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DICER1 syndrome is a rare autosomal dominant familial tumor predisposition disorder characterized by a heterozygous loss-of-function I DICER1 i germline mutation occurring in conjunction with a somatic missense hotspot mutation on the second allele. However, sporadic DICER1-associated neoplasms with biallelic I DICER1 i alterations have been identified in the absence of germline alterations.[1] Although the most common tumor association is the pleuropulmonary blastoma (PPB), I DICER1 i mutations have been increasingly associated with sarcomas, particularly embryonal rhabdomyosarcoma occurring in the Mullerian or genitourinary tract.[2] In the kidney, I DICER1 i -related anaplastic sarcoma has been described in association with pediatric cystic nephroma, likely following a similar paradigm of tumor progression from type I PPB to clinically aggressive type II/III solid components. In this study, we are reporting two young adult patients with anaplastic sarcomas of the kidney (ASK) with coexisting biallelic somatic I DICER1 i mutations and activating I PDGFRA i D842V mutation. [Extracted from the article]

Recent molecular advances have shed significant light on the classification of vascular tumours. Except for haemangiomas, vascular lesions remain difficult to diagnose, owing to their rarity and overlapping clinical, radiographic and histological features across malignancies. In particular, challenges still remain in the differential diagnosis of epithelioid vascular tumours, including epithelioid haemangioma and epithelioid haemangioendothelioma at the benign/low‐grade end of the spectrum, and epithelioid angiosarcoma at the high‐grade end. Historically, the classification of vascular tumours has been heavily dependent on the clinical setting and histological features, as traditional immunohistochemical markers across the group have often been non‐discriminatory. The increased application of next‐generation sequencing in clinical practice, in particular targeted RNA sequencing (such as Archer, Illumina), has led to numerous novel discoveries, mainly recurrent gene fusions (e.g. those involving FOS, FOSB, YAP1, and WWTR1), which have resulted in refined tumour classification and improved diagnostic reproducibility for vascular tumours. However, other molecular alterations besides fusions have been discovered in vascular tumours, including somatic mutations (e.g. involving GNA family and IDH genes) in a variety of haemangiomas, as well as copy number alterations in high‐grade angiosarcomas (e.g. MYC amplifications). Moreover, the translation of these novel molecular abnormalities into diagnostic ancillary markers, either fluorescence in‐situ hybridisation probes or surrogate immunohistochemical markers (FOSB, CAMTA1, YAP1, and MYC), has been remarkable. This review will focus on the latest molecular discoveries covering both benign and malignant vascular tumours, and will provide practical diagnostic algorithms, highlighting frequently encountered pitfalls and challenges in the diagnosis of vascular lesions. [ABSTRACT FROM AUTHOR]

Aims: Angiofibroma of soft tissue is a benign soft tissue tumour characterised by bland spindle cells and a distinct branching vascular network. The majority of soft tissue angiofibromas harbour AHRR::NCOA2 gene fusions. Here we present three cases of EWSR1::GFI1B‐fused soft tissue tumours that are morphologically most reminiscent of soft tissue angiofibroma. Methods and results: All three cases presented in male patients with an age range of 35–78 years (median = 54 years). Two cases presented as subcutaneous nodules on the trunk (posterior neck and chest wall); one was an intramuscular foot mass. The tumours were unencapsulated nodules with infiltrative margins ranging from 2.2 to 3.4 cm in greatest dimension. Histologically, the tumours contained uniformly bland fibroblastic spindle cells with ovoid to fusiform nuclei and delicate cytoplasmic processes embedded in a myxoid to myxocollagenous stroma. All three cases were characterised by a thin‐walled, branching vascular network evenly distributed throughout the tumour. Overt cytological atypia or conspicuous mitotic activity was absent. The spindle cells had an essentially null immunophenotype. By targeted RNA sequencing, an in‐frame gene fusion between EWSR1 exons 1–7 and GFI1B exons 6–11 or 7–11 was detected in all three cases. The tumours were marginally excised. For all three cases, there were no documented local recurrence or distant metastases during a limited follow‐up period of 6–10 months. Conclusions: We propose that EWSR1::GFI1B may represent a novel fusion variant of soft tissue angiofibroma. [ABSTRACT FROM AUTHOR]

Clear cell sarcoma shares features with melanoma, but frequently shows EWSR1 rearrangements. It is an aggressive tumor typically occurring in the soft tissues of the extremities, with a gastrointestinal variant with less consistent melanocytic differentiation. It is extremely rare in the head and neck region, with no reported cases in the oral cavity. We report a case of an 82-year-old woman with a clear cell sarcoma arising in the tongue, with cervical lymph node metastases. Histologically, the tumor showed some features of gastrointestinal clear cell sarcoma. No osteoclast-type giant cells were present. The tumor cells were positive for S100 protein and negative for other melanocytic markers. Fluorescence in situ hybridization showed rearrangements of EWSR1 and ATF1. This case expands the spectrum of clear cell sarcoma with a gastrointestinal-like variant in a novel site, emphasizing the need to consider it as a differential diagnosis to melanoma in mucosal sites. [ABSTRACT FROM AUTHOR]

Background: Little is known about the outcomes of patients with microscopically positive (R1) resections for primary gastrointestinal stromal tumors (GIST) because existing retrospective series contain small numbers of patients. The objective of this study was to analyze factors associated with R1 resection and assess the risk of recurrence with and without imatinib. Study Design: We reviewed operative and pathology reports for 819 patients undergoing resection of primary GIST from the North American branch of the American College of Surgeons Oncology Group (ACOSOG) Z9000 and Z9001 clinical trials at 230 institutions testing adjuvant imatinib after resection of primary GIST. Patient, tumor, operative characteristics, factors associated with R1 resections, and disease status were analyzed. Results: Seventy-two (8.8%) patients had an R1 resection and were followed for a median of 49 months. Factors associated with R1 resection included tumor size (≥10 cm), location (rectum), and tumor rupture. The risk of disease recurrence in R1 patients was driven largely by the presence of tumor rupture. There was no significant difference in recurrence-free survival for patients undergoing an R1 vs R0 resection of GIST with (hazard ratio [HR] 1.095, 95% CI 0.66, 1.82, p = 0.73) or without (HR 1.51, 95% CI 0.76, 2.99, p = 0.24) adjuvant imatinib. Conclusions: Approximately 9% of 819 GIST patients had an R1 resection. Significant factors associated with R1 resection include tumor size ≥ 10 cm, location, and rupture. The difference in recurrence-free survival with or without imatinib therapy in those undergoing an R1 vs R0 resection was not statistically significant at a median follow-up of 4 years. [ABSTRACT FROM AUTHOR]

The article offers protocols developed by the College of American Pathologists that will help pathologists in reporting clinically useful and pertinent information about the results of surgical specimen examinations of patients with bone tumors. These protocols are presented in the"Surgical Pathology Cancer Case Summary (Checklist)" that are essentials to pathologic reporting. Moreover, discussions of bone tumor evaluation, classification and biopsies, and cancer grading are also presented.

Background. Epstein-Barr virus (EBV)-related smooth muscle neoplasms (SMNs) have been associated with immune dysregulation, most notably in patients who have undergone solid organ transplantation or in patients with HIV/AIDS. Objective. to report our experience with EBV-related neoplasms as well as describing the first EBV-related SMN in the setting of administration of glucocorticoids and the tumor necrosis factor inhibitor etanercept. Design. We have case reports, of minimum 3-year follow-up, 2002-2005. Setting. It was held in an academic and tertiary referral cancer center. Patients. Patients are with dysregulated immunity after solid organ transplantation, HIV/AIDS, or with psoriasis after treatment with etanercept. Interventions. There were discontinuation of etanercept, right hepatic trisegmentectomy, and chemotherapy.Measurements.We use survival as a measurement here. Results. Patients who were able to withstand reduction in immunosuppression survived. Surgical resection or chemotherapy was successful in delaying progression of disease. Limitations. There was a relatively short follow-up for these slow-growing neoplasms. Conclusion. EBV-related SMNs have variable aggressiveness.While chemotherapymay slow disease progression, resection and improving the host immune status provide the best opportunity for primary tumor control. [ABSTRACT FROM AUTHOR]

High-density microarrays are used to measure in a comprehensive manner large-scale ("profile") gene expression patterns (when tumor RNA is tested) or gene copy number changes (when tumor genomic DNA is tested). Microarray-based studies are increasingly useful in addressing a wide variety of questions in sarcoma biology. This review includes a brief description of the microarray methodology and data analysis, followed by few examples of the recent applications of gene expression in the diagnosis, classification, and treatment of sarcomas. [ABSTRACT FROM AUTHOR]

