Treatment of De-Differentiated Liposarcoma in the Era of Immunotherapy.

Well-differentiated/de-differentiated liposarcoma (WDLPS/DDLPS) is one of the most common histologic subtypes of soft tissue sarcoma (STS); however, treatment options remain limited. WDLPS and DDLPS both exhibit the characteristic amplification of chromosome region 12q13-15, which contains the genes CDK4 and MDM2. DDLPS exhibits higher amplification ratios of these two and carries additional genomic lesions, including the amplification of chromosome region 1p32 and chromosome region 6q23, which may explain the more aggressive biology of DDLPS. WDLPS does not respond to systemic chemotherapy and is primarily managed with local therapy, including multiple resections and debulking procedures whenever clinically feasible. In contrast, DDLPS can respond to chemotherapy drugs and drug combinations, including doxorubicin (or doxorubicin in combination with ifosfamide), gemcitabine (or gemcitabine in combination with docetaxel), trabectedin, eribulin, and pazopanib. However, the response rate is generally low, and the response duration is usually short. This review highlights the clinical trials with developmental therapeutics that have been completed or are ongoing, including CDK4/6 inhibitors, MDM2 inhibitors, and immune checkpoint inhibitors. This review will also discuss the current landscape in assessing biomarkers for identifying tumors sensitive to immune checkpoint inhibitors.

Deciphering the Prognostic and Therapeutic Significance of Cell Cycle Regulator CENPF: A Potential Biomarker of Prognosis and Immune Microenvironment for Patients with Liposarcoma.

Liposarcoma (LPS) is one of the most common subtypes of sarcoma with a high recurrence rate. CENPF is a regulator of cell cycle, differential expression of which has been shown to be related with various cancers. However, the prognostic value of CENPF in LPS has not been deciphered yet. Using data from TCGA and GEO datasets, the expression difference of CENPF and its effects on the prognosis or immune infiltration of LPS patients were analyzed. As results show, CENPF was significantly upregulated in LPS compared to normal tissues. Survival curves illustrated that high CENPF expression was significantly associated with adverse prognosis. Univariate and multivariate analysis suggested that CENPF expression could be an independent risk factor for LPS. CENPF was closely related to chromosome segregation, microtubule binding and cell cycle. Immune infiltration analysis elucidated a negative correlation between CENPF expression and immune score. In conclusion, CENPF not only could be considered as a potential prognostic biomarker but also a potential malignant indicator of immune infiltration-related survival for LPS. The elevated expression of CENPF reveals an unfavorable prognostic outcome and worse immune score. Thus, therapeutically targeting CENPF combined with immunotherapy might be an attractive strategy for the treatment of LPS.

Three dimensional models of dedifferentiated liposarcoma cell lines: scaffold-based and scaffold-free approaches.

Sarcomas are rare malignancies, the number of reports is limited, and this rarity makes further research difficult even though liposarcoma is one of major sarcomas. 2D cell culture remains an important role in establishing basic tumor biology research, but its various shortcomings and limitations are still of concern, and it is now well-accepted that the behavior of 3D-cultured cells is more reflective of in vivo cellular responses compared to 2D models. This study aimed to establish 3D cell culture of liposarcomas using two different methods: scaffold-based (Matrigel extracellular matrix [ECM] scaffold method) and scaffold-free (Ultra-low attachment [ULA] plate). Lipo246, Lipo224 and Lipo863 cell lines were cultured, and distinctive differences in structures were observed in Matrigel 3D model: Lipo224 and Lipo863 formed spheroids, whereas Lipo246 grew radially without forming spheres. In ULA plate approaches, all cell lines formed spheroids, but Lipo224 and Lipo863 spheroids showed bigger size and looser aggregation than Lipo246. Formalin fixed, paraffin embedded (FFPE) blocks were obtained from all 3D models, confirming the spheroid structures. The expression of MDM2, Ki-67 positivity and MDM2 amplification were confirmed by IHC and DNAscope™, respectively. Protein and DNA were extracted from all samples and MDM2 upregulation was confirmed by western blot and qPCR analysis. After treatment with MDM2 inhibitor SAR405838, DDLPS spheroids demonstrated different sensitivity patterns from 2D models. Taken together, we believed that 3D models would have a possibility to provide us a new predictability of efficacy and toxicity, and considered as one important process in in vitro pre-clinical phase prior to moving forward to clinical trials.

