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Zhou Y, Li L, Lan F, Qin L, Huang D. Difficulties in the diagnosis and treatment of axillary malignant triton tumors: A case report. Oncol Lett 2025; 29:147. [PMID: 39877059 PMCID: PMC11774139 DOI: 10.3892/ol.2025.14893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 12/06/2024] [Indexed: 01/31/2025] Open
Abstract
Malignant triton tumor (MTT), a subtype of malignant peripheral nerve sheath tumor, is a rare soft-tissue sarcoma with a difficult diagnosis and poor prognosis. The course of MTT progression is rapid and the degree of malignancy is high. Patients with MTT can be treated with postoperative adjuvant radiotherapy and chemotherapy; however, treatment results are still poor. The present study describes a case of MTT of the axilla, which was diagnosed using histopathology with immunohistochemical staining and gene mutation detection. Complete surgical excision of the left axillary mass was performed in September 2023. Postoperative therapeutics included radiation therapy and deep hyperthermia; nine-field intensity-modulated radiation was delivered to the left axilla (46 Gy in 23 fractions over 5 weeks) and concurrent deep hyperthermia was performed three times per week for 5 weeks. In February 2024, the patient received oral anlotinib at a dose of 10 mg daily (before breakfast) for 2 weeks. It was demonstrated that a combination of surgery, radiation therapy, deep hyperthermia and targeted therapy may improve the survival of patients with MTT. After 1 month of comprehensive treatment, the patient's tumor had disappeared upon reexamination. As of the latest follow-up in October 2024, the patient had achieved a disease-free survival period of ~7 months, the patient was stable and remained on anlotinib treatment with good tolerance. With no standardized treatment recommendations available, the present study demonstrated that the combination of surgery, radiation therapy, deep hyperthermia and targeted therapy may provide a new strategy for the clinical treatment of MTT.
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Affiliation(s)
- Yanhua Zhou
- Department of Oncology, The Liuzhou Worker's Hospital, Liuzhou, Guangxi Zhuang Autonomous Region 545005, P.R. China
| | - Lu Li
- Department of Radiology, The Liuzhou Worker's Hospital, Liuzhou, Guangxi Zhuang Autonomous Region 545005, P.R. China
| | - Feifeng Lan
- Department of Oncology, The Liuzhou Worker's Hospital, Liuzhou, Guangxi Zhuang Autonomous Region 545005, P.R. China
| | - Li Qin
- Department of Oncology, The Liuzhou Worker's Hospital, Liuzhou, Guangxi Zhuang Autonomous Region 545005, P.R. China
| | - Dongning Huang
- Department of Oncology, The Liuzhou Worker's Hospital, Liuzhou, Guangxi Zhuang Autonomous Region 545005, P.R. China
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McAfee JL, Alban TJ, Makarov V, Rupani A, Parthasarathy PB, Tu Z, Ronen S, Billings SD, Diaz CM, Chan TA, Ko JS. Genomic Landscape of Superficial Malignant Peripheral Nerve Sheath Tumor. J Transl Med 2025; 105:102183. [PMID: 39532239 DOI: 10.1016/j.labinv.2024.102183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 09/28/2024] [Accepted: 10/27/2024] [Indexed: 11/16/2024] Open
Abstract
Superficial malignant peripheral nerve sheath tumors (SF-MPNSTs) are rare cancers and can be difficult to distinguish from spindle cell (SCM) or desmoplastic (DM) melanomas. Their biology is poorly understood. We performed whole-exome sequencing and RNA sequencing (RNA-seq) on SF-MPNST (n = 8) and compared them with cases of SCM (n = 7), DM (n = 8), and deep MPNST (D-MPNST, n = 8). Immunohistochemical staining for H3K27me3 and PRAME was also performed. SF-MPNST demonstrated intermediate features between D-MPNST and melanoma. Patients were younger than those with melanoma and older than those with D-MPNST; the outcome was worse and better, respectively. SF-MPNST tumor mutational burden (TMB) was higher than D-MPNST and lower than melanoma; differences were significant only between SF-MPNST and SCM (P = .0454) and between D-MPNST and SCM (P = .001, Dunn's Kruskal-Wallis post hoc test). Despite having an overlapping mutational profile in some common cancer-associated genes, the COSMIC mutational signatures clustered DM and SCM together with UV light exposure signatures (SBS7a, 7b), and SF- and D-MPNST together with defective DNA base excision repair (SBS30, 36). RNA-seq revealed differentially expressed genes between SF-MPNST and SCM (1670 genes), DM (831 genes), and D-MPNST (614 genes), some of which hold promise for development as immunohistochemical markers (SOX8 and PLCH1) or aids (MLPH, CALB2, SOX11, and TBX4). H3K27me3 immunoreactivity was diffusely lost in most D-MPNSTs (7/8, 88%) but showed variable and patchy loss in SF-MPNSTs (2/8, 25%). PRAME was entirely negative in the majority (0+ in 20/31, 65%), including 11/15 melanomas, and showed no significant difference between groups (P = .105, Kruskal-Wallis test). Expression of immune cell transcripts was upregulated in melanomas relative to MPNSTs. Next-generation sequencing revealed multiple differential features between SF- MPNST, D-MPNST, SCM, and DM, including tumor mutation burden, mutational signatures, and differentially expressed genes. These findings help advance our understanding of disease pathogenesis and improve diagnostic modalities.
