Radiation-induced Sarcoma Research Articles

Proposal for Modification of Cahan's Criteria Utilizing Molecular Genetic Analyses for Cases without Baseline Histopathology: A Unique Method Applicable to Primary Radiosurgery.

Background Cahan's criteria have been utilized since 1948 to establish causality between prior radiation treatment and the development of secondary malignancy. One major criterion specifies that histological and radiographic evidence collected before and after radiation treatment must confirm separate tumor types; however, pretreatment biopsy is rarely obtained prior to radiosurgery for vestibular schwannoma and many other skull base and cranial lesions. Therefore, in these cases Cahan's criteria cannot be validly applied. Objective This article proposes an update to Cahan's criteria using modern molecular genetic analysis for cases lacking baseline histopathology. Methods Mate-pair sequencing and whole exome sequencing of a cerebellopontine angle undifferentiated high-grade pleomorphic sarcoma (UHGPS) that developed after stereotactic radiosurgery of a presumed benign vestibular schwannoma. Results Mate-pair sequencing and whole exome sequencing of the sarcoma revealed complex chromosomal aberrations. Notably, the tumor contained a deletion in the NF2 gene at 22q12 and an in-frame deletion on exon 5 of the remaining copy of NF2 . Biallelic events impacting NF2 are atypical for UHGPS but are characteristic for vestibular schwannoma. These findings help support the conclusion that the UHGPS arose from a benign vestibular schwannoma all along. Conclusions Next-generation sequencing can be successfully applied to a radiation-induced sarcoma when both the original and malignant tumors harbor separate signature genetic markers. As our understanding of the genetic profile of various tumors expand, we believe that next-generation sequencing and other genomic tools will play an increasingly important role in establishing causality between radiation and the development of secondary malignancy.

Author Correction: Chemotherapy with radiotherapy influences time-to-development of radiation-induced sarcomas: a multicenter study.

Since the publication of this paper, the authors noticed an error in Fig. 1. The X-axis on all the figure panels should read 'Time (years)', not 'Time (months)'. The corrected Fig. 1 is shown below.

Radiation-associated Pituitary Sarcoma

Background: Radiation therapy is commonly used as primary or adjuvant treatment for pituitary adenomas. Frequent side effects of this modality include hypopituitarism, visual disturbances, short-term memory loss and secondary tumors, sarcomas being among the rarest of the sellar region, with only 55 reported cases to date. Clinical Presentation: A 57-year old man with hypopituitarism and a 20-year history of a non-functioning pituitary macroadenoma subtotally resected four times and undergoing whole brain radiotherapy and bromocriptine, who developed acute visual deterioration due to compression of the optic chiasm by rapid growth of the residual tumor. An endoscopic transplanum approach was performed achieving gross total resection. Histopathological examination was consistent with an undifferentiated low-grade pituitary sarcoma. The patient’s vision improved after surgery, but healthcare-associated complications compromised his clinical outcome, succumbing to a pulmonary embolism a month after surgery. Conclusion: Radiation-induced pituitary sarcoma is a very rare complication of radiotherapy. There is no distinctive feature on imaging that can predict its occurrence. Prognosis is grim, without effective management and a mean survival of 6.5 months after diagnosis.

Radiation-induced chondrosarcoma of the scapula after radiotherapy for lung cancer: a case report and review of the literature

BackgroundRadiotherapy associated with chemotherapy is a well-established treatment modality for locally advanced non-small cell lung cancers. Radiation-induced second malignancies, particularly radiation-induced sarcomas, are rare. Some authors reported a recent increase in the incidence of this rare complication, especially because of the improved prognosis and survival of patients after radiotherapy. Pathogenic mechanisms of radiation-induced sarcomas are poorly understood. However, diagnosis criteria are well established. Treatment options must be discussed and adapted to the patient’s profile. Surgery in irradiated tissue is challenging, with limited treatment options with chemotherapy and radiotherapy.Case presentationWe report the case of a 62-year-old Moroccan man diagnosed as having chondrosarcoma of his right scapula, who was irradiated 10 years ago for stage IIIB non-small cell lung cancer. This case was managed by a complete resection of the tumor with good functional and oncological outcomes. To the best of our knowledge, the scapular location of radiation-induced sarcoma after irradiation for lung cancer has never been described in the literature.ConclusionRadiation-induced sarcoma of the scapula represents a rare situation that must be actively researched to have access to an optimal therapeutic approach.

