Novel KMT2B gene mutation in MUC4 positive low-grade fibromyxoid sarcoma.

BACKGROUND: Low-grade Fibromyxoid Sarcoma(LGFM)is a rare fibrosarcoma, which mainly occurs in young people and is mostly seen in the trunk and limbs. The tumor is usually FUS-CREB3L2 fusion caused by t(7;16)(q32-34;p11)chromosome translocation, and rarely FUS-CREB3L1 and EWSR1-CREB3L1 fusion. MUC4 diffuse strong positive can be used as a specific index of LGFM. LGFM is similar to Sclerosing Epithelioid Fibrosarcoma(SEF) and may have the same origin. CASE PRESENTATION: We report a case of LGFM in the chest wall. A female who is 59 years old. In 2016, CT showed dense nodule shadow and focal thickening of the left pleura, the patient underwent surgery, Pathological report that low to moderate malignant fibrosarcoma(fibromyxoid type). The CT re-examination in 2021 showed that the tumors on the left chest wall were significantly larger than before. Pathological examination showed the disease is composed of alternating collagen like and mucinous areas. Under high-power microscope, the tumor cells are consistent in shape, spindle or short spindle, and the tumor cells are arranged in bundles. In local areas, the density of tumor cells is significantly increased, mixed with collagen fibers, and small focal SEF appear. The result of immunohistochemistry showed that SMA, Desmin, CD34, STAT6, S100, SOX10, HMB45 and Melan A were negative, EMA was weakly positive, MUC4 was diffuse and strongly positive, and Ki67 index was low (3%). CONCLUSION: Sequencing results showed that MET, EGFR, KMT2B and RET gene were mutated in LGFM, and KMT2B gene had cancer promoting effect, but there was no literature report in LGFM, which may be of certain significance for the diagnosis and treatment of LGFM.

Analysis of clinical factors impacting recurrence in myxofibrosarcoma.

Myxofibrosarcoma (MFS) is a malignant fibroblastic/myofibroblastic neoplasm with a prominent myxoid area. It has the clinical features of frequent local recurrence (LR) and occasional distant metastasis. Robust epidemiological data on MFS in China are lacking. The aim of this retrospective analysis was to determine the natural history of MFS, identify prognostic factors for recurrence and describe the real-life outcomes of MFS. We reviewed 52 patients with primary MFS from the First Affiliated Hospital of Nanjing Medical University diagnosed between 2016 and 2020. All tumors were subjected to retrospective univariate analysis for prognostic factors of the disease, including tumor size, grade, location and sex; patient age; planned operation; surgical margin; and laboratory results. The significant factors identified by univariate analysis were subsequently analyzed via multivariate analysis. Overall survival (OS), post-treatment LR and metastatic-free survival were assessed as outcomes. The median age was 61 years (range, 13-93). Fourteen (26.92%) patients exhibited low grade disease, and 38 (73.08%) exhibited high grade disease. Among the 29 males, and 23 females, 15 (28.85%) had tumors in the trunk, 37 (71.15%) had tumors in the extremities, 26 had undergone planned surgery, and 26 had unexpected unplanned operation. The margin was negative in 39 (75%) patients and positive in 13 patients (25%). The serum creatine kinase (CK) concentration was high level in 33 (63.46%) patients and low level in 19 (36.54%) patients. The serum lactate dehydrogenase (LDH) levels were low in 23 (44.23%) patients and high in 29 (55.77%) patients. LR was observed in 25 patients (48.08%), and 4 patients developed metastasis. A worse LR rate was found for patients with a low CK level (84.21%) than for those with a high CK level (27.27%) at 5 years (p < 0.05). The LR rate of patients who underwent planned surgery was lower than that of patients who underwent unplanned surgery (p < 0.05). There were significantly more patients with positive margins than patients with negative margins (92.30%, and 33.33%, respectively; p < 0.05). Moreover, superficial tumors were also associated with greater recurrence rate (2/20 [10%]) than deep tumors, (23/32 [71.86%]) [p < 0.05]. The probability of LR in patients with MFS was significantly greater in association with unplanned operations, positive margins, low serum CK levels or superficial tumor depth. These data could help identify high-risk patients; thus, more careful follow-up should be performed for higher-risk patients. Diagnosis and treatment at qualified regular medical centers can reduce the local recurrence rate of MFS.

