FTS (n = 49), desmoplastic fibroblastoma (n = 6), or nodular fasciitis (n = 3); the latter two at the predilection sites for FTS. After review of the original slides, 28 lesions were morphologically classified as FTS (13 "classic" and 15 "cellular") and 23 as desmoplastic fibroblastoma. Among originally diagnosed FTS at the more cellular end of the spectrum, we identified seven lesions that shared many morphologic features of FTS but, in addition, showed several distinct morphologic features consistent with myofibroma, such as myoid appearance, branching thin-walled vessels, and perivascular growth. Targeted RNA sequencing showed a USP6 fusion in 17 of 18 analyzed FTS, regardless of cellularity, 0 of 5 desmoplastic fibroblastomas and 0 of 4 myofibromas. MYH9, COL1A1, and ASPN were identified as fusion partners in three cases each, and MIR22HG, CTNNB1, SPARC, CAP1, EMP1, LINC00152, NR1D1, and RAB1A in a single case each. FTS, regardless of cellularity, can be defined by a USP6 fusion with a variety of fusion partners. More cellular lesions exhibiting some morphologic features of FTS but lacking a USP6 fusion tend to be myofibromas.

Molecular Alterations in Pediatric Fibroblastic/Myofibroblastic Tumors: An Appraisal of a Next Generation Sequencing Assay in a Retrospective Single Centre Study.

BACKGROUND: Pediatric fibroblastic/myofibroblastic tumors (PFMTs) can be challenging to definitively classify. Large case series or diagnostic updates have not been recently published despite identification of molecular alterations that could improve diagnostic accuracy. Our review of the literature found that over two-thirds of the more than 30 types of PFMTs harbor recurrent molecular alterations. We performed an institutional review of PFMTs to highlight limitations of a predominantly morphological classification, and evaluated the utility of a next-generation sequencing assay to aid diagnosis. METHODS: PFMTs identified over a period of 12 years were reviewed, categorized per the new WHO classification, and tested using the Oncomine Childhood Cancer Research Assay. RESULTS: Eighty-seven specimens from 58 patients were reviewed; 50 were chosen for molecular analysis, 16 (32%) lacking definitive classification. We identified alterations, some novel, in 33% of assayed cases. Expected alterations were identified for most known diagnoses and mutations were identified in 6 of 16 tumors (38%) that were initially unclassified. CONCLUSION: We confirmed a significant subset of PFMTs remain difficult to classify using current criteria, and that a combined DNA/RNA assay can identify alterations in many of these cases, improving diagnostic certainty and suggesting a clinical utility for challenging cases.

Novel COL4A1-VEGFD gene fusion in myofibroma.

Myofibroma is a benign pericytic tumour affecting young children. The presence of multicentric myofibromas defines infantile myofibromatosis (IMF), which is a life-threatening condition when associated with visceral involvement. The disease pathophysiology remains poorly characterized. In this study, we performed deep RNA sequencing on eight myofibroma samples, including two from patients with IMF. We identified five different in-frame gene fusions in six patients, including three previously described fusion transcripts, SRF-CITED1, SRF-ICA1L and MTCH2-FNBP4, and a fusion of unknown significance, FN1-TIMP1. We found a novel COL4A1-VEGFD gene fusion in two cases, one of which also carried a PDGFRB mutation. We observed a robust expression of VEGFD by immunofluorescence on the corresponding tumour sections. Finally, we showed that the COL4A1-VEGFD chimeric protein was processed to mature VEGFD growth factor by proteases, such as the FURIN proprotein convertase. In conclusion, our results unravel a new recurrent gene fusion that leads to VEGFD production under the control of the COL4A1 gene promoter in myofibroma. This fusion is highly reminiscent of the COL1A1-PDGFB oncogene associated with dermatofibrosarcoma protuberans. This work has implications for the diagnosis and, possibly, the treatment of a subset of myofibromas.

Myofibromatosis.

