Leiomyoadenomatoid Tumor of Epididymis: A Variant of Adenomatoid Tumor.

Adenomatoid tumor is a rare tumor of mesothelial origin, usually arising in the epididymis. It is the most common paratesticular tumor of middle-aged men. A rare variant of adenomatoid tumor is leiomyoadenomatoid tumor which is characterized by prominent spindle cell myoblastic and myofibroblastic proliferation in the background of an adenomatoid tumor with tubular spaces lined by mesothelial cells. In some cases, the spindle cell component obscures the adenomatoid tumor component, complicating accurate diagnosis. Here, we report two cases of paratesticular leiomyoadenomatoid tumor in 28-year-old and 50-year-old patients. The tumors from both cases were centered in the epididymis and measured 1.0 cm and 3.0 cm, respectively. Both had similar morphology with myofibroblastic proliferation in one case and myoblastic (smooth muscle) proliferation in the other. Both cases followed a benign course without local recurrence or distant metastasis for 14 and 22 months postoperatively, respectively. We propose the use of the term "adenomyomatoid tumor" to describe a neoplasm exhibiting adenomatoid tumor admixed with either leiomyomatous or myofibroblastic proliferation.

AXL Inhibition Enhances MEK Inhibitor Sensitivity in Malignant Peripheral Nerve Sheath Tumors.

Dysregulation of the receptor tyrosine kinase AXL is known to promote cancer cell growth and survival in many sarcomas, including the rare subtype, malignant peripheral nerve sheath tumors (MPNST). MPNSTs are largely chemoresistant and carry a poor prognosis. AXL is an attractive potential therapeutic target, as it is aberrantly expressed, and its activation may be an early event in MPNST. However, the effect of AXL inhibition on MPNST development and progression is not known. Here, we investigated the role of AXL in MPNST development and the effects of AXL and MEK1/2 co-inhibition on MPNSTs. We used western blotting to examine AXL expression and activation in MPNST cell lines. We analyzed the effects of exogenous growth arrest-specific 6 (GAS6) expression on downstream signaling and the proliferation, migration, and invasion of MPNST cells. The effect of AXL knockdown with or without mitogen-activated protein kinase (MAPK) inhibition on downstream signal transduction and tumorigenesis was also examined in vivo and in vitro. We found that AXL knockdown increased MAPK pathway signaling. This compensation, in turn, abrogated the antitumorigenic effects linked to AXL knockdown in vivo. AXL knockdown, combined with pharmacological MEK inhibition, reduced the proliferation and increased the apoptosis of MPNST cells both in vitro and in vivo. The pharmacological co-inhibition of AXL and MEK1/2 reduced MPNST volumes. Together these findings suggest that AXL inhibition enhances the sensitivity of MPNST to other small molecule inhibitors. We conclude that combination therapy with AXL inhibitor may be a therapeutic option for MPNST.

Dermal Hemorrhage: A Clue to Lichen Sclerosus et Atrophicus.

Lichen sclerosus et atrophicus (LSA) may present in a rare bullous and hemorrhagic form that is often difficult to recognize both clinically and histopathologically. Clinically, the lesions may be characterized by atrophic and ivory-white sclerotic plaques in both genital and extragenital regions. Histologically, fully developed lesions of LSA are characterized by a thinned, effaced epidermis with interface change, a wide band of hyalinization in the upper dermis, and a lymphohistiocytic infiltrate below the hyalinized area. Extensive vacuolar degeneration weakens the integrity of the dermoepidermal junction, which contributes to the development of marked edema in the papillary dermis and subepidermal vesiculation. With increased fragility of dermal capillaries, hemorrhage can accumulate within the bullae. Recognizing prominent upper dermal hemorrhage as a secondary change may lead to a prompt diagnosis of LSA. We present a case of extragenital LSA that mimics a dermal hemorrhage clinically and histologically in a 71-year-old Caucasian woman.

Cardiac paragangliomas: A case series with clinicopathologic features and succinate dehydrogenase B immunostaining.