Imaging characterization of paediatric tumours with the neurotrophic tyrosine receptor kinase fusion transcript.

OBJECTIVES: The neurotrophic tyrosine receptor kinase (NTRK) fusion transcript (FT) is a major genetic landmark of infantile fibrosarcoma (IFS) and cellular congenital mesoblastic nephroma (cCMN) but is also described in other tumours. The recent availability of NTRK-targeted drugs enhances the need for better identification. We aimed to describe the anatomic locations and imaging features of tumours with NTRK-FT in children. CASE SERIES: Imaging characteristics of NTRK-FT tumours of 41 children (median age: 4 months; 63% <1 year old; range: 0-188) managed between 2001 and 2019 were retrospectively analysed. The tumours were located in the soft tissues (n = 24, including 19 IFS), kidneys (n = 9, including 8 cCMN), central nervous system (CNS) (n = 5), lung (n = 2), and bone (n = 1). The tumours were frequently deep-located (93%) and heterogeneous (71%) with necrotic (53%) or haemorrhagic components (29%). Although inconstant, enlarged intratumoural vessels were a recurrent finding (70%) with an irregular distribution (63%) in the most frequent anatomical locations. CONCLUSION: Paediatric NTRK-FT tumours mainly occur in infants with very variable histotypes and locations. Rich and irregular intra-tumoural vascularization are recurrent findings. ADVANCES IN KNOWLEDGE: Apart from IFS of soft tissues and cCMN of the kidneys, others NTRK-FT tumours locations have to be known, as CNS tumours. Better knowledge of the imaging characteristics may help guide the pathological and biological identification.

Comprehensive clinicopathological, molecular, and methylation analysis of mesenchymal tumors with NTRK and other kinase gene aberrations.

Alterations in kinase genes such as NTRK1/2/3, RET, and BRAF underlie infantile fibrosarcoma (IFS), the emerging entity 'NTRK-rearranged spindle cell neoplasms' included in the latest WHO classification, and a growing set of tumors with overlapping clinical and pathological features. In this study, we conducted a comprehensive clinicopathological and molecular analysis of 22 cases of IFS and other kinase gene-altered spindle cell neoplasms affecting both pediatric and adult patients. Follow-up periods for 16 patients ranged in length from 10 to 130 months (mean 38 months). Six patients were treated with targeted therapy, achieving a partial or complete response in five cases. Overall, three cases recurred and one metastasized. Eight patients were free of disease, five were alive with disease, and two patients died. All cases showed previously reported morphological patterns. Based on the cellularity and level of atypia, cases were divided into three morphological grade groups. S100 protein and CD34 were at least focally positive in 12/22 and 14/22 cases, respectively. Novel PWWP2A::RET, NUMA1::RET, ITSN1::RAF1, and CAPZA2::MET fusions, which we report herein in mesenchymal tumors for the first time, were detected by RNA sequencing. Additionally, the first uterine case with BRAF and EGFR mutations and CD34 and S100 co-expression is described. DNA sequencing performed in 13 cases uncovered very rare additional genetic aberrations. The CNV profiles showed that high-grade tumors demonstrate a significantly higher percentage of copy number gains and losses across the genome compared with low- and intermediate-grade tumors. Unsupervised clustering of the tumors' methylation profiles revealed that in 8/9 cases, the methylation profiles clustered with the IFS methylation class, irrespective of their clinicopathological or molecular features. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Myxoid neurofibroma masquerading as lymphatic-venous malformation and poses a diagnostic challenge on fine needle aspiration biopsy.