Radiation-Induced CNS Pleomorphic Sarcoma after Adjuvant Therapy for Glioma

Radiation-Induced CNS Pleomorphic Sarcoma after Adjuvant Therapy for Glioma

Paclitaxel-dependent prolonged and persistent complete remission four years from first recurrence of secondary breast angiosarcoma.

Among angiosarcomas, radiation-induced breast sarcomas (RIBS) represent a well-known entity generally characterized by a poor outcome, especially in patients with advanced disease. Despite the unfavorable prognosis, some chemotherapeutic agents have been used to treat these malignancies, occasionally with success. Treatments with demonstrated activity against sarcomas include ifosfamide-based regimens and, more recently, taxane derivatives. We report a case of a patient having a secondary breast angiosarcoma recurring early after surgery, who achieved complete remission following treatment with weekly paclitaxel. After 4 years of maintenance therapy, with an interval between consecutive administrations of no longer than 3 weeks, the patient is still in complete remission. A locoregional recurrence was documented twice during this period, the first as a consequence of a brief treatment interruption and the second because of a treatment delay. Nonetheless, in both instances a new complete remission was rapidly achieved with the resumption of the same treatment, without evidence of any significant adverse effects. We discuss the highly unusual behavior of this malignancy and the possible role of the two different mechanisms of action of paclitaxel-antiangiogenic versus cytotoxic-depending on the schedule of administration, with evidence of "false" drug-resistance.

Salvage Carbon Ion Radiation Therapy for Locally Recurrent or Radiation-Induced Second Primary Sarcoma of the Head and Neck.

Purpose: Salvage radiation therapy (RT) is a potentially curative treatment option for head and neck sarcomas (HNS) that did not respond to previous treatment(s). We report the first clinical experience of carbon ion radiotherapy (CIRT) for salvage treatment of locally recurrent (LR) or RT-induced secondary HNS after surgery and/or radiotherapy.Methods and Materials: A retrospective analysis of the ongoing prospective data registries from the Shanghai Proton and Heavy Ion Center was conducted. Patients with LR-HNS who underwent surgery and/or RT and those with RT-induced second primary HNS were included. Acute and late toxicities were evaluated using the Common Terminology Criteria for Adverse Events version 4.0 and the Radiation Therapy Oncology Group late radiation toxicity scoring system, respectively. The actuarial 12-month local progression-free and overall survival rates (LPFS and OS) were calculated using the Kaplan-Meier method.Results: Between 10/2015 and 7/2017, 19 consecutive and non-selected patients with LR-HNS or RT-induced secondary HNS received definitive doses of CIRT delivered with pencil beam scanning technology for salvage. Six patients had locally recurrent soft-tissue sarcoma, and another 6 had chondrosarcoma. Among these 12 patients, 4 had received one prior course of RT. Seven additional patients had an RT-induced second primary soft tissue sarcoma (STS)/osteosarcoma after RT. The median time between the completion of initial treatment (either surgery only or surgery followed by adjuvant RT) and salvage CIRT was 30.6 months.The median follow-up time was 13.1 (range 1.6-41.1) months. All patients except one (for re-irradiation) completed the planned CIRT for salvage. The median dose of salvage CIRT was 60 GyE. Three patients developed local progression, and another 3 developed distant metastasis after salvage CIRT. Deaths occurred (3 patients) only in patients with radiation-induced second primary sarcoma at the time of analysis. The actuarial 12-month LPFS, DMFS and OS rates were 74.6%, 82.6% and 86.5%, respectively.Two patients irradiated for a second primary sarcoma had Grade 4 bleeding during CIRT, including one who experienced the rupture of an optic artery aneurysm unrelated to his disease or the salvage treatment. No patient had Grade 5 toxicity during treatment. Except for one patient who died of hemorrhage 3.5 months after the completion of CIRT, no moderate or severe late toxicities were observed.Conclusions: With few observed acute and late toxicities, salvage CIRT can provide effective short-term tumor control. Further research, preferably in a prospective fashion, will be required to confirm the efficacy and safety of salvage CIRT in this patient population.

Radiation-Induced Gliomas.