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Affiliation(s)
- John L McAfee
- Department of Pathology, Cleveland Clinic Pathology and Laboratory Medicine Institute, Cleveland, Ohio
| | - Tyler J Alban
- Center for Immunotherapy and Precision Immuno-Oncology and Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Vladimir Makarov
- Center for Immunotherapy and Precision Immuno-Oncology and Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Amit Rupani
- Center for Immunotherapy and Precision Immuno-Oncology and Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Prerana B Parthasarathy
- Center for Immunotherapy and Precision Immuno-Oncology and Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Zheng Tu
- Department of Pathology, Cleveland Clinic Pathology and Laboratory Medicine Institute, Cleveland, Ohio
| | - Shira Ronen
- Department of Pathology, Cleveland Clinic Pathology and Laboratory Medicine Institute, Cleveland, Ohio
| | - Steven D Billings
- Department of Pathology, Cleveland Clinic Pathology and Laboratory Medicine Institute, Cleveland, Ohio
| | - C Marcela Diaz
- Center for Immunotherapy and Precision Immuno-Oncology and Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Timothy A Chan
- Center for Immunotherapy and Precision Immuno-Oncology and Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio; National Center for Regenerative Medicine, Cleveland, Ohio
| | - Jennifer S Ko
- Department of Pathology, Cleveland Clinic Pathology and Laboratory Medicine Institute, Cleveland, Ohio; Center for Immunotherapy and Precision Immuno-Oncology and Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
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Na K, Kim HJ. CD274/PD-L1 copy number gained malignant peripheral nerve sheath tumor: A case report and literature review. Medicine (Baltimore) 2025; 104:e41165. [PMID: 40184088 PMCID: PMC11709148 DOI: 10.1097/md.0000000000041165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 12/09/2024] [Accepted: 12/13/2024] [Indexed: 04/05/2025] Open
Abstract
RATIONALE Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas with a poor prognosis, particularly in metastatic cases. Traditional treatments have shown limited effectiveness, highlighting the need for innovative therapeutic approaches. This case report aims to emphasize the critical role of genomic profiling in identifying therapeutic targets, particularly immune checkpoint inhibitors, to improve treatment strategies for MPNST. PATIENT CONCERNS An 82-year-old male presented with a long-standing history of MPNST, multiple recurrences, and a recent rapid enlargement of a mass in the right axillary region. The patient also reported a 10% weight loss over the last 6 months. DIAGNOSES Comprehensive genomic profiling of the tumor revealed significant alterations, including CD274/PD-L1 amplification, CDKN2A loss, and TP53 mutation. These genetic findings were aligned with previous cases that responded favorably to immune checkpoint inhibitors. INTERVENTIONS Despite the potential for targeted immunotherapy, the patient's economic constraints prevented the initiation of immune checkpoint inhibitor therapy. The patient underwent multiple surgical interventions, including an above-elbow amputation. OUTCOMES The patient experienced severe wound bleeding and a significant decline in general condition, requiring intensive care unit support. Given the poor prognosis and high surgical risks, the patient's caregivers opted for hospice care. LESSONS Genomic profiling identifies genetic alterations that could guide immune checkpoint inhibitor therapy, offering the promise of personalized treatment for MPNST patients. By highlighting the potential of genomic profiling, this case demonstrates the importance of integrating personalized immunotherapy into future treatment paradigms for MPNST.