INTRODUCTION: Myofibromatosis is a distinctive mesenchymal disorder occurring predominantly in childhood, which on microscopy shows peripheral light areas of spindle cells and central cellular areas of primitive oval to spindle cells arranged around hemagiopercytomatous vessels. PDFGRB mutations in the familial and multifocal sporadic forms and SRF-RELA fusions in the cellular variants have been identified. The index case is being presented to discuss the clinico-pathological features, differential diagnosis, and management of the lesion. CASE PRESENTATION: An 11-year-old male presented with an infraorbital mass of 3 months duration. The mass was excised and microscopy revealed the morphological features of myofibroma with tram-track SMA immunopositivity. Nodular fasciitis and fibromatosis were the differentials considered. CONCLUSION: The SRF-RELA gene fusion may represent a subset that in the future may be used to differentiate these myofibromas/myopericytomas from the ACTB-GLI fusion myopericytomas, and PDGFRB may be used to perhaps separate out familial myofibromas from other myofibromas.

Genetic variant of SRF-rearranged myofibroma with a misleading nuclear expression of STAT6 and STAT6 involvement as 3' fusion partner.

Pediatric neoplasms with a myofibroblastic differentiation are frequent in children, in particular myofibroma. Recently, a novel deep soft tissue myofibroblastic neoplasm has been described with high cellularity, a smooth muscle phenotype and SRF-RELA fusion. We report the case of a 15-year-old boy who presented with a tumor of the deep soft tissue of the arm, with overlapping histological features with the recently described SRF-RELA group of myofibromas but differing by the presence of calcifications, a novel SRF-STAT6 fusion transcript and nuclear expression of STAT6. No local recurrence nor distant metastasis was detected at the current follow-up of 29 months. The clinical relevance of this novel fusion requires further investigations.

A Molecular Reappraisal of Glomus Tumors and Related Pericytic Neoplasms With Emphasis on NOTCH-gene Fusions.

Glomus tumors (GTs), together with myofibroma (MF), myopericytoma (MP), and angioleiomyoma (AL) are classified as members of the perivascular myoid family of tumors. The reported genetic abnormalities across these neoplasms is dissimilar, arguing against a pathogenetically unified family; half of the GT showing NOTCH-gene fusions and a smaller subset BRAF V600E mutations, while PDGFRB mutations are noted in a subset of MF and MP. This study aimed to investigate the prevalence and specificity of NOTCH-gene fusions in a large group of GT and correlate with clinical features. BRAF-VE1 and PDGFRB immunoexpression was also investigated in this cohort. A total of 93 GT and 43 other pericytic lesions (11 MP, 13 MF, and 19 AL) were selected. All cases were tested by fluorescence in situ hybridization for NOTCH1-4 and MIR143 gene abnormalities and 6 cases were investigated by targeted RNA-sequencing. Fluorescence in situ hybridization revealed NOTCH-gene rearrangements in 50 (54%) GT, 2 MP (18%), and 2 AL (11%). NOTCH-rearrangements were present in 34 (68%) benign and 16 (32%) malignant GT. Fusion-positive benign GT were overwhelmingly seen in males with a predilection for extremities, while the malignant GT occurred mostly in viscera. Among the fusion-negative GT, 88% were benign, 9% uncertain malignant potential, and 2% malignant. Half of the fusion-negative GTs occurred in the finger/subungual region. In summary, rearrangements of NOTCH genes are seen in over half of GT, with NOTCH2-MIR143 being the most common fusion (73%), while only a small subset of AL and MP share these abnormalities. The common subungual GT subset lack NOTCH-gene fusions suggesting an alternative pathogenesis. BRAF-VE1 was negative in all 37 cases studied, while strong PDGFRB staining was seen in 14 (21%) cases. Additional studies are needed to investigate the genetic alterations in the fusion-negative cases.

Benign infiltrative myofibroblastic neoplasms of childhood with USP6 gene rearrangement.