We report a method, Expression-Microarray Copy Number Analysis (ECNA) for the detection of copy number changes using Affymetrix Human Genome U133 Plus 2.0 arrays, starting with as little as 5 ng input genomic DNA. An analytical approach was developed using DNA isolated from cell lines containing various X-chromosome numbers, and validated with DNA from cell lines with defined deletions and amplifications in other chromosomal locations. We applied this method to examine the copy number changes in DNA from 5 frozen gastrointestinal stromal tumors (GIST). We detected known copy number aberrations consistent with previously published results using conventional or BAC-array CGH, as well as novel changes in GIST tumors. These changes were concordant with results from Affymetrix 100K human SNP mapping arrays. Gene expression data for these GIST samples had previously been generated on U133A arrays, allowing us to explore correlations between chromosomal copy number and RNA expression levels. One of the novel aberrations identified in the GIST samples, a previously unreported gain on 1q21.1 containing the PEX11B gene, was confirmed in this study by FISH and was also shown to have significant differences in expression pattern when compared to a control sample. In summary, we have demonstrated the use of gene expression microarrays for the detection of genomic copy number aberrations in tumor samples. This method may be used to study copy number changes in other species for which RNA expression arrays are available, e.g. other mammals, plants, etc., and for which SNPs have not yet been mapped. [ABSTRACT FROM AUTHOR]

The term malignant fibrous histiocytoma was coined by Stout and associates in the 1960s to encompass pleomorphic soft tissue sarcomas presumably derived from histiocytes that are capable of fibroblastic transformation. The concept was reaffirmed in the following 2 decades and malignant fibrous histiocytoma thus was regarded as the most common soft tissue tumor in older adults. However, recent more critical clinicopathologic, ultrastructural, and immunohistochemical studies have shown that malignant fibrous histiocytomas are not derived from histiocytic "facultative fibroblasts" and many neoplasms so diagnosed actually are pleomorphic subtypes of other sarcomas. Meticulous electron microscopic and immunohistochemical investigations also found that the more common storiform-pleomorphic, myxoid, and perhaps the giant cell subtypes are composed of variable mixtures of fibroblasts and phenotypically modulated fibroblastic cells, notably myofibroblasts and histiofibroblasts. On the basis of these findings, we propose a new classification for the above subtypes of so called malignant fibrous histiocytoma, the majority of which are variants of pleomorphic fibrosarcoma. [ABSTRACT FROM AUTHOR]

Low-grade fibrosarcomas have recently gained increasing attention in the literature, especially with the fall in popularity polls of the ubiquitous malignant fibrous histiocytoma (MRH). Firstly, most tumors previously known as myxoid MFH are labeled presently as myxofibrosarcomas. Secondly, the recognition and better understanding of a family of fibrosing- type fibrosarcoma, encompassing 3 members: fibromyxoid sarcoma (FMS), hyalinizing spindle cell tumor with giant rosettes (HSTGR), and sclerosing epithelioid fibrosarcoma (SEF). To expand further their understanding of the overlapping arid distinct features of members included in the spectrum of low-grade fibrosarcoma. the authors carried out a comparative ultrastructural study among 15 low-grade myxofibrosarcomas (MFS) and 12 fibromyxoid sarcomas (FMS), after review of pathology and confirmation of diagnosis. The ultrastructural findings of the LG MFS identified spindle to plump cells, with abundant cytoplasm, rich in well-developed RER cisternae, often distended and sometimes cystically dilated, containing an electronlucent granular material. These results were in keeping with a well-differentiated fibroblastic-type cell phenotype. In addition, a less prominent cellular component included cells with RER, well-developed Golgi apparatus, lysosomes, and filopodia. These latter features define a fibroblastic variant with histiocytic like properties, also known as histiofibroblasts. Myofibroblastic differentiation was quite limited and mostly absent in most of the cases. in summary, these findings recapitulate a similar spectrum with the cell constituents of so-called MFH. In contrast, the fine microscopic findings of the 12 FMS cases showed an inactive or more primitive form of fibroblastic type cells, The RER cisternae were generally underdeveloped, as expected for a generic fibroblastic-type proliferation. The cytoplasm was scant and showed a paucity of organelIes, with the exception of abundant arrays of vimentin-type intermediate filaments. The very long, thin cell processes, sometimes associated with pinocytotic vesicles, were reminiscent of perineurioma ultrastructure. [ABSTRACT FROM AUTHOR]

A specific TLS-CHOP fusion gene derived from the t(12;16) is present in at least 95% of myxoid/round cell liposarcomas (MLS). Rare cases of MLS show a variant t(12;22) translocation, resulting in EWS-CHOP fusion gene. The CHOP gene encodes a leucine-zipper transcription factor, which is implicated in both oncogenic transformation and inhibition of adipogenesis To examine whether the molecular variability of TLS-CHOP or EWS-CHOP fusion transcript structure is associated with the degree of inhibition of adipogenesis, a comparative ultrastructural and RT-PCR-based analysis of 14 MLS was performed. The specimens consisted of 9 primary, 2 locally recurrent tumors, and one representative sample each from 3 patients with multifocal soft tissue metastases. Histologically, there were 8 high-grade and 6 low-grade MLS using 5% round cell (RC) component as the cutoff point. By RT-PCRassay there were 13 cases with TLS-CHOP fusion transcripts: 7 cases of type 5-2 (known as type II), 4 cases of type 7-2 (known as type I). 1 case of type 8-2 (known as type III), and 1 unique case of type 6-2. The remaining 1 case showed an EWS-CHOP fusion transcript. Ultrastructural examination revealed that tumor cells were composed of a moderate-to-predominant proportion of well-formed lipoblasts in 4 cases, while in 6 cases such lipoblasts were very scant, The remaining 4 tumors were arrested in the stage of transitional cells. The heterogeneity of TLS-CHOP fusion transcript showed no apparent impact on adipogenesis. since both TLS-CHOP type I and II cases could randomly display various levels of lipoblastic differentiation. Furthermore, the 4 cases without definite lipoblasts showed no preference for any specific fusion variants and consisted of one each of TLS-CHOP subtypes. In addition, the fusion transcript variants did not correlate with other Ultrastructural features, such as the presence and amount of glycogen, mitochondria, rough endoplasmic reticulum, vimentin-like intermediate filaments, and external lamina. However, there appeared to have a trend suggesting the predilections of glycogen particles and vimentin-like intermediate filaments in primitive mesenchymal cells and/or transitional cells. These findings cannot substantiate the hypothesis that the molecular variability of fusion transcripts has a biological impact on adipogenesis of MLS. and other factors might be implicated in their level of differentiation. [ABSTRACT FROM AUTHOR]

Context.--Smooth muscle tumors (SMTs) of the sinonasal tracts are very rare mesenchymal neoplasms, and the literature includes very limited data correlating histologic parameters with clinical outcome. As the behavior of SMTs is site-dependent, defining applicable criteria to distinguish among low-grade leiomyosarcoma, SMT of uncertain malignant potential (SMTUMP), and cellular leiomyoma is sometimes difficult and arbitrary. Objective.--To correlate the clinicopathologic features of 12 well-differentiated sinonasal SMTs with MIB-1 index and clinical outcomes so as to better classify this group of tumors. Design.--Twelve cases of sporadic well-differentiated SMTs arising from the sinonasal tract were retrieved from both institutions. High-grade leiomyosarcomas were excluded from this analysis. The histologic parameters assessed included circumscription, mucosal ulceration, cellularity, nuclear atypia, mitotic count, necrosis, and destruction of adjacent bony structures. The histologic classification of these tumors was based on the guidelines for SMTs of deep soft tissues, using greater than 4 mitotic figures (MF)/10 high-power fields (HPF) to separate SMTUMP from leiomyosarcoma and the presence of 1 to 4 MF/10 HPF to distinguish between leiomyoma and SMTUMP. Immunostaining of MIB-1 index was performed in 7 cases with available material. Results.---This study showed a 1:1.5 male-female ratio and a mean age of 40 years (range, 20-67 years). The most frequent symptoms were nasal stuffiness and/or epistaxis. The tumors involved nasal cavity in 8 cases (67%), paranasal sinus alone in 2 cases (16.5%), and both nasal cavity and paranasal sinuses in 2 cases (16.5%). The tumors ranged in size from 0.3 to 5.5 cm (mean, 2 cm) and were classified as follows: 7 leiomyomas, 2 SMTUMPs, and 3 low-grade leiomyosarcomas. All 7 leiomyomas, 1 SMTUMP, and 1 leiomyosarcoma originated from vessel walls. Bone involvement was seen in both the SMTUMPs (1 of 2) and leiomyosarcomas (2 of... [ABSTRACT FROM AUTHOR]

