The ever-increasing availability and affordability of molecular genetic testing has revolutionized our understanding of the pathogenesis and proper classification of soft tissue tumors but has also brought new challenges. As is known, many soft tissue tumors harbor gene fusion events, and while it was initially thought that individual entities would be defined by single, specific fusions, it quickly became clear that some entities could be caused by several different fusion events (e.g., EWSR1::FLI1, EWSR1::ERG, EWSR1:FEV and others in Ewing sarcoma). More recently, it has become apparent that these fusion events themselves are "promiscuous", appearing in more than one discrete entity (e.g., EWSR1::CREB1 in clear cell sarcoma, angiomatoid fibrous histiocytoma and others). This review article will briefly discuss the best known examples of genetic promiscuity, the EWSR1/FUS::ATF1/CREB1 and ETV6::NTRK3 fusions, and more comprehensively cover recently discovered and less well-known examples of genetic promiscuity, including EWSR1::WT1, MALAT1::GLI1, YAP1::TFE3 and fusions involving members of the FET and ETS gene families.

Plexiform fibromyxoma (PF) is an extremely rare mesenchymal tumor, which was first reported by Takahashi et al. in 2007 and named by the World Health Organization (WHO) in 2010 in the classification of digestive system tumors. Currently, only 123 cases have been reported globally, and complete surgical resection is the only effective treatment. On October 20, 2023, we successfully performed a robot-assisted partial gastrectomy with Billroth I anastomosis to remove gastric PF. Since the operation, the child has recovered well. After literature search and novelty confirmation, it was confirmed to be the first case globally (novelty confirmation number: 44011120230247C). Based on this, we reviewed relevant literature and summarized the surgical experience of this case.

A 7-year-old Chinese female patient was admitted to Guangzhou Women and Children's Medical Center in October 2023. Due to "pallor for 4 months and the discovery of a tumor in the gastric antrum over 2 weeks ago", an enhancement CT scan revealed a mass in her gastric antrum, approximately 4.0 cm × 3.5 cm × 3.0 cm in size, but its nature remains to be determined. On electronic gastroscopy, a mass was identified in the gastric antrum and pylorus orifice. It exhibited a smooth surface, with its base located on the lesser curvature side and pylorus. We did robot-assisted partial gastrectomy with Billroth I anastomosis for her to remove the mass. Now it has been 11 months after the operation, and the child has recovered well with no sign of mass recurrence.

This study confirms that the robot-assisted partial gastrectomy with Billroth I anastomosis for the treatment of gastric PF in children is safe and feasible, and there are no complications of the operation.

Pathogenic alterations, namely, fusions and amplifications, of the GLI1 gene have been identified in various mesenchymal tumors, including pericytoma with t(7;12), plexiform fibromyxoma, gastroblastoma, and other malignant mesenchymal neoplasms arising in the soft tissues, as well as in various visceral organs. However, only three cases of GLI1-rearranged renal tumors have been reported to date, comprising two low-grade spindle cell tumors with GLI1::FOXO4 fusion along with one GLI1-rearranged case with an unknown fusion partner. In this study, we analyzed three cases with GLI1::FOXO4 fusion and overlapping morphology. One of the cases was reported previously, but an extended clinical and immunohistochemical information is provided. The studied cases occurred in 2 female and 1 male patients aged 35, 55, and 62 years (mean 51 years). All three tumors affected the renal parenchyma and grew as unencapsulated but well-circumscribed solid masses containing occasional entrapped and dilated renal tubules. The tumor cells were organized in cords, nests, or fascicles, had a round to spindled shape, and exhibited only mild nuclear atypia and minimal mitotic activity. They had a sparse eosinophilic to clear cytoplasm and were embedded in myxocollagenous stroma. Immunohistochemically, all cases expressed GLI1 (albeit with variable intensity) and harbored GLI1::FOXO4 fusion. All three patients were treated solely by complete surgical excision. Case 1 was alive with unknown disease status, case 2 was alive without evidence of disease, and case 3 died of unrelated causes. Our study doubles the number of reported cases with GLI1::FOXO4 fusion. The so far absolute predilection of this fusion for renal tumors, coupled with the absence of reports of other GLI1 fusions in tumors of the kidney, might indicate the potential existence of a distinct renal subtype with morphological features similar to other GLI1-altered tumors. All four reported cases had an uneventful follow-up which, together with their low-grade morphological features, suggests that these tumors might have a favorable prognosis.

Mesenchymal neoplasms of the gastrointestinal tract are rare compared with epithelial lesions. However, over the past few decades, the increasing volume of gastrointestinal endoscopy has expedited the recognition of several novel entities with varying clinical significance. Its spectrum extends from reactive changes and benign neoplasms to highly aggressive sarcomas. At the malignant end of the spectrum, the importance of correctly diagnosing these tumors is underscored by the specific therapeutic implications available for some tumor types (eg, tyrosine kinase inhibitors for gastrointestinal stromal tumors) that allow personalized treatments. Benign lesions frequently surface among routine polypectomy specimens, sometimes offering diagnostic challenges. However, precise classification is the only way to avoid prognostic uncertainty and overtreatment, and to recognize possible syndromic associations. Hereby, we offer a pragmatic review of the topic from the gastrointestinal pathologist's perspective, who, although more accustomed to epithelial neoplasms, can use an algorithmic approach to diagnose mesenchymal entities successfully.

GLI1-altered mesenchymal tumors represent a rare category of soft tissue tumors that have recently been incorporated into the classification of head and neck soft tissue tumors in the fifth edition of the World Health Organization (WHO) classification. However, their precise nature remains undefined, and they have yet to be assigned an ICD code. These tumors are predominantly located in the head and neck region and display distinctive pathological morphology and molecular characteristics. We present the first documented case of a GLI1-altered mesenchymal tumor occurring in the pleura. Microscopic examination revealed that the tumor was composed of ovoid-to-round and vaguely epithelioid cells, as well as a few spindle cells, all exhibiting a uniform morphology and organized in a nested and reticular arrangement, accompanied by a rich capillary network in the stroma. Immunohistochemical staining demonstrated positivity for CD56, S-100, and SMA. Next-generation sequencing (NGS) revealed a PTCH1-GLI1 fusion. Based on the morphological and immunophenotypic characteristics, molecular studies confirmed the diagnosis of a GLI1-altered mesenchymal tumor. At the 15-month follow-up, the patient was alive. We conducted a review of all cases of recurrence and metastasis, concluding that this type of tumor has a distinct propensity to metastasize to the lungs. The tumor exhibits malignant potential, and factors such as its occurrence outside the head and neck region, high-grade histological morphology, active mitosis (>5/10HPF), necrosis and PTCH1-GLI1 fusion are all considered potential risk factors.

Recent advances in molecular genetics, particularly in identifying and characterizing genetic abnormalities within mesenchymal neoplasms, have led to a more comprehensive and evolving classification system. Modern technological developments in cytogenetics and next-generation sequencing have enabled the analysis of small clinical samples, expanded our understanding of tumor biology, and improved the diagnostic, prognostic, and predictive precision by identifying targeted genetic alterations, confirming the presence of fusion transcripts, and/or revealing the overexpression of specific genes and their targets. In this review, we focus specifically on the GLI1-rearranged enteric tumor, a recent clinicopathological entity that has emerged within the expanding classification of mesenchymal tumors. Herein, we aim to explore the histopathological features, molecular genetic characteristics, and clinical outcomes in these tumors. Due to their rarity and the extensive overlapping in their histopathological and molecular features with other neoplasms, continued research and systematic documentation of GLI1-rearranged enteric tumors is necessary to better understand their biological behavior, develop more accurate prognostic indicators, and establish optimal treatment strategies.