Cardiac paragangliomas (PGs) are very rare tumors that comprise less than 1% of all cardiac tumors. PGs can occur sporadically, but inherited syndromes may also play a role in the development of PGs. Approximately one-third of PGs are associated with mutations in the succinate dehydrogenase (SDH) complex, specifically SDHB, as part of syndrome-associated PGs or sporadic PGs. SDH mutations have been assessed by SDHB immunohistochemistry, as negative staining indicates a high likelihood of mutation in PGs in other sites, but not in cardiac PGs. This study aims to evaluate the clinical and pathologic characteristic of cardiac PG cases and assess the expression of SDHB by immunohistochemistry. A retrospective chart analysis of 10 patients with cardiac PG was performed to assess the patient age, sex, size, site of the tumor, and clinical symptoms. Histologically the tumors showed the classic pattern of nested tumor cells surrounded by sustentacular cells. Immunohistochemistry for SDHB was performed in five cases. One case showed a complete absence of SDHB immunohistochemical staining and the others showed staining ranging from a weak-to-strong granular cytoplasmic staining pattern. We conclude that SDHB immunostaining is cost-effective in identifying cases with SDH mutation. It is recommended to assess SDH mutation in patients with cardiac PG to predict the aggressive behavior that has been reported by previous studies from PGs of other sites.

Clinicopathological variables of sporadic schwannomas of peripheral nerve in 291 patients and expression of biologically relevant markers.

OBJECTIVE While sporadic peripheral schwannomas (SPSs) are generally well treated with surgery, their biology is not well understood. Consequently, treatment options are limited. The aim of this study was to provide a comprehensive description of SPS. The authors describe clinicopathological features and treatment outcomes of patients harboring these tumors, and they assess expression of biomarkers using a clinically annotated tissue microarray. Together, these data give new insight into the biology and management of SPS. METHODS Patients presenting with a primary SPS between 1993 and 2011 (n = 291) were selected from an institutional registry to construct a clinical database. All patients underwent follow-up, and short- and long-term outcomes were assessed. Expression of relevant biomarkers was assessed using a new tissue microarray (n = 121). RESULTS SPSs were generally large (mean 5.5 cm) and frequently painful at presentation (55%). Most patients were treated with surgery (80%), the majority of whom experienced complete resolution (52%) or improvement (18%) of their symptoms. Tumors that were completely resected (85%) did not recur. Some patients experienced short-term (16%) and long-term (4%) complications postoperatively. Schwannomas expressed higher levels of platelet-derived growth factor receptor-ß (2.1) than malignant peripheral nerve sheath tumors (MPNSTs) (1.5, p = 0.004) and neurofibromas (1.33, p = 0.007). Expression of human epidermal growth factor receptor-2 was greater in SPSs (0.91) than in MPNSTs (0.33, p = 0.002) and neurofibromas (0.33, p = 0.026). Epidermal growth factor receptor was expressed in far fewer SPS cells (10%) than in MPNSTs (58%, p < 0.0001) or neurofibromas (37%, p = 0.007). SPSs more frequently expressed cytoplasmic survivin (66% of tumor cells) than normal nerve (46% of cells), but SPS expressed nuclear survivin in fewer tumor cells than in MPNSTs (24% and 50%, respectively; p = 0.018). CONCLUSIONS Complete resection is curative for SPS. Left untreated, however, these tumors can cause significant morbidity, and not all patients are candidates for resection. SPSs express a pattern of biomarkers consistent with the dysregulation of the tumor suppressor merlin observed in neurofibromatosis Type 2-associated schwannomas, suggesting a shared etiology. This SPS pattern is distinct from that of other tumors of the peripheral nerve sheath.

Patterns of recurrence and survival in sporadic, neurofibromatosis Type 1-associated, and radiation-associated malignant peripheral nerve sheath tumors.