How to treat liposarcomas located in retroperitoneum.

Almost half of retroperitoneal (RP) sarcomas are liposarcomas (LPS). The large majority of RP LPS are either well-differentiated LPS (WDLPS) or dedifferentiated LPS (DDLPS), these latter further classified according to grading in G2 and G3 DDLPS. Surgery is the only potentially curative treatment to achieve local control and possibly cure in primary localized disease. Over the last decade, a better delineation of the different histology-specific patterns of failure and the development of nomograms predictors of outcome has led to a better management of these rare tumors, with a special focus on non-surgical treatments. Available evidences - although far from exhaustive - show that radiation therapy might have a role, if any, as neoadjuvant treatment in locally aggressive histologies (i.e. WDLPS and G2 DDLPS), while it does not seem beneficial for histologies with a higher metastatic risk (i.e. G3 DDLPS and leiomyosarcoma). Neoadjuvant chemotherapy, instead, can be considered to reduce the risk of distant metastasis while waiting for the results of an ongoing RCT (STRASS-2) evaluating its effect in these tumors. However, given the rarity of these diseases and the subsequent lack of strong evidences to guide treatment, outcome improvement in these patients remains a challenge. Patients' referral to a sarcoma center where a dedicated specialized multidisciplinary team tailor optimal treatment on a case-by-case basis is crucial to ensure these patients the best outcome. Refining available nomograms - e.g including molecular variables - and identifying predictors of response/toxicity to chemotherapy and immunotherapy might be significantly helpful in tailoring treatments to the patient's characteristics. Also, new systemic agents are eagerly awaited for improving the management further.

Current molecular and therapeutic advances in liposarcoma, rhabdomyosarcoma, leiomyosarcoma, synovial sarcoma, and angiosarcoma.

Sarcomas probably develop after malignant transformation of embryonic mesenchymal cells and have broad spectrum histopathologically since they can develop from striated skeletal muscle and smooth muscle, fat and fibrous tissue, bone, cartilage and other mesenchymal tissues. The most common histological subtypes of soft tissue sarcoma in adults are: liposarcoma, leiomyosarcoma, poorly differentiated pleomorphic sarcoma, and gastrointestinal stromal tumor. Molecular and genetic studies of soft tissue sarcomas, which are considered as heterogeneous groups in terms of their molecular and clinical characteristics, are still an important area of ​​interest The heterogeneity of the molecular and genetic alterations of these malignancies, which are mostly treated with surgery and chemotherapy, also offers hope to the researchers in terms of treatment targets. In this article, molecular biologic features of the soft tissue sarcomas including liposarcoma, rhabdomyosarcoma, leiomyosarcoma, synovial sarcoma, and angiosarcoma are discussed in the light of recent developments in molecular biology, targeted therapies and immunotherapy.

Pediatric liposarcoma: A case series and literature review.

Liposarcoma is arare soft tissue sarcoma in children. While prognosis, clinical behavior, and response to therapy among the various histologic subtypes are well described in adults, data in children are limited. Here, we describe our experience treating 14 children with liposarcoma at a large, academic pediatric center and review the available pediatric literature. This comprehensive report adds treatment, survival, and genomic data to pediatric liposarcoma literature.

Survival analysis and treatment strategies for limb liposarcoma patients with metastasis at presentation.

ABSTRACT: Limited data exist on patients with limb liposarcoma (LLS) with metastasis at presentation Moreover, the potential prognostic factors of this patient population are poorly documented because of its rarity. Therefore, we conducted this study to evaluate the clinicopathologic characteristics and prognostic factors for patients with metastatic LLS.All patients with LLS with metastasis at presentation from 1975 to 2016 were identified by using the Surveillance, Epidemiology, and End Results (SEER) database. The following clinical data were derived from this clinical database: age, sex, histologic grade, subtype, size of tumor, surgery, radiotherapy, chemotherapy, vital status, cause of death, and survival duration. The Kaplan-Meier method was performed to calculate median survival time and draw survivorship curves. Cox-proportional hazards regression model was used to reveal the statistical independence between various variables.The present study collected 184 cases from SEER database for survival analysis. Mean age was 57.8 years with 63.6% (n = 117) men. The 3-year overall survival (OS) and cancer-specific survival (CSS) rates of this population were 27.8% and 30.1%, respectively. Univariate analysis revealed that age, tumor grade, and surgery were significantly correlated with survival. Sex and tumor size did not reach significant predictor status of survival. Multivariate analysis revealed that age at diagnosis <60, low tumor grade, and local surgery were significantly correlated with improved OS and CSS.Patients with LLS with metastasis at diagnosis experienced quite poor prognosis. Currently, surgery for the primary tumor significantly prolonged the survival of those patients, whereas chemotherapy and radiotherapy need to be further confirmed.