Plexiform fibromyxoma (PFM) and gastroblastoma (GB) are rare gastric tumors with a specific MALAT1::GLI1 rearrangement, included in the conditional spectrum of neoplasms with alterations of the GLI1 gene. The article presents a clinical case of PFM in a 6-year-old girl and a literature review highlighting current data on the morphology, immunophenotype and molecular genetic characteristics of PFM and GB. Despite the common genetic anomaly, differences in the morphology and clinical course of these tumors indicate the need for further research to clarify their relationship and potential reclassification in the light of new data on tumors with GLI1 gene abnormalities. Integrating the accumulated knowledge about tumors with GLI1 gene alterations into diagnostic algorithms and therapeutic approaches will help improve the treatment outcomes of patients with these rare neoplasms.

GLI1-altered mesenchymal tumors have recently emerged as a distinctive group of neoplasms characterized by GLI1 fusions or amplifications. Although there is clearly metastatic potential, the clinicopathologic features predicting for metastasis are currently unknown. Herein, we present 6 cases of GLI1-altered mesenchymal tumors with multiomics analysis. The median patient age was 50 years (range, 3-68 years). They arose from the extremities and trunk (2/6), head and neck region (2/6), and gastrointestinal tract (2/6). Histologically, they featured uniform round to ovoid cells with nested architecture and a rich vascular network. One case displayed abundant multinucleated giant cells. All stained positive for GLI1 (5/5) and CD56 (6/6). Molecularly, they featured GLI1 fusion (5/6) and amplification (1/6). Fusion partners included ACTB (3/5), TXNIP (1/5), and novel TUBA1B (1/5). Multiomics analysis revealed they possessed distinct expression and epigenomic profiles. All the 6 cases had follow-up information, with 5 of them having no evidence of disease at a median follow-up of 30 months (range, 17.3-102 months), and 1 case being died of disease with regional neck lymph node and bilateral lung metastasis at 81.5 months of follow-up. By incorporating cases reported in the literature, we analyzed clinicopathologic features of a total of 167 cases predictive of malignant behavior. We found that size ≥6 cm and mitotic count ≥5 per 10 high-power fields are predictive of metastasis. Cases with both high-risk features had significantly poorer survival. This study expands the literature database of GLI1-altered mesenchymal tumors and identifies features that can be used for risk stratification.

Plexiform fibromyxoma (PF) is a rare mesenchymal tumor that primarily occurs in gastric origin with a benign behavior. PF commonly harbors the MALAT1::GLI1 fusion gene. Here, we describe a case of a 36-year-old female with a PF. Abdominal computed tomography (CT) showed a 3.3 cm mass in the stomach. She underwent laparoscopic partial gastrectomy. Immunohistochemistry (IHC) of the tumor revealed strongly positive staining for CD34, SDHB, STAT6, MDM2, and CDK4. And the tumor showed TP53 mutant expression. Next-generation sequencing (NGS) comprehensive genomic profiling identified GLI1, CDK4, and MDM2 co-amplification and TP53 mutations. Here, we first report a case of a young woman with a PF harboring co-amplification of GLI1, CDK4, and MDM2 genes. The patient underwent complete removal of the tumor without the use of radiotherapy or chemotherapy. No recurrence was observed during the follow-up period of 8 months. This study aims to improve our understanding of PF by analyzing the clinicopathological characteristics of this case, including immunohistochemical (IHC) and genetic examination, and reviewing relevant literature.

GLI1-altered tumors form a diverse group occurring in various anatomic locations. In the alimentary tract, the most established are gastroblastoma, a biphasic epithelial-mesenchymal neoplasm of the stomach, and plexiform fibromyxoma, a pure spindle cell neoplasm. The spectrum of GLI1-rearranged gastrointestinal tumors has recently expanded with reports of cases in other parts of the GI tract, some exhibiting gastroblastoma-like features and others being pure mesenchymal neoplasms. These tumors often display a nonspecific immunophenotype, with only CD56 and cyclin D1 expression being common. Biphasic GLI1-altered tumors show diffuse keratin positivity in the epithelial component only, and GLI1-altered mesenchymal tumors typically lack or show only focal keratin expression. This study details 2 GLI1-rearranged gastrointestinal tract tumors with diffuse keratin and CD56 expression, composed entirely of epithelial cells with a nested growth pattern and finely stippled monotonous nuclei, leading to an initial suspicion of neuroendocrine tumor in both cases, despite lack of synaptophysin and chromogranin expression. Diffuse strong nuclear cyclin D1 expression was seen in both cases, and conversely, strong cyclin D1 staining was only seen in 5.4% (4/74) of well-differentiated neuroendocrine tumors tested. These 2 GI tract neoplasms highlight a widened spectrum of GLI1-rearranged tumors, now including monophasic epithelial neoplasms with diffuse keratin expression.

We hereby report the case of an epithelioid neoplasm arising from pterygopalatine fossa in a 13-year-old child harboring PANX3::GLI1 fusion and MDM2 amplification. Identified chimeric gene can explain observed signs of osteogenic differentiation. We discuss the challenges in differential diagnosis from osteogenic tumors and soft tissue neoplasms with epithelioid morphology. Our case is the first report of a tumor with such genetic abnormalities and it is about to replenish the spectrum of rare GLI1-rearranged tumors.

GLI1 -altered mesenchymal tumor is a recently described distinct pathologic entity with an established risk of malignancy, being defined molecularly by either GLI1 gene fusions or amplifications. The clinicopathologic overlap of tumors driven by the 2 seemingly distinct mechanisms of GLI1 activation is still emerging. Herein, we report the largest series of molecularly confirmed GLI1 -altered mesenchymal neoplasms to date, including 23 GLI1- amplified and 15 GLI1 -rearranged new cases, and perform a comparative clinicopathologic, genomic, and survival investigation. GLI1- rearranged tumors occurred in younger patients (42 vs. 52 y) and were larger compared with GLI1 -amplified tumors (5.6 cm vs. 1.5 cm, respectively). Histologic features were overall similar between the 2 groups, showing a multinodular pattern and a nested architecture of epithelioid, and less commonly spindle cells, surrounded by a rich capillary network. A distinct whorling pattern was noted among 3 GLI1 -amplified tumors. Scattered pleomorphic giant cells were rarely seen in both groups. The immunoprofile showed consistent expression of CD56, with variable S100, CD10 and SMA expression. Genomically, both groups had overall low mutation burdens, with rare TP53 mutations seen only in GLI1- amplified tumors. GLI1 -amplified mesenchymal tumors exhibit mostly a single amplicon at the 12q13-15 locus, compared with dedifferentiated liposarcoma, which showed a 2-peak amplification centered around CDK4 (12q14.1) and MDM2 (12q15). GLI1 -amplified tumors had a significantly higher GLI1 mRNA expression compared with GLI1 -rearranged tumors. Survival pooled analysis of current and published cases (n=83) showed a worse overall survival in GLI1 -amplified patients, with 16% succumbing to disease compared with 1.7% in the GLI1- rearranged group. Despite comparable progression rates, GLI1 -amplified tumors had a shorter median progression-free survival compared with GLI1 -rearranged tumors (25 mo vs. 77 mo). Univariate analysis showed that traditional histologic predictors of malignancy (mitotic count ≥4/10 high-power fields, presence of necrosis, and tumor size ≥5 cm) are associated with worse prognosis among GLI1 -altered mesenchymal tumors.