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Affiliation(s)
- Kiyong Na
- Department of Pathology, College of Medicine, Kyung Hee University Hospital, Seoul, Korea
| | - Hong Jun Kim
- Department of Medical Oncology, College of Medicine, Kyung Hee University Hospital, Seoul, Korea
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Williams KB, Larsson AT, Keller BJ, Chaney KE, Williams RL, Bhunia MM, Draper GM, Jubenville TA, Hudson WA, Moertel CL, Ratner N, Largaespada DA. Pharmacogenomic synthetic lethal screens reveal hidden vulnerabilities and new therapeutic approaches for treatment of NF1-associated tumors. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.25.585959. [PMID: 38585724 PMCID: PMC10996510 DOI: 10.1101/2024.03.25.585959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2024]
Abstract
Neurofibromatosis Type 1 (NF1) is a common cancer predisposition syndrome, caused by heterozygous loss of function mutations in the tumor suppressor gene NF1. Individuals with NF1 develop benign tumors of the peripheral nervous system (neurofibromas), originating from the Schwann cell linage after somatic loss of the wild type NF1 allele, some of which progress further to malignant peripheral nerve sheath tumors (MPNST). There is only one FDA approved targeted therapy for symptomatic plexiform neurofibromas and none approved for MPNST. The genetic basis of NF1 syndrome makes associated tumors ideal for using synthetic drug sensitivity approaches to uncover therapeutic vulnerabilities. We developed a drug discovery pipeline to identify therapeutics for NF1-related tumors using isogeneic pairs of NF1-proficient and deficient immortalized human Schwann cells. We utilized these in a large-scale high throughput screen (HTS) for drugs that preferentially kill NF1-deficient cells, through which we identified 23 compounds capable of killing NF1-deficient Schwann cells with selectivity. Multiple hits from this screen clustered into classes defined by method of action. Four clinically interesting drugs from these classes were tested in vivo using both a genetically engineered mouse model of high-grade peripheral nerve sheath tumors and human MPNST xenografts. All drugs tested showed single agent efficacy in these models as well as significant synergy when used in combination with the MEK inhibitor Selumetinib. This HTS platform yielded novel therapeutically relevant compounds for the treatment of NF1-associated tumors and can serve as a tool to rapidly evaluate new compounds and combinations in the future.
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Affiliation(s)
- Kyle B Williams
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Alex T Larsson
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Bryant J Keller
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Katherine E Chaney
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45229-0713, USA
| | - Rory L Williams
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Minu M Bhunia
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
- Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA
| | - Garrett M Draper
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Tyler A Jubenville
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Wendy A Hudson
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Christopher L Moertel
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Nancy Ratner
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45229-0713, USA
| | - David A Largaespada
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
- Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA
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Chen Y, Chen T, Zhu W, Li L, Fang C, Zhang H. Rare primary intrapulmonary malignant peripheral nerve sheath tumor showing significant response to sintilimab: A case report and literature review. Oncol Lett 2024; 28:423. [PMID: 39035047 PMCID: PMC11258603 DOI: 10.3892/ol.2024.14556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Accepted: 06/11/2024] [Indexed: 07/23/2024] Open
Abstract
Primary pulmonary malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue sarcoma with a low incidence, poor prognosis and limited treatment options. The present study reported a case of lung MPNST in a 63-year-old male patient without any pulmonary symptoms. Immunohistochemical analysis of the tumor indicated a programmed death-ligand 1 (PD-L1) expression tumor proportion score of 60%. A total of six courses of sintilimab were used in this patient and a remarkable response was achieved. In summary, sintilimab single-agent immunotherapy may be a novel treatment for pulmonary MPNST. When encountering analogous cases in the future, oncologists can test for the expression of PD-L1 in patients to guide the therapy's design.