Radiation therapy has been a cornerstone of cancer management for many decades and is an integral part of the multi-modality care of patients with brain tumors. The known serious side effects of radiation therapy on the head or central nervous system are uncommon and include radiation necrosis, microangiopathy, and progressive leukencephalopathy. In addition, there have been descriptions of radiation-induced tumors including sarcomas, gliomas, lymphomas, and carcinomas of the thyroid. Patients who have received radiation therapy of the head or face may rarely develop radiation-induced tumors, a majority of which are meningiomas, followed by radiation-induced gliomas (RIGs) and sarcomas. The increased risk of RIGs is well described in both the pediatric and adult populations and after the use of both therapeutic and diagnostic radiations. The incidence of RIGs is estimated at approximately 0.5-2.7% at a latent period of approximately 15 years. The risk appears to be dependent on patient age at treatment, as well as radiation dose and treatment volume considerations. The scope of this review focuses on the etiology, clinical features, and management of RIGs as they relate to previous radiation therapy.

Radiation-induced undifferentiated pleomorphic sarcoma of the heart: A case report

Radiation-induced undifferentiated pleomorphic sarcoma of the heart: A case report

Sarcomas of the Breast

Sarcomas of the breast can be sporadic (primary) or secondary (postradiation). In this review, we discuss clinical presentation, imaging characteristics, diagnostic evaluation, and histologic classification of these rare tumors. Evidence-based management of breast sarcoma with regard to surgery, neoadjuvant or adjuvant chemotherapy and radiation, nodal staging, and outcomes are also discussed. Finally, a clinical case with radiologic and pathologic correlates is presented. This review contains 3 figures, 5 tables, and 44 references. Key words: angiosarcoma, breast sarcoma, radiation-induced sarcoma

Sarcomas of the Breast

Sarcomas of the breast can be sporadic (primary) or secondary (postradiation). In this review, we discuss clinical presentation, imaging characteristics, diagnostic evaluation, and histologic classification of these rare tumors. Evidence-based management of breast sarcoma with regard to surgery, neoadjuvant or adjuvant chemotherapy and radiation, nodal staging, and outcomes are also discussed. Finally, a clinical case with radiologic and pathologic correlates is presented. This review contains 3 figures, 5 tables, and 44 references. Key words: angiosarcoma, breast sarcoma, radiation-induced sarcoma

Chemotherapy with radiotherapy influences time-to-development of radiation-induced sarcomas: a multicenter study

Background:An increasing number and proportion of cancer patients with apparently localised disease are treated with chemotherapy and radiation therapy in contemporary oncology practice. In a pilot study of radiation-induced sarcoma (RIS) patients, we demonstrated that chemotherapy was associated with a reduced time to development of RIS. We now present a multi-centre collaborative study to validate this association.Methods:This was a retrospective cohort study of RIS cases across five large international sarcoma centres between 1 January 2000 to 31 December 2014. The primary endpoint was time to development of RIS.Results:We identified 419 patients with RIS. Chemotherapy for the first malignancy was associated with a shorter time to RIS development (HR 1.37; 95% CI: 1.08–1.72; P=0.009). In the multi-variable model, older age (HR 2.11; 95% CI 1.83–2.43; P<0.001) and chemotherapy for the first malignancy (HR 1.61; 95% CI 1.26–2.05; P<0·001) were independently associated with a shorter time to RIS. Anthracyclines and alkylating agents significantly contribute to the effect.Conclusions:This study confirms an association between chemotherapy given for the first malignancy and a shorter time to development of RIS.

Influence of chemotherapy combined with radiotherapy on the time-to-development of radiation-induced sarcomas: A multicenter, retrospective analysis.