Complete pathological response to neoadjuvant treatment is associated with better survival outcomes in patients with soft tissue sarcoma: Results of a retrospective multicenter study.

BACKGROUND: Locally advanced soft tissue sarcoma (STS) management may include neoadjuvant or adjuvant treatment by radiotherapy (RT), chemotherapy (CT) or chemoradiotherapy (CRT) followed by wide surgical excision. While pathological complete response (pCR) to preoperative treatment is prognostic for survival in osteosarcomas, its significance for STS is unclear. We aimed to evaluate the prognostic significance of pCR to pre-operative treatment on 3-year disease-free survival (3y-DFS) in STS patients. METHODS: This is an observational, retrospective, international, study of adult patients with primary non-metastatic STS of the extremities and trunk wall, any grade, diagnosed between 2008 and 2012, treated with at least neoadjuvant treatment and surgical resection and observed for a minimum of 3 years after diagnosis. The primary objective was to evaluate the effect of pCR. (≤5% viable tumor cells or ≥95% necrosis/fibrosis) on 3y-DFS. Effect on local recurrence-free survival (LRFS), distant recurrence-free survival (MFS) overall survival (OS) at 3 years was also analyzed. Statistical univariate analysis utilized chi-square independence test and odds ratio confidence interval (CI) estimate, multivariate analysis was performed using LASSO. RESULTS: A total of 330 patients (median age 56 years old, range:19-95) treated by preoperative RT (67%), CT (15%) or CRT (18%) followed by surgery were included. pCR was achieved in 74/330 (22%) of patients, of which 56/74 (76%) had received RT. 3-yr DFS was observed in 76% of patients with pCR vs 61% without pCR (p < 0.001). Multivariate analysis showed that pCR is statistically associated with better MFS (95% CI, 1.054-3.417; p = 0.033), LRFS (95% CI, 1.226-5.916; p = 0.014), DFS (95% CI, 1.165-4.040; p = 0.015) and OS at 3 years (95% CI, 1.072-5.210; p = 0.033). CONCLUSIONS: In a wide, heterogeneous STS population we showed that pCR to preoperative treatment is prognostic for survival.

Changes of the hepatic subcapsular blood flow in a case of high-grade retroperitoneal liposarcoma: what to expect?

Changes of the hepatic subcapsular blood flow with the early appearance of hypervascularity near the falciform ligament are rare radiologic findings. They present most frequently in cases of superior vena cava (SVC) obstruction and are related to the recruitment of the cavo-mammary-phrenic-hepatic-capsule-portal and the cavo-superficial-umbilical-portal pathways. We present the case of a 52-year-old female patient with an highly aggressive retroperitoneal liposarcoma with SVC obstruction caused by external compression due to a mediastinal metastatic mass. The patient exhibited no symptoms of SVC obstruction due to the collateral cavo-portal pathways.

Primary dedifferentiated Liposarcoma of vagina: a first case report.

BACKGROUND: Dedifferentiated liposarcoma, one of the most deadly types of soft tissue sarcoma, is an aggressive and high-grade form of liposarcoma. Liposarcoma occurs most commonly in the retroperitoneum, extremities and trunk, but less frequently in the female genital tract. The vagina is a very rare site of origin. Herein we report the first case of dedifferentiated Liposarcoma deriving from vagina and discuss its clinical course. CASE PRESENTATION: A 38-year-old female patient presented to our institution with a painless vaginal mass. Abdominal computed tomography showed a 17.6 cm× 10.4 cm solid mass originating from the right lateral wall of her vagina. Then she underwent complete surgical resection of the tumor mass, and postoperative pathological result confirmed the diagnosis of dedifferentiated liposarcoma deriving from vagina. Six courses of combination chemotherapy with pirarubicin plus ifosfamide were performed after surgery. The patient remains with no evidence of disease recurrence with 13 months of follow-up. CONCLUSIONS: Liposarcoma is very rare in female genital tract, and more rare for dedifferentiated liposarcoma in gynecologic field. Little is known about the clinical characteristics, pathological diagnosis, prognosis and optimal management strategy of vaginal dedifferentiated liposarcoma. Complete surgical resection followed by systemic chemotherapy is suggested to be standard treatment for dedifferentiated liposarcoma. Combination chemotherapy with pirarubicin and ifosfamide may be effective for treating vaginal dedifferentiated liposarcoma.

