Radiation-associated Sarcomas Research Articles

Clinical Characteristics, Patterns of Care, and Treatment Outcomes of Radiation-Associated Sarcomas.

Radiation-associated sarcomas (RASs) are rare tumors with limited contemporary data to inform prognostication and management. We sought to identify the clinical presentation, patterns of care, and prognostic factors of RASs. RAS patients treated at a single institution from 2015 to 2021 were retrospectively reviewed for clinicopathologic variables, treatment strategies, and outcomes. Thirty-eight patients were identified with a median follow-up of 30.5 months. The median age at RAS diagnosis was 68.4 years (27.9-85.4), with a median latency from index radiotherapy (RT) of 9.1 years (3.7-46.3). RAS histologies included angiosarcoma (26%), undifferentiated pleomorphic sarcoma (21%), and osteosarcoma (18%). Most were high-grade (76%). Genomic profiling revealed low tumor mutational burden, frequent inactivating TP53 mutations (44%), CDKN2A deletions (26%), and MYC amplifications (22%), particularly in breast angiosarcomas. Of 38 patients, 33 presented with localized disease, 26 of whom were treated with curative intent. Overall, the median progression-free survival (PFS) was 9.5 months (1.4-34.7), and the overall survival (OS) was 11.1 months (0.6-31.6). Patients with localized vs. metastatic RASs had a longer PFS (HR, 3.0 [1.1-8.5]; p = 0.03) and OS (HR, 3.0 [1.04-8.68]; p = 0.03). Among localized RAS patients, high grade was associated with shorter OS (HR, 4.6 [1.04-20.30]; p = 0.03) and resection with longer OS (mean 58.8 vs. 6.1 months, HR, 0.1 [0.03-0.28]; p < 0.001). Among patients undergoing resection, negative margins were associated with improved OS (mean 71.0 vs. 15.5 months, HR, 5.1 [1.4-18.2]; p = 0.006). Patients with localized disease, particularly those undergoing R0 resection, demonstrated significantly better outcomes. Novel strategies are urgently needed to improve treatment outcomes in this challenging group of diseases.

Radiation-associated sarcomas of bone and soft tissue: a clinicopathological analysis of 46 cases

Objective: To investigate the clinical, imaging, histological, and molecular features and the differential diagnosis of radiation-associated sarcomas of bone and soft tissue. Methods: Forty-six cases of radiation-associated sarcomas of the bone and soft tissue in Beijing Jishuitan Hospital from January 2010 to January 2022 were retrospectively analyzed; and the imaging, histological features and immunophenotype were examined. Results: There were 33 females and 13 males, aged from 18 to 74 years, with a mean of 52 years. The most common site of radiation-associated sarcomas were the limbs and spine (15 cases), followed by the chest (9 cases). The primary diseases included epithelial tumors (15 breast cancer, 6 cervical cancer, and 5 bowel cancer), hematolymphoid tumors, bone and soft tissue tumors and infectious lesions. The latent period of radiation-associated sarcomas ranged from 2-22 years, with an average of 11.6 years. Histopathologically, the morphology was divergent from the primary tumor. The most common malignant tumor type was undifferentiated sarcoma (22 cases), followed by osteosarcoma (16 cases). The immunophenotype of radiation-related sarcoma was almost the same as the corresponding soft tissue sarcoma. Conclusions: Radiation-induced sarcoma has a wide range of primary tumor types and its imaging, morphology and immunohistochemical features are similar to those of the primary sarcoma of bone and soft tissue. Clinical correlation is often recommended for the differential diagnosis.