BACKGROUND: Myxoid neurofibromas (NF) are uncommon, benign spindle cell tumors that originate from peripheral nerve sheaths, often posing a diagnostic challenge due to their hypocellularity on cytology specimens. Distinguishing myxoid spindle cell lesions can be challenging, given the broad range of potential differential diagnoses. CASE PRESENTATION: A 26-year-old female with a past medical history of embolized inguinal, flank, and retroperitoneal venolymphatic malformation presented with a left pelvic pain causing significant disability. CT scan showed an extensive 8.7 cm × 6.6 cm retroperitoneal mass. FNA was performed and alcohol-fixed papanicolaou-stained smears showed a hypocellular specimen with loosely arranged clusters of bland spindle cell proliferation in the background of a mucoid matrix. Spindle cells showed scant cytoplasm and elongated oval-shaped regular nuclei. Prominent nucleoli were not seen. An excisional biopsy revealed a bland spindle cell proliferation in a myxoid background associated with shredded collagen bundles. Immunohistochemical staining showed diffuse positivity for S100 and CD34. Based on the overall findings, a definitive diagnosis of myxoid neurofibroma was rendered. DISCUSSION: Cytological features of myxoid neurofibroma include the presence of hypocellular spindle-shaped cells arranged in small, loosely organized groups within a myxoid matrix background. Cells exhibit scant cytoplasm with regular oval and elongated nuclei. Nucleoli are typically not identified. The differential diagnosis includes myxoid neurofibroma, myxoma, myxoid liposarcoma, myxoid chondrosarcoma, myxoid dermatofibrosarcoma protuberans, low-grade fibromyxoid sarcoma, and low-grade myxo-fibrosarcoma. CONCLUSION: We aim to highlight the importance of considering myxoid neurofibroma in the differential diagnosis of hypocellular myxoid spindle cell lesions encountered on fine-needle aspiration cytology.

The Regulatory Network of CREB3L1 and Its Roles in Physiological and Pathological Conditions.

CREB3 subfamily belongs to the bZIP transcription factor family and comprises five members. Normally they are located on the endoplasmic reticulum (ER) membranes and proteolytically activated through RIP (regulated intramembrane proteolysis) on Golgi apparatus to liberate the N-terminus to serve as transcription factors. CREB3L1 acting as one of them transcriptionally regulates the expressions of target genes and exhibits distinct functions from the other members of CREB3 family in eukaryotes. Physiologically, CREB3L1 involves in the regulation of bone morphogenesis, neurogenesis, neuroendocrine, secretory cell differentiation, and angiogenesis. Pathologically, CREB3L1 implicates in the modulation of osteogenesis imperfecta, low grade fibro myxoid sarcoma (LGFMS), sclerosing epithelioid fibrosarcoma (SEF), glioma, breast cancer, thyroid cancer, and tissue fibrosis. This review summarizes the upstream and downstream regulatory network of CREB3L1 and thoroughly presents our current understanding of CREB3L1 research progress in both physiological and pathological conditions with special focus on the novel findings of CREB3L1 in cancers.

Sclerosing Epithelioid Fibrosarcoma.

Sclerosing epithelioid fibrosarcoma (SEF) is a distinctive sarcoma that may arise in nearly any soft tissue site or bone. While there has been past controversy as to whether it is related to low-grade fibromyxoid sarcoma (LGFMS), it has been shown to behave far more aggressively than LGFMS. SEF has a propensity to metastasize to the lungs and bone and arise within the abdominal cavity. Histologically, it is characterized by uniform nuclei embedded in a densely collagenous stroma simulating osteoid. By immunohistochemistry, it is often strongly positive for MUC4. The majority (75%) have EWSR1 gene rearrangement, most commonly with CREB3L1 as a fusion partner, although a variety of FUS/EWSR1 and CREB3L1/CREB3L2/CREB3L3 fusions have been described in addition to others. SEF is currently recalcitrant to nearly all chemotherapy and radiation therapy.

Myxoinflammatory Fibroblastic Sarcoma.

MIFS is a low-grade fibroblastic sarcoma that predilects to superficial distal extremity soft tissue. It is composed of plump spindled and epithelioid cells, inflammatory infiltrates, and mucin deposits in a fibrosclerotic stroma. Large epithelioid cells harboring bizarre nuclei and virocyte-like macronucleoli and pleomorphic pseudolipoblasts are characteristic. While conventional MIFS has locally recurrent potential but minimal metastatic risk, tumors with high-grade histologic features have a greater risk for recurrence and metastasis. Wide local excision is the recommended treatment.