GLI1-altered mesenchymal tumors are an emerging entity in soft tissue pathology. In the head and neck region, they are most commonly in the tongue. Limited published data indicate a propensity for local recurrence, regional spread, and distant metastasis in both GLI1-rearranged and GLI1-amplified tumors. The purpose of this report is to present the rare case of a GLI1-amplified spindle cell tumor of the orbit and a focused review of the literature. A 54-year-old woman presented with proptosis, eye pain, and ocular motility restriction in the left eye. Imaging demonstrated a tumor occupying the superomedial intraconal orbit that was distinct from the extraocular muscles, optic nerve, and globe. The tumor was totally resected with a combined open transorbital and endoscopic, endonasal approach. Pathological analysis demonstrated a spindled and epithelioid mesenchymal tumor with diffuse nuclear GLI1 expression. PCR-based, next*-generation sarcoma fusion panel was negative for GLI1 fusions, including GLI1::ACTB fusions; however, DDIT3 breaks apart fluorescence in situ hybridization (FISH), which can be used as a surrogate for GLI1 alterations due to proximity to 12q13.3, showing amplification. Post-operatively, the patient had recovered visual acuity. She received adjuvant radiation therapy (60 Gy in 30 fractions). Surveillance for recurrence, regional spread, and distant metastasis has been negative at a 6-month follow-up. Ultimately, we report the first case of a GLI1-amplified mesenchymal neoplasm of the intraconal orbit managed with gross total resection via a combined approach followed by adjuvant radiation therapy.

Cancer chimeric, or fusion, transcripts are thought to most frequently appear due to chromosomal aberrations that combine moieties of unrelated normal genes. When being expressed, this results in chimeric RNAs having upstream and downstream parts relatively to the breakpoint position for the 5'- and 3'-fusion components, respectively. As many other types of cancer mutations, fusion genes can be of either driver or passenger type. The driver fusions may have pivotal roles in malignisation by regulating survival, growth, and proliferation of tumor cells, whereas the passenger fusions most likely have no specific function in cancer. The majority of research on fusion gene formation events is concentrated on identifying fusion proteins through chimeric transcripts. However, contemporary studies evidence that fusion events involving non-coding RNA (ncRNA) genes may also have strong oncogenic potential. In this review we highlight most frequent classes of ncRNAs fusions and summarize current understanding of their functional roles. In many cases, cancer ncRNA fusion can result in altered concentration of the non-coding RNA itself, or it can promote protein expression from the protein-coding fusion moiety. Differential splicing, in turn, can enrich the repertoire of cancer chimeric transcripts, e.g. as observed for the fusions of circular RNAs and long non-coding RNAs. These and other ncRNA fusions are being increasingly recognized as cancer biomarkers and even potential therapeutic targets. Finally, we discuss the use of ncRNA fusion genes in the context of cancer detection and therapy.

GLI1(12q13.3) amplification is identified in a subset of mesenchymal neoplasms with a distinct nested round cell/epithelioid phenotype. MDM2 and CDK4 genes are situated along the oncogenic 12q13-15 segment, amplification of which defines well-differentiated liposarcoma (WDLPS)/dedifferentiated liposarcoma (DDLPS). The 12q amplicon can occasionally include GLI1, a gene in close proximity to CDK4. We hereby describe the first cohort of GLI1/MDM2/CDK4 coamplified WD/DDLPS. The departmental database was queried retrospectively for all cases of WD/DDLPS having undergone next-generation (MSK-IMPACT) sequencing with confirmed MDM2, CDK4, and GLI1 coamplification. Clinicopathologic data was obtained from a review of the medical chart and available histologic material. Four hundred eighty-six WD/DDLPS cases underwent DNA sequencing, 92 (19%) of which harbored amplification of the GLI1 locus in addition to that of MDM2 and CDK4. These included primary tumors (n = 60), local recurrences (n = 29), and metastases (n = 3). Primary tumors were most frequently retroperitoneal (47/60, 78%), mediastinal (4/60, 7%), and paratesticular (3/60, 5%). Average age was 63 years, with a male:female ratio of 3:2. The cohort was comprised of DDLPS (86/92 [93%], 6 of which were WDLPS with early dedifferentiation) and WDLPS without any longitudinal evidence of dedifferentiation (6/92, 7%). One-fifth (13/86, 17%) of DDLPS cases showed no evidence of a well-differentiated component in any of the primary, recurrent, or metastatic specimens. Dedifferentiated areas mostly showed high-grade undifferentiated pleomorphic sarcoma-like (26/86,30%) and high-grade myxofibrosarcoma-like (13/86,16%) morphologies. A disproportionately increased incidence of meningothelial whorls with/without osseous metaplasia was observed as the predominant pattern in 16/86 (19%) cases, and GLI1-altered morphology as described was identified in a total of 10/86 (12%) tumors. JUN (1p32.1), also implicated in the pathogenesis of WD/DDLPS, was coamplified with all 3 of MDM2, CDK4, and GLI1 in 7/91 (8%) cases. Additional loci along chromosomal arms 1p and 6q, including TNFAIP3, LATS1, and ESR1, were also amplified in a subset of cases. In this large-scale cohort of GLI1 coamplified WD/DDLPS, we elucidate uniquely recurrent features including meningothelial whorl-like and GLI-altered morphology in dedifferentiated areas. Assessment of tumor location (retroperitoneal or mediastinal), identification of a well-differentiated liposarcoma component, and coamplification of other spatially discrete genomic segments (1p and 6q) might aid in distinction from tumors with true driver GLI1 alterations.

Sarcomas of the cervical spine with osteolytic lesions and intradural extension are extremely uncommon. This is a case report of a woman in her late 30s who had experienced numbness and gradual weakness of her four limbs. MRI with enhanced T1-weighted contrast showed a heterogeneously enhancing intradural extramedullary mass lesion over C2-C4 levels compressing the spinal cord. Over the corresponding levels, the computed tomography scan showed an osteolytic lesion. Surgical intervention was performed under intraoperative neuromonitoring. Histopathological findings demonstrated a low-grade tumor with round to ovoid nuclei with a moderate amount of eosinophilic cytoplasm with minimal nuclear pleomorphism. Next-generation sequencing technology was employed and findings revealed PTCH1::GLI1 and GLI1::KDM2B fusion with strongly positive findings on GLI1 immunohistochemical staining. The final diagnosis was GLI1 fusion sarcoma. The patient recovered well under multidisciplinary treatment with stringent follow-up, which are required for this rare disease entity.

BACKGROUND Soft tissue tumors have various subtypes, among which sarcomas exhibit high malignant potential and poor prognosis. Malignant epithelioid tumor with GLI1 alterations was originally found in myopericytoma with t(7;12) translocation. However, recent studies indicated that it is a distinct tumor type characterized by multiple nodular distributions of oval or round epithelioid cells with a rich capillary network and a lack of specific immunophenotype. There are only a few cases reported worldwide and the optimal treatment is still being explored. CASE REPORT We report the case of a 31-year-old patient who presented with severe anemia and a large soft tissue mass in the duodenum. The patient underwent surgical resection with a negative margin, and none of the 15 lymph nodes tested positive for the tumor. Postoperative pathology and FISH testing further confirmed the presence of GLI1 disruption and S-100 and SMA negativity. Genetic testing revealed the ACTB-GLI1 fusion. No specific medication was offered after the surgery. No tumor recurrence was found during the 23-month follow-up period. The patient's quality of life is currently satisfactory. CONCLUSIONS Soft tissue sarcomas characterized by GLI1 gene rearrangement have a relatively less aggressive and metastatic nature, with the solid mass spreading minimally even as it grows. Patients can benefit from surgical resection, resulting in a relatively long period of tumor-free survival.