Clinical Characteristics, Patterns of Care, and Treatment Outcomes of Radiation-Associated Sarcomas

In this study, we describe the clinical presentation, patterns of care, and treatment outcomes for radiation-associated sarcomas (RAS) patients seen at our institution. Patients with RAS treated at The Ohio State University Comprehensive Cancer Center between January 1, 2015 and January 20, 2021 were included. Demographic and clinical variables, as well as outcomes, were abstracted from chart review. Differences in outcomes were assessed based on log-rank test. A total of 38 patients with a diagnosis of RAS were identified (17 males, 21 females). The median age at radiotherapy for index malignancy was 55.3 years (range 0.2-77.5). The median latency following index radiotherapy until the RAS diagnosis was 9.1 years (range 3.7-46.3). The median age at RAS diagnosis was 68.4 years (range 27.9-85.4). The most common index malignancy associated with a subsequent RAS was breast carcinoma (n = 9 [23.7%]). The most common RAS histology was angiosarcoma (n = 10 [26.3%]). Median RAS tumor size was 5.25 cm (range 0.4-30.5). RAS grade was most commonly grade 3 (n = 25 [65.8%]). RAS locations included abdominopelvic (n = 15 [39.5%]); head & neck (n = 10 [26.3%]); and thorax (n = 10 [26.3%]). Genomic profiling identified mutations in TP53 (n = 12 [31.6%]); MYC (n = 6 [15.8%]); and CDK2A/4 (n = 5 [13.2%]). Median tumor mutation burden (TMB) was 2.6 mutations/megabase (range 0.5-6.3). Among the 33 patients with non-metastatic RAS at presentation, 78.8% (n = 26) underwent oncologic resection. Margins were R0 in 69.2% (n = 18), R1 in 19.2% (n = 5), and R2 in 11.5% (n = 3). 54.5% (n = 18) received systemic therapy and 24.2% (n = 8) received radiotherapy as part of curative-intent treatment (median dose 50.4 Gy [range 45-57.5]). For the entire cohort, median PFS was 9.0 months and median OS was 11.1 months. Among patients who presented with non-metastatic RAS, the median LRFS was 9.5 months (range 2.0-34.7); median PFS was 9.0 months (range 2.0-34.7); and median OS was 10.6 months (range 0.6-31.6). Amongst patients with metastatic RAS at presentation, median PFS was 7.4 months (range 1.4-15.8) and median OS was 13.1 months (range 6.0-14.9). Patients who presented with non-metastatic vs metastatic RAS had a significantly longer PFS (p = 0.025) and OS (p = 0.033). Amongst non-metastatic RAS, an R0 resection was associated with significantly improved mean OS (75.3 months [95% CI 54.9-95.8]) in comparison to R1 (15.2 months [95% CI 5.3-25.1]) and R2 margins (19.7 months [95% CI 10.7-28.7]), p = 0.016. Among patients managed with curative intent, there was no significant association between receipt of either systemic therapy or radiotherapy and duration of LC, PFS, or OS. Outcomes for RAS are strikingly poor. Patients with non-metastatic RAS had a significantly longer PFS and OS compared to patients who presented with metastatic RAS. As part of a curative-intent treatment, R0 surgical margins, but not receipt of systemic therapy or radiotherapy, were associated with improved OS in our cohort.

Risk of Radiation-Associated Secondary Malignancies among Patients with Breast Cancer Harboring TP53 Germline Variants

Radiation-associated malignancies are rare and poorly understood. TP53 encodes a multifunctional protein that maintains genome integrity and is the most common somatically mutated gene in cancer. Germline pathogenic variants of TP53 predispose carriers to several cancers comprising the Li-Fraumeni syndrome. It is hypothesized that carriers are also at increased risk of radiotherapy (RT)-associated secondary malignancies; however, reports are mixed. We evaluated the risk of secondary malignancies after breast RT among patients with Li-Fraumeni syndrome. This multi-institutional cohort study included carriers of TP53 germline variants who underwent surgical treatment for breast cancer between 1980 and 2020. Patients were stratified based on germline TP53 classification (pathogenic variants [PV] vs variants of uncertain significance [VUS]). The primary outcome of interest was the cumulative incidence risk of developing an in-field secondary cancer after radiotherapy for primary breast carcinoma. Ninety-one patients (57 PV and 34 VUS) were evaluated with a median age of 36 years (interquartile range [IQR] 31, 42) and a median follow up of 7.9 years (IQR 4.7, 14.4). Among those with PV who received RT (n = 22), 4 secondary non-breast cancers developed in the radiation field (15-year cumulative incidence 19% [95% CI: 4-43%]), whereas, among those with PV who did not receive RT (n = 35), 0 secondary non-breast cancers were observed in the treated breast (15-year cumulative incidence 0%; p = 0.043). We observed 3 radiation-associated sarcomas among patients with PV who received RT (15-year risk 12% [95% CI 2-33%]) compared with 0 among those who did not receive RT (p = 0.08). No RT-associated sarcomas were observed among 18 patients with TP53 VUS who received RT. RT was not associated with overall survival, despite higher T and N breast cancer stage among those receiving RT (p = 0.33). As expected, patients with PV were more likely than those with VUS to develop any secondary cancer following breast cancer treatment (15-year risk: 54% [95% CI: 33-72%] vs. 14% [95% CI: 3-36%]). Carriers of pathogenic variants of TP53 are at elevated risk of developing secondary malignancies after breast cancer treatment. This population is at particular risk of developing in-field secondary cancers following RT. This iatrogenic risk must be weighed against the anticipated therapeutic benefit of tumor control. Shared decision making is crucial in the radiotherapeutic management of breast cancer patients harboring the Li-Fraumeni syndrome.