Myxoinflammatory fibroblastic sarcoma: ultrastructural study of 7 cases.

Since first described, several studies about Myxoinflammatory fibroblastic sarcomas (MIFS) have been published stating the clinicopathological, morphological and immunohistochemical features. However, the ultrastructural findings of these MIFS are limited. Thus, the objective of the present paper is to describe the ultrastructural characteristics of these type of tumors by utilizing tissue that was embedded in paraffin and submitted for immunohistochemistry.The tissue of seven different cases was obtained for ultrastructural study with automatized staining devices, that were later observed by using transmission electron microscopy. Histologically all cases displayed conventional structures of Myxoinflammatory fibroblastic sarcoma (Reed-Sternberg like cells, pseudolipoblasts and emperipolesis). Conversely, two of them exhibited high-grade components, one rich in osteoclastic type giant cells and hypercellular areas, and another one rich in inflammation (Hodgkin-like).After immunohistochemistry, all the samples revealed positivity for CD68 with six cases CD163 and five being positive to CD34, Cyclin-D1, and D2-40. Ultrastructural findings indicated rough endoplasmic reticulum with dilatation of the cisterns that indented the nuclei ("soccer ball" cells), abundant lysosomes, phagolysosomes, and intermediate filaments evidencing this entity as a morphologic continuum that exhibited modified fibroblastic phenotype and variable proportion of macrophagic differentiation.

A novel patient-derived immortalised cell line of myxofibrosarcoma: a tool for preclinical drugs testing and the generation of near-patient models.

BACKGROUND: Myxofibrosarcoma is a rare malignant soft tissue sarcoma characterised by multiple local recurrence and can become of higher grade with each recurrence. Consequently, myxofibrosarcoma represents a burden for patients, a challenge for clinicians, and an interesting disease to study tumour progression. Currently, few myxofibrosarcoma preclinical models are available. METHODS: In this paper, we present a spontaneously immortalised myxofibrosarcoma patient-derived cell line (MF-R 3). We performed phenotypic characterization through multiple biological assays and analyses: proliferation, clonogenic potential, anchorage-independent growth and colony formation, migration, invasion, AgNOR staining, and ultrastructural evaluation. RESULTS: MF-R 3 cells match morphologic and phenotypic characteristics of the original tumour as 2D cultures, 3D aggregates, and on the chorioallantoic membrane of chick embryos. Overall results show a clear neoplastic potential of this cell line. Finally, we tested MF-R 3 sensitivity to anthracyclines in 2D and 3D conditions finding a good response to these drugs. CONCLUSIONS: In conclusion, we established a novel patient-derived myxofibrosarcoma cell line that, together with the few others available, could serve as an important model for studying the molecular pathogenesis of myxofibrosarcoma and for testing new drugs and therapeutic strategies in diverse experimental settings.

Myxofibrosarcoma involving brachial plexus diagnoses by contrast-enhanced ultrasound: A case report.

RATIONALE: Myxofibrosarcoma most commonly arises as a slowly enlarging, painless mass. We describe an unusual case of low-grade myxofibrosarcoma in the axillary fossa, which infiltrated the brachial plexus, axillary artery, and axillary vein, causing severe pain. The low incidence and complex anatomical structure make imaging examination and surgery face great challenges. To the best of our knowledge, such presentation of a low-grade myxofibrosarcoma that showed an extreme infiltrative growth pattern and presented severe pain has not been reported before. PATIENT CONCERNS: We reported a case of low-grade myxofibrosarcoma developed around the axillary neurovascular bundle, with multiple peripheral metastases in an 87-year-old male. Physical examination revealed a mass on the right axillary fossa measuring 5 × 4 cm. The patient underwent computed tomography but no definite diagnosis was obtained. Because he had claustrophobia and could not perform MRI examination. Thus, he underwent conventional ultrasound and contrast-enhanced ultrasound. Ultrasonic examination not only accurately determines the invasion scope of the tumor, but also clearly shows that the nerve has suffered from the invasion of the exogenous tumor and multiple metastatic foci around it. The contrast enhancement mode of the tumor showed centripetal high-enhancement, uneven internal enhancement, visible enhanced bridge, and non-enhancing central area. DIAGNOSES: Combined with the results of conventional ultrasound and contrast-enhanced ultrasound, we highly suspected it to be soft tissue sarcoma, giving strong clinical assistance. INTERVENTIONS: Given the risk of sarcoma implantation along the needle track and the underestimation of tumor malignancy, an excisional biopsy was considered the most practical choice to avoid unnecessary pain and potential implantation. OUTCOMES: The patient underwent surgery and a histopathological examination of the lesion confirmed it as low-grade myxofibrosarcoma. LESSONS SUBSECTIONS: This report describes a rare case of myxofibrosarcoma of the axillary fossa. High-resolution ultrasound is increasingly used for the initial assessment of soft-tissue masses. However, there are few reports about the ultrasound and contrast-enhanced ultrasound examinations of myxofibrosarcoma. Accurate preoperative diagnosis and proper treatment strategies are critical in managing patients with myxofibrosarcoma. Our case may provide diagnosis experiences and will help better understand and treat this disease.