Gastroblastoma is a rare gastric biphasic tumor composed of mesenchymal and epithelial elements in variable proportions. These tumors usually arise in the gastric antrum of children and young adults and are reported to harbor a recurrent MALAT1::GLI1 fusion. Herein we report a case of gastroblastoma in a 19-year-old male who presented with intermittent epigastric abdominal discomfort. Antrectomy revealed a 5.6-cm multi-lobulated, tan-pink mass with solid and focally cystic areas involving the submucosa, muscularis propria, and subserosa. All tumor cells demonstrated immunoreactivity for GLI-1, CD56, and vimentin; epithelial elements expressed pancytokeratins (AE1/AE3 and Oscar), and mesenchymal cells demonstrated focal positivity for CD10. Next generation sequencing revealed a novel ACTB::GLI1 fusion without evidence of the recurrent MALAT1::GLI1 fusion. Nine months after surgery, the patient is well without evidence of recurrence or metastases. To our knowledge, this is the first case of gastroblastoma harboring this novel ACTB::GLI1 fusion.

There is a diverse group of non-gastrointestinal stromal tumor (GIST), mesenchymal neoplasms of the gastrointestinal (GI) tract that demonstrate characteristic pathology and histogenesis as well as variable imaging findings and biological behavior. Recent advancements in tumor genetics have unveiled specific abnormalities associated with certain tumors, influencing their molecular pathogenesis, biology, response to treatment, and prognosis. Notably, giant fibrovascular polyps of the esophagus, identified through MDM2 gene amplifications, are now classified as liposarcomas. Some tumors exhibit distinctive patterns of disease distribution. Glomus tumors and plexiform fibromyxomas exhibit a pronounced affinity for the gastric antrum. In contrast, smooth muscle tumors within the GI tract are predominantly found in the esophagus and colorectum, surpassing the incidence of GISTs in these locations. Surgical resection suffices for symptomatic benign tumors; multimodality treatment may be necessary for frank sarcomas. This article aims to elucidate the cross-sectional imaging findings associated with a wide spectrum of these tumors, providing insights that align with their histopathological features.

Mesenchymal neoplasms with GLI1 alterations have recently been reported in several anatomic locations. Their morphology and immunohistochemistry (IHC) are nonspecific, making their recognition a true challenge. To assess the diagnostic value of GLI1 and p16 IHC for identifying GLI1-altered neoplasms, we evaluated 12 such neoplasms (6 GLI1-amplified and 6 with GLI1-fusions) using the GLI1 IHC. Additionally, we evaluated some of their morphological and molecular mimickers, including glomangiomas, Ewing sarcomas (ES), myxoid liposarcomas, and MDM2/CDK4-amplified sarcomas (well-differentiated liposarcoma/WDLPS, dedifferentiated liposarcoma/DDLPS, and intimal sarcoma). All successfully tested GLI1-altered tumors (11/11) demonstrated at least moderate/strong nuclear and/or cytoplasmic GLI1 IHC positivity. GLI1-amplified tumors exhibited a moderate/strong predominantly nuclear staining, compared to a moderate, patchy, and predominantly cytoplasmic GLI1 positivity in GLI1-fusion tumors. Among their mimics, GLI1 immunoreactivity, either cytoplasmic or nuclear, was observed in intimal sarcoma (3/3) and WDLPS/DDLPS (22/25). GLI1 IHC demonstrated 92% sensitivity and 90.8% specificity in diagnosing GLI1-altered neoplasms. Strong/moderate nuclear/cytoplasmic p16 immunoexpression was noted in all GLI1-amplified tumors compared to none of fused cases. Overall, the GLI1/p16 combination demonstrated a sensitivity and specificity of 100% and 93% for GLI1-amplified tumors. In conclusion, we confirm that GLI1 IHC represents a good, quick, and cheap helpful screening tool. The inclusion of p16 may aid in pre-screening for potential GLI1-amplified neoplasms and provide insights on which tumors warrant further molecular testing.

Plexiform fibromyxoma (PF), also referred to as plexiform angiomyxoid myofibroblast tumor, is an exceedingly rare mesenchymal neoplasm primarily affecting the stomach. Herein, we present a case of PF diagnosed in a 71-year-old male with a history of lung cancer, initially suspected to have a gastrointestinal stromal tumor (GIST) of the stomach, who subsequently underwent subtotal gastrectomy. The histopathological and molecular features of the tumor, including mutations in ABL1, CCND1, CSF1R, FGFR4, KDR, and MALAT1-GLI1 fusion, are elucidated and discussed in the context of diagnostic, prognostic, and therapeutic considerations.

Gastroblastoma is an extremely rare gastric tumor. Its pathogenesis remains unclear and there is a lack of specific clinical symptoms. The aim of this paper is to report a case of gastroblastoma and provide references for the diagnosis, treatment, and prognosis of this disease.

The diagnosis and treatment of a 51-year-old female patient with gastroblastoma were retrospectively reported. Analyzing this case by combining the clinical data such as imaging and pathological results of patients with the relevant literature.

The patient's chief complaint was the presence of melena persisted for over two weeks. Abdominal contrast-enhanced CT showed gastric antral nodules, and micro-probe endoscopic ultrasonography was considered as "gastric antral protruding lesions". The initial diagnosis of "gastric stromal tumor" was made after admission, and surgical treatment was performed on September 23, 2021. Postoperative pathology showed that gastric mixed epithelial and stromal tumor, combined with immunohistochemical staining, was suggestive of gastroblastoma. No signs of tumor recurrence or metastasis were observed during the 2-year follow-up.

Combined with the existing literature reports, the incidence of gastroblastoma is mainly higher in young men, and the predilection site is gastric antrum. The biological behavior of the tumor tends to be indolent, and the prognosis of most cases is favorable. However, due to the extremely small number of cases, this conclusion still needs a large number of cases and follow-up data to support. Postoperative pathological and immunohistochemical examination results are the only methods for definite diagnosis at present, and surgery is the first choice for treatment.

Plexiform fibromyxoma is a rare mesenchymal tumor identified in recent years and presents as a gastrointestinal submucosal tumor that is typically located in the gastric antrum. We report a case of gastric plexiform fibromyxoma in which the diagnosis was difficult despite repeated tissue sampling. Before visiting our hospital, the patient had been followed up for 3 years without a definitive diagnosis despite serial examinations, including computed tomography, endoscopy, endoscopic ultrasound, and endoscopic ultrasound-guided fine-needle aspiration. Endoscopic ultrasound-guided fine-needle aspiration was reperformed, and endoscopic submucosal dissection for deep biopsy was conducted for differential diagnosis of the tumor. However, histological analysis with immunostaining of tumor samples obtained using these techniques cannot provide a reliable diagnosis. Finally, the tumor was resected surgically because of its increasing size, and subsequent microscopic analysis revealed a multinodular plexiform growth pattern of spindle-like cells with myxoid stroma. Immunohistochemically, the tumor cells were positive for smooth muscle actin but negative for c-kit, CD34, and S100. Based on these findings, the patient was diagnosed with plexiform fibromyxoma. No evidence of residual or recurrent tumors was observed at 24 months postoperatively.

