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Calcified chondroid neoplasms with FN1::FGFR1 or FGFR2 constitute a recently described category of mesenchymal neoplasms mostly encountered in the extremities and temporomandibular joint. Herein, we report a case of FNI1-fused calcified chondroid neoplasm of the hand with a novel FGFR3 fusion partner. The tumor exhibited a multilobulated growth pattern composed of epithelioid cells embedded in abundant stroma with myxoid, chondroid and fibrous areas and scattered osteoclast-like giant cells. RNA sequencing revealed an in-frame fusion between exon 31 of FN1 and exon 3 of FGFR3, which was subsequently confirmed by reverse transcription-polymerase chain reaction. Our findings expand on the spectrum of potential fusion partners in FN1-fused calcified chondroid neoplasms. This article is protected by copyright. All rights reserved.

Originally described in a rare subset of poorly differentiated squamous cell carcinomas termed NUT carcinomas, NUTM1 rearrangements are now known to characterize a wide spectrum of neoplasms including sarcomas, poromas/porocarcinomas, unclassified adnexal carcinomas and pediatric acute lymphoblastic leukemia. The advent of next-generation sequencing (NGS) has led to the identification of a multitude of novel fusion partners in addition to BRD4, which was initially reported in the majority of NUT carcinomas. NUTM1-rearranged sarcomas usually harbor fusions with the MAD gene family ( MXD1, MXD4, MGA) and present as spindle cell proliferations in diverse locations in patients of all ages. Herein, we present a very rare case of spindle cell sarcoma of the lung, which harbored a NUTM1::MGA fusion and offer a comprehensive update of the recent data.

Objectives To explore the presence of neutrophil extracellular traps (NETs) in inflamed temporal artery biopsies (TABs) of patients with GCA. Methods Ten patients with GCA [five with limited and five with associated generalized vascular involvement, as defined by 18F-fluorodeoxyglucose PET with CT (PET/CT)] and eight with PMR were studied. The presence, location, quantitation and decoration of NETs with IL-6, IL-1β and IL-17A were assessed in TABs at the time of disease diagnosis by tissue immunofluorescence and confocal microscopy. Paired serum levels of IL-6 and IL-17A were also evaluated in all patients. Results All temporal artery biopsies from GCA, but not PMR, patients had NETs located mainly in the adventitia, adjacent to the vasa vasorum. NETs decorated with IL-6 were present in 8/10 TABs of GCA patients, of whom 5 were PET/CT(+) and 3 PET/CT(–) patients. IL-17A(+) NETs were observed in all GCA patients. IL-1β(+) NETs were not detected in any GCA patient. No relation was found between serum IL-6 and IL-17A levels and NETs containing IL-6 and/or IL-17A. Conclusions NETs bearing pro-inflammatory cytokines are present in inflamed GCA-TABs. Future studies with a larger number of patients from different centres will show whether the findings regarding neutrophils/NETs in the TAB are consistent and disclose their clinical impact.

Poromas, and their malignant counterparts, porocarcinomas, harbor recurrent translocations involving YAP1-MAML2, YAP1-NUTM1, and infrequently WWTR1-NUTM1; YAP1-NUTM1 being the most common in porocarcinomas. NUT immunohistochemistry (IHC) can be used to identify NUTM1-translocated tumors. This study sought to investigate potential novel NUTM1-fusion partners among NUT IHC-positive poromas and porocarcinomas.Thirteen NUT IHC-positive poroid tumors (four poromas and nine porocarcinomas) were identified within a multi-institutional international cohort. Next-generation sequencing (NGS) assessed for NUTM1 fusion partners.NGS detected a NUTM1 fusion in 12 of 13 cases: YAP1-NUTM1 (11/12 cases) and WWTR1-NUTM1 (1/12 cases). Two of the cases (2/12) with NUTM1 fusion were not called by the NGS algorithm but had at least one read-spanning YAP1-NUTM1 break point upon manual review. A NUTM1 fusion was not identified in one case; however, the sample had low RNA quality. The following fusion events were identified: YAP1 exon 4::NUTM1 exon 3 in six cases, YAP1 exon 6::NUTM1 exon 2 in one case, YAP1 exon 3::NUTM1 exon 3 in three cases, WWTR1 exon 3::NUTM1 exon 3 in one case, and YAP1 exon 8::NUTM1 exon 3 fusion in one case.While no novel NUTM1 fusion partners were identified within our cohort, 12 of 13 cases had discoverable NUTM1 fusions; YAP1-NUTM1 fusion was detected in 11 cases (92%) and WWTR1-NUTM1 in 1 case (8%). These data corroborate findings from other recent investigations and further substantiate the utility of NUT IHC in diagnosing a subset of poroid neoplasms. In addition, two of our cases harbored fusions of YAP1 exon 6 to NUTM1 exon 3 and YAP1 exon 8 to NUTM1 exon 2, which have not been reported before in poroid neoplasms and indicate novel break points of YAP1.