OBJECTIVE Malignant peripheral nerve sheath tumors (MPNSTs) are an aggressive group of soft tissue sarcomas that can arise sporadically, in the context of neurofibromatosis Type 1 (NF1) or at a site of prior irradiation. Large series profiling the features and outcomes of sporadic, NF1-associated, and radiation-associated MPNSTs are limited. The goal of this study was to elucidate differences between MPNST etiologies in a large single-institution retrospective study. METHODS Patients (n = 317) were identified through the tumor registry of The University of Texas MD Anderson Cancer Center. Clinicopathological features were retrospectively collected. Features were compared among MPNST subtypes for patients who had sufficient clinical history (n = 289), and clinicopathological features were used to identify adverse predictors of recurrence and survival outcomes. RESULTS Five-year local recurrence-free survival (LRFS), distant recurrence-free survival (DRFS), and disease-specific survival (DSS) estimates were 56.6%, 49.6%, and 53.6%, respectively, for the high-grade MPNST cohort. Five-year DSS was lower in NF1-associated and radiation-associated MPNST than in sporadic MPNST (52%, 47%, and 67%, respectively, p = 0.140). Patients with radiation-associated MPNST had worse 5-year LRFS than those with the sporadic and NF1-associated subtypes (RT-associated vs sporadic, p = 0.010; RT-associated vs NF1-associated, p = 0.232). Truncally located tumors, positive surgical margins, local recurrence, and metastasis were predictors of adverse DSS in multivariate analysis. CONCLUSIONS Radiation-associated MPNSTs are associated with poorer local recurrence-free and disease-specific survival than sporadic and NF1-associated tumors. NF1-associated MPNSTs may have worse survival outcomes owing to large tumor size, compromising truncal location, and lower rate of negative resection margins compared with sporadic tumors.

An isolated inflammatory myofibroblastic tumor of adrenal gland.

Inflammatory myofibroblastic tumor (IMT) is an uncommon lesion that shows a wide range of anatomic distribution. The adrenal gland, however, is a distinctly rare site of occurrence. To date, only a few cases of IMT arising in the adrenal gland have been reported in the English literature. Here, we report another case of isolated adrenal IMT. A 34-year-old man presented to the emergency department with a complaint of a sudden severe right-sided back pain. Subsequent computed tomographic scan imaging studies demonstrated a large right adrenal mass associated with a hematoma. The right adrenal gland was resected. Microscopic examination revealed an encapsulated cellular spindle cell proliferation with a prominent inflammatory infiltrate. Immunohistochemically, those spindle cells were diffusely and strongly positive for anaplastic lymphoma kinase-1, and focally and weakly positive for smooth muscle actin. S-100 protein and cytokeratin were negative. The findings were consistent with IMT arising from the adrenal gland. Although IMTs in the adrenal gland are rare, they should be considered in the differential diagnosis of adrenal masses. The clinical behavior of IMTs in general is currently indeterminate and a close clinical follow-up is recommended. The behavior of adrenal IMTs remains uncertain because of rare reported cases and lack of long-term follow-up. Further follow-up of reported cases and recognition of additional new cases is warranted to unmask the true biological behavior of adrenal IMTs.

Sarcoma Brain Metastases: 28 Years of Experience at a Single Institution.

BACKGROUND: Brain metastasis from sarcoma is rare, thus limited information is available. We examined sarcoma brain metastases diagnosed at our institution over a period of 28 years. METHODS: This is a retrospective study of 112 cases. Clinical records were reviewed and clinical, pathological, and survival data were tabulated. RESULTS: Undifferentiated sarcoma was the most common source. In 50 % of cases, the primary sarcoma was in the extremities. Most patients were adults at the time of first brain metastasis, and median age was 34.8 years. Although most patients evidenced metastatic disease to other sites prior to developing brain metastasis, in almost one quarter, brain was the initial site. Most of the metastatic foci were parenchymal, nonhemorrhagic, and solitary. Forty percent of the brain metastatic deposits were located in the frontal lobes. Thirty-one percent recurred-all within 5.3 years. Seventy-six percent of patients succumbed to the disease, with a median survival time of only 0.6 years. Hemorrhagic metastatic foci were found to be associated with significantly lower recurrence-free, as well as disease-specific survivals. No difference in survival was noted between single versus multiple deposits or primary soft tissue versus bone sarcomas. No statistically significant effect on survival was found when neurosurgical resection was combined with radiotherapy. Chemotherapy, on the other hand, was found to significantly improve disease-specific survival when combined with metastasectomy. CONCLUSIONS: Undifferentiated sarcoma was the most common source of brain metastasis. Most cases showed evidence of prior metastatic disease. Surgical resection is employed to manage symptoms, but prognosis remains dismal.