11046 Background: An increasing number and proportion of cancer patients with apparently localised disease are treated with chemotherapy and radiation therapy in contemporary oncology practice. In a pilot study of radiation-induced sarcoma (RIS) patients, we demonstrated that chemotherapy was associated with a reduced time to development of RIS. We now present an international multi-centre collaborative study to validate this association. Methods: This was a retrospective cohort study of RIS cases across five large international sarcoma centres between the 1st January, 2000 to 31st December, 2014. The primary endpoint was time to development of RIS, defined as the date of diagnosis of the first malignancy to date of the RIS diagnosis. We also assessed the relationship between chemotherapy, patient and cancer characteristics, and time to RIS. Results: We identified 419 patients with RIS, who were predominantly diagnosed with their first malignancy at adulthood. The median interval from the index cancer to development of RIS for the entire cohort was 11 years (range 1-64). Chemotherapy for the first malignancy was associated with a shorter time to RIS development (HR 1·37; 95% CI: 1·08-1·72; P = 0·009). In the multi-variable model, older age (HR 2·11; CI 1·83-2·43; P &lt; 0·001) and chemotherapy for the first malignancy (HR 1·61; CI 1·26-2·05; P &lt; 0·001) were independently associated with a shorter time to RIS. Anthracyclines and alkylating agents significantly contribute to the effect. Conclusions: This study confirms an association between chemotherapy given for the first malignancy and a shorter time to development of a RIS. Our data highlights the importance of vigilance in surveillance for RIS after chemotherapy and radiation therapy, particularly in younger patients who also have a longer potential time to develop a second malignancy.

Survival and Margin Status in Head and Neck Radiation-Induced Sarcomas and De Novo Sarcomas.

Objective To describe histologic subtypes and oncologic outcomes among patients with radiation-induced and de novo sarcomas of the head and neck. Study Design Retrospective case series with chart review. Setting Tertiary academic center. Subject and Methods In total, 166 adult patients with sarcoma of the head and neck treated from January 1, 1985, to January 1, 2010, were included. Tumors were characterized as radiation induced (15.1%) vs de novo sarcomas (84.9%). Clinical and tumor characteristics were compared. The primary outcomes were overall survival (OS) and disease-specific survival (DSS). Results Radiation-induced sarcomas were more likely to be high grade ( P = .006) and advanced stage ( P = .03). Chondrosarcoma was more common in de novo tumors ( P = .02) while leiomyosarcoma ( P = .01), sarcoma not otherwise specified ( P = .02), and undifferentiated pleomorphic sarcoma ( P < .001) were more common in radiation-induced sarcomas. Radiation-induced sarcomas were associated with statistically significantly worse DSS ( P = .019) and OS ( P = .005) compared with de novo sarcomas, but when only high-grade soft tissue sarcomas were analyzed, neither DSS ( P = .48) nor OS ( P = .29) differed. Margin status was a significant predictor of survival as both R0 and R1 resections correlated with statistically better DSS and OS compared with R2 ( P < .001) resections and patients treated with radiation therapy/chemoradiation therapy alone ( P = .005). Conclusion Radiation-induced sarcomas of the head and neck correlate with worse survival compared with de novo tumors; however, when controlling for tumor grade and resection status, there is no statistically significant difference in observed outcomes.

Abstract #808: A Lethal Consequence of Radiotherapy: Radiation-Induced Sarcoma in a Patient with Giant Prolactinoma

Abstract #808: A Lethal Consequence of Radiotherapy: Radiation-Induced Sarcoma in a Patient with Giant Prolactinoma

Somatic and Germline TP53 Alterations in Second Malignant Neoplasms from Pediatric Cancer Survivors.

Purpose: Second malignant neoplasms (SMNs) are severe late complications that occur in pediatric cancer survivors exposed to radiotherapy and other genotoxic treatments. To characterize the mutational landscape of treatment-induced sarcomas and to identify candidate SMN-predisposing variants, we analyzed germline and SMN samples from pediatric cancer survivors.Experimental Design: We performed whole-exome sequencing (WES) and RNA sequencing on radiation-induced sarcomas arising from two pediatric cancer survivors. To assess the frequency of germline TP53 variants in SMNs, Sanger sequencing was performed to analyze germline TP53 in 37 pediatric cancer survivors from the Childhood Cancer Survivor Study (CCSS) without any history of a familial cancer predisposition syndrome but known to have developed SMNs.Results: WES revealed TP53 mutations involving p53's DNA-binding domain in both index cases, one of which was also present in the germline. The germline and somatic TP53-mutant variants were enriched in the transcriptomes for both sarcomas. Analysis of TP53-coding exons in germline specimens from the CCSS survivor cohort identified a G215C variant encoding an R72P amino acid substitution in 6 patients and a synonymous SNP A639G in 4 others, resulting in 10 of 37 evaluable patients (27%) harboring a germline TP53 variant.Conclusions: Currently, germline TP53 is not routinely assessed in patients with pediatric cancer. These data support the concept that identifying germline TP53 variants at the time a primary cancer is diagnosed may identify patients at high risk for SMN development, who could benefit from modified therapeutic strategies and/or intensive posttreatment monitoring. Clin Cancer Res; 23(7); 1852-61. ©2016 AACR.