GLI1-altered mesenchymal tumors comprise an emerging group of neoplasms characterized by fusions or amplifications involving GLI1, a gene that encodes a key regulator of the Hedgehog signaling pathway. In recent years, tumors with GLI1 alterations have been reported across a variety of anatomic sites and a broad age range. Although these tumors can exhibit a wide morphologic spectrum and a variable immunophenotype, they frequently present with monomorphic ovoid cells arranged in distinctive nests with a rich, arborizing vascular network. Recent evidence indicates that they have the potential to metastasize, which suggests that they may be best considered a sarcoma.

Mesenchymal tumors with GLI1 fusions or amplifications have recently emerged as a distinctive group of neoplasms. The terms GLI1-altered mesenchymal tumor or GLI1-altered soft tissue tumor serve as a nosological category, although the exact boundaries/criteria require further elucidation. We examined 16 tumors affecting predominantly adults (median age: 40 years), without sex predilection. Several patients had tumors of longstanding duration (>10 years). The most common primary site was soft tissue (n = 9); other sites included epidural tissue (n = 1), vertebra (n = 1), tongue (n = 1), hard palate (n = 1), and liver (n = 1). Histologically, the tumors demonstrated multinodular growth of cytologically uniform, ovoid-to-epithelioid, occasionally short spindled cells with delicate intratumoral vasculature and frequent myxoid stroma. Mitotic activity ranged from 0 to 8 mitoses/2 mm2 (mean 2). Lymphovascular invasion/protrusion of tumor cells into endothelial-lined vascular spaces was present or suspected in 6 cases. Necrosis, significant nuclear pleomorphism, or well-developed, fascicular spindle-cell growth were absent. Half demonstrated features of the newly proposed subset, "distinctive nested glomoid neoplasm." Tumors were consistently positive for CD56 (n = 5/5). A subset was stained with S100 protein (n = 7/13), SMA (n = 6/13), keratin (n = 2/9), EMA (n = 3/7), and CD99 (n = 2/6). Tumors harbored ACTB::GLI1 (n = 15) or PTCH1::GLI1 (n = 1) fusions. The assays used did not capture cases defined by GLI1 amplification. We also identified recurrent cytogenetic gains (1q, 5, 7, 8, 12, 12q13.2-ter, 21, and X). For patients with available clinical follow-up (n = 8), half were disease free. Half demonstrated distant metastases (lungs, bone, or soft tissue). Of cases without follow-up (n = 8), 2 were known recurrences, and 1 was presumed metastasis. Our results imply a more aggressive biological potential than currently reported. Given the possibility for metastasis and disease progression, even in cytologically bland, nested tumors, close clinical surveillance, akin to that for sarcoma management, may be indicated. The term GLI1-altered mesenchymal tumor with malignant potential is proposed.

In spite of its high mortality rate and difficulty in finding a cure, scientific advancements have contributed to a reduction in cancer-related fatalities. Aberrant gene expression during carcinogenesis emphasizes the importance of targeting the signaling networks that control gene expression in cancer treatment. Long noncoding RNAs (lncRNAs), which are transcribed RNA molecules that play a role in gene expression regulation, are a recent innovative therapeutic approach for diagnosing and treating malignancies. MALAT1, a well-known lncRNA, functions in gene expression, RNA processing, and epigenetic control. High expression levels of MALAT1 are associated with several human disorders, including metastasis, invasion, autophagy, and proliferation of cancer cells. MALAT1 affects various signaling pathways and microRNAs (miRNAs), and this study aims to outline its functional roles in cancer metastasis and its interactions with cellular signaling pathways. Moreover, MALAT1 and its interactions with signaling pathways can be promising target for cancer treatment.

New tumour types are being described at increasing frequency, and most new tumour types are now identified via retrospective review of next-generation sequencing data. This contrasts with the traditional, morphology-based method of identifying new tumour types, and while the sequencing-based approach has accelerated progress in the field, it has also introduced novel and under-recognised biases. Here, we discuss tumour types identified based on morphology, including superficial CD34-positive fibroblastic tumour, pseudoendocrine sarcoma and cutaneous clear cell tumour with melanocytic differentiation and ACTIN::MITF fusion. We also describe tumour types identified primarily by next-generation sequencing, including epithelioid and spindle cell rhabdomyosarcoma, round cell neoplasms with EWSR1::PATZ1 fusion, cutaneous melanocytic tumour with CRTC1::TRIM11 fusion, clear cell tumour with melanocytic differentiation and MITF::CREM fusion and GLI1-altered mesenchymal neoplasms, including nested glomoid neoplasm.

GLI1-altered mesenchymal tumor is an emerging entity with distinctive clinicopathologic features. It shows a distinctive monomorphic round to epithelioid morphology, nested to trabecular pattern of growth, and S100+/SOX10-/SMA-immunophenotype. We report an example of this entity arising in the duodenum. A 31-year-old man presented with anemia for 1 year, a mass in the duodenal bulb was found for 9 days. Histopathologic examination revealed the tumor with distinct multilobulated architecture, a monomorphic appearance of round to epithelioid cells arranged in papillary structures, nests, cords, solid, reticular patterns, and hyalinized stroma surrounding a rich capillary network. The neoplastic cells had amphophilic to light eosinophilic or clear cytoplasm, uniform round nuclei with fine chromatin and inconspicuous nucleoli. Immunohistochemical analysis revealed strong positivity for vimentin, S100, CD56, CyclinD1, and negativity for SOX10, SMA, melan-A, HMB-45, synaptophysin, and a variety of other markers. Based on the morphology and immunophenotype, molecular studies were performed, which revealed the presence of an ACTB::GLI1 fusion transcript, confirming the diagnosis of GLI1-altered mesenchymal tumor.

Gastroblastoma is an extremely rare biphasic tumor that typically occurs in the stomach in patients between the ages of 10 and 30. Only 16 cases have been reported previously. These tumors are important to diagnose and distinguish from more aggressive neoplasms; although numbers are small, prognosis appears excellent overall with complete excision, with only occasional metastasis and/or local recurrence. We report a case of gastroblastoma in a 26-year-old male arising from the pylorus and extending through the first and second portions of the duodenum. This is the first case to be reported from this specific location.

Fusion genes are well-known cancer drivers. However, most known oncogenic fusions are protein-coding, and very few involve non-coding sequences due to lack of suitable detection tools. We develop SFyNCS to detect fusions of both protein-coding genes and non-coding sequences from transcriptomic sequencing data. The main advantage of this study is that we use somatic structural variations detected from genomic data to validate fusions detected from transcriptomic data. This allows us to comprehensively evaluate various fusion detection and filtering strategies and parameters. We show that SFyNCS has superior sensitivity and specificity over existing algorithms through extensive benchmarking in cancer cell lines and patient samples. We then apply SFyNCS to 9565 tumor samples across 33 tumor types in The Cancer Genome Atlas cohort and detect a total of 165,139 fusions. Among them, 72% of the fusions involve non-coding sequences. We find a long non-coding RNA to recurrently fuse with various oncogenes in 3% of prostate cancers. In addition, we discover fusions involving two non-coding RNAs in 32% of dedifferentiated liposarcomas and experimentally validated the oncogenic functions in mouse model.

To report a rare gastroblastoma; discuss its clinical features, histopathological morphology, diagnosis, differential diagnosis, treatment, and prognosis; and so as to improve the understanding on this disease and provide reference for its diagnosis, treatment, and prognosis.