Histology-Specific Prognostication for Radiation-Associated Soft Tissue Sarcoma.

Radiation-associated sarcomas (RAS) are rare but aggressive malignancies. We sought to characterize the histology-specific presentation and behavior of soft tissue RAS to improve individualized prognostication. A single-institutional prospectively maintained database was queried for all patients with primary, nonmetastatic RAS treated with surgical resection from 1982 to 2019. Patients presenting with the five most common RAS histologies were propensity-matched to those with sporadic tumors of the same histology. Incidence of disease-specific death (DSD) was modeled using cumulative incidence analyses. Among 259 patients with RAS, the five most common histologies were malignant peripheral nerve sheath tumor (MPNST; n = 19), myxofibrosarcoma (n = 20), leiomyosarcoma (n = 24), undifferentiated pleomorphic sarcoma (UPS; n = 55), and angiosarcoma (AS; n = 62). DSD varied significantly by histology (P = .002), with RAS MPNST and UPS having the highest DSD. In unadjusted analysis, RAS MPNST was associated with increased DSD compared with sporadic MPNST (75% v 38% 5-year DSD, P = .002), as was RAS UPS compared with sporadic UPS (49% v 28% 5-year DSD, P = .004). Unadjusted DSD was similar among patients with RAS AS, leiomyosarcoma, or myxofibrosarcoma and sporadic sarcoma of the same histology. After matching RAS to sporadic patients within each histology, DSD only differed between RAS and sporadic MPNST (83% v 46% 5-year DSD, P = .013). Patients with RAS AS presented in such a distinct manner to those with sporadic AS that a successful match was not possible. The aggressive presentation of RAS is histology-specific, and DSD is driven by RAS MPNST and UPS histologies. Despite the aggressive presentation, standard prognostic factors can be used to estimate risk of DSD among most RAS. In MPNST, radiation association should be considered to independently associate with markedly higher risk of DSD.

Clinical and Pathologic Characterization of 94 Radiation-Associated Sarcomas: Our Institutional Experience.

Radiation-associated sarcomas are an uncommon complication of therapeutic radiation. However, their prevalence has increased with the more widespread use of this treatment modality. The clinical, pathologic and genetic characteristics of radiation-associated sarcomas are not fully understood. In this study we describe the features of 94 radiation-associated sarcomas reviewed at our institution between 1993 and 2018, evaluate their overall survival (OS) and progression-free survival (PFS) outcomes, and compare them with their sporadic counterparts reviewed within the same time period. Histologic subtypes of all radiation-associated sarcomas included 31 (33%) undifferentiated sarcomas, 20 (21%) osteosarcomas, 17 (18%) angiosarcomas, 10 (11%) malignant peripheral nerve sheath tumor (MPNST), 9 (10%) leiomyosarcomas, 4 (4%) myxofibrosarcomas, and 3 (3%) rhabdomyosarcomas. Six patients had a documented cancer predisposition syndrome. The most common preceding neoplasms included adenocarcinoma (47%) and squamous cell carcinoma (19%), with a mean latency of 13 years. Multivariable Cox survival analysis demonstrated that advanced stage at diagnosis based on pT category (AJCC eighth edition) and fragmented resection were associated with worse survival outcomes. In addition, there was a statistically significant difference in PFS between radiation-associated undifferentiated sarcomas and MPNST when compared to their sporadic counterparts using the Kaplan-Meier method and Log-rank analysis. Overall, our study shows that radiation-associated sarcomas comprise a wide clinico-pathologic spectrum of disease, with a tendency for aggressive clinical behavior. This study further delineates the understanding of these uncommon diseases. Future studies are necessary to better understand the genetic and epigenetic changes that drive the differences in behavior between these tumors and their sporadic counterparts, and to offer better treatment options.