AIMS: Several morphologically overlapping (myo)fibroblastic neoplasms harbour USP6 fusions, including aneurysmal bone cysts, nodular fasciitis, myositis ossificans, cranial fasciitis, fibro-osseous pseudotumour of the digits, and cellular fibroma of the tendon sheath. USP6-induced neoplasms are almost universally benign and cured by local excision. We aim to highlight the diagnostic value of USP6 fusion detection in a series of aggressive-appearing paediatric myofibroblastic tumours. METHODS AND RESULTS: Three deep-seated, radiographically aggressive, and rapidly growing childhood myofibroblastic neoplasms were morphologically and molecularly characterised by USP6 break-apart fluorescence in-situ hybridisation (FISH), transcriptome sequencing, and targeted capture analysis. Each tumour occurred in the lower-extremity deep soft tissue of a child presenting with pain, limping, or a mass. In all three patients, imaging studies showed a solid mass that infiltrated into surrounding skeletal muscle or involved/eroded underlying bone. The biopsied tumours consisted of variably cellular myofibroblastic proliferations with variable mitotic activity that lacked overt malignant cytological features. FISH showed that all tumours had USP6 rearrangements. On the basis of these results, all three patients were treated with conservative excision with positive margins. The excised tumours had foci resembling nodular fasciitis, fibromatosis, and pseudosarcomatous proliferation. Next-generation sequencing revealed COL1A1-USP6 fusions in two tumours and a COL3A1-USP6 fusion in the third tumour. One tumour had a subclonal somatic APC in-frame deletion. No recurrence was observed during follow-up (8-40 months). CONCLUSION: We present a series of benign, but aggressive-appearing, USP6-rearranged myofibroblastic tumours. These deep-seated tumours had concerning clinical and radiographic presentations and did not fit into one distinct histological category. These cases highlight the diagnostic value of USP6 fusion detection to identify benign nondescript tumours of this group, especially those with aggressive features, to avoid overtreatment.

A Novel COL1A1-CAMTA1 Rearrangement in Cranial Fasciitis.

Cranial fasciitis is an uncommon benign fibroblastic tumor, generally histologically identical to nodular fasciitis. It develops almost exclusively in children. Cranial fasciitis manifests clinically as a painless rapidly growing solitary nodule in the head and neck area, frequently eroding the underlying bone. Thus, this entity is often confused with aggressive lesions such as sarcomas, both clinically and radiologically. Histopathologic examination is essential to differentiate between cranial fasciitis and fibrohistiocytic or even sarcomatous lesions observed in children. In this article, we present a case of cranial fasciitis with intracranial extension in a 2-year-old boy. Although USP6 rearrangement has recently been recognized as a recurring alteration in nodular fasciitis, we present a novel COL1A1-CAMTA1 fusion in this lesion.

Odontogenic myxomas lack PDGFRB mutations reported in myofibromas.

BACKGROUND: The molecular pathogenesis of odontogenic myxoma has not been established yet. Considering that odontogenic myxoma may show myofibroblastic differentiation and myxoid areas can be observed in intra-osseous myofibromas, we tested the hypothesis whether both tumors share a common molecular profile. As recent studies have reported PDGFRB recurrent driver mutations in myofibroma, we evaluated PDGFRB mutations in odontogenic myxomas. METHODS: A convenience sample of 15 odontogenic myxomas cases was selected. We direct sequenced PDGFRB exons 12 and 14, where p.R561C (c.1681C>T) and p.N666K (c.1998C>G) hotspot mutations have been reported among others in single and/or multiple myofibromas. RESULTS: All 15 odontogenic myxoma samples were successfully sequenced, and all 15 had wild-type sequences for the PDGFRB mutations investigated. CONCLUSION: Our findings suggest that PDGFRB mutations do not play a role in odontogenic myxoma pathogenesis, which might be helpful in the differential diagnosis of challenging cases.

A Distinctive Genomic and Immunohistochemical Profile for NOTCH3 and PDGFRB in Myofibroma With Diagnostic and Therapeutic Implications.