The diagnosis and treatment, imaging examination, pathological, and genetic data of a 19-year-old young female patient with gastroblastoma were analyzed retrospectively, and the relevant literature was reviewed and summarized.

The patient was found to have a "gastrointestinal stromal tumor" for 3 days by physical examination in another hospital. Abdominal CT and MRI considered "solid pseudopapilloma of pancreas" and clinically planned to perform "radical pancreatoduodenectomy." During the operation, the tumor was observed to bulge from the posterior wall of the gastric antrum, and the root was located in the gastric antrum, so it was changed to "partial gastrectomy + Ronx-y gastrojejunal anastomosis." The postoperative pathology showed that the tumor was bi-differentiated between gastric epithelium and mesenchymal. Combined with the results of IHC and the opinions of several consultation units, the diagnosis of gastric blastoma (low-grade malignancy) was supported. However, the fracture rearrangement of GLI1 and EWSR1 genes was not detected by FISH. After 19 months of follow-up, no signs of tumor recurrence and metastasis were found.

Combined with existing literature reports, gastroblastoma occurs in young people, equally in men and women, and tends to occur in the gastric antrum. The biological behavior of the tumor tends to be inert, and the prognosis of most cases is good. Postoperative pathology and IHC are reliable methods for the diagnosis of gastric blastoma, and surgical resection of the lesion is the preferred treatment.

GLI1 gene alterations (rearrangement or amplification) have been found in several bone and soft tissue tumors including pericytic tumors, gastric plexiform fibromyxoma, gastroblastoma, and a various group of epithelioid tumors with regional recurrence or distant metastasis. In this article, we describe a case of primary cutaneous epithelioid mesenchymal tumor harboring hitherto not reported ATP2B4::GLI1 gene fusion. A 42-year-old man presented with a growing firm lesion on the left postauricular scalp. Microscopically, the shave biopsy specimen revealed a dermal-based nodular proliferation of relatively monotonous epithelioid cells with round to ovoid nuclei and pale eosinophilic cytoplasm, accompanied by prominent stromal vasculature. Significant cytologic atypia, necrosis, and mitotic activity were absent. The tumor cells were partially positive for CD34 and S-100 protein, but were negative for other markers, including SOX-10, keratins, and myogenic markers. An ATP2B4::GLI1 gene fusion was identified by next-generation sequencing. Array CGH was also performed, but it did not show relevant chromosomal copy number changes. Awareness of this rare cutaneous tumor, and thus, reporting of additional cases is necessary for further delineating its full clinicopathologic spectrum.

The long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a cancer biomarker. Furthermore, fusion of the MALAT1 gene with glioma-associated oncogene 1 (GLI1) is a diagnostic marker of plexiform fibromyxoma and gastroblastoma; however, the function of this fusion gene remains unexplored.

In this study, we elucidate the structure and function of the MALAT1::GLI1 fusion gene. To this end, we determined a transcriptional start site (TSS) and promoter region for truncated GLI1 expression using rapid amplification of the 5' cDNA end and a luciferase reporter assay in cultured cells transfected with a plasmid harboring the MALAT1::GLI1 fusion gene.

We found that the TATA box, ETS1 motif, and TSS were located in MALAT1 and that MALAT1 exhibited transcriptional activity and induced expression of GLI1 from the MALAT1::GLI1 fusion gene. Truncated GLI1, lacking SUMOylation and SUFU binding sites and located in the nucleus, upregulated mRNA expression of GLI1 target genes in the hedgehog signaling pathway.

We demonstrate a distinct and alternative function of MALAT1 as a transcriptional promoter for expression of the MALAT1::GLI1 fusion gene. Our findings will aid future research on MALAT1 and its fusion gene partners.

Cutaneous mesenchymal neoplasms are diagnostically challenging because of their overlapping morphology, and, often, the limited tissue in skin biopsy specimens. Molecular and cytogenetic techniques have identified characteristic gene fusions in many of these tumor types, findings that have expanded our understanding of disease pathogenesis and motivated development of useful ancillary diagnostic tools. Here, we provide an update of new findings in tumor types that can occur in the skin and superficial subcutis, including dermatofibrosarcoma protuberans, benign fibrous histiocytoma, epithelioid fibrous histiocytoma, angiomatoid fibrous histiocytoma, glomus tumor, myopericytoma/myofibroma, non-neural granular cell tumor, CIC-rearranged sarcoma, hybrid schwannoma/perineurioma, and clear cell sarcoma. We also discuss recently described and emerging tumor types that can occur in superficial locations and that harbor gene fusions, including nested glomoid neoplasm with GLI1 alterations, clear cell tumor with melanocytic differentiation and ACTIN::MITF translocation, melanocytic tumor with CRTC1::TRIM11 fusion, EWSR1::SMAD3-rearranged fibroblastic tumor, PLAG1-rearranged fibroblastic tumor, and superficial ALK-rearranged myxoid spindle cell neoplasm. When possible, we discuss how fusion events mediate the pathogenesis of these tumor types, and we also discuss the related diagnostic and therapeutic implications of these events.

Fusion genes are well-known cancer drivers. However, very few known oncogenic fusions involve non-coding sequences. We develop SFyNCS with superior performance to detect fusions of both protein-coding genes and non-coding sequences from transcriptomic sequencing data. We validate fusions using somatic structural variations detected from the genomes. This allows us to comprehensively evaluate various fusion detection and filtering strategies and parameters. We detect 165,139 fusions in 9,565 tumor samples across 33 tumor types in the Cancer Genome Atlas cohort. Among them, 72% of the fusions involve non-coding sequences and many are recurrent. We discover two long non-coding RNAs recurrently fused with various partner genes in 32% of dedifferentiated liposarcomas and experimentally validated the oncogenic functions in mouse model.