Primary cardiac myxofibrosarcoma of the left atrium and pericardium: a case report.

BACKGROUND: Primary cardiac myxofibrosarcoma is rare and commonly occurs in the left atrium. Myxofibrosarcoma is aggressive and has a high mortality rate due to its high rate of recurrence. Complete surgical resection is considered important; however, effective treatment options have not been established. CASE PRESENTATION: We report the case of a 75-year-old woman who developed a myxofibrosarcoma spreading to the left atrium and pericardium. We performed surgical resection of the tumor to prevent sudden death due to mitral valve obstruction or cerebral infarction due to embolism of the scattered mass. However, we were unable to complete the resection of the tumors. The patient developed brain metastasis 2 months after surgery and eventually died due to brain hemorrhage 3 months after surgery. CONCLUSIONS: In this report, we described a rare case of primary cardiac myxofibrosarcoma located not only in the left atrium but also in the pericardium. Considering preoperative laboratory findings, surgical and adjuvant therapy, and the patient's wishes are important for the best therapeutic course for an individual.

Rhabdomyosarcoma or Fibrosarcoma? A Case of Large Ulcerated and Necrotic Lesion on the Forearm of a Newborn.

Congenital infantile fibrosarcoma (CIFS) is a rare malignant soft tissue tumor. The incidence of fibrosarcoma is estimated to be 0.3 per 100 000 population per year, and it accounts for less than 1% of all soft tissue sarcomas. We present a case of a 7-day-old newborn with a large ulcerated and necrotic lesion on the left forearm, which was initially misdiagnosed as rhabdomyosarcoma. Magnetic resonance imaging (MRI) revealed a soft tissue mass with cystic components affecting the forearm and distal humerus muscles. Fine-needle biopsy was performed and initially diagnosed as rhabdomyosarcoma but later confirmed as low-grade fibrosarcoma with positive immunostaining for vimentin. The patient underwent a transhumeral amputation with follow-up chemotherapy at a specialized oncology center. This case underscores the importance of interdisciplinary collaboration and specialized care in managing complex medical conditions in infants. Early detection and appropriate management of these tumors are essential for improving outcomes and reducing morbidity and mortality. Despite the rarity of this case, it serves as a reminder of the importance of considering neoplastic lesions in the differential diagnosis of soft tissue masses in newborns.

Therapeutic strategies and clinical evolution of patients with infantile fibrosarcoma: a unique paediatric case series

Background Infantile fibrosarcoma is the most frequent soft tissue sarcoma in newborns or children under one year of age. This tumour often implies high local aggressiveness and surgical morbidity. The large majority of these patients carry the ETV6–NTRK3 oncogenic fusion. Hence, the TRK inhibitor larotrectinib emerged as an efficacious and safe alternative to chemotherapy for NTRK fusion-positive and metastatic or unresectable tumours. However, real-world evidence is still required for updating soft-tissue sarcoma practice guidelines. Objective To report our experience with the use of larotrectinib in pediatric patients. Methods Our case series shows the clinical evolution of 8 patients with infantile fibrosarcoma under different treatments. All patients enrolled in this study received informed consent for any treatment. Results Three patients received larotrectinib in first line. No surgery was needed with larotrectinib, which led to the rapid and safe remission of tumours, even in unusual anatomical locations. No significant adverse effects were observed with larotrectinib. Conclusion Our case series supports that larotrectinib may be a therapeutic option for newborn and infant patients with infantile fibrosarcoma, especially in uncommon locations (AU)

Heart Transplantation as a Treatment Option for Recurrent Myxofibrosarcoma: A Clinical Case.