Introduction. Myofibromas are rare tumors of pericytic lineage, typically affecting children, and are sometimes aggressive. A subset of sporadic and familial myofibromas have activating variants in PDGFRB. The relationship of myofibroma and PDGFRB to the NOTCH pathway has not yet been described. Methods. Ten myofibroma cases were sequenced with a targeted panel of 447 genes, including copy number variation and selected fusions. Immunohistochemical analysis of total NOTCH3 and activated NOTCH3 was assessed for all 10 myofibroma cases, and a series of histologic mimics (n = 20). Results. Alterations identified by next-generation sequencing included PDGFRB sequence variants in 8/10 cases (80%), a NOTCH3 variant in 1/10 cases (10%), and a NOTCH2 variant in 1/10 cases (10%). All 10 cases also showed a pattern of low-amplitude (1.5- to 2-fold) copy number alterations including gains in PDGFRB and NOTCH3. Ten of 10 myofibromas (100%) showed cytoplasmic staining for total NOTCH3 and 9 of 10 cases (90%) showed nuclear staining for activated NOTCH3. Within the control cohort of histologic mimics, 3 of 3 nodular fasciitis cases (100%) were positive for activated and total NOTCH3, and the remaining 17 cases were negative for pan NOTCH3, while 3 of 3 desmoid-type fibromatosis cases (100%) showed patchy weak nuclear staining for activated NOTCH3. Discussion. Our findings suggest a common pathway of PDGFRB/NOTCH3 activation in myofibromas, even in cases that lack PDGFRB sequence variants. These results support the pericytic lineage of myofibroma. Identification of the characteristic genomic alterations or immunohistochemical staining pattern may facilitate a difficult pathologic diagnosis, and support the use of targeted treatments.

USP6 Gene Rearrangement by FISH Analysis in Cranial Fasciitis: A Report of Three Cases.

Cranial fasciitis (CF) is an uncommon benign myofibroblastic proliferation involving the soft and hard tissues of the cranium. It typically occurs in the pediatric population with a male predilection (male-to-female ratio 1.5:1). The clinical presentation is usually a rapidly expanding, painless nodule. Bone erosion may be appreciated radiographically. Histopathologic sections of CF show plump, fibroblast-like cells with pale, oval shaped nuclei and prominent nucleoli in a fibrous or myxoid background. Growth is self-limited and surgical excision is considered curative. Due to these features, CF is thought to be a variant of nodular fasciitis (NF). As with NF, CF may mimic a sarcomatous process and pose a diagnostic challenge to clinicians and pathologists alike. Erickson-Johnson et al. identified rearrangements of the ubiquitin-specific protease 6 (USP6) gene in 44 of 48 cases of NF. MYH9 was the fusion partner in 12 of these cases. To date, the molecular profile of CF has not been studied. Here we present the molecular findings in three cases of CF identified at our institution. Each case was subjected to fluorescence in-situ hybridization with appropriate negative controls. Two of three cases were positive for the USP6 gene rearrangement. The third case failed to hybridize, likely related to nucleic acid damage secondary to decalcification. Negative controls did not demonstrate the genetic rearrangement. These findings warrant further investigation of the USP6 gene rearrangement in CF, as it may prove helpful as a diagnostic adjunct in challenging cases.

A Novel ALK-THBS1 Fusion in a Laryngeal Inflammatory Myofibroblastic Tumour: A Case Report and Literature Review.

Inflammatory myofibroblastic tumor (IMT) is an uncommon neoplasm most frequently seen in the abdomino-pelvic region and lungs of children and young adults. Laryngeal tumors are rare. We present a case of a 23-year-old patient with a 5 month history of laryngitis and aphonia unresolved by corticotherapy. Laryngoscopy revealed a small, non-ulcerated, subepithelial, polypoid mass arising from the right vocal cord. The diagnosis of IMT with ALK expression was supported by histopathologic and molecular analysis. The THBS1 fusion partner was identified by RNA-sequencing analysis for the first time in a laryngeal IMT. This fusion partner has only been identified in six uterine IMTs thus far. Conservative excision of the lesion yielded excellent functional results for the patient. The voice was preserved and no recurrences were seen after 6 months of follow-up.

Novel SRF-ICA1L Fusions in Cellular Myoid Neoplasms With Potential For Malignant Behavior.