Complex Surgical Management of Radiation-Associated Left Retroperitoneal Sarcoma.

Radiation-associated sarcomas (RASs) are rare entities that tend to have an aggressive course and poor prognosis. Criteria for diagnosis of radiation-associated sarcoma include therapeutic radiation preceding the development of sarcoma, sarcoma arising within or near the irradiated field, and tumor histology that is distinct from the primary tumor necessitating radiation. Despite their relatively uncommon occurrence, RASs are a well-established complication of radiation therapy. We present the complex, multidisciplinary surgical management of a patient with multi-compartmental radiation-associated sarcoma of the left retroperitoneum occurring nearly 25years after undergoing whole trunk radiation for Hodgkin's lymphoma.

Radiation-Associated Sarcoma of the Head and Neck: Incidence, Latency, and Survival.

Radiation-associated sarcomas of the head and neck (RASHN) are known but rare sequelae after radiation for squamous cell carcinoma. The purpose of this study was to characterize RASHN, estimate the risk of RASHN in head and neck squamous cell patients after therapeutic radiation, and compare their survival to that of patients with de novo sarcomas of the head and neck (dnSHN). Retrospective database analysis. RASHN and dnSHN cases were collected from the Surveillance, Epidemiology, and End Results Database to identify risk factors and calculate incidence and latency. Survival was compared between RASHN and dnSHN. The risk of RASHN was 20.0 per 100,000 person-years. The average latency period was 124.2 months (range 38-329). The cumulative incidence of RASHN at 20 years was 0.13%. Oral cavity and oropharynx primaries demonstrate increased risk. Five-year overall survival of RASHN was 22.4% compared to 64.5% for dnSHN. RASHN are confirmed to be rare. RASHN have poor overall survival and worse survival compared to dnSHN. The impact of intensity-modulated radiation therapy protocols on this risk is unknown. Modifiable risk factors of smoking and alcohol consumption continue to dwarf radiation therapy as risk factors of second primary head and neck cancers. 3 Laryngoscope, 132:1034-1041, 2022.

Rare bone sarcomas: A retrospective analysis of 145 adult patients from the French Sarcoma Group.

The benefit of chemotherapy (CT) in rare bone sarcomas is not documented in prospective studies. Our retrospective study from the French sarcoma network for bone tumors ResOs was performed in adult patients (pts) from 1976 to 2014, with histologically verified diagnosis of leiomyosarcomas (LMS), undifferentiated pleomorphic sarcoma (UPS) or radiation-associated sarcomas of bone. The median follow-up was 4.7 years (95% CI: 3.7-6.5). Clinical features, treatment modalities and outcomes were recorded and analyzed from 145 pts (median age 53 years [range 20-87]). Site of disease was extremities (66%) or axial skeleton (34%), 111 (77%) presented with localized and potentially resectable disease. The most common histological subtypes were UPS (58%) and LMS (33%); 58% were high-grade tumors. Surgery was performed in 127 pts. In the 111 localized pts, 28 pts (25%) underwent upfront surgery or exclusive radiotherapy (RT; >50 Gy) without CT, whereas 83 pts (75%) received either neoadjuvant (n=26) or adjuvant CT (n=13) or both (n=44). Neoadjuvant and adjuvant CT was mostly doxorubicin-based (95%/86%) and cisplatin-based (67%/63%). R0 resection was achieved in 59 pts, and a good histological response in 15 patients (25%). Adjuvant RT was performed in 24 (22%) pts. For the whole cohort (n=145), the 5-year overall survival (OS) rate was 53% [42; 62]. In univariate analysis, age ≤ 60 was associated with a longer disease-free survival (DFS) (P=.0436). Neoadjuvant and adjuvant CT tended to be associated with better DFS (P=.056) with no significant impact on OS in this retrospective series.