Pleomorphic liposarcoma (PL) is the least common subtype of liposarcoma, displaying a lipoblastic, malignant fibrous histiocytoma (MFH)-like and, less frequently, an epithelioid growth pattern. The epithelioid morphology in PL is still underrecognized and may closely simulate other epithelial neoplasms, mainly adrenal cortical carcinoma (ACC). No electron microscopic (EM) studies of the epithelioid variant of PL have been previously described, nor have there been studies of its immunoreactivity with A103 or α-inhibin. The purpose of this study is to analyze the histological, immunohistochemical, and EM features of epithelioid PL in an attempt to better explore the distinction from their epithelial mimickers, such as ACC. A panel of 5 antibodies was studied, including A103, α-inhibin, smooth muscle actin (SMA), AE1/AE3, and Cam 5.2. Out of 22 cases of PLs, 6 cases characterized by the presence of both epithelioid phenotype and pleomorphic lipoblasts were identified from the EM archives. There were 4 females and 2 males, with a mean age of 58 (range, 39-78). Two lesions arose in the thigh and 1 each in the abdominal wall, chest wall, anterior mediastinum, and retroperitoneum, with tumor size ranging from 7 to 17 cm (mean, 13 cm). Histologically, 2 PLs were pure epithelioid, whereas the other 4 had a mixed epithelioid and MFH-like appearance. Immunohistochemically, A103 (4/6), SMA (4/6), and AE1/AE3 (1/6) revealed a various degree of positive reactions. No immunolabeling for α-inhibin or Cam5.2 was detected in any case. By EM, the epithelioid areas revealed round or polyhedral cells with lipid droplets of various sizes and number, intimately apposed cell surfaces, occasional junction-like structures (4/6), and micropinocytotic vesicles (4/6). Interestingly, the ribosome-lamellar complexes, once thought to be characteristic of hairy cell leukemia but rarely seen in solid tumors, were noted in one pure epithelioid PL. When compared to the MFH-like area, rough endoplasmic reticula (RER) were less well developed, but mitochondria were more prominent in the epithelioid components. Neither mitochondria with tubulovesicular cristae nor prominent smooth endoplasmic reticula indicative of ACC were seen. Well-formed external lamina was not present. Other features to support a higher level of epithelial differentiation, such as lumen formation, microvilli, and tonofilaments, were not found. In conclusion, focal A103 reactivity in epithelioid undifferentiated tumors should be interpreted with caution before rendering the diagnosis of a primary or metastatic ACC, especially when examining biopsy specimens. The possibility of an epithelioid variant of PL must be excluded; α-inhibin can serve as a useful adjunct in this regard. In addition to variable intracytoplasmic fat droplets, the distinctive ultrastructural features of epithelioid variant of PL include numerous mitochondria, pinocytotic vesicles, junction-like structures, and, rarely, ribosome-lamellar complex. Despite some overlapping features, electron microscopy remains a useful tool to distinguish between epithelioid PL and ACC. [ABSTRACT FROM AUTHOR]

Because the fibroblast has a remarkable capability of phenotypic modulations, reflected in both morphologic and immunohistochemical (IHC) changes, ultrastructural studiesare mandatory to identify the variants of fibroblasts. Myofibroblasts or histiofibroblasts are such examples, demonstrating chimeric ultrastructural features of fibroblastic cells in common with smooth muscle cells or with histiocytes, respectively. The presence of epithelioid fibroblastic cells sharing morphologic features with epithelial or plasma cells has not been yet characterized. The authors identified 4 cases of fibrosarcomas (FS) characterized by an unusual phenotype and associated with peculiar ultrastructural findings. The electron microscopic (EM) findings were correlated with the histologic appearance and immunoprofile. All tumors were located in the extremities, 3 in soft tissues and 1 in the bone. By light microscopy 2 cases were composed predominantly by round uniform cells with a striking plasmacytoid appearance. One case mimicked carcinoma, composed predominantly by epithelioid cells and scattered giant tumor cells. The fourth case showed a mixture of plasmacytoid-like and epithelioid cells. By IHC, tumor cells were positive for vimentin and in 2 cases also for epithelial membrane antigen. Kappa/lambda light chain and cytokeratins markers were negative. By EM all 4 tumors showed in addition to classic features of fibroblasts, unusual epithelial-type features, such as secretory granules of "neurosecretory-type" (3 cases), rudimentary cell junctions (3 cases), microvilli (2 cases), and lumen-like structures (1 case). One plasmacytoid-type tumor showed finely granular extracellular deposits. The study describe 4 examples of fibrosarcomas with unusual features at the ultrastructural level, which are associated microscopically with a peculiar phenotype, mimicking plasmacytoma or carcinoma. These findings broaden the spectrum of fibroblastic cell variants in neoplasia. [ABSTRACT FROM AUTHOR]

This unusual case is that of a middle-aged man exhibiting a tumor diathesis including a basal cell adenocarcinoma with features of adenoid cystic carcinoma arising in minor salivary gland of lip in association with multiple primary malignant cylindromas of skin. The labial lesion showed invasive tubules, solid epithelial sheets and cribriform structures. It did not exhibit PAS positive juxta-tubular basement membrane material. The skin lesions all showed features of a highly infiltrative cylindromatous carcinoma with two cell types, peripheral palisading and prominent PAS positive juxta-tubular basement membrane material. Immunocytochemical studies of the lip lesion and one of the skin lesions showed similarities, including positive staining for high and low molecular weight keratins and S-100 with negative staining for CEA. The previous descriptions of tumor diatheses involving dermal cylindromas and dermal analogue tumors of salivary glands and the distinctions with the present study are noted. If benign and even malignant cylindromas were described in the literature to be associated with basal cell adenocarcinoma of the major salivary glands, our case is unique by its association with this rare malignant tumor in a minor salivary gland. [ABSTRACT FROM AUTHOR]

Background: Recurrent/metastatic adenoid cystic carcinoma (ACC) is a rare, incurable disease. MYB is a putative oncogenic driver in ACC that is often overexpressed through an MYB‐NFIB rearrangement. The authors hypothesized that AKT inhibition with the allosteric inhibitor MK‐2206 could decrease MYB expression and induce tumor regression in patients with incurable ACC (ClinicalTrials.gov identifier NCT01604772). Methods: Patients with progressive, incurable ACC were enrolled and received MK‐2206 150 mg weekly; escalation to 200 mg was allowed. The primary end point was confirmed response. Secondary end points were progression‐free survival, overall survival, and safety. An exploratory analysis evaluating the effect of MK‐2206 on MYB expression was conducted in a subset of patients. Results: Sixteen patients were enrolled, and 14 were evaluable for efficacy. No confirmed responses were observed. Thirteen patients had stable disease, and one had disease progression as their best response. The median progression‐free survival was 9.7 months (95% CI, 3.8–11.8 months), and the median overall survival was 18.0 months (95% CI, 11.8–29.9 months). Nine of 16 patients (56%) had at least one grade 3 treatment‐related adverse event, and the most common were rash (38%), fatigue (19%), decreased lymphocyte count (13%), and hyperglycemia (13%). Twelve of 14 tumors (86%) had detectable MYB expression by immunohistochemistry, and seven of 14 tumors (50%) had an MYB‐NFIB gene rearrangement. Serial biopsies revealed decreased MYB levels with MK‐2206 in four of five patients. Conclusions: MK‐2206 failed to induce clinical responses in patients with incurable ACC. AKT inhibition may diminish MYB protein levels, although the effect was highly variable among patients. Novel approaches to target MYB in ACC are needed. This phase 2 clinical trial demonstrated that the AKT inhibitor MK‐2206 failed to induce clinical responses in patients with recurrent/metastatic adenoid cystic carcinoma. Tumor tissue analyses suggest that MK‐2206 treatment may have diminished intratumoral MYB protein levels. [ABSTRACT FROM AUTHOR]

Simple Summary: CIC-DUX4-rearranged sarcoma (CDS) is a rare and aggressive soft tissue tumor predominantly affecting young adults for which the only oncogenic driver is the CIC-DUX4 fusion protein, resulting from chromosomal rearrangements. The molecular mechanisms by which CIC-DUX4 drives CDS development remain largely unknown, hindering the development of targeted therapies. This study conducted genome-wide profiling of CIC-DUX4 DNA occupancy and associated chromatin states in CDS cell models and tumors. Our findings reveal CIC-DUX4 as a potent transcriptional activator at its binding sites, facilitated by direct interaction with the acetyltransferase p300. Significantly, inhibiting p300 impedes CDS tumor cell proliferation, suggesting a potential therapeutic avenue. This research enhances understanding of CIC-DUX4-mediated transcriptional regulation and proposes targeting p300 as a promising strategy for the clinical management of CDS. CIC-DUX4-rearranged sarcoma (CDS) is a rare and aggressive soft tissue tumor that occurs most frequently in young adults. The key oncogenic driver of this disease is the expression of the CIC-DUX4 fusion protein as a result of chromosomal rearrangements. CIC-DUX4 displays chromatin binding properties, and is therefore believed to function as an aberrant transcription factor. However, the chromatin remodeling events induced by CIC-DUX4 are not well understood, limiting our ability to identify new mechanism-based therapeutic strategies for these patients. Here, we generated a genome-wide profile of CIC-DUX4 DNA occupancy and associated chromatin states in human CDS cell models and primary tumors. Combining chromatin profiling, proximity ligation assays, as well as genetic and pharmacological perturbations, we show that CIC-DUX4 operates as a potent transcriptional activator at its binding sites. This property is in contrast with the repressive function of the wild-type CIC protein, and is mainly mediated through the direct interaction of CIC-DUX4 with the acetyltransferase p300. In keeping with this, we show p300 to be essential for CDS tumor cell proliferation; additionally, we find its pharmacological inhibition to significantly impact tumor growth in vitro and in vivo. Taken together, our study elucidates the mechanisms underpinning CIC-DUX4-mediated transcriptional regulation. [ABSTRACT FROM AUTHOR]