Analysis of Clinical and Molecular Factors Impacting Oncologic Outcomes in Undifferentiated Pleomorphic Sarcoma.

BACKGROUND: Undifferentiated pleomorphic sarcomas (UPS) present a diagnostic and therapeutic challenge. Identification of prognostic molecular markers is required for the discovery of novel treatment approaches. The purpose of this study was to correlate clinicopathologic variables, expression of tyrosine kinase receptors, and markers of cell cycle progression and survival with oncologic outcomes. METHODS: A tissue microarray containing 208 primary UPS samples was analyzed by immunohistochemistry for protein markers and in situ hybridization for microRNA. Staining results were correlated with clinicopathologic features and oncologic outcomes. Univariate and multivariate analyses were conducted to assess associations between expression of protein markers, mi-RNA, and outcome. RESULTS: At a median follow-up of 3.9 years (9 years for survivors), 5-year disease-specific survival (DSS) was 63 %. Clinical variables associated with improved DSS included age <61 years, tumor size <10 cm, margin-negative resection, and sporadic-tumor status. At the protein level, loss of cyclin D1 (p = 0.06), pEGFR (p = 0.023), pIGF-1R (p = 0.022), and PTEN (p < 0.001) and overexpression of AXL (p = 0.015) were associated with reduced DSS on univariate analysis. Ki67, PCNA, and pEGFR were more highly expressed in sporadic UPS than radiation-associated (RA-UPS), whereas RA-UPS samples expressed higher levels of both phosphorylated and total IGF-1R. DISCUSSION: Loss of cyclin D1, overexpression of AXL, and loss of PTEN are associated with poor cancer-specific outcomes and warrant further investigation in UPS. The differences in protein expression in sporadic versus RA-UPS may indicate that the activated molecular signaling nodes may be different for each specific histology and also could explain the aggressive phenotype seen in RA-UPS compared with the sporadic lesions.

Clinical Observations and Molecular Variables of Primary Vascular Leiomyosarcoma.

IMPORTANCE: Vascular leiomyosarcomas are a rare subtype of leiomyosarcomas that most commonly affect the inferior vena cava and account for 5% of all leiomyosarcomas. These tumors are aggressive malignant tumors for which adjuvant modalities have not shown increased efficacy compared with surgery. OBJECTIVES: To evaluate the outcomes of patients with vascular leiomyosarcoma and the association between vascular leiomyosarcomas and immunohistochemical molecular markers, to determine their potential prognostic and therapeutic utility. DESIGN, SETTING, AND PARTICIPANTS: Retrospective medical record review of a cohort of 77 patients who presented to the University of Texas MD Anderson Cancer Center in Houston during the period from January 1993 to April 2012. Data were analyzed during the period from November 2012 to May 2015. All of the patients received a confirmed diagnosis of vascular leiomyosarcoma. Immunohistochemical studies for biomarkers were performed on a tissue microarray that included 26 primary specimens of vascular leiomyosarcoma. MAIN OUTCOMES AND MEASURES: Demographic and clinical factors were evaluated to assess clinical course, patterns of recurrence, and survival outcomes for patients with primary vascular leiomyosarcoma. A univariate Cox proportional hazards model was used to correlate disease-specific survival and time to recurrence with potential prognostic indicators. RESULTS: Sixty-three patients with localized disease who underwent surgical resection formed the study population, and their data were used for subsequent outcomes analysis. The median age at diagnosis was 58 years (range, 22-78 years). The majority of patients were female (41 patients [65%]) and white (51 patients [81%]). The 5-year disease-specific survival rate after tumor resection was 65%. The median time to local recurrence was 43 months, the median time to distant recurrence was 25 months, and the median time to concurrent local and distant recurrences was 15 months (P = .04). Strong expressions of cytoplasmic ß-catenin (hazard ratio, 5.33 [95% CI, 0.97-29.30]; P = .06) and insulinlike growth factor 1 receptor (hazard ratio, 2.74 [95% CI, 1.14-6.56]; P = .02) were associated with inferior disease-specific survival. CONCLUSIONS AND RELEVANCE: Vascular leiomyosarcomas are aggressive malignant tumors, with high recurrence rates. Expressions of ß-catenin and insulinlike growth factor 1 receptor were associated with poor disease-specific survival. Prospective studies should evaluate the clinical and therapeutic utility of these molecular markers.