Epithelioid fibrous histiocytoma (EFH) is a rare cutaneous neoplasm, which is characterized by the presence of rearrangements involving the ALK gene. Although EFH was long considered a variant of fibrous histiocytoma, the identification of its unique genetic signature confirmed that it represents a distinct entity. The aim of the present study was to examine a cohort of ALK-immunoreactive EFH cases to further characterize gene fusion partners. Next generation sequencing detected ALK fusions in 11 EFH cases identified in the pathology archives of two different institutions. The most common fusion partner was DCTN1 (N = 4) followed by CLTC (N = 2) and VCL (N = 2), while the remaining cases harbored fusions involving SPECC1L, PPFIBP1, and PRKAR1A. In one case no fusion was detected by NGS and FISH despite suitable sample quality. Notably, IHC demonstrated positive ALK expression and the level of aligned ALK reads was comparable to the fusion-positive cases. To the best of our knowledge, this is the first report of CLTC as a fusion partner in EFH. The two CLTC rearranged cases in our cohort also represent the first two EFH cases in the literature that involve exon 19 of ALK, instead of exon 20. These findings underscore the remarkable plasticity of ALK as an oncogenic driver and further expand the list of its potential fusion partners in EFH. Lastly this is also the first report of ALK-immunoreactive EFH with no underlying fusion suggesting a fusion independent transcription mechanism as seen in other tumors.

Castleman disease is a rare benign lymphoproliferative disorder that includes a spectrum of distinct histopathological entities. The differential diagnosis of Castleman disease is broad and includes lymphomas, HIV-related lymphadenopathy, autoimmune disorders, and inflammatory liposarcoma. When Castleman disease occurs in the retroperitoneum, the distinction from the inflammatory variant of well-differentiated liposarcoma can be very challenging in small biopsies. Herein we report a case of Castleman disease that presented as a retroperitoneal mass and expressed MDM2 and CDK4 by immunohistochemistry. To our knowledge, this is the first report of Castleman disease staining positively for MDM2/CDK4, and it underscores how immunohistochemistry can potentially serve as a pitfall when differentiating this rare entity from retroperitoneal sarcomas.

Migrating cells must interpret chemical gradients to guide themselves within tissues. A long-held principle is that gradients guide cells via reorientation of leading-edge protrusions. However, recent evidence indicates that protrusions can be dispensable for locomotion in some contexts, raising questions about how cells interpret endogenous gradients in vivo and whether other mechanisms are involved. Using laser wound assays in zebrafish to elicit acute endogenous gradients and quantitative analyses, we demonstrate a two-stage process for leukocyte chemotaxis in vivo: first a “search” phase, with stimulation of actin networks at the leading edge, cell deceleration, and turning. This is followed by a “run” phase, with fast actin flows, cell acceleration, and persistence. When actin dynamics are perturbed, cells fail to resolve the gradient, suggesting that pure spatial sensing of the gradient is insufficient for navigation. Our data suggest that cell contractility and actin flows provide memory for temporal sensing, while expansion of the leading edge serves to enhance gradient sampling.

Dedifferentiated liposarcoma is a nonlipogenic sarcoma of variable histological grade that frequently arises in association with a well-differentiated liposarcoma. Dedifferentiation occurs in approximately 10% of well-differentiated liposarcomas and is most commonly encountered in the retroperitoneum. Dedifferentiated liposarcoma of the upper respiratory tract is an extremely rare occurrence. Herein, we report a very rare case of low-grade dedifferentiated liposarcoma of the pharynx that presented as a polyp mimicking a benign process clinically and microscopically. We discuss the relevant molecular findings and review the current literature.