Glioma-associated oncogene 1 ( GLI1 ) alterations have been described in pericytoma with t(7;12), gastroblastoma, plexiform fibromyxoma, and an emerging class of GLI1 -rearranged or amplified mesenchymal neoplasms including "nested glomoid neoplasm". The immunophenotype of these tumor types is nonspecific, making some cases difficult to diagnose without sequencing. The utility of GLI1 immunohistochemistry (IHC) in distinguishing nested glomoid neoplasms and pericytomas with t(7;12) from morphologic mimics is unknown. To investigate the diagnostic value of GLI1 IHC, we determined its sensitivity and specificity in a "test cohort" of 23 mesenchymal neoplasms characterized by GLI1 alterations, including 12 nested glomoid neoplasms (7 GLI1 -rearranged, 4 GLI1 amplified, and 1 unknown GLI1 status), 9 pericytomas with t(7;12), 1 gastroblastoma, and 1 malignant epithelioid neoplasm with PTCH1 :: GLI1 fusion. GLI1 IHC was 91.3% sensitive in this cohort; all tumors except 2 pericytomas with t(7;12) expressed GLI1. GLI1 was also expressed in 1 of 8 (12%) plexiform fibromyxomas. Nineteen of 22 GLI1-positive tumors showed nuclear and cytoplasmic staining, while 3 showed nuclear staining only. GLI1 IHC was 98.0% specific; among morphologic mimics [40 well-differentiated neuroendocrine tumors, 10 atypical lung carcinoids, 20 paragangliomas, 20 glomus tumors, 20 solitary fibrous tumors, 10 Ewing sarcomas, 10 alveolar rhabdomyosarcomas (ARMS), 10 BCOR -altered sarcomas, 10 myoepitheliomas, 9 myopericytomas, 9 epithelioid schwannomas, 9 ossifying fibromyxoid tumors, 10 biphasic synovial sarcomas, 10 PEComas, 31 gastrointestinal stromal tumors, 10 inflammatory fibroid polyps, 11 pseudoendocrine sarcomas], 5 of 249 tumors expressed GLI1 (2 well-differentiated neuroendocrine tumors, 1 ARMS, 1 Ewing sarcoma, 1 BCOR -altered sarcoma). GLI1 IHC was also performed on a separate cohort of 13 molecularly characterized mesenchymal neoplasms in which GLI1 copy number gain was identified as a putatively secondary event by DNA sequencing (5 dedifferentiated liposarcoma [DDLPS], 2 adenosarcomas, 2 unclassified uterine sarcomas, 1 leiomyosarcoma, 1 ARMS, 1 intimal sarcoma, 1 osteosarcoma); 2 DDLPS, 1 ARMS, and 1 unclassified uterine sarcoma expressed GLI1. Lastly, because pleomorphic sarcomas sometimes show GLI1 amplification or copy number gain, GLI1 IHC was performed on a separate "pleomorphic sarcoma" cohort: GLI1 was expressed in 1 of 27 DDLPS, 1 of 9 leiomyosarcomas, and 2 of 10 pleomorphic liposarcomas, and it was negative in 23 well-differentiated liposarcomas and 9 unclassified pleomorphic sarcomas. Overall, GLI1 IHC was 91.3% sensitive and 98.0% specific for mesenchymal tumor types with driver GLI1 alterations among morphologic mimics. GLI1 expression was less frequent in other tumor types with GLI1 copy number gain. Given its specificity, in the appropriate morphologic context, GLI1 IHC may be a useful diagnostic adjunct for mesenchymal neoplasms with GLI1 alterations.

Our aim was to utilise a 241-gene RNA hybridisation capture sequencing (CaptureSeq) gene panel to identify unexpected fusions in undifferentiated, unclassified or partly classified sarcomas of young individuals (<40 years). The purpose was to determine the utility and yield of a large, targeted fusion panel as a tool for classifying tumours that do not fit typical diagnostic entities at the time of the original diagnosis. RNA hybridisation capture sequencing was performed on 21 archival resection specimens. Successful sequencing was obtained in 12 of 21 samples (57%), two of which (16.6%) harboured translocations. A novel NEAT1::GLI1 fusion, not previously reported in the literature, presented in a young patient with a tumour in the retroperitoneum, which displayed low grade epithelioid cells. The second case, a localised lung metastasis in a young male, demonstrated a EWSR1::NFATC2 translocation. No targeted fusions were identified in the remaining 83.4% (n=10) of cases. Forty-three per cent of the samples failed sequencing as a result of RNA degradation. RNA-based sequencing is an important tool, which helps to redefine the classification of unclassified or partly classified sarcomas of young adults by identifying pathogenic gene fusions in up to 16.6% of the cases. Unfortunately, 43% of the samples underwent significant RNA degradation, falling below the sequencing threshold. As CaptureSeq is not yet available in routine pathology practice, increasing awareness of the yield, failure rate and possible aetiological factors for RNA degradation is fundamental to maximise laboratory procedures to improve RNA integrity, allowing the potential identification of significant gene alterations in solid tumours.

Bizarre parosteal osteochondromatous proliferation (BPOP) (Nora lesion) is a benign bone surface lesion, which most commonly occurs in the digits of young patients and has a high rate of recurrence. Histologically, it is composed of a mixture of disorganized bone, cartilage, and spindle cells in variable proportions and characterized by amorphous "blue bone" mineralization. Recurrent chromosomal abnormalities, including t(1;17)(q32-42;q21-23) and inv(7)(q21.1-22q31.3-32), have been reported in BPOP. However, the exact genes involved in the rearrangements remain unknown. In this study, we analyzed 8 BPOP cases affecting the fingers, toe, ulna, radius, and fibula of 5 female and 3 male patients, aged 5 to 68 years. RNA sequencing of 5 cases identified genetic fusions between COL1A2 and LINC-PINT in 3 cases and COL1A1::MIR29B2CHG fusion in 1, both validated using fluorescence in situ hybridization and reverse transcription (RT)-PCR. The remaining fusion-negative case harbored 3 COL1A1 mutations as revealed by whole-exome sequencing and confirmed using Sanger sequencing. All these genetic alterations were predicted to cause frameshift and/or truncation of COL1A1/2. The chromosomal locations of COL1A2 (7q21.3), LINC-PINT (7q32.3), COL1A1 (17q21.33), and MIR29B2CHG (1q32.2) were consistent with the breakpoints identified in the previous cytogenetic studies. Subsequent screening of 3 BPOPs using fluorescence in situ hybridization identified 1 additional case each with COL1A1 or COL1A2 rearrangement. Our findings are consistent with reported chromosomal abnormalities and implicate the disruption of type I collagen, and perhaps of either noncoding RNA gene as a tumor suppressor, in the tumorigenesis of BPOP. The prevalence and tumorigenic mechanisms of these COL1A1/2 alterations in BPOP require further investigation.

Plexiform fibromyxoma (PF) is a rare mesenchymal tumor of which the pathogenesis and molecular changes are still unclear. Histologically, it is characterized by a cluster of bland spindle or ovoid cells growing in the mucoid or fibromyxoid stroma rich in small blood vessels. At present, surgical resection is the primary treatment for PF.

Recently, it has been recognized that a subset of primary soft tissue neoplasms with GLI1 gene alterations exhibit nested architecture and can mimic glomus tumors or well-differentiated neuroendocrine tumors. Here, we report a series of 20 such neoplasms, which we have provisionally termed "distinctive nested glomoid neoplasm." Eleven patients (55%) were female and 9 were male. The median age at presentation was 41.5 years (range: congenital to 74 y). The anatomic distribution was wide, with body sites including the trunk (7 tumors), lower extremity (5), tongue (4), upper extremity (3), and neck (1). Excluding tumors of the tongue, 10 tumors (62%) arose in deep soft tissue and 6 (38%) arose primarily in the subcutis. Tumor size ranged from 0.9 to 11.1 cm (median: 3 cm). Distinctive nested glomoid neoplasms are composed of nests of round-to-ovoid cells with scant, palely eosinophilic cytoplasm and monomorphic nuclei with vesicular chromatin and small nucleoli. The nests are invested by prominent capillary networks, and they are situated within large lobules separated by irregular, thick fibrous septa. Among 18 tumors for which adjacent non-neoplastic tissue could be assessed, perivascular proliferation of tumor cells was identified in 16 tumors (89%). Microcystic architecture was present at least focally in 8 tumors (40%), and myxoid stroma was identified at least focally in 5 (25%). Seven tumors (35%) showed clear cell features. By immunohistochemistry, some tumors expressed MDM2 (7/15; 47%), S100 (5 of 19; 26%), STAT6 (2 of 5; 20%), and AE1/AE3 (1/5; 20%). Tumors rarely expressed pan-keratin (1/10; 10%) or CAM5.2 (1/10), and all tumors were negative for β-catenin (12 tumors), chromogranin (12), synaptophysin (11), epithelial membrane antigen (10), desmin (10), smooth muscle actin (9), INSM1 (7), and CD34 (6). GLI1 break-apart fluorescence in situ hybridization was performed on 7 tumors, and next-generation sequencing was performed on 15 tumors (10 DNA sequencing only, 1 RNA sequencing only, 4 both DNA and RNA sequencing). Sixteen tumors, including all 15 tested by next-generation sequencing and an additional case tested by fluorescence in situ hybridization only, were found to harbor GLI1 gene alterations: 10 harbored GLI1 gene rearrangements (3 ACTB :: GLI1 , 2 PTCH1 :: GLI1 , 1 HNRNPA1 :: GLI1 , 1 NEAT1 :: GLI1 , 1 TXNIP :: GLI1 , 2 undetermined fusion partners), and 6 harbored GLI1 amplification. Clinical follow-up was available for 10 patients (50%; range: 3 mo to 10 y; median: 6.4 y), including 8 with >1 year of follow-up. Three patients (30%) experienced local recurrence (at intervals of 3 mo to 10 y). None developed distant metastases or died of disease as yet. Overall, our findings support the notion that a subset of GLI1 -altered soft tissue neoplasms are indolent, morphologically distinctive nested glomoid neoplasms that should not be classified as sarcomas.