Myxofibrosarcoma is one of the most rare tumors of the heart. Surgical resection is the principal method of treatment; however, in some cases, radical removal of the tumor is not possible. Here, we present a case of heart transplant in a patient who experienced recurrent myxofibrosarcoma of the left atrium and examine the morphological features of this tumor. A 40-year-old female patient presented for treatment for heart failure of a high functional class. An examination revealed a tumor in the left atrial cavity, which was subsequently surgically removed. Morphological examination revealed an inflammatory myofibroblastic tumor. After 2 years, the patient's tumor recurred. The tumor was removed, and a morphological study again diagnosed myxofibrosarcoma of the heart. A year later, recurrence was again diagnosed. Instrumental examination determined that the tumor had incurred into the mitral valve and possibly spread to the myocardium. Tumor resection was not possible, and the need to perform a heart transplant was determined. The given case contributes to the practical conclusion that heart transplant contributes to an increase in the life expectancy for patients with inoperable cases of cardiac sarcoma.

KMT2A-rearranged sarcoma with unusual fusion gene CBX6::KMT2A::PYGO1.

Recently, rare sarcomas harboring KMT2A rearrangements have been reported. They occur in relatively young individuals, exhibit a sclerosing epithelioid fibrosarcoma-like morphology, and often have an aggressive prognosis. YAP1::KMT2A::YAP1 is the most common fusion gene, followed by VIM::KMT2A. We report the case of a 47-year-old man with a spindle cell tumor arising from the subcutaneous tissue of the right anterior chest. The tumor harbored an unusual novel fusion gene, CBX6::KMT2A::PYGO1. Histologically, the tumor consisted of proliferating spindle-shaped cells with uniform nuclei, which varied in cell density and the amount of intervening collagen fibers. After 2 years and 8 months without postoperative treatment, the patient showed no recurrence or metastasis. Although highly likely irreproducible, tumors with the CBX6::KMT2A::PYGO1 fusion gene were morphologically somewhat different from those containing the YAP1::KMT2A::YAP1. This suggests that KMT2A rearrangements with fusion gene partners different from YAP1 result in purely spindle-shaped cell tumors that produce collagen fibers.

Myxofibrosarcoma in adolescents and young adults: a clinicopathologic study of 17 cases.

Myxofibrosarcoma is a locally aggressive sarcoma that characteristically arises in the extremities of older patients. Cases arising at a younger age are rare, leading to diagnostic challenges. Our aim was to study the clinicopathologic features of myxofibrosarcoma in patients aged ≤40 years. Cases of myxofibrosarcoma and myxoid malignant fibrous histiocytoma arising in patients aged ≤40 years with clinical follow-up were collected from multiple institutions. Hematoxylin and eosin slides were evaluated for mitoses, necrosis, and epithelioid areas. Seventeen cases were identified (13 females, 4 males; 16-39 years; median 32 years), tumors ranged from 2.2 to 34 cm (median 4.1 cm). Anatomic sites included proximal extremity (9), distal extremity (4), trunk (1), and head/neck (3). Ten were superficial, and 6 were deep-seated. Three cases were predominantly epithelioid. In untreated resection specimens, 6 were FNCLCC grade 1, 4 grade 2, and 2 grade 3. Follow-up (6-204 months, median 36 months) revealed that 2 patients experienced local recurrences, 1 distant metastasis, and 2 patients both. The 5-year overall survival (OS) and event-free survival (EFS) were 84% and 55.9%, respectively. Tumor depth and necrosis were correlated with inferior OS (P = .025, P = .005), while tumor depth was also associated with worse EFS (P = <.001). We conclude that myxofibrosarcomas arising in adolescents and young adults show similar behavior compared to their older adult counterparts. Tumor depth and necrosis are poor prognostic factors in myxofibrosarcoma in this age group. Awareness that myxofibrosarcoma can rarely present in this population is important for accurate diagnosis.