The impact of MYC gene amplification on the clinicopathological features and prognosis of radiation-associated angiosarcomas of the breast.

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

Soft Tissue Sarcoma Follow-up Imaging: Strategies to Distinguish Post-treatment Changes from Recurrence.

Soft tissue sarcomas encompass multiple entities with differing recurrence rates and follow-up intervals. The detection of recurrences and their differentiation from post-therapeutic changes is therefore complex, with a central role for the clinical radiologist. This article describes approved recommendations. Prerequisite is a precise knowledge of the current clinical management and surgical techniques. We review recurrence rates and treatment modalities. An adequate imaging technique is paramount, and comparison with previous imaging is highly recommended. We describe time-dependent therapy-related complications on magnetic resonance imaging compared with the spectrum of regular post-therapeutic changes. Early complications such as seromas, hematomas, and infections, late complications such as edema and fibrosis, and inflammatory pseudotumors are elucidated. The appearance of recurrences and radiation-associated sarcomas is contrasted with these changes. This systematic approach in follow-up imaging of soft tissue sarcoma patients will facilitate the differentiation of post-therapeutic changes from recurrences.

Radiation‐associated sarcomas other than malignant peripheral nerve sheath tumours demonstrate loss of histone H3K27 trimethylation†

Complete loss of histone H3 lysine 27 trimethylation (H3K27me3) has recently emerged as a biomarker for malignant peripheral nerve sheath tumours (MPNST). Loss of H3K27me3 staining has also been reported in post-radiation MPNST; however, it has not been evaluated in a large series of radiation-associated sarcomas of different histological subtypes. The aim of this study was to assess H3K27me3 labelling by immunohistochemistry in radiation-associated sarcomas and to determine the prevalence of H3K27me3 loss in these tumours. Radiation-associated sarcomas (n=119) from two tertiary care referral centres were evaluated for loss of H3K27me3, defined as complete loss of staining within tumour cells in the presence of a positive internal control. Twenty-three cases (19%) showed H3K27me3 loss, including nine of 10 (90%) MPNST, seven of 77 (9%) undifferentiated spindle cell/pleomorphic sarcomas, five of 25 (20%) angiosarcomas, one of five (20%) leiomyosarcomas and one of two (50%) osteosarcomas. Complete H3K27me3 loss was present in 19% of radiation-associated sarcomas in our series. Our findings demonstrate that loss of H3K27me3 is not specific for radiation-associated MPNST and may also occur in other histological subtypes of RAS, including radiation-associated undifferentiated spindle cell/pleomorphic sarcoma, angiosarcoma, leiomyosarcoma and osteosarcoma.

MYC expression has limited utility in the distinction of undifferentiated radiation-associated sarcomas from sporadic sarcomas and sarcomatoid carcinoma.