The MDM2 inducible promoter folds into four-tetrad antiparallel G-quadruplexes targetable to fight malignant liposarcoma.

Well-differentiated liposarcoma (WDLPS) is a malignant neoplasia hard to diagnose and treat. Its main molecular signature is amplification of the MDM2-containing genomic region. The MDM2 oncogene is the master regulator of p53: its overexpression enhances p53 degradation and inhibits apoptosis, leading to the tumoral phenotype. Here, we show that the MDM2 inducible promoter G-rich region folds into stable G-quadruplexes both in vitro and in vivo and it is specifically recognized by cellular helicases. Cell treatment with G-quadruplex-ligands reduces MDM2 expression and p53 degradation, thus stimulating cancer cell cycle arrest and apoptosis. Structural characterization of the MDM2 G-quadruplex revealed an extraordinarily stable, unique four-tetrad antiparallel dynamic conformation, amenable to selective targeting. These data indicate the feasibility of an out-of-the-box G-quadruplex-targeting approach to defeat WDLPS and all tumours where restoration of wild-type p53 is sought. They also point to G-quadruplex-dependent genomic instability as possible cause of MDM2 expansion and WDLPS tumorigenesis.

Tratamiento con radioyodo de la patología tiroidea / Radioiodine treatment of thyroid diseases

INTRODUCCIÓN Y OBJETIVO: El tratamiento de la patología con radioyodo (RAI) se viene realizando desde hace más de 7 décadas. Sin embargo, no existe consenso en cuanto a indicaciones, dosis y otros aspectos relacionados con el cuidado de los pacientes. La razón de ello es la ausencia de ensayos clínicos prospectivos bien diseñadospara resolver estos interrogantes en cuanto al tratamiento con 131I, a pesar de la alta prevalencia de las enfermedades tiroideas. El tratamiento con 131I está indicado en el tratamiento del hipertiroidismo, producido por la enfermedad de Graves, por el adenoma tóxico y por el bocio multinodular tóxico; del bocio multinodular no tóxico y del carcinoma diferenciado de tiroides (CDT). El objetivo del tratamiento con RAI en caso del hipertiroidismo y del bocio multinodular no tóxico es disminuir la función tiroidea o disminuir el volumen de la glándula tiroides. En el caso del CDT, los objetivos de la administración de RAI tras la cirugía son la ablación de los restos tiroideos, el tratamiento adyuvante de la enfermedad microscópica sospechada no confirmada y el tratamiento de la enfermedad persistente loco-regional o metastásica. A la espera de los resultados de ensayos clínicos actualmente en: marcha, el tratamiento con 131I está justificado no solo en los pacientes de alto riesgo, sino también en los pacientes de riesgo bajo (T > 1 cm) e intermedio

Introduction and ojective: Radioiodine (RAI) therapy of the thyroid diseases has been used for seven decades. However, there is no consensus regarding indications, doses, procedures, and other aspects related to the clinical care of the patients considered for 131I therapy. The reason for this is the lack of large well-designed prospective clinical trials resolving fundamental questions in relation to 131I therapy, despite the high prevalence of thyroid diseases. Radioiodine therapy is indicated for the treatment of hyperthyroidism (Graves'disease, toxic nodular goiter and toxic multinodular goiter), multinodular nontoxic goiter and differentiated thyroid carcinoma (DTC). In benign thyroid diseases, RAI is administered to decrease the thyroid function and/or reduction of the thyroid volume. In DTC, post-operative administration of RAI may includeremnant ablation to eliminate residual normal thyroid tissue after thyroidectomy, adjuvant therapy to destroy suspected, but unproven residual disease and RAI therapy to treat persistent disease in higher risk patients. Pending the results of the prospective clinical trials that are currently underway, the use of 131I seems to be justified not only in high-risk patients, but also in low-intermediate-risk patients

Single centre 30-year experience in treating retroperitoneal liposarcomas.