Aims: Secretory carcinoma (SC) of the salivary gland typically harbours ETV6–NTRK3 fusion, which can be utilised clinically to assist with diagnosis. Pan‐Trk inhibitor therapy has demonstrated drastic responses in patients with NTRK‐translocated tumours, including SC. Pan‐Trk immunohistochemistry (IHC) is emerging as a sensitive and specific tool for detecting NTRK1, NTRK2 and NTRK3 fusions in various cancers. We aimed to establish the specificity and sensitivity of pan‐Trk IHC in diagnosing SC and detecting ETV6–NTRK3 fusion. A literature review on the utility of pan‐Trk IHC was conducted. Methods and results: Pan‐Trk IHC was performed on 83 salivary gland neoplasms (29 SCs and 54 non‐SCs). ETV6–NTRK3 fusion status was established in 25 cases. With any staining (nuclear or cytoplasmic) as a positive threshold, the sensitivity and specificity of pan‐Trk IHC were 90% and 70% in diagnosing SC, and 100% and 0% in detecting NTRK3 fusion. When only pan‐Trk nuclear staining was considered as positive, the sensitivity and specificity were 69% and 100% in diagnosing SC, and 92% and 100% in detecting NTRK3 fusion. Conclusions: Nuclear pan‐Trk IHC is highly specific for SC diagnosis, with a specificity approaching 100%, making it a useful and precise diagnostic tool for differentiating SC from its histological mimics. On the other hand, any pan‐Trk staining (nuclear or cytoplasmic) is highly sensitive for SC, and can serve as an attractive, cheap, fast and accessible screening tool for selecting patients to undergo confirmative molecular testing for clinical trials using TRK inhibitors. [ABSTRACT FROM AUTHOR]

Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms, believed to originate from the interstitial cells of Cajal (ICC), often caused by overexpression of tyrosine kinase receptors (TKR) KIT or PDGFRA. Here, we present evidence that the embryonic stem cell factor FOXD3, first identified as ‘Genesis’ and involved in both gastrointestinal and neural crest cell development, is implicated in GIST pathogenesis; its involvement is investigated both in vitro and in zebrafish and a mouse model of FOXD3 deficiency. Samples from a total of 58 patients with wild-type GISTs were used for molecular analyses, including Sanger sequencing, comparative genomic hybridization, and methylation analysis. Immunohistochemistry and western blot evaluation were used to assess FOXD3 expression. Additionally, we conducted in vitro functional studies in tissue samples and in transfected cells to confirm the pathogenicity of the identified genetic variants. Germline partially inactivating FOXD3 sequence variants (p.R54H and p.Ala88_Gly91del) were found in patients with isolated GISTs. Chromosome 1p loss was the most frequent chromosomal abnormality identified in tumors. In vitro experiments demonstrate the impairment of FOXD3 in the presence of those variants. Animal studies showed disruption of the GI neural network and changes in the number and distribution in the ICC. FOXD3 suppresses KIT expression in human cells; its inactivation led to an increase in ICC in zebrafish, as well as mice, providing evidence for a functional link between FOXD3 defects and KIT overexpression leading to GIST formation. [ABSTRACT FROM AUTHOR]

Objective: To describe the imaging features of plexiform fibrohistiocytic tumor and its associated clinical findings.Materials and Methods: An institutional database was searched to identify all patients with a pathological diagnosis of plexiform fibrohistiocytic tumor. The electronic medical record was reviewed for relevant clinical data. Radiologic images of the primary tumor site were reviewed by two radiologists to assess primary, residual, or recurrent tumor with respect to tumor location, size, morphology, MR signal characteristics and enhancement, and involvement of adjacent structures.Results: Thirteen patients with imaging of the primary tumor site were identified [eight female, five male; mean age, 15.9 years (range, 3-41 years)]. Plexiform fibrohistiocytic tumor typically manifested as a solitary, painless, firm, slow-growing lesion centered in the subcutaneous tissues, with a predilection for the upper extremity or head and neck region. Most tumors had a purely plaque-like or infiltrative morphology at MRI; some demonstrated no round or oval mass. Tumors were predominantly isointense to muscle on T1-weighted imaging and hyperintense on fluid-sensitive imaging, and enhanced after gadolinium contrast administration. Five patients (38%) had residual tumor after initial surgery, resembling postoperative changes. No patient had recurrent tumor. One patient (8%) developed metastases to local lymph nodes and to the lung. No patient died from plexiform fibrohistiocytic tumor.Conclusions: Plexiform fibrohistiocytic tumor often manifests as a plaque-like or infiltrative process, sometimes without a round or oval mass, most commonly in the subcutaneous tissues of the upper extremity or head and neck region. Residual tumor is often present after initial surgery, and may be indistinguishable from postoperative changes. [ABSTRACT FROM AUTHOR]

PURPOSE: Extremity rhabdomyosarcoma (RMS) is associated with a very poor outcome compared with other sites, mainly because of its high incidence of alveolar histology and regional lymph node involvement. To better define prognostic markers in this clinical subset, we investigated our experience of 61 patients with extremity RMS treated at our tertiary cancer center for the past 2 decades. PATIENTS AND METHODS: The patients had a median age of 8 years at diagnosis, equal gender distribution, and two-thirds occurred in the lower extremity. Most (85%) patients had FOXO1 fusion–positive alveolar RMS (ARMS), with 70% having a PAX3::FOXO1 transcript. Remaining were seven patients with fusion-negative embryonal RMS (ERMS) and two with MYOD1- mutant spindle cell/sclerosing RMS (SRMS). In 40% of the patients, material was available for DNA-based targeted sequencing using MSK-IMPACT cancer gene panel. RESULTS: One-third of patients presented with localized disease at diagnosis while the remaining had regional nodal (18%) or distant metastases (51%). Metastatic disease, high-risk group, and age 10 years or older significantly affected the overall survival (OS; hazard ratio [HR], 2.68 [ P =.004], 2.78 [ P =.010] and 2.26 [ P =.034], respectively). Although the presence of metastatic disease had a dismal impact on 5-year EFS and OS (19% and 29%, respectively), nodal involvement had a comparatively lower impact on 5-year EFS and 5-year OS (43% and 66%, respectively). PAX3::FOXO1 ARMS had worse prognosis and afflicted older children compared with PAX7::FOXO1 (HR = 3.45, P =.016). The most common events in the ARMS group included MED12 alterations, CDK4 amplifications, and CDKN2A deletions (8%-17%). The latter two abnormalities were mutually exclusive, enriched for acral and high-risk lesions, and correlated with poor outcome on OS (P =.02). CONCLUSION: Our data provide rationale for considering the integration of molecular abnormalities to refine risk stratification in extremity RMS. A clinical and genomic investigation of extremity RMS shows that CDKN2A and CDK4 alterations are associated with poor OS. [ABSTRACT FROM AUTHOR]

We report two novel cases of Xp11 translocation renal cell carcinomas with the MED15::TFE3 gene fusion in adult females aged 40 and 74 years. Both cases were extensively cystic and contained only minimal clear cells lining cysts and within septal walls, raising the differential diagnosis of multilocular cystic renal neoplasm of low malignant potential. By immunohistochemistry, both neoplasms labeled for PAX8, TFE3, cathepsin K and Melan A but not for HMB45. On review of the published literature and the two cases reported herein, over 90% of MED15::TFE3 renal cell carcinomas (RCCs) have been described as cystic. The correlation of the MED15::TFE3 fusion with extensively cystic morphology represents the strongest association of TFE3 fusion partner with clinicopathological features among TFE3 -rearranged RCC reported to date. [ABSTRACT FROM AUTHOR]

Adenoid cystic carcinoma ( ACC) is a relatively rare slow-growing and often-aggressive epithelial-myoepithelial neoplasm that arises in multiple organs including the skin. The t(6;9) (q22-23;p23-24) translocation, resulting in a MYB-NFIB gene fusion has been found in ACCs from the salivary glands and other organs. Recently, MYB aberrations occurring in a subset (40%) of primary cutaneous ACC ( PCACC) examples was described. Herein, we report three additional cases of PCACC harboring MYB aberrations. The tumors presented in three males aged 43, 81 and 55 years old and affected the extremities in the first two patients and the scalp in the third one. None of the patients had history of prior or concurrent ACC elsewhere. Lesions exhibited the classic ACC morphology of nests of basaloid cells arranged in cribriform and adenoid patterns. Sentinel lymph node biopsy was performed in two cases with one case showing lymph node positivity. Fluorescence in situ hybridization with break-apart probes for MYB and NFIB loci revealed that two cases showed MYB rearrangements while one case showed loss of one MYB signal. None of the cases showed NFIB rearrangements. We contribute with three additional cases of PCACC exhibiting MYB aberrations, the apparent driving genetic abnormality in these tumors. [ABSTRACT FROM AUTHOR]