MYC is a proto-oncogene that is frequently dysregulated in various malignancies, through translocation or amplification. Radiation-associated angiosarcoma frequently shows MYC amplification, and immunohistochemical expression has been shown to be a reliable surrogate marker for amplification, but less is known about MYC expression in other sarcoma types, despite reports of MYC amplification in some undifferentiated/unclassified radiation-associated sarcomas (RASs). Distinguishing putative RAS from non-radiation-associated sarcoma or sarcomatoid carcinoma can be difficult. The aim of this study was to determine the prevalence and potential diagnostic utility of MYC in this context, by evaluating MYC expression in a cohort of RASs, non-radiation-associated sarcomas, and sarcomatoid carcinomas. Three hundred and eighty-five neoplasms were evaluated, including 81 RASs (18 angiosarcomas; 57 undifferentiated sarcomas; three leiomyosarcomas; and three malignant peripheral nerve sheath tumours), 267 non-radiation-associated sarcomas, and 37 sarcomatoid carcinomas. Immunohistochemistry was performed with a monoclonal anti-MYC antibody. Staining in tumour cells was scored on the basis of extent (focal, 1-4%; multifocal, 5-49%; and diffuse, ≥50%) and intensity (strong, moderate, and weak). One hundred percent of radiation-associated angiosarcomas expressed MYC diffusely. Expression was infrequent among other types of RAS (9.5%), and the frequency was similar to that in non-radiation-associated sarcomas (9.7%). MYC expression was more common in sarcomatoid carcinomas, occurring in 43%. The extent and intensity of staining were variable in all groups. MYC expression is infrequent among RASs other than angiosarcoma, and has a similar prevalence in sporadic sarcomas. Given the frequency of expression in sarcomatoid carcinomas, MYC expression outside the context of radiation-associated angiosarcoma is of limited diagnostic utility, and should be interpreted with caution after exclusion of sarcomatoid carcinoma where relevant.

A Comparison of Outcomes and Prognostic Features for Radiation-Associated Angiosarcoma of the Breast and Other Radiation-Associated Sarcomas

Radiation-associated sarcomas (RAS) are considered to have a poor prognosis. Although the incidence is anticipated to rise, contemporary data regarding predictors of outcomes are few. We performed a retrospective analysis to identify RAS prognostic factors and subset analyses for radiation-associated angiosarcoma arising after treatment for breast cancer (RAAB) and other RAS subtypes (other-RAS). Patients with localized RAS evaluated at an institutional multidisciplinary sarcoma clinic were identified. Clinical and histologic review was performed, and outcomes were assessed to identify prognostic features. A subset of cases underwent molecular analysis by next-generation sequencing. Among 176 patients, histologic subtypes of RAS included angiosarcoma (41%), undifferentiated/unclassified sarcoma (40%), leiomyosarcoma (8%), malignant peripheral nerve sheath tumor (6%), and osteosarcoma (2%). Sixty-seven patients (38%) had RAAB, and 109 (62%) had other-RAS. RAAB had significantly shorter latency from time of initial radiation compared with other-RAS (8 vs. 15years; P<.001). Treatment approaches included surgery (91%), chemotherapy (44%), and radiation therapy (27%). Median follow-up was 3.2years; 3-year overall survival (OS) was 74%. On multivariate analysis, positive margins (P<.0001), deep tumor location (intrathoracic/intra-abdominal, P=.002), and high grade (P<.0001) were associated with worse OS. In particular, 3-year OS with negative versus positive margins was 90% versus 66%. Patients with RAAB versus other-RAS showed a trend for higher 3-year OS (84% vs 68%; P=.09), significantly higher 3-year metastasis-free survival (82% vs 67%; P=.001), but similar 3-year local recurrence-free survival (54% vs 61%; P=.28). Next-generation sequencing identified overall low tumor mutational burden, recurrent MYC amplification in RAAB, and few clinically actionable mutations. Margin negative excision, superficial tumor location, and low tumor grade are determinants of improved OS for RAS, suggesting that complete surgical excision, when possible, is an optimal component of treatment. RAAB is a clinicopathologically distinct type of RAS with shorter latency from initial RT, different recurrence patterns, and when aggressively managed has potentially better outcomes compared with other-RAS.

Radiation-Associated Sarcoma of the Neck: Case Series and Systematic Review.

Radiation-associated soft tissue sarcomas of the neck (RASN) constitute a rare and aggressive tumor type. A retrospective chart review at the authors' institution revealed 3 patients with RASN. A systematic review of the literature was also conducted using MEDLINE, Ovid, the Cochrane Library, and Embase. Patients within the authors' institutional chart review presented from 6 to 26 years after neck radiation with neck masses. All patients underwent surgical resection with clear margins, and adjuvant radiation was offered when feasible. Patients had no evidence of disease at most recent follow-up. A total of 867 articles were screened for systematic review, revealing 9 articles detailing outcomes of RASN. Studies were small and heterogeneous, precluding pooled data. The importance of complete surgical extirpation was noted. Complete surgical resection appears to be the mainstay of therapy, but there are limited data on management and outcomes of patients with RASN.