PAK1 overexpression promotes myxofibrosarcoma angiogenesis through STAT5B-mediated CSF2 transactivation: clinical and therapeutic relevance of amplification and nuclear entry.

Myxofibrosarcoma is genetically complex without established nonsurgical therapies. In public datasets, PAK1 was recurrently gained with mRNA upregulation. Using myxofibrosarcoma cells, we explored the oncogenic underpinning of PAK1 with genetic manipulation and a pan-PAK inhibitor (PF3758309). Myxofibrosarcoma specimens were analyzed for the levels of PAK1, phospho-PAKT423, CSF2 and microvascular density (MVD) and those of PAK1 gene and mRNA. PAK1-expressing xenografts were assessed for the effects of PF3758309 and CSF2 silencing. Besides pro-proliferative and pro-migrator/pro-invasive attributes, PAK1 strongly enhanced angiogenesis in vitro, which, not phenocopied by PAK2-4, was identified as CSF2-mediated using antibody arrays. PAK1 underwent phosphorylation at tyrosines153,201,285 and threonine423 to facilitate nuclear entry, whereby nuclear PAK1 bound STAT5B to co-transactivate the CSF2 promoter, increasing CSF2 secretion needed for angiogenesis. Angiogenesis driven by PAK1-upregulated CSF2 was negated by CSF2 silencing, anti-CSF2, and PF3758309. Clinically, overexpressed whole-cell phospho-PAKT423, related to PAK1 amplification, was associated with increased grades, stages, and PAK1 mRNA, higher MVD, and CSF2 overexpression. Overexpressed whole-cell phospho-PAKT423 and CSF2 independently portended shorter metastasis-free survival and disease-specific survival, respectively. In vivo, both CSF2 silencing and PF3758309 suppressed PAK1-driven tumor proliferation and angiogenesis. Conclusively, the nuclear entry of overexpressed/activated PAK1 endows myxofibrosarcomas with pro-angiogenic function, highlighting the vulnerable PAK1/STAT5B/CSF2 regulatory axis.

Low-Grade Myofibroblastic Sarcoma of the Oral and Maxillofacial Region: An International Clinicopathologic Study of 13 Cases and Literature Review.

Low-grade myofibroblastic sarcoma (LGMS) represents an atypical tumor composed of myofibroblasts with a variety of histological patterns and with a high tendency to local recurrence and a low probability of distant metastases. LGMS has predilection for the head and neck regions, especially the oral cavity. This study aimed to report 13 new cases of LGMS arising in the oral and maxillofacial region. This study included LGMS cases from five oral and maxillofacial pathology laboratories in four different countries (Brazil, Peru, Guatemala, and South Africa). Their clinical, radiographic, histopathological, and immunohistochemical findings were evaluated. In this current international case series, most patients were females with a mean age of 38.7 years, and commonly presenting a nodular lesion in maxilla. Microscopically, all cases showed a neoplasm formed by oval to spindle cells in a fibrous stroma with myxoid and dense areas, some atypical mitoses, and prominent nucleoli. The immunohistochemical panel showed positivity for smooth muscle actin (12 of 13 cases), HHF35 (2 of 4 cases), ß-catenin (3 of 5 cases), desmin (3 of 11 cases), and Ki-67 (range from 5 to 50%). H-caldesmon was negative for all cases. The diagnosis of LGMS was confirmed in all cases. LGMS shows predominance in young adults, with a slight predilection for the female sex, and maxillary region. LGMS should be a differential diagnosis of myofibroblastic lesions that show a proliferation of spindle cells in a fibrous stroma with myxoid and dense areas and some atypical mitoses, supporting the diagnosis with a complementary immunohistochemical study. Complete surgical excision with clear margins is the treatment of choice. However, long-term follow-up information is required before definitive conclusions can be drawn regarding the incidence of recurrence and the possibility of metastasis.