BACKGROUND AND OBJECTIVES: Liposarcomas form a diverse group of tumors that represent the majority of retroperitoneal soft tissue sarcomas. Radical excision of these retroperitoneal liposarcomas is often challenging due to their large size and proximity to visceral organs and major vessels. Here we present the 30-year experience of our multidisciplinary sarcoma team in the treatment of these tumors and analysis of factors influencing survival. METHODS: Patients with retroperitoneal liposarcomas treated in Helsinki University Hospital from 1987 to 2017 were reviewed. Local recurrence-free survival, metastases-free survival, and disease-specific survival were assessed with Kaplan-Meier analysis, and factors influencing survival were evaluated with Cox regression. RESULTS: A total of 107 patients were identified. The median follow-up time was 5.4 years (interquartile range: 2.2-8.8 years). Local recurrence developed in 72% and metastases in 15% during follow-up. The 5-year disease-free survival was 31% and disease-specific survival was 66%. The multifactorial analysis revealed histological type and grade as predictors of disease-specific survival (P < .01) while multifocality carried a poor prognosis for local recurrence (P = .02) and higher histological grade for metastases (P < .01). CONCLUSIONS: Retroperitoneal liposarcomas rarely metastasize but tend to recur locally. For tumors that have been resected with macroscopically clear margins, histological, type, and grade are significant predictors of survival.

Optimal treatment strategy for paratesticular liposarcoma: retrospective analysis of 265 reported cases.

BACKGROUND: Liposarcoma is one of the most common subtypes of soft tissue sarcoma. Although the standard treatment for localized liposarcoma is surgical resection with negative margins, a treatment specific to paratesticular liposarcoma has yet to be quantitatively evaluated. METHODS: A systematic search of Medline, Web of Science, Embase, and Google was performed to find articles describing localized paratesticular liposarcoma published between 1979 and 2018 in English. The final cohort included 265 patients in 183 articles. The starting point was the time of surgical treatment, and the endpoint was the time of recurrence, including local recurrence, or distant metastasis. RESULTS: The median patient age was 62 years and the median tumor size was 9.5 cm. In total, 178 patients underwent high inguinal orchiectomy and 40 underwent simple tumorectomy. Based on the Kaplan-Meier curves, recurrence-free survival rates were significantly higher for those who underwent high inguinal orchiectomy than for those who underwent tumorectomy. Moreover, those with microscopic positive margins had a higher risk of recurrence than those with negative margins, but adjuvant radiation therapy after resection had no statistically significant effect on recurrence-free survival, even in subgroup analysis of patients with positive margins. Regarding the pathological subtypes, dedifferentiated, pleomorphic, and round-cell liposarcoma had a higher risk of recurrence than well-differentiated or myxoid liposarcoma. In the multivariate analysis, high inguinal orchiectomy greatly affected recurrence-free survival. The tumor size and histological subtype were independent risk factors for recurrence. CONCLUSION: Complete resection with high inguinal orchiectomy is the optimal treatment for paratesticular liposarcoma.

Giant paratesticular liposarcoma with lung metastases: a case report and review of the literature.

BACKGROUND: Due to its rarity, little is known about the clinical presentations and responses to systemic chemotherapies in advanced and/or metastatic cases of paratesticular liposarcoma. CASE PRESENTATION: Here, we report the case of a 75-year-old Japanese man with giant paratesticular liposarcoma. Imaging studies revealed a 26 cm tumor in his right scrotum and lung metastases at presentation. He underwent radical orchiectomy followed by systemic chemotherapies. Pathological findings of the resected primary tumor confirmed a dedifferentiated liposarcoma. He then started chemotherapy treatment with gemcitabine plus docetaxel. His disease status was stable for 1 year. Eribulin was used for second-line chemotherapy. He had a relapse at 5 months after eliburin and died at 22 months after diagnosis. CONCLUSION: Early diagnosis and curative radical surgery are important for treatment of paratesticular liposarcoma. However, a giant paratesticular liposarcoma could cause metastases, and systemic chemotherapy may be helpful for prolonging survival in patients with metastatic paratesticular liposarcoma.

Impact of centralization in primary retroperitoneal sarcoma treatment: analysis using hospital-based cancer registry data in Japan.