Locally Aggressive Connective Tissue Tumors.

In this review, we highlight the complexities of the natural history, biology, and clinical management of three intermediate connective tissue tumors: desmoid tumor (DT) or aggressive fibromatosis, tenosynovial giant cell tumor (TGCT) or diffuse-type pigmented villonodular synovitis (dtPVNS), and giant cell tumor of bone (GCTB). Intermediate histologies include tumors of both soft tissue and bone origin and are locally aggressive and rarely metastatic. Some common aspects to these tumors are that they can be locally infiltrative and/or impinge on critical organs, which leads to disfigurement, pain, loss of function and mobility, neurovascular compromise, and occasionally life-threatening consequences, such as mesenteric, bowel, ureteral, and/or bladder obstruction. DT, PVNS, and GCTB have few and recurrent molecular aberrations but, paradoxically, can have variable natural histories. A multidisciplinary approach is recommended for optimal management. In DT and PVNS, a course of observation may be appropriate, and any intervention should be guided by symptoms and/or disease progression. A surgical approach should take into consideration the infiltrative nature, difficulty in obtaining wide margins, high recurrence rates, acute and chronic surgical morbidities, and impact on quality of life. There are similar concerns with radiation, which especially relate to optimal field and transformation to high-grade radiation-associated sarcomas. Systemic therapies must be considered carefully in light of acute and chronic toxicities. Although standard and novel therapies are promising, many unanswered questions, such as duration of therapy and optimal end points to evaluate efficacy of drugs in clinical practice and trials, exist. Predictive biomarkers and novel clinical trial end points, such as volumetric measurement, magnetic resonance imaging T2 weighted mapping, nuclear imaging, and patient-reported outcomes, are in development and will require validation in prospective trials.

Radiation-Associated Angiosarcoma of the Breast: Clinical and Pathologic Features.

Breast angiosarcoma is an unusual malignancy accounting for approximately 1% of soft tissue sarcomas. It can occur as a primary form without a known precursor or as a secondary form associated with radiotherapy. Adjuvant radiotherapy has a significant role in preventing local recurrence in women treated with conservation therapy for early stage breast carcinoma or multicentric tumors. Postradiation angiosarcoma usually affects the dermis of the breast within the radiation field and may occasionally develop in the breast parenchyma. Compared with the latency of other radiation-associated sarcomas, the latency for breast radiation-associated angiosarcoma is relatively short with a median of 6 years. The risk of developing secondary angiosarcoma does not outweigh the benefit of treatment; therefore, radiation therapy continues to be a mainstay modality in the treatment of breast cancer patients. Early detection is essential because angiosarcomas are associated with a poor prognosis. Wide surgical resection is the standard treatment for these tumors.

Comprehensive screening of alternative lengthening of telomeres phenotype and loss of ATRX expression in sarcomas

According to cytogenetic aberrations, sarcomas can be categorized as complex or simple karyotype tumors. Alternative lengthening of telomeres is a telomere-maintenance mechanism common in sarcomas. Recently, this mechanism was found to be associated with loss of either α-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated (DAXX) protein. We previously reported that alternative lengthening of telomeres and loss of ATRX expression were common in leiomyosarcoma, angiosarcoma, pleomorphic liposarcoma, and dedifferentiated liposarcoma. In the present study, we screened an additional 245 sarcomas of other types to determine the prevalence of alternative lengthening of telomeres, loss of ATRX/DAXX expression, and their relationship. Undifferentiated pleomorphic sarcomas were frequently alternative lengthening of telomeres positive (65%) and loss of ATRX was seen in approximately half of the alternative lengthening of telomeres-positive tumors. Nineteen of 25 myxofibrosarcomas were alternative lengthening of telomeres-positive, but only one was ATRX deficient. Three of 15 radiation-associated sarcomas were alternative lengthening of telomeres positive, but none of them was ATRX deficient. Alternative lengthening of telomeres and/or loss of ATRX were uncommon in malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, and embryonal rhabdomyosarcomas. By contrast, none of the 71 gene fusion-associated sarcomas was ATRX deficient or alternative lengthening of telomeres positive. All tumors exhibited preserved DAXX expression. Combining our previous studies and this study, a total of 384 sarcomas with complex karyotypes were examined, 83 of which were ATRX deficient (22%). By telomere-specific fluorescence in situ hybridization, 45% (138/308) were alternative lengthening of telomeres positive, 55% (76/138) of which were ATRX deficient. Loss of ATRX was highly associated with alternative lengthening of telomeres (P<0.001). We conclude that alternative lengthening of telomeres is a frequent telomere-maintenance mechanism in cytogenetically complex sarcomas. Loss of ATRX is highly associated with this feature.