Immune cells congregate at specific loci to fight infections during inflammatory responses, a process that must be transient and self-resolving. Cell dispersal promotes resolution, but it remains unclear how transition from clustering to dispersal is regulated. Here we show, using quantitative live imaging in zebrafish, that differential ligand-induced trafficking of chemokine receptors such as Cxcr1 and Cxcr2 orchestrates the state of neutrophil congregation at sites of tissue damage. Through receptor mutagenesis and biosensors, we show that Cxcr1 promotes clustering at wound sites, but is promptly desensitized and internalized, which prevents excess congregation. By contrast, Cxcr2 promotes bidirectional motility and is sustained at the plasma membrane. Persistent plasma membrane residence of Cxcr2 prolongs downstream signaling and is required for sustained exploratory motion conducive to dispersal. Thus, differential trafficking of two chemokine receptors allows coordination of antagonistic cell behaviors, promoting a self-resolving migratory response., Inflammatory responses must be induced and resolved timely to serve protection from pathogens without inducing excessive tissue damage. Here the authors use live imaging in zebrafish to show that the intracellular trafficking of two chemokine receptors, Cxcr1 and Cxcr2, is differentially regulated on activated neutrophils to control their clustering and dispersal, respectively.

Simple Summary Adrenocortical carcinoma is a rare but aggressive malignancy with poor outcomes even for patients with early-stage disease. Several immunotherapy clinical trials, many of which are still in progress, have yielded modest results so far. In-depth understanding of the tumor microenvironment in other cancer types has helped the scientific community to identify novel therapeutic targets and gain a better insight of cancer biology. The present review aims to provide an update of the current knowledge regarding adrenocortical carcinoma tumor microenvironment and describe how the latter potentially affects patient response to immunotherapy. Following the paradigm of other cancer types, exploiting tumor microenvironment could open new therapeutic avenues. Abstract Adrenocortical carcinoma is a rare malignancy with aggressive behavior, with up to 40% of patients presenting with metastases at the time of diagnosis. Both conventional chemotherapeutic regimens and novel immunotherapeutic agents, many of which are currently being tested in ongoing clinical trials, have yielded modest results so far, bringing the need for a deeper understanding of adrenal cancer behavior to the forefront. In the recent years, the tumor microenvironment has emerged as a major determinant of cancer response to immunotherapy and an increasing number of studies on other solid tumors have focused on manipulating the microenvironment in the favor of the host and discovering new potential target molecules. In the present review we aim to explore the characteristics of adrenocortical cancer’s microenvironment, highlighting the mechanisms of immune evasion responsible for the modest immunotherapeutic results, and identify novel potential strategies.

Migrating cells must interpret chemical gradients to guide themselves within tissues. A general premise has been that gradients influence the direction of leading-edge protrusions. However, recent evidence indicates that actin flows correlate better with directed motion than protrusions. A unified chemotaxis model that integrates the role of protrusions and actin flows and that accounts forin vivocell motion patterns is lacking. Here, we provide direct experimental evidence of how neutrophils sense gradients in real-timein vivoand demonstrate a two-stage process: first a ‘search’ phase, that requires actin network expansion by Arp2/3, whereby cells slow down, explore the environment and execute path corrections. This is followed by a ‘run’ phase, that requires Myosin-II-driven contractility and fast actin flows, whereby cells accelerate and persist in the source direction. Thus, protrusive forces support chemotaxis by enhancing signal detection, while actin flows act as the ultimate output of gradient processing.

Exosomes are extracellular vesicles, enriched in biomolecular cargo consisting of nucleic acids, proteins, and lipids, which take part in intercellular communication and play a crucial role in both physiologic functions and oncogenesis. Bladder cancer is the most common urinary malignancy and its incidence is steadily rising in developed countries. Despite the high five-year survival in patients diagnosed at early disease stage, survival substantially drops in patients with muscle-invasive or metastatic disease. Therefore, early detection of primary disease as well as recurrence is of paramount importance. The role that exosomal biomarkers could play in bladder cancer patient diagnosis and surveillance, as well as their potential therapeutic applications, has not been extensively studied in this malignancy. In the present review, we summarize all relevant data obtained so far from cell lines, animal models, and patient biofluids and tissues. Current literature suggests that urine is a rich source of extracellular vesicle-derived biomarkers, compared with blood and bladder tissue samples, with potential applications in bladder cancer management. Further studies improving sample collection procedures and optimizing purification and analytical methods should augment bladder cancer diagnostic, prognostic, and therapeutic input of extracellular vesicles biomarkers in the future.