BACKGROUND: To elucidate the clinicopathological features, hospital-based care volume and prognoses associated with primary retroperitoneal sarcoma (PRS). METHODS: Clinical data on PRS cases, diagnosed from 2008 to 2009 (cohort A) and from 2012 to 2015 (cohort B), were obtained from the national hospital-based cancer registry in Japan. Since data on survival, 5 years after PRS diagnosis, were available only for cohort A, patient prognoses were analyzed in this group alone. RESULTS: The numbers of participating hospitals were 154 in cohort A and 537 in cohort B. In total, 380 and 2011 patients with PRS were identified in cohorts A and B, respectively. The incidence of PRS among all the registered urogenital malignancies was 0.52% (2391/462,866). Liposarcoma was the most commonly observed PRS subtype (55.8%), followed by leiomyosarcoma (19.0%). In cohort A, the 5-year overall survival (OS) was 40.4%. The 5-year OS associated with stage I (n = 107), stages II and III (n = 61), and stage IV (n = 59) disease were 59%, 39%, and 6%, respectively. Only two institutions treated over ten patients per year in each cohort. When institutions were divided by hospital care volume (8 hospitals with ≥ = 3 cases and 149 with < 3 cases/year), there were any statistic differences in the OS. CONCLUSIONS: We presented the distribution and prognoses associated with PRS using a real-world large cohort database. Centralization for PRS management was not established in Japan, while the prognosis did not significantly depend on the treatment volume of hospitals.

Liposarcoma of oral cavity: Systematic review of cases reported to date and analysis of prognostic factors.

The aim of this study was to integrate the available data published on Liposarcomas (LPSs) of the oral cavity into an analysis of its clinical features, treatment modalities, and prognostic factors. An electronic search was undertaken in January 2019. The eligibility criteria included publications that had enough clinical and histological information to confirm the diagnosis. Forty-five publications (104 LPSs) were included. The lesion was more prevalent in males from the fifth to seventh decades of life. Treatment (P = .03) and distant metastasis (P = .0001) were independently associated with survival. A lower possibility of recurrence was statistically associated with age (younger patients) (P = .03), tumor size (smaller than 2.8 cm) (P = .001), and treatment (radical surgery) (P = .04). LPS presents a good survival for patients after 5 years of follow-up (66.4%). Patients who were treated with conservative surgery and presented with distant metastasis showed poor prognosis.

A Multi-Modality Treatment of Retroperitoneal De-Differentiated Liposarcoma.

BACKGROUND Retroperitoneal sarcomas are rare tumors, only affecting 2 to 5 people per million population and accounting for 0.1% of all malignancies. Liposarcoma is the most common of all retroperitoneal sarcomas, responsible for approximately 20% of all sarcomas in adults. The most important prognostic factors are tumor grade, the presence of positive margins, tumor integrity, and degree of resection. CASE REPORT Our patient was a 73-year-old man with abdominal pain whose CT scan of the abdomen and pelvis demonstrated a 15×15 cm heterogeneous, left-sided intra-abdominal mass. He underwent resection of the retroperitoneal tumor, left colectomy, and left nephrectomy. Final pathology demonstrated a high-grade, de-differentiated liposarcoma with a rhabdosarcomatous component. The postoperative course was complicated by a small intra-abdominal abscess and abdominal dehiscence. a CT scan after surgery showed a residual tumor of the retroperitoneal posterior margin. Re-exploration to resect the residual tumor and repair the fascial dehiscence were performed. The patient underwent an initial chemotherapy regimen with doxorubicin, then moved to targeted therapy with Palbociclib, and is now on chemotherapy using Eribulin. CONCLUSIONS Achieving complete resection and the grade of the tumor at diagnosis are the 2 most important prognostic factors for patient survival in retroperitoneal liposarcoma, as survival rates are inversely proportional to the grade of the tumor. Even with the best resection attempts, there is always a risk of residual tumor cells within the tumor bed, which contribute to recurrence and need for additional surgical interventions. It is important to approach this disease process with a multidisciplinary team that includes surgical, medical, and radiation oncology to ensure the best survival outcomes. Retroperitoneal sarcoma recurrence and survival are directly related to the ability to achieve negative margins of resection, as well as the grade and size of the primary tumor. Adjuvant therapies that include radiation and immunotherapy may be effective in treating recurrent disease.