GLI1 encodes a transcription factor that targets cell cycle regulators affecting stem cell proliferation. GLI1 gene fusions were initially described in pericytomas with a t[7;12] translocation and more recently in gastric plexiform fibromyxomas and gastroblastomas. This study describes the clinicopathologic, immunohistochemical, and molecular features of three intestinal-based neoplasms harboring GLI1 gene fusions. We studied three unique mesenchymal small bowel tumors. Paraffin embedded tumor tissues from these cases and 62 additional tumor samples that included a plexiform fibromyxoma were sequenced using a targeted RNAseq method to detect fusion events. The study patients included two women and one man who were 52, 80, and 22 years of age at the time of diagnosis. The tumors involved the submucosa and muscularis propria of the duodenum, jejunum, and ileum. All 3 tumors contained a proliferation of monotonous oval or spindle cells with scattered, somewhat dilated vessels. Two cases showed epithelioid structures such as glands, tubules, or nests. Immunohistochemical analysis revealed cytokeratin expression in the epithelioid components of both tumors displaying these features, and variable numbers of mesenchymal cells. Diffuse CD56 positivity was seen in the mesenchymal component of 2 tumors and desmin and smooth muscle actin staining in the other tumor. Immunostains for S-100 protein, DOG-1, and CD117 were negative in all cases. GLI1 fusions with different partner genes were detected in all tumors, and in the plexiform fibromyxoma, used as a control. Validation by fluorescence in situ hybridization was performed. None of the tumors have recurred or metastasize after surgery. We describe novel GLI1 fusions in 3 mesenchymal neoplasms of the small intestine, including 2 with biphenotypic features. Thus far, all cases have pursued indolent clinical courses. We propose the term " GLI1 -rearranged enteric tumor" to encompass this group of unique neoplasms of the small intestine that harbor GLI1 gene fusions and expand the spectrum of gastrointestinal neoplasms with these alterations.

Hedgehog (Hh) signaling primarily functions in the control of mammalian embryonic development but also has roles in cancer. The Hh activation depends on ciliogenesis, a cellular process that describes outgrowth of the primary cilium from cell membrane. Ciliogenesis initiation requires a set of proteins known as planar cell polarity (PCP) effectors. Inturned (INTU) is a PCP effector that reportedly functions synergistically with Hh signaling in basal cell carcinoma, suggesting that INTU has an oncogenic role. In this study, we carried out a pan-cancer investigation on the prognostic significance of INTU in different types of cancer. We demonstrated that INTU downregulation correlated with reduced survival probabilities in lung adenocarcinoma (LUAD) and uterine corpus endometrial carcinoma (UCEC) patients. Similar expression patterns and prognostic values were identified for intraflagellar transport 88 (IFT88), another Hh pathway-associated gene. We elucidated multiple mechanisms at transcriptional, post-transcriptional and translational levels that involved transcription factor 4 and non-coding RNAs-associated regulatory networks contributing to the reduction of INTU and IFT88 levels in LUAD and UCEC samples. Taken together, this study demonstrates the prognostic significance of the Hh-related genes INTU and IFT88 in LUAD and UCEC and further delineates multifaceted mechanisms leading to INTU and IFT88 downregulation in tumor samples.

A novel subset of epithelioid soft tissue tumors with GLI1 gene fusions or amplifications has recently been characterized. Histologically, these tumors typically exhibit multinodular or plexiform growth of ovoid, round to epithelioid neoplastic cells, with a distinctive nested architecture separated by a rich delicate arborizing vascular network. The immunoprofile is variable and nonspecific, indicating no definitive line of differentiation. GLI1-altered epithelioid soft tissue tumor is considered to be a low-grade sarcoma; however, with a limited number of cases reported, the biologic behavior of this entity is unclear. Interestingly, these tumors frequently occur in the head and neck, with a clear predilection for the tongue. To date, 11 cases of lingual GLI1-altered epithelioid soft tissue tumors have been reported in the English literature, and none showed evidence of recurrence or metastasis. Herein, we report an additional case of lingual GLI1-altered epithelioid soft tissue tumor harboring GLI1 fusion in a 56-year-old man with regional nodal metastasis and distant metastasis to increase the awareness of this entity among oral pathologists and clinicians. An accumulation of similar cases is mandatory to clarify biological behaviors and also for the development of new therapeutic strategies.

Hedgehog (Hh) is a conserved signaling pathway that is involved in embryo development as well as adult tissue maintenance and repair in invertebrates and vertebrates. Abnormal activation of this pathway in various types of malignant drug- and apoptosis-resistant tumors has made it a therapeutic target against tumorigenesis. Thus, understanding the molecular mechanisms that promote the activation or inhibition of this pathway is critical. Long non-coding RNAs (lncRNAs), a subclass of non-coding RNAs with a length of > 200 nt, affect the expression of Hh signaling components via a variety of transcriptional and post-transcriptional processes. This review focuses on the crosstalk between lncRNAs and the Hh pathway in carcinogenesis, outlines the broad role of Hh-related lncRNAs in tumor progression, and illustrates their clinical diagnostic, prognostic, and therapeutic potential in tumors.

We report 4 neoplasms of the kidney (2 cases) and uterus (2 cases) harboring rearrangements or amplifications of the GLI1 gene, which because of their unusual clinical presentation, morphology, and immunoprofile mimicked other neoplasms, causing significant diagnostic challenge. The neoplasms occurred in 4 female patients ages 33 to 88 years. Histologically they all demonstrated nodular growth, solid architecture, bland epithelioid to ovoid-spindle cells with pale cytoplasm set in a variably myxoid or hyalinized stroma. One uterine tumor also demonstrated a focal round cell pattern, while another demonstrated focal pleomorphism. Unlike most previously reported neoplasms with these genetic abnormalities, the neoplasms in the current series were negative for S100 protein and minimally reactive for actin. All labeled for CD10 and cyclin D1, while 2 labeled for estrogen receptor and BCOR and 1 labeled for desmin, raising consideration of endometrial stromal sarcoma, myxoid leiomyosarcoma, metastatic breast carcinoma, and glomus tumor. One renal neoplasm demonstrated a GLI1-FOXO4 gene fusion and the other harbored a GLI1 gene rearrangement (unknown partner). The 2 uterine neoplasms exhibited GLI1 gene amplifications. GLI1-altered neoplasms (particularly those with GLI1 amplification) show variable morphology and lack a consistent immunophenotype, and thus may trigger diagnostic challenges which can be resolved by molecular testing.