Response to nivolumab in radiation induced, BRCA-2 N372H variant, programed death ligand-1 negative, pleomorphic undifferentiated sarcoma.

61 Background: Early results from recent studies using immune checkpoint blockade targeting programmed death 1 (PD-1) have suggested that pleomorphic undifferentiated sarcomas may have response rates of over 40%. As of now predictive biomarkers for response and resistance have been incompletely characterized. Methods: A 58-year-old man who received radiation for a head and neck squamous cell cancer, developed a radiation-induced undifferentiated pleomorphic sarcoma (UPS) in his neck in 2014. His sarcoma was resected but recurred in 2015. He received adjuvant radiation after surgical debulking in September 2015 and was found on radiation simulation scan to have new widespread metastatic disease involving liver, lung, and bone. He started treatment on nivolumab in November 2015 and has had a sustained near complete response in all lesions. Results: All sites had a near complete response to nivolumab treatment. Pre treatment tissue analysis revealed no mutations or amplifications in 134 cancer-related genes, on the Oncomine Assay (Life Technologies, Inc.). Normal tissue was noted to be heterozygous for BRCA2 N372H, while the allelic fraction of the 372H variant in the tumor was found to be 85%. Programmed death ligand-1 (PDL-1) immunohistochemistry staining of the tumor tissue was negative. Tumor infiltrating lymphocytes were not noted in the tumor tissue specimen. Conclusions: This patient exhibited a near complete response to all sites of disease, with remaining PET avidity in a single hilar node. The role of the BRCA2 variant and radiation just prior to starting nivolumab is unknown. BRCA2 N372H is a common single nucleotide polymorphism (SNP) in the population with a minor allele frequency of 0.25. Although the effect of the 372H variant on BRCA2 protein structure is predicted to be minimal, population studies have suggested a slightly increased risk of breast and ovarian cancer in homozygotes. It is possible that the radiation treatment to the site of recurrence in the head and neck, resulted in an abscopal effect enhancing the therapeutic effect of nivolumab therapy. Additional testing on his tissue is being done to further investigate the response.

舌下腺原発腺様囊胞癌治療後に発生した放射線誘発軟部肉腫の1例

The patient was a 79-year-old woman. In August 201X–15, she noted a mass in the floor of the mouth in the left mandibular molar region, and consulted the dental department of a local hospital. The resected mass was diagnosed as neurofibroma. Thereafter, in June 200X–6, she consulted our hospital primarily due to a mass and pain in the same site. In December of the same year, she underwent resection of the floor of the mouth, and the histopathological diagnosis of the resected specimen was primary adenoid cystic carcinoma of the sublingual gland. From January 200X–5, she received postoperative radiotherapy (total dose: 60Gy) and was followed-up. After 5 years, in April 201X, she noted swelling and pain of the floor of the mouth in the left mandibular region. Panoramic radiography showed a fracture line in the left mandible, and radiation-induced osteomyelitis of the mandible was suspected. Although she was treated with antimicrobial medication, around July of the same year, she was admitted to our department due to aggravation of the swelling of the left floor of the mouth and submental region. The mass was diagnosed histopathologically as soft tissue sarcoma, which was suspected to be myogenic, and was considered as radiation-induced sarcoma.

CT and MRI of radiation-induced osteosarcoma of the mandibular ramus following radiotherapy for nasopharyngeal carcinoma: A rare entity

Radiotherapy is the main treatment modality for nasopharyngeal carcinoma. However, ionizing radiation is itself a known carcinogen, and sarcomas can be a complication of treatment. Radiation-induced osteosarcomas in the head and neck are particular rare. Imaging studies of radiation-induced sarcomas in patients with head and neck carcinoma have been limited to case reports and relatively small case series. We report an unusual case of a radiation-induced osteosarcoma of the mandibular ramus following radiotherapy for nasopharyngeal carcinoma with computed tomography (CT) and magnetic resonance imaging (MRI). These findings can be helpful for differentiating osteosarcoma from other tumors of the mandible.

Radiation-induced sarcomas of the head and neck in post-radiation nasopharyngeal carcinoma

Radiation-induced sarcomas of the head and neck in post-radiation nasopharyngeal carcinoma