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Affiliation(s)
- Yunqi Chen
- Oncology Department, Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Traditional Chinese Medicine, Zhongshan, Guangdong 528400, P.R. China
| | - Ting Chen
- Oncology Department, Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Traditional Chinese Medicine, Zhongshan, Guangdong 528400, P.R. China
| | - Wanshan Zhu
- Oncology Department, Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Traditional Chinese Medicine, Zhongshan, Guangdong 528400, P.R. China
| | - Luzhen Li
- Oncology Department, Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Traditional Chinese Medicine, Zhongshan, Guangdong 528400, P.R. China
| | - Cantu Fang
- Oncology Department, Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Traditional Chinese Medicine, Zhongshan, Guangdong 528400, P.R. China
| | - Huatang Zhang
- Oncology Department, Zhongshan Hospital of Traditional Chinese Medicine Affiliated to Guangzhou University of Traditional Chinese Medicine, Zhongshan, Guangdong 528400, P.R. China
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Chen Q, Cui H, Zheng K, Xu M, Yu X. Denosumab combined with chemotherapy followed by anlotinib in the treatment of multiple metastases of malignant peripheral nerve sheath tumor: a case report and literature review. Front Oncol 2024; 14:1399021. [PMID: 39119091 PMCID: PMC11306154 DOI: 10.3389/fonc.2024.1399021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 07/10/2024] [Indexed: 08/10/2024] Open
Abstract
Primary intraosseous malignant peripheral nerve sheath tumors (MPNSTs) are rare yet highly aggressive neoplasms originating from peripheral nerves. Typically manifesting as soft tissue masses accompanied by pain or functional impairment, these tumors pose significant challenges in management. Surgical intervention remains the cornerstone of treatment for patients with MPNST lacking distant metastasis, with generally modest success rates. In cases of recurrence and metastasis, the pursuit of effective systemic therapies has been a focus of clinical investigation. Herein, we present a case study involving an elderly female patient with refractory MPNST. In light of surgical limitations, a multimodal therapeutic approach combining chemotherapy, denosumab, and subsequent administration of anlotinib was pursued following collaborative consultation. This regimen yielded noteworthy clinical benefits, exemplifying a promising avenue in the management of challenging MPNST cases.
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Affiliation(s)
| | | | | | | | - Xiuchun Yu
- Department of Orthopedics, The 960th Hospital of the People’s Liberation Army, Jinan, Shandong, China
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Xi Z, Aobo Z, Li X, Yue W, Yan G, Lin Z, Zhang G, Xia X, Lian L, Li W. Radiotherapy and surgery remain effective treatment options for retroperitoneal MPNST: a retrospective study based on SEER database. Front Surg 2024; 11:1339170. [PMID: 38872723 PMCID: PMC11169571 DOI: 10.3389/fsurg.2024.1339170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 05/10/2024] [Indexed: 06/15/2024] Open
Abstract
Introduction The proportion of retroperitoneal malignant peripheral nerve sheath tumours (RMPNST) in retroperitoneal tumors is less than 5%, but the mortality rate is very high. However, there is no relevant research focused on RMPNST only. Methods We retrospectively analyzed data from the SEER database of patients with primary RMPNST from 2000 to 2019, by leveraging the advantages of the Seer database, we can explore the prognosis of such rare diseases. Kaplan-Meier method was used to construct the survival curve, and cox regression model was used to analyze the factors affecting the prognosis of patients. In addition, a model was developed to distinguish high-risk and low-risk patients. Results This study included a total of 52 patients, with a median survival time of 39 months (95% CI 12.740-65.260) and a 5-year survival rate of 44.2% (95% CI 0.299-0.565). Radiotherapy (p = 0.004, OR: 1.475, 95% CI 0.718-3.033), metastasis disease (p = 0.002, OR: 5.596, 95% CI 2.449-47.079) and surgery (p = 0.003, OR: 5.003, 95% CI 0.011-0.409) were associated with overall survival (OS). The 5-year distant metastasis rate was 36% (95% CI 0.221-0.499). We used the above risk factors to separate patients into high and low groups and evaluate the results through the receiver operating characteristic (ROC) curve. This model is beneficial for guiding the selection of treatment strategies. Conclusion The majority of RMPNST patients have a good prognosis after surgery, and the establishment of high-low group is helpful for clinical decision-making.