Poly (ADP) ribose polymerase inhibition: A potential treatment of malignant peripheral nerve sheath tumor.

Poly (ADP) ribose polymerase (PARP) inhibitors, first evaluated nearly a decade ago, are primarily used in malignancies with known defects in DNA repair genes, such as alterations in breast cancer, early onset 1/2 (BRCA1/2). While no specific mutations in BRCA1/2 have been reported in malignant peripheral nerve sheath tumors (MPNSTs), MPNST cells could be effectively targeted with a PARP inhibitor to drive cells to synthetic lethality due to their complex karyotype and high level of inherent genomic instability. In this study, we assessed the expression levels of PARP1 and PARP2 in MPNST patient tumor samples and correlated these findings with overall survival. We also determined the level of PARP activity in MPNST cell lines. In addition, we evaluated the efficacy of the PARP inhibitor AZD2281 (Olaparib) in MPNST cell lines. We observed decreased MPNST cell proliferation and enhanced apoptosis in vitro at doses similar to, or less than, the doses used in cell lines with established defective DNA repair genes. Furthermore, AZD2281 significantly reduced local growth of MPNST xenografts, decreased the development of macroscopic lung metastases, and increased survival of mice with metastatic disease. Our results suggest that AZD2281 could be an effective therapeutic option in MPNST and should be further investigated for its potential clinical use in this malignancy.

AXL is a potential therapeutic target in dedifferentiated and pleomorphic liposarcomas.

BACKGROUND: AXL is a well-characterized, protumorigenic receptor tyrosine kinase that is highly expressed and activated in numerous human carcinomas and sarcomas, including aggressive subtypes of liposarcoma. However, the role of AXL in the pathogenesis of well-differentiated (WDLPS), dedifferentiated (DDLPS), and pleomorphic liposarcoma (PLS) has not yet been determined. METHODS: Immunohistochemical analysis of AXL expression was conducted on two tissue microarrays containing patient WDLPS, DDLPS, and PLS samples. A panel of DDLPS and PLS cell lines were interrogated via western blot for AXL expression and activity and by ELISA for growth arrest-specific 6 (GAS6) production. AXL knockdown was achieved by siRNA or shRNA. The effects of AXL knockdown on cell proliferation, migration, and invasion were measured in vitro. In addition, AXL shRNA-containing DDLPS cells were assessed for their tumor-forming capacity in vivo. RESULTS: In this study, we determined that AXL is expressed in a subset of WDLPS, DDLPS, and PLS patient tumor samples. In addition, AXL and its ligand GAS6 are expressed in a panel of DDLPS and PLS cell lines. We show that the in vitro activation of AXL via stimulation with exogenous GAS6 resulted in a significant increase in cell proliferation, migration, and invasion in DDLPS and PLS cell lines. Transient knockdown of AXL resulted in attenuation of these protumorigenic phenotypes in vitro. Stable AXL knockdown not only decreased migratory and invasive characteristics of DDLPS and PLS cells in vitro but also significantly diminished tumorigenicity of two dedifferentiated liposarcoma xenograft models in vivo. CONCLUSIONS: Our results suggest that AXL signaling contributes to the aggressiveness of DDLPS and PLS, and that AXL is therefore a potential therapeutic target for treatment of these rare, yet devastating tumors.

Targeting the Notch pathway: A potential therapeutic approach for desmoid tumors.