Pericytic tumors comprise a histologic continuum of neoplasms with perivascular myoid differentiation, which includes glomus tumors, myopericytoma, myofibroma, and angioleiomyoma. Despite their morphologic overlap, recent data suggest a dichotomy in their genetic signatures, including recurrent NOTCH gene fusions in glomus tumors and PDGFRB mutations in myofibromas and myopericytomas. Moreover, SRF-RELA fusions have been described in a subset of cellular variants of myofibroma and myopericytoma showing myogenic differentiation. Triggered by an index case of an unclassified cellular myoid tumor showing a novel SRF-ICA1L fusion we have investigated our files for cases showing similar histology and screened them using a combined approach of targeted RNA sequencing and fluorescence in situ hybridization. A fusion between SRF exon 4 and ICA1L exon 10 or 11 was identified in a total of 4 spindle cell tumors with similar clinicopathologic features. Clinically, the tumors were deep-seated and originated in the trunk or proximal lower extremity of adult patients (age range: 23 to 55 y). Histologically, the tumors were composed of cellular fascicles of monomorphic eosinophilic spindle cells showing increased mitotic activity, harboring densely hyalinized stroma, often with focal areas of necrosis. All 4 tumors had similar immunoprofiles with positivity for smooth muscle actin, calponin, and smooth muscle myosin heavy chain. Tumors were negative for desmin and caldesmon, markers often seen in SRF-RELA-positive tumors with similar morphology. Follow-up information was available in 3 patients. Two patients had no evidence of disease, 2 and 5 years after surgical resection. One patient, a 35-year-old male patient with a 19 cm deep-seated tumor with brisk mitotic activity (>20 mitoses in 10 HPF), developed lung metastases 7 years after initial diagnosis. In summary, we report a series of 4 cellular myoid tumors with novel SRF-ICA1L gene fusions, characterized by bland spindle cell fascicular growth, expression of specific smooth muscle markers, elevated mitotic activity, marked stromal hyalinization, focal coagulative necrosis, and potential for malignant behavior. Given the morphologic overlap with related cellular myopericytic tumors with SRF-RELA fusions, it is likely that SRF-ICA1L fusions define a similar subset of neoplasms composed of immature smooth muscle cells.

Uterine Inflammatory Myofibroblastic Tumor Showing an Atypical ALK Signal Pattern by FISH and DES-ALK Fusion by RNA Sequencing: A Case Report.

Inflammatory myofibroblastic tumors (IMTs) are spindle cell neoplasms of intermediate (borderline) biologic potential with tendency for local recurrence but low risk of metastasis. They affect children more than adults. The most common sites of involvement are the lung, soft tissue, peritoneum, bladder, and less commonly the gynecologic tract. IMTs are characterized by spindle to epithelioid cells with myofibroblastic differentiation, some degree of smooth muscle differentiation, myxoid stroma and usually associated with brisk lymphoplasmacytic infiltrates. In about half of the cases, IMTs are associated with rearrangements of the anaplastic lymphoma kinase (ALK) gene located at chromosome 2p23. The ALK rearrangement can be detected by immunohistochemistry for ALK protein expression (mostly cytoplasmic with or without perinuclear accentuation) or by fluorescent in situ hybridization (FISH) using dual-color break-apart probes for which the typical pattern is seen as split 3' end (red) and 5' end (green) probe signals in addition to single normal, unsplit red-green signal pair (yellow). Herein we describe a case of uterine IMT initially misdiagnosed intraoperatively as leiomyoma which showed sparse lymphocytic infiltrates, positive ALK expression by immunohistochemistry, a predominantly atypical FISH signal pattern (1 yellow and 1 red signal only) and few typical signal patterns (1 yellow, 1 red, and 1 green signal) in a smaller population of tumor cells. The RNA sequencing showed a recently described DES-ALK fusion transcript in the tumor cells, suggesting an intrachromosomal inversion and deletion as the likely underlying mechanism for the atypical FISH pattern. Familiarity with the unusual morphology and atypical FISH pattern is crucial given that this tumor has an activating ALK rearrangement and may benefit from targeted tyrosine kinase inhibitors in the future.

What is new in pericytomatous, myoid, and myofibroblastic tumors?

Recent advances in molecular techniques in soft tissue pathology, including the widespread application of next-generation sequencing, have led to significant progress in our understanding of mesenchymal tumors. Recognition of the genetic signatures of these neoplasms not only clarifies the relationship of these entities but also provides a mechanism for more accurate diagnosis. More importantly, insight into the genetic underpinnings of these lesions may offer therapeutic targets for cases not amenable to surgical treatment. This review highlights the clinicopathologic features and novel molecular findings in pericytic, myoid, and myofibroblastic tumors.