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Affiliation(s)
- Zhe Xi
- School of Medicine, Cancer Research Center, Xiang'an Hospital of Xiamen University, Xiamen University, Xiamen, Fujian, China
| | - Zhuang Aobo
- School of Medicine, Cancer Research Center, Xiang'an Hospital of Xiamen University, Xiamen University, Xiamen, Fujian, China
| | - Xi Li
- College of Arts and Science, Boston University, Boston, MA, United States
| | - Wang Yue
- School of Medicine, Cancer Research Center, Xiang'an Hospital of Xiamen University, Xiamen University, Xiamen, Fujian, China
| | - Guangting Yan
- School of Medicine, Cancer Research Center, Xiang'an Hospital of Xiamen University, Xiamen University, Xiamen, Fujian, China
| | - Zhenhang Lin
- School of Medicine, Cancer Research Center, Xiang'an Hospital of Xiamen University, Xiamen University, Xiamen, Fujian, China
| | - Geng Zhang
- School of Medicine, Cancer Research Center, Xiang'an Hospital of Xiamen University, Xiamen University, Xiamen, Fujian, China
| | - Xiaogang Xia
- Department of Hepatobiliary and Pancreatic & Organ Transplantation Surgery, School of Medicine, Xiang'an Hospital of Xiamen University, Xiamen University, Xiamen, Fujian, China
| | - Lanlan Lian
- Department of Laboratory Medicine, Xiang'an Hospital of Xiamen University, Xiamen University, Xiamen, Fujian, China
| | - Wengang Li
- School of Medicine, Cancer Research Center, Xiang'an Hospital of Xiamen University, Xiamen University, Xiamen, Fujian, China
- Department of Hepatobiliary and Pancreatic & Organ Transplantation Surgery, School of Medicine, Xiang'an Hospital of Xiamen University, Xiamen University, Xiamen, Fujian, China
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Rizvi SWA, Rizvi SAR, Qadri S, Khalid S, Siddiqui MA, Khan AA, Akhter A. Orbital malignant peripheral nerve sheath tumor: A case report and review. Oman J Ophthalmol 2024; 17:254-260. [PMID: 39132121 PMCID: PMC11309527 DOI: 10.4103/ojo.ojo_299_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 12/07/2023] [Accepted: 05/25/2024] [Indexed: 08/13/2024] Open
Abstract
Malignant peripheral nerve sheath tumor of the orbit is an exceedingly rare entity. These tumors exhibit locally aggressive behavior, recurrences, distant metastasis, and poor response to existing treatment protocols. Orbital nerve sheath tumors are often associated with neurofibromatosis 1, and malignant transformation of neurofibroma into malignant nerve sheath tumor has also been seen. The recommended treatment for localized disease is radical or wide surgical excision to achieve negative margins followed by chemoradiation. For extensive disease, chemotherapy and radiotherapy can be utilized to stabilize the disease. Due to poor response and outcomes with current regimens, the focus has been shifted to approaches utilizing molecular targets and immunological agents. Despite all the advancements, the outcomes still remain discouraging for moderate- to high-grade lesions and thus necessitate studies to design promising treatment modalities.
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Affiliation(s)
- Syed Wajahat Ali Rizvi
- Department of Ophthalmology, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | | | - Shagufta Qadri
- Department of Pathology, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - Saifullah Khalid
- Department of Radiology, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | | | - Adeeb Alam Khan
- Department of Ophthalmology, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - Afeefa Akhter
- Department of Ophthalmology, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
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Jansma CYMN, Acem I, Grünhagen DJ, Verhoef C, Martin E. Local recurrence in malignant peripheral nerve sheath tumours: multicentre cohort study. BJS Open 2024; 8:zrae024. [PMID: 38620136 PMCID: PMC11018273 DOI: 10.1093/bjsopen/zrae024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Accepted: 01/29/2024] [Indexed: 04/17/2024] Open
Abstract