Does Post–Neoadjuvant Therapy PET Response Predict Pathologic Outcomes in the Treatment of Sarcomas?

sarcomas (10), and other malignancies (2). 4 of these patients had radiation associated sarcomas within prior radiation field for different malignancies. Materials/Methods: The median age of the patients at diagnosis was 51 (range 7-75). The patients were treated from Feb, 2000 to Oct, 2013. 6 patients were treated with dural plaques during both stages of planned 2-stage operations. 46 patients were planned for treatment during one of the staged resection. The types of plaques used included Y-90, P-32 and Ir-192. Median dose was 10 Gy (range 7.5 e 17 Gy) prescribed to the dural surface in a single fraction. The median length of the dural plaque is 36mm, and the median arc of the dural plaque is 153 . All patients had also received preand/or postoperative photon/proton external beam radiation therapy. We limit spinal cord dose to 63/54 Gy RBE to surface/center. Results: In 7 of 51 patients, dural plaque brachytherapy was not given (4 because of intraoperative anatomic constraints, and 3 because of dural tears). Results are based on intention to treat analysis. The median follow up time from date of planned dural plaque brachytherapy is 17.7 months. Of the 3 patients treated for primary disease and had local recurrence, 2 presented with radiation associated sarcoma, which significantly limited their external beam radiation dose. No acute or late myelopathy could be attributed to dural plaque brachytherapy. 6 patients had intraoperative dural tear (none directly caused by plaque placement). In 3 of these 6 patients, dural plaque treatments were given. In 1 of the 3 patients, a persistent CSF leak developed postoperatively, and it eventually resolved without intervention. Conclusions: Dural plaque brachytherapy allows high dose of radiation to be safely delivered to the dural surface. Dural plaque shall be considered in situation when tumors are in close proximity to spinal cord, and sufficient dose of radiation cannot be delivered with external beam radiation therapy alone. Author Disclosure: D.D. Yip: None. T.F. DeLaney: None. A. Jacobson: None. F.J. Hornicek: None. J.H. Schwab: None. T.C. Mauceri: None. Y. Chen: None.

Systemic treatment options for radiation-associated sarcomas.

Sarcomas are rare malignant tumors that develop from mesenchymal tissue. Most sarcomas are idiopathic, however, a significant minority develops as a consequence of prior radiation exposure. Although the absolute risk of developing a radiation-associated sarcoma is small, these tumors represent significant clinical challenges. For recurrent, unresectable or metastatic disease, the standard treatment is systemic chemotherapy. Radiation-associated sarcomas tend to be undifferentiated sarcomas, angiosarcomas, or leiomyosarcomas, which are variably sensitive to chemotherapy. The best general approach is to treat each radiation-associated sarcoma as one would its sporadic histologic counterpart. There are limited data to guide the best treatment for radiation-associated sarcoma, therefore, the standard chemotherapy options are reasonable choices. These include doxorubicin, ifosfamide, gemcitabine, docetaxel, and pazopanib. Patients with radiation-associated sarcomas may have received prior anthracyclines to treat antecedent malignancies such as breast cancer or lymphoma. Thus, if additional doxorubicin cannot be used, liposomal doxorubicin is a reasonable substitute. More prospective research is needed on how radiation-associated sarcomas respond to systemic therapy. Future clinical trials of new agents in sarcoma should identify and include patients with radiation-associated sarcoma.