As primary bone fibrosarcoma (FS) and malignant fibrous histiocytoma (MFH) have similar clinical, radiographic, or survival manifestations, ultrastructural and immunohistochemical studies were undertaken to determine the differentiation pathways of constituent malignant cells. Twelve cases of primary intraosseous FS and MFH were selected for this ultrastructural comparative study and were analyzed for fibroblastic or modified fibroblastic differentiation. There were 4 FS cases and 8 MFH cases, of which 5 were storiform-pleomorphic, 2 were giant cell, and 1 was myxoid type. All FS consisted of spindle fibroblasts with a prominent rough endoplasmic reticulum and Golgi apparatus, variable amounts of vimentin intermediate filaments, and extracellular collagen fibrils. The MFH were composed of a mixture of spindle and pleomorphic fibroblasts (8/8), histiofibroblasts (4/8), and myofibroblasts (3/8). Variable numbers of undifferentiated cells were found in both tumors. In conclusion, fibroblastic differentiation and collagen production was noted in all cases. The often pleomorphic histiofibroblasts present in some MFH cases most likely represent "modified fibroblasts," similar to myofibroblasts. These findings support the hypothesis that the fibroblast and its variants are the predominant cell types found in these tumors, suggesting that the diagnostic entity MFH should be classified as a pleomorphic fibrosarcoma. [ABSTRACT FROM AUTHOR]

Aims: Radiation‐associated angiosarcomas (RT‐ASs) of the breast are rare tumours with a poor prognosis. MYC gene amplification is considered to be the hallmark of RT‐AS, and is sometimes used as a diagnostic tool to distinguish it from other radiation‐associated vascular lesions. However, a small subset of RT‐ASs lacks MYC amplification, and this may be associated with better outcome. Loss of trimethylation at lysine 27 of histone 3 (H3K27me3) expression by immunohistochemistry (IHC) has been recently postulated as an additional diagnostic marker for RT‐AS. The aims of this study were to evaluate the impact of MYC amplification as detected by fluorescence in‐situ hybridisation and/or next‐generation sequencing on clinicopathological features and outcome in a large cohort of RT‐ASs, compare outcome with those of radiation‐associated sarcomas (RT‐Ss) of the breast other than angiosarcoma, and evaluate expression of H3K27me3 IHC in these groups. Methods and results: Eighty‐one RT‐ASs were identified, including 73 that were MYC‐amplified and 8 (10%) that were MYC‐non‐amplified. MYC‐amplified RT‐ASs were diagnosed in older patients (median age, 69 years versus 61 years). The 5‐year disease‐specific survival and 5‐year overall survival rates were 56% and 47%, respectively. Older age, larger tumour size, positive margin and MYC amplification were associated with worse prognosis. None of the RT‐ASs showed complete loss of H3K27me3 IHC expression. All 18 RT‐Ss were MYC‐non‐amplified, and complete loss of H3K27me3 expression was seen in 2 cases. We found no difference in prognosis between RT‐AS and RT‐S. Conclusions: RT‐AS of the breast is associated with a poor prognosis. Older age at diagnosis, larger tumour size, positive margin at excision and MYC amplification are associated with worse prognosis. [ABSTRACT FROM AUTHOR]

Gastrointestinal stromal tumors (GISTs) are rare but treatable soft tissue sarcomas. Nearly all GISTs have somatic mutations in either the KIT or PDGFRA gene, but there are no known inherited genetic risk factors. We assessed the relationship between KIT/PDGFRA mutations and select deletions or single nucleotide polymorphisms (SNPs) in 279 participants from a clinical trial of adjuvant imatinib mesylate. Given previous evidence that certain susceptibility loci and carcinogens are associated with characteristic mutations, or “signatures” in other cancers, we hypothesized that the characteristic somatic mutations in the KIT and PDGFRA genes in GIST tumors may similarly be mutational signatures that are causally linked to specific mutagens or susceptibility loci. As previous epidemiologic studies suggest environmental risk factors such as dioxin and radiation exposure may be linked to sarcomas, we chose 208 variants in 39 candidate genes related to DNA repair and dioxin metabolism or response. We calculated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the association between each variant and 7 categories of tumor mutation using logistic regression. We also evaluated gene-level effects using the sequence kernel association test (SKAT). Although none of the association p-values were statistically significant after adjustment for multiple comparisons, SNPs in CYP1B1 were strongly associated with KIT exon 11 codon 557-8 deletions (OR = 1.9, 95% CI: 1.3-2.9 for rs2855658 and OR = 1.8, 95% CI: 1.2-2.7 for rs1056836) and wild type GISTs (OR = 2.7, 95% CI: 1.5-4.8 for rs1800440 and OR = 0.5, 95% CI: 0.3-0.9 for rs1056836). CYP1B1 was also associated with these mutations categories in the SKAT analysis (p = 0.002 and p = 0.003, respectively). Other potential risk variants included GSTM1, RAD23B and ERCC2. This preliminary analysis of inherited genetic risk factors for GIST offers some clues about the disease's genetic origins and provides a starting point for future candidate gene or gene-environment research. [ABSTRACT FROM AUTHOR]

A response by J. L. Hornick and colleagues to a letter to the editor about their article "Inflammatory Myofibroblastic Tumours: Where Are We Now?" in a 2008 issue of the "Journal of Clinical Pathology" is presented.

The article presents a study seeking to determine if an adjuvant treatment with imatinib mesylate would improve recurrence-free survival following resection of localized gastrointestinal stromal tumor. The methods of the randomized controlled trial involving patients who had complete resection of a primary gastrointestinal stromal tumor at least 3 cm in size is described. Researchers found imatinib significantly improved recurrence-free survival in patients compared to the placebo group. The findings indicate adjuvant imatinib therapy is safe and effective in improving survival after resection of primary gastrointestinal stromal tumor.

Hepatic embryonal (undifferentiated) sarcoma (ES) is a rare pediatric tumor occurring predominantly in the first decade of life, but a few examples of adult ES have also been described. Isolated ultrastructural reports describe contradictory lines of differentiation in these tumors. Four pediatric and 3 adult ES cases were studied ultrastructurally and features were correlated with morphology. Morphologically, tumors were composed of mixture of plump spindle cells and bizarre giant cells, showing abundant cytoplasmic eosinophilic globules. Ultrastructurally, the hallmark features in all cases included dilated RERs and secondary lysosomes with dense precipitates. Dilated mitochondria and mitochondrial–RER complexes were often seen. Other features included intracytoplasmic fat droplets, scant actin microfilaments, and focal glycogen pools. In summary, pediatric and adult ES show similar morphologic and ultrastructural features. Ultrastructurally, hepatic ES have distinctive findings, including dilated RER and electron-dense lysosomal precipitates, which correlate with the eosinophilic hyaline bodies seen microscopically. These findings suggest that ES are composed of fibroblastic, fibrohistiocytic, and undifferentiated cells. Other lines of differentiation were not identified. [ABSTRACT FROM AUTHOR]

Follicular dendritic cell sarcoma of the liver is an uncommon pathologic entity, and only 5 cases have been reported previously. Herein, we report the first case, to our knowledge, of hepatic follicular dendritic cell sarcoma without evidence of Epstein-Barr virus infection. The patient is an elderly man who was found to have an incidental liver mass and then developed weight loss and fever. The diagnosis was based on the typical morphologic appearance of spindle cell proliferation associated with a brisk lymphoplasmacytic infiltrate and strong immunoreactivity to CD21 and CD35. Based on our experience and a review of the published reports, we summarize the clinical and pathologic features of hepatic follicular dendritic cell sarcoma and its surgical management. [ABSTRACT FROM AUTHOR]

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

Background: The evaluation of malignant cutaneous spindle cell tumors is challenged by a diagnostic differential that comprises neoplasms of diverse histogenesis, and a broad immunohistochemical panel may confound the diagnosis when the results suggest multiple lines of differentiation, such as with a combined myofibroblastic and epithelial phenotype. Methods: We report the case of a solitary scalp nodule that quickly became locally metastatic. A comprehensive panel of immunohistochemistry markers and electron microscopy was evaluated to determine the differentiation of the spindle cells. Results: The tumor, consisting of wavy and slender spindle cells with predominantly bland nuclei, showed immunoreactivity to vimentin, smooth muscle actin, and muscle-specific actin. AE1/AE3, CK5/6, and MNF-116 antibodies were weakly positive in rare cells. However, 34βE12 showed diffuse positivity in the spindle cell population, thus supporting the diagnosis of a sarcomatoid carcinoma with myofibroblastic differentiation. Conclusions: The use of 34βE12 is essential for the evaluation of myofibroblastic spindle cell tumors with rare cytokeratin reactivity. However, even with immunohistochemical and electron microscopic studies, the diagnosis of spindle cell tumors can be confounded by the multiplicity of nosologic equivalents, such as carcinosarcoma, spindle cell carcinoma, and metaplastic carcinoma. The nomenclature of these spindle cell tumors is discussed. [ABSTRACT FROM AUTHOR]