BACKGROUND Malignant peripheral nerve sheath tumours (MPNSTs) have high local recurrence (LR) rates. Literature varies on LR risk factors and treatment. This study aimed to elucidate treatment options and risk factors for first and second LRs (LR1 and LR2) in a large multicentre cohort. METHOD Surgically treated primary MPNSTs between 1988 and 2019 in the MONACO multicentre cohort were included. Cox regression analysed LR1 and LR2 risk factors and overall survival (OS) after LR1. Treatment of LR1 and LR2 was evaluated. RESULTS Among 507 patients, 28% developed LR1. Median follow-up was 66.9 months, and for survivors 111.1 months. Independent LR1 risk factors included high-grade tumours (HR 2.63; 95% c.i. 1.15 to 5.99), microscopically positive margins (HR 2.19; 95% c.i. 1.51 to 3.16) and large tumour size (HR 2.14; 95% c.i. 1.21 to 3.78). Perioperative radiotherapy (HR 0.62; 95% c.i. 0.43 to 0.89) reduced the risk. LR1 patients had poorer OS. Synchronous metastasis worsened OS (HR 1.79; 95% c.i. 1.02 to 3.14) post-LR1, while surgically treated LR was associated with better OS (HR 0.38; 95% c.i. 0.22 to 0.64) compared to non-surgical cases. Two-year survival after surgical treatment was 71% (95% c.i. 63 to 82%) versus 28% (95% c.i. 18 to 44%) for non-surgical LR1 patients. Most LR1 (75.4%) and LR2 (73.7%) patients received curative-intent treatment, often surgery alone (64.9% versus 47.4%). Radiotherapy combined with surgery was given to 11.3% of LR1 and 7.9% of LR2 patients. CONCLUSION Large, high-grade MPNSTs with R1 resections are at higher LR1 risk, potentially reduced by radiotherapy. Surgically treated recurrences may provide improved survival in highly selected cases.
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Affiliation(s)
- Christianne Y M N Jansma
- Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
- Department of Plastic and Reconstructive Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Ibtissam Acem
- Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Dirk J Grünhagen
- Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Cornelis Verhoef
- Department of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Enrico Martin
- Department of Plastic and Reconstructive Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
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Ozden SB, Simsekoglu MF, Sertbudak I, Demirdag C, Gurses I. Epithelioid malignant peripheral nerve sheath tumor of the bladder and concomitant urothelial carcinoma: A case report. World J Clin Cases 2024; 12:551-559. [PMID: 38322457 PMCID: PMC10841956 DOI: 10.12998/wjcc.v12.i3.551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 08/08/2023] [Accepted: 08/17/2023] [Indexed: 01/18/2024] Open
Abstract
BACKGROUND Epithelioid malignant peripheral nerve sheath tumor (EMPNST) of the bladder is a rare entity with devastating features. These tumors are thought to originate from malignant transformation of pre-existing schwannomas of pelvic autonomic nerve plexuses, and unlike the conventional malignant peripheral nerve sheath tumor (MPNST), are not associated with neurofibromatosis. The tumor has distinctive morphological, immunohistochemical and molecular features. Additionally, it tends to be more aggressive and have a higher mortality. This is the first case that presents with a synchronous urothelial carcinoma of the bladder and the epithelioid variant of MPNST in the literature. It's also the second reported case of EMPNST originating from the bladder wall. CASE SUMMARY In this case report, we present the detailed clinical course of a 71-year-old patient with EMPNST of the bladder alongside a literature review. CONCLUSION During the management of EMPNST cases, offering aggressive treatment modalities to the patient, such as radical cystectomy, is appropriate for the best chance to contain the disease, regardless of the tumor stage and the extent of local disease at initial diagnosis.
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Affiliation(s)
- Sami Berk Ozden
- Istanbul University-Cerrahpasa, Cerrahpasa School of Medicine Department of Urology, Istanbul 34100, Fatih, Turkey
| | - Muhammed Fatih Simsekoglu
- Istanbul University-Cerrahpasa, Cerrahpasa School of Medicine Department of Urology, Istanbul 34100, Fatih, Turkey
| | - Ipek Sertbudak
- Istanbul University-Cerrahpasa, Cerrahpasa School of Medicine Department of Pathology, Istanbul 34100, Fatih, Turkey
| | - Cetin Demirdag
- Istanbul University-Cerrahpasa, Cerrahpasa School of Medicine Department of Urology, Istanbul 34100, Fatih, Turkey
| | - Iclal Gurses
- Istanbul University-Cerrahpasa, Cerrahpasa School of Medicine Department of Pathology, Istanbul 34100, Fatih, Turkey
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Høland M, Berg KCG, Eilertsen IA, Bjerkehagen B, Kolberg M, Boye K, Lingjærde OC, Guren TK, Mandahl N, van den