BACKGROUND: Desmoid tumors (DTs) are rare mesenchymal lesions that can recur repeatedly. When it is feasible, DTs are surgically resected; however, this often results in high recurrence rates. Recently, treatment with PF-03084014, a potent γ-secretase inhibitor, has been shown to have antitumor activity in several tumor types by affecting the WNT/ß-catenin pathway. Consequently, Notch pathway inhibition by PF-03084014 might be a promising approach for DT treatment. METHODS: The expression of Notch pathway components was analyzed in DT tissues and cell strains with immunohistochemistry and Western blotting, respectively. A panel of DT cell strains was exposed to PF-03084014 and evaluated for cell proliferation. Antitumor effects were assessed via cell cycle, apoptosis, and migration and invasion analysis. Cells treated with PF-03084014 were characterized with a gene array analysis combined with Ingenuity Pathway Analysis. RESULTS: The results showed that Notch pathway components were expressed at different levels in DTs. Hes1 (Hes Family BHLH Transcription Factor 1) was overexpressed in DT tumors versus dermal scar tissue, and PF-03084014 caused significant decreases in Notch intracellular domain and Hes1 expression in DT cell strains. PF-03084014 decreased DT cell migration and invasion and also caused cell growth inhibition in DT cell strains, most likely through cell cycle arrest. Gene array analysis combined with Ingenuity Pathway Analysis showed that Wnt1-inducible signaling pathway protein 2 possibly regulated Notch and WNT pathways after treatment with PF-03084014 through integrin. CONCLUSION: Our findings suggest that the Notch pathway is an important DT therapeutic target. Furthermore, PF-03084014 has significant antitumor activity against DTs, and it may be an alternative strategy for DT treatment.

Increased H3K9me3 drives dedifferentiated phenotype via KLF6 repression in liposarcoma.

Liposarcoma (LPS) can be divided into 4 different subtypes, of which well-differentiated LPS (WDLPS) and dedifferentiated LPS (DDLPS) are the most common. WDLPS is typically low grade, whereas DDLPS is high grade, aggressive, and carries a worse prognosis. WDLPS and DDLPS frequently co-occur in patients. However, it is not clear whether DDLPS arises independently from WDLPS, or whether epigenomic alterations underly the histopathological differences of these subtypes. Here, we profiled 9 epigenetic marks in tumor samples from 151 patients with LPS and showed elevated trimethylation of histone H3 at Lys9 (H3K9me3) levels in DDLPS tumors. Integrated ChIP-seq and gene expression analyses of patient-derived cell lines revealed that H3K9me3 mediates differential regulation of genes involved in cellular differentiation and migration. Among these, Kruppel-like factor 6 (KLF6) was reduced in DDLPS, with increased H3K9me3 at associated regulatory regions. Pharmacologic inhibition of H3K9me3 with chaetocin decreased DDLPS proliferation and increased expression of the adipogenesis-associated factors PPARγ, CEBPα, and CEBPß, suggesting that increased H3K9me3 may mediate DDLPS-associated aggressiveness and dedifferentiation properties. KLF6 overexpression partially phenocopied chaetocin treatment in DDLPS cells and induced phenotypic changes that were consistent with adipocytic differentiation, suggesting that the effects of increased H3K9me3 may be mediated through KLF6. In conclusion, we provide evidence of an epigenetic basis for the transition between WDLPS and DDLPS.

The value of ¹8F-FDG PET/CT in the management of malignant peripheral nerve sheath tumors.