Since 1980 when Sibley and coworkers first described a nodal neoplasm of unknown histogenesis with striking surface microvilli for which they introduced the term "anemone cell," a series of reports have appeared in the literature illustrating tumors with similar ultrastructural features. While most reported cases showed differentiation along a particular line, rare cases remained histogenetically unclear. In this report a case is described of epithelioid gastric gastrointestinal stromal tumor metastatic to the liver, showing conspicuous long microvillus-type cell processes partially or circumferentially coating the cell surfaces, thus qualifying as yet another tumor type with anemone cell features. [ABSTRACT FROM AUTHOR]

Alveolar soft part sarcoma (ASPS) is an unusual tumor with highly characteristic histopathology and ultrastructure, controversial histogenesis, and enigmatic clinical behavior. Recent cytogenetic studies have identified a recurrent der(17) due to a non-reciprocal t(X;17)(p11.2;q25) in this sarcoma. To define the interval containing the Xp11.2 break, we first performed FISH on ASPS cases using YAC probes for OATL1 (Xp11.23) and OATL2 (Xp11.21), and cosmid probes from the intervening genomic region. This localized the breakpoint to a 160 kb interval. The prime candidate within this previously fully sequenced region was TFE3, a transcription factor gene known to be fused to translocation partners on 1 and X in some papillary renal cell carcinomas. Southern blotting using a TFE3 genomic probe identified non-germline bands in several ASPS cases, consistent with rearrangement and possible fusion of TFE3 with a gene on 17q25. Amplification of the 5′ portion of cDNAs containing the 3′ portion of TFE3 in two different ASPS cases identified a novel sequence, designated ASPL, fused in-frame to TFE3 exon 4 (type 1 fusion) or exon 3 (type 2 fusion). Reverse transcriptase PCR using a forward primer from ASPL and a TFE3 exon 4 reverse primer detected an ASPL-TFE3 fusion transcript in all ASPS cases (12/12: 9 type 1, 3 type 2), establishing the utility of this assay in the diagnosis of ASPS. Using appropriate primers, the reciprocal fusion transcript, TFE3-ASPL, was detected in only one of 12 cases, consistent with the non-reciprocal nature of the translocation in most cases, and supporting ASPL-TFE3 as its oncogenically significant fusion product. ASPL maps to chromosome 17, is ubiquitously expressed, and matches numerous ESTs (Unigene cluster Hs.84128) but no named genes. The ASPL cDNA open reading frame encodes a predicted protein of 476 amino acids that contains within its carboxy-terminal portion of a UBX-like domain that shows significant similarity to... [ABSTRACT FROM AUTHOR]

Purpose. Extraskeletal osteosarcoma represents an unusual soft-tissue sarcoma that historically is reported to carry an exceptionally poor prognosis. The objectives of this study were to use a prospectively gathered sarcoma database to test the prevailing clinical bias and more accurately describe the natural history, characterize the prognostic features, estimate survival and evaluate treatment strategies for this unusual sarcoma. Patients and methods. From a large database of nearly 4000 sarcomas at a single institution, 15 patients with pathologically confirmed extraskeletal osteosarcoma were analysed. Results and discussion. Extraskeletal osteosarcoma usually occurs as a large, deep, high-grade lesion in the lower extremity of older patients. Overall and disease-specific survival at 5 years was 50%, with a median follow-up of 35 months (range 3-200 months). Use of adjuvant chemotherapy or radiation therapy did not appear to influence survival, but an effect may have been missed by the relatively low numbers in each group. When matched to a comparable group of patients with stage III extremity sarcomas, there was no significant difference in overall or disease-specific survival between groups. Treatment for extraskeletal osteosarcoma should follow established guidelines for treatment of soft-tissue sarcomas, with the decision regarding adjuvant therapy to be based on individual risk factors. [ABSTRACT FROM AUTHOR]

Introduction: Neoadjuvant imatinib (Neo-IM) therapy may facilitate R0 resection in primary gastrointestinal stromal tumors (GISTs) that are large or in difficult anatomic locations. While response to preoperative tyrosine kinase inhibitors is associated with better outcome in metastatic GIST, little is known about prognostic factors after Neo-IM in primary GIST. Study Design: Patients with primary GIST with or without synchronous metastases who underwent Neo-IM were retrospectively analyzed from a prospective maintained institutional database for Response Evaluation Criteria in Solid Tumors (RECIST), tumor viability, and mitotic rate. Overall survival (OS) was estimated by Kaplan-Meier and compared by log-rank test. Cox proportionate hazard models were used for univariate and multivariate analysis. Results: One hundred and fifty patients were treated for a median of 7.1 months (range 0.2–160). By RECIST, partial response, stable disease, and progressive disease were seen in 40%, 51%, and 9%, respectively. By pathologic analysis, ≤ 50% of the tumor was viable in 72%, and the mitotic rate was ≤ 5/50HPF in 74%. On multivariate analysis, RECIST response and tumor viability were not associated with OS, while post-treatment high mitotic rate (hazard ratio (HR) for death 5.3, CI 2.3–12.4), R2 margins (HR 6.0, CI 2.3–15.5), and adjuvant imatinib (HR 0.4, CI 0.2–0.9) were (p < 0.05). Five-year OS was 81 vs. 38% for low vs. high mitotic rate; 81, 59, and 39% for R0, R1, and R2 margins; and 75 vs 61% for adjuvant vs. no adjuvant imatinib therapy (p < 0.05). Conclusions: In primary GIST undergoing Neo-IM therapy, progression was uncommon, but substantial down-sizing occurred in the minority. High tumor mitotic rate and incomplete resection following Neo-IM were associated with poor outcome, while adjuvant imatinib was associated with prolonged survival. [ABSTRACT FROM AUTHOR]

Background: Giant cell tumor of bone is a benign, locally aggressive neoplasm. Surgical resection is the preferred treatment method. However, for cases in which resection poses an increased risk to the patient, denosumab (anti-RANKL monoclonal antibody) is considered. Secukinumab is an anti-IL-17 antibody that is used in psoriatic arthritis to reduce bone resorption and articular damage.Case Presentation: One case of giant cell tumor of bone (GCTB) in a patient treated with secukinumab for psoriatic arthritis demonstrated findings significant for intra-lesional calcifications. Histologic examination showed ossification, new bone formation, and remodeling. A paucity of osteoclast type giant cells was noted. Real-time quantitative polymerase-chain-reaction (qRT-PCR) analysis revealed decreased osteoclast function compared to treatment-naive GCTB.Conclusions: Secukinumab may play a role in bone remodeling for GCTB. Radiologists, surgeons, and pathologists should be aware of this interaction, which can cause lesional ossification. Further research is required to define the therapeutic potential of this drug for GCTB and osteolytic disease. [ABSTRACT FROM AUTHOR]

PURPOSE: To detect alterations in DNA damage repair (DDR) genes, measure homologous recombination deficiency (HRD), and correlate these findings with clinical outcome in patients with leiomyosarcoma (LMS). PATIENTS AND METHODS: Patients with LMS treated at Memorial Sloan Kettering (MSK) Cancer Center who consented to prospective targeted next-generation sequencing with MSK-IMPACT were screened for oncogenic somatic variants in one of 33 DDR genes; where feasible, an experimental HRD score was calculated from IMPACT data. Progression-free survival (PFS) and overall survival (OS) were estimated after stratifying patients by DDR gene alteration status and HRD score. RESULTS: Of 211 patients with LMS, 20% had an oncogenic DDR gene alteration. Univariable analysis of PFS in 117 patients who received standard frontline chemotherapy in the metastatic setting found that an altered homologous recombination pathway gene was significantly associated with shorter PFS (hazard ratio [HR], 1.79; 95% CI, 1.04 to 3.07; P =.035). Non- BRCA homologous recombination gene alteration was associated with shorter PFS (HR, 2.61; 95% CI, 1.35 to 5.04; P =.004) compared with BRCA -altered and wild-type homologous recombination genes. Univariable analysis of OS from diagnosis in the entire cohort of 211 patients found that age, tumor size, number of metastatic sites, localized disease, and non- BRCA homologous recombination gene alteration were significantly associated with OS. On multivariable analysis, non- BRCA homologous recombination pathway gene alteration remained significant (HR, 4.91; 95% CI, 2.47 to 9.76; P <.001). High HRD score was not associated with a different PFS or OS. CONCLUSION: Patients with LMS with homologous recombination pathway gene alterations have poor clinical outcomes, particularly those with non- BRCA gene alterations. HRD score calculated from a targeted exome panel did not discern disparate clinical outcomes. [ABSTRACT FROM AUTHOR]

Among sarcomas with a round‐cell morphology that lack rearrangement of the EWSR1 gene, rearrangements involving the CIC gene are the most common. In comparison with Ewing Sarcoma, CIC‐rearranged sarcomas present at an older average age, arise almost exclusively in soft tissues, are clinically more aggressive, and are more likely to be resistant to the chemotherapy regimens used for Ewing sarcoma. CIC‐rearranged sarcomas present more commonly in a deep location, and we suspect that superficial presentations may be under‐recognized. In this case series, we report three of such cases. Overall, the morphology is similar to CIC‐rearranged sarcomas of deeper locations. We hope to raise awareness among the dermatopathology community by expanding the differential of superficial tumors with round cell morphology. [ABSTRACT FROM AUTHOR]

Purpose: Recent studies revealed divergent gene expression patterns in Ewing sarcoma (EwS) with canonical EWSR1–ETS gene fusions and undifferentiated round cell sarcomas (URCS) with EWSR1 rearrangements fused to the non-ETS gene NFATc2. Thus, the question arises whether the latter tumors really belong to EwS. Methods: We collected five cases matching the group of URCS with EWSR1–NFATc2 fusion and performed DNA methylation and copy number profiling. Results were compared to methylation data of 30 EwS with various EWSR1–ETS fusions and one EwS with FUS–ERG fusion, 16 URCS with CIC rearrangement and 10 URCS with BCOR alteration and a total of 81 EWSR1-associated soft tissue sarcomas including 7 angiomatoid fibrous histiocytomas, 7 clear cell sarcomas of the soft tissue, 28 desmoplastic small round cell tumors, 10 extraskeletal myxoid chondrosarcomas and 29 myxoid liposarcomas. Results: Unsupervised hierarchical clustering and t-distributed stochastic neighbor embedding analysis of DNA methylation data revealed a homogeneous methylation cluster for URCS with EWSR1–NFATc2 fusion, which clearly segregated from EwS and the other subtypes. Copy number profiles of EWSR1–NFATc2 cases showed recurrent losses on chromosome 9q and segmental gains on 20q13 and 22q12 involving the EWSR1 and NFATc2 loci, respectively. Conclusion: In summary, URCS with EWSR1–NFATc2 fusion share a distinct DNA methylation signature and carry characteristic copy number alterations, which emphasizes that these sarcomas should be considered separately from EwS. [ABSTRACT FROM AUTHOR]

Aberrant activation of MAPK signaling leads to the activation of oncogenic transcriptomes. How MAPK signaling is coupled with the transcriptional response in cancer is not fully understood. In 2 MAPK-activated tumor types, gastrointestinal stromal tumor and melanoma, we found that ETV1 and other Pea3-ETS transcription factors are critical nuclear effectors of MAPK signaling that are regulated through protein stability. Expression of stabilized Pea3-ETS factors can partially rescue the MAPK transcriptome and cell viability after MAPK inhibition. To identify the players involved in this process, we performed a pooled genome-wide RNAi screen using a fluorescence-based ETV1 protein stability sensor and identified COP1, DET1, DDB1, UBE3C, PSMD4, and COP9 signalosome members. COP1 or DET1 loss led to decoupling between MAPK signaling and the downstream transcriptional response, where MAPK inhibition failed to destabilize Pea3 factors and fully inhibit the MAPK transcriptome, thus resulting in decreased sensitivity to MAPK pathway inhibitors. We identified multiple COP1 and DET1 mutations in human tumors that were defective in the degradation of Pea3-ETS factors. Two melanoma patients had de novo DET1 mutations arising after vemurafenib treatment. These observations indicate that MAPK signaling-dependent regulation of Pea3-ETS protein stability is a key signaling node in oncogenesis and therapeutic resistance to MAPK pathway inhibition. [ABSTRACT FROM AUTHOR]

Background: Patients with metastatic sarcoma have limited treatment options. Nivolumab and ipilimumab are monoclonal antibodies targeting PD-1 and CTLA-4, respectively. We investigated the activity and safety of nivolumab alone or in combination with ipilimumab in patients with locally advanced, unresectable, or metastatic sarcoma.Methods: We did a multicentre, open-label, non-comparative, randomised, phase 2 study that enrolled patients aged 18 years or older and had central pathology confirmation of sarcoma with at least one measurable lesion by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, evidence of metastatic, locally advanced or unresectable disease, an ECOG performance status of 0-1, and received at least one previous line of systemic therapy. Patients were assigned to treatment in an unblinded manner, as this trial was conducted as two independent, non-comparative phase 2 trials. Enrolled patients were assigned (1:1) via a dynamic allocation algorithm to intravenous nivolumab 3 mg/kg every 2 weeks, or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses. Thereafter, all patients received nivolumab monotherapy (3 mg/kg) every 2 weeks for up to 2 years. The primary endpoint was the proportion of patients with locally advanced, unresectable or metastatic soft tissue sarcoma achieving a confirmed objective response. Analysis was per protocol. This study is ongoing although enrolment is closed. It is registered with ClinicalTrials.gov, number NCT02500797.Findings: Between Aug 13, 2015, and March 17, 2016, 96 patients from 15 sites in the USA underwent central pathology review for eligibility and 85 eligible patients, including planned over-enrolment, were allocated to receive either nivolumab monotherapy (43 patients) or nivolumab plus ipilimumab (42 patients). The primary endpoint analysis was done according to protocol specifications in the first 76 eligible patients (38 patients per group). The number of confirmed responses was two (5% [92% CI 1-16] of 38 patients) in the nivolumab group and six (16% [7-30] of 38 patients) in the nivolumab plus ipilimumab group. The most common grade 3 or worse adverse events were anaemia (four [10%] patients), decreased lymphocyte count (three [7%]), and dehydration, increased lipase, pain, pleural effusion, respiratory failure, secondary benign neoplasm, and urinary tract obstruction (two [5%] patients each) among the 42 patients in the nivolumab group and anaemia (eight [19%] patients), hypotension (four [10%] patients), and pain and urinary tract infection (three [7%] patients each) among the 42 patients in the nivolumab plus ipilimumab group. Serious treatment-related adverse events occurred in eight (19%) of 42 patients receiving monotherapy and 11 (26%) of 42 patients receiving combination therapy, and included anaemia, anorexia, dehydration, decreased platelet count, diarrhoea, fatigue, fever, increased creatinine, increased alanine aminotransferase, increased aspartate aminotransferase, hyponatraemia, pain, pleural effusion, and pruritus. There were no treatment-related deaths.Interpretation: Nivolumab alone does not warrant further study in an unselected sarcoma population given the limited efficacy. Nivolumab combined with ipilimumab demonstrated promising efficacy in certain sarcoma subtypes, with a manageable safety profile comparable to current available treatment options. The combination therapy met its predefined primary study endpoint; further evaluation of nivolumab plus ipilimumab in a randomised study is warranted.Funding: Alliance Clinical Trials in Oncology, National Cancer Institute Cancer Therapy Evaluation Program, Bristol-Myers Squibb, Cycle for Survival. [ABSTRACT FROM AUTHOR]

Aims Pleomorphic adenoma gene 1 ( PLAG1) gene rearrangement is the most common genetic abnormality in pleomorphic adenoma (PA), resulting in overexpression of PLAG1 protein. PA and carcinoma ex pleomorphic adenoma (CA ex-PA) can mimic various benign and malignant salivary gland tumours. The aims of this study are to evaluate the sensitivity and specificity of PLAG1 immunohistochemistry (IHC) in the differential diagnosis of PA and CA ex-PA and to compare the PLAG1 immunohistochemical results to PLAG1 gene abnormalities as detected by fluorescence in-situ hybridisation (FISH). Methods and results PLAG1 immunostaining was performed on 83 salivary gland tumours, including 23 PA, 15 CA ex-PA and 45 other salivary gland tumours. In addition, PLAG1 FISH was performed in 44 cases for the presence of gene rearrangements/amplifications. The results showed high sensitivity of PLAG1 IHC in 96% of PA; however, discordant results between PLAG1 FISH abnormalities and IHC were noted in 15 of 44 cases (34%). Seven PA, four de-novo myoepithelial carcinomas and one basal cell adenocarcinoma had negative FISH results, but were positive for IHC; while three salivary duct carcinomas (SDC) ex-PA were positive for FISH but negative for IHC. PLAG1 IHC can differentiate CA ex-PA from de-novo SDC ( P = 0.02), but not from de-novo myoepithelial carcinoma. PLAG1 IHC is a sensitive marker for PA. This could be due to PLAG1 gene abnormalities beyond FISH resolution. Conclusions A negative PLAG1 IHC might be helpful in excluding a PA diagnosis. Interestingly, in the context of CA ex-PA, FISH is more sensitive than IHC in detecting PLAG1 abnormalities. [ABSTRACT FROM AUTHOR]

Aims Surgical excision of all benign vascular lesions of the breast identified by core needle biopsy has been recommended in the past to rule out a more serious lesion. In this study we investigated the clinical, radiological and pathological findings in patients diagnosed with a benign vascular lesion at our institution to assess whether excision may be spared for lesions without atypia. Methods and results We searched the electronic medical record for patients with a vascular lesion of the breast diagnosed between 2000 and 2015. The study population consisted of 84 patients, 83 females and one male. The index diagnoses included 76 benign vascular lesions, five vascular lesions with cytological atypia and three angiosarcomas. A radiologist reviewed all pre- and post-biopsy imaging studies; all cases had concordant radiological and pathological findings. Based on radiological and histological correlation, the vascular lesion accounted for the radiological target in 40 (48%) cases and was deemed an incidental finding in 44 (52%). Seven of 32 (22%) targeted and 10 of 44 (23%) incidental benign vascular lesions underwent surgical excision; there were no upgrades at excision. No recurrences or clinical events were observed in patients with a targeted or incidental benign vascular lesion with a median follow-up of 39 months and 40.6 months, respectively. Conclusion Our data suggest that benign vascular lesions diagnosed on core biopsy with concordant radiological and pathological findings do not warrant surgical excision. [ABSTRACT FROM AUTHOR]

Gastrointestinal stromal tumors (GISTs) predominantly harbor activating mutations in the receptor tyrosine kinase KIT. To genetically dissect in vivo the requirement of different signal transduction pathways emanating from KIT for tumorigenesis, the oncogenic KitV558Δ mutation was combined with point mutations abrogating specific phosphorylation sites on KIT. Compared with single-mutant KitV558Δ/+ mice, double-mutant KitV558Δ;Y567F/Y567F knock-in mice lacking the SRC family kinase-binding site on KIT (pY567) exhibited attenuated MAPK signaling and tumor growth. Surprisingly, abrogation of the PI3K-binding site (pY719) in KitV558Δ;Y719F/Y719F mice prevented GIST development, although the interstitial cells of Cajal (ICC), the cells of origin of GIST, were normal. Pharmacologic inhibition of the PI3K pathway in tumor-bearing KitV558Δ/+ mice with the dual PI3K/mTOR inhibitor voxtalisib, the pan-PI3K inhibitor pilaralisib, and the PI3K-alpha-restricted inhibitor alpelisib each diminished tumor proliferation. The addition of the MEK inhibitor PD-325901 or binimetinib further decreased downstream KIT signaling. Moreover, combining PI3K and MEK inhibition was effective against imatinib-resistant KitV558Δ;T669I/+ tumors. [ABSTRACT FROM AUTHOR]

Gastrointestinal stromal tumor (GIST) is the most common subtype of sarcoma. Despite clinical advances in the treatment of KIT/PDGFRA-mutant GIST, similar progress against KIT/PDGFRA wild-type GIST, including mutant BRAF-driven tumors, has been limited by a lack of model systems. ETV1 is a master regulator in the intestinal cells of Cajal (ICC), thought to be the cells of origin of GIST. Here, we present a model in which the ETV1 promoter is used to specifically and inducibly drive Cre recombinase in ICC as a strategy to study GIST pathogenesis. Using a conditional allele for BrafV600E, a mutation observed in clinical cases of GIST, we observed that BrafV600E activation was sufficient to drive ICC hyperplasia but not GIST tumorigenesis. In contrast, combining BrafV600E activation with Trp53 loss was sufficient to drive both ICC hyperplasia and formation of multifocal GIST-like tumors in the mouse gastrointestinal tract with 100% penetrance. This mouse model of sporadic GIST model was amenable to therapeutic intervention, and it recapitulated clinical responses to RAF inhibition seen in human GIST. Our work offers a useful in vivo model of human sporadic forms of BRAF-mutant GIST to help unravel its pathogenesis and therapeutic response to novel experimental agents. [ABSTRACT FROM AUTHOR]

Objective: To determine clinicopathologic factors on survival in patients with head and neck synovial sarcoma.Patients and Methods: We retrospectively identified patients with molecularly confirmed synovial sarcomas of the head and neck (SS-HN), either by the presence of SS18-SSX fusion transcript by RT-PCR or SS18 gene rearrangement by FISH, who were managed at our institution over a 20-year period (1996-2015). Kaplan-Meier survival analysis and log-rank test were performed to evaluate variables related to disease specific survival (DSS). Fisher exact test was performed to evaluate variables related to local recurrence.Results: Thirty-four patients (20 males and 14 females, mean of 31years) with SS18-SSX fusion-positive SS-HN were identified. The parapharyngeal region of the neck was the most common site. The mean tumor size was 4.8cm (0.8-10cm). Two-thirds (n=23) of cases had a monophasic histology. The 2, 5 and 10-year DSS rates were 97%, 79% and 68%. The 5-year DSS rates for the adult/pediatric cohort were 74%/88%. Recurrence showed significant effect on DSS (p=0.021). There was no significant effect on DSS with age, therapy modality, tumor site, surgical margin, tumor size (⩽5cm vs. >5cm) and histopathologic subtype. Tumor site (i.e. skull base/paranasal sinus region) was associated with local recurrence (p=0.003).Conclusion: In our cohort DSS rate was associated with recurrence. Tumors located in the skull base/paranasal sinus region were associated with a higher rate of local recurrence. Thus appropriate selection of high risk patients who can benefit from multimodality therapies might improve survival. [ABSTRACT FROM AUTHOR]

Background: Based on their distinctive histologic and genetic features, the latest WHO classification of soft tissue tumors includes four pathologic variants of rhabdomyosarcoma (RMS): embryonal (ERMS), alveolar (ARMS), spindle cell-sclerosing (SRMS-ScRMS) and pleomorphic RMS. The aim of this study focused on a detailed clinicopathologic and survival analysis of head and neck RMS (HNRMS) using the latest pathologic and molecular criteria reflecting this new subclassification in a large cohort.Patients and Methods: Patients managed for HNRMS in our institution (1996-2015) were analyzed. The presence of a FOXO1 fusion was required for the classification of ARMS. MYOD1 mutations in SRMS-ScRMS were tested when material available. Univariate and multivariate analyses were performed to evaluate variables related to overall survival (OS).Results: Ninety-nine HNRMS patients (52 males and 47 females, mean of 16years) were included in the study after pathologic re-review. The most common location was parameningeal (PM) (n=64), followed by non-orbital/non-PM (n=25) and orbital (n=10). There were 53 ERMS, 33 fusion-positive ARMS and 13 SRMS-ScRMS [SRMS (8); ScRMS (5)]. The 5-year OS rate for ERMS patients was significantly higher (82%) compared to ARMS (53%) and SRMS-ScRMS (50%) [SRMS (75%); ScRMS (30%)]. Univariate analysis showed that survival was dependent on histology (P=0.012), tumor size >5cm (P<0.001), regional lymph node involvement (P=0.002), metastasis at initial presentation (P<0.001), stage (P<0.001), and recurrence (P=0.002). Multivariate analysis confirmed histologic subtype to be significant (P=0.043).Conclusion: Our findings reinforce that HNRMS is a heterogenous disease with ARMS and SRMS-ScRMS having an equally unfavorable outcome. [ABSTRACT FROM AUTHOR]

Dentofacial developmental abnormalities have been reported in head and neck rhabdomyosarcoma (HNRMS) patients treated with conventional radiotherapy technique and chemotherapy. This current study investigates dentofacial long-term effects among HNRMS survivors managed with intensity-modulated radiotherapy (IMRT) and chemotherapy. In general, IMRT is a more effective 3D-conformal radiotherapy technique, which delivers high doses of radiation to the tumor target while minimizing doses received by the surrounding normal tissues. The medical records and radiographs of thirteen patients were reviewed to identify the following: 1. Facial asymmetry and jaw hypoplasia. 2. Effects on the dental tissue causing tooth agenesis/hypodontia, root agenesis/stunting/malformation, and/or enamel hypoplasia. 3. Trismus, hyposalivation/xerostomia. Seven patients presented with facial asymmetry and jaw hypoplasia, 9 patients presented with effects on the dental tissue [root agenesis/stunting/malformation (9), tooth agenesis/hypodontia (7) and enamel hypoplasia (3)] and 7 patients developed trismus and /or xerostomia. All patients with facial asymmetry and jaw hypoplasia also developed dental abnormalities. Patients with dentofacial developmental abnormalities were ≤7 years of age at treatment. Our study shows that dentofacial developmental abnormalities are still a burden in the era of IMRT and as prognosis of childhood malignancy improves and more patients survive, these late dentofacial sequelae among childhood cancer survivors will become more common. Dental oncologists should be integral members in the management of children with head and neck cancers. [ABSTRACT FROM PUBLISHER]