PURPOSE: Our objective was to determine how positron emission tomography (PET)/CT had been used in the clinical treatment of malignant peripheral nerve sheath tumor (MPNST) patients at The University of Texas MD Anderson Cancer Center. METHODS: We reviewed a database of MPNST patients referred to MD Anderson Cancer Center during 1995-2011. We enrolled 47 patients who underwent PET/CT imaging. Disease stage was based on conventional imaging and PET/CT findings using National Comprehensive Cancer Network (NCCN) guidelines. Treatment strategies based on PET/CT and conventional imaging were determined by chart review. The maximum and mean standardized uptake values (SUVmax, SUVmean), metabolic tumor volume (MTV), total lesion glycolysis (TLG), change in SUVmax, change in MTV, and change in TLG were calculated from the PET/CT studies before and after treatment. Response prediction was based on imaging studies performed before and after therapy and categorized as positive or negative for residual tumor. Clinical outcome was determined from chart review. RESULTS: PET/CT was performed for staging in 16 patients, for restaging in 29 patients, and for surveillance in 2 patients. Of the patients, 88 % were correctly staged with PET/CT, whereas 75 % were correctly staged with conventional imaging. The sensitivity to detect local recurrence and distant metastasis at restaging was 100 and 100 % for PET/CT compared to 86 and 83 % for conventional imaging, respectively. PET/CT findings resulted in treatment changes in 31 % (5/16) and 14 % (4/29) of patients at staging and restaging, respectively. Recurrence, MTV, and TLG were prognostic factors for survival, whereas SUVmax and SUVmean were not predictive. For 21 patients who had imaging studies performed both before and after treatment, PET/CT was better at predicting outcome (overall survival, progression-free survival) than conventional imaging. A decreasing SUVmax ≥ 30 % and decrease in TLG and MTV were significant predictors for overall and progression-free survival. CONCLUSION: PET/CT is valuable in MPNST management because of its high accuracy in staging and high sensitivity and accuracy in restaging as well as improvements in treatment planning. MTV from baseline staging studies is predictive of survival. Additionally, change in SUVmax, TLG, and MTV accurately predicted outcomes after treatment.

Recurrent PTPRB and PLCG1 mutations in angiosarcoma.

Angiosarcoma is an aggressive malignancy that arises spontaneously or secondarily to ionizing radiation or chronic lymphoedema. Previous work has identified aberrant angiogenesis, including occasional somatic mutations in angiogenesis signaling genes, as a key driver of angiosarcoma. Here we employed whole-genome, whole-exome and targeted sequencing to study the somatic changes underpinning primary and secondary angiosarcoma. We identified recurrent mutations in two genes, PTPRB and PLCG1, which are intimately linked to angiogenesis. The endothelial phosphatase PTPRB, a negative regulator of vascular growth factor tyrosine kinases, harbored predominantly truncating mutations in 10 of 39 tumors (26%). PLCG1, a signal transducer of tyrosine kinases, encoded a recurrent, likely activating p.Arg707Gln missense variant in 3 of 34 cases (9%). Overall, 15 of 39 tumors (38%) harbored at least one driver mutation in angiogenesis signaling genes. Our findings inform and reinforce current therapeutic efforts to target angiogenesis signaling in angiosarcoma.

EZH2-miR-30d-KPNB1 pathway regulates malignant peripheral nerve sheath tumour cell survival and tumourigenesis.

Malignant peripheral nerve sheath tumours (MPNSTs), which develop sporadically or from neurofibromatosis, recur frequently with high metastatic potential and poor outcome. The polycomb group protein enhancer of zeste homologue 2 (EZH2) is an important regulator for various human malignancies. However, the function of EZH2 in MPNSTs is unknown. Here we report that the EZH2-miR-30d-KPNB1 signalling pathway is critical for MPNST tumour cell survival in vitro and tumourigenicity in vivo. Up-regulated EZH2 in MPNST inhibits miR-30d transcription via promoter binding activity, leading to enhanced expression of the nuclear transport receptor KPNB1 that is inhibited by miR-30d targeting of KPNB1 3' UTR region. Furthermore, inhibition of EZH2 or KPNB1, or miR-30d over-expression, induces MPNST cell apoptosis in vitro and suppresses tumourigenesis in vivo. More importantly, forced over-expression of KPNB1 rescues MPNST cell apoptosis induced by EZH2 knockdown. Immunohistochemical analyses show that EZH2 and KPNB1 over-expression is observed in human MPNST specimens and is negatively associated with miR-30d expression. Our findings identify a novel signalling pathway involved in MPNST tumourigenesis, and also suggest that EZH2-miR-30d-KPNB1 signalling represents multiple potential therapeutic targetable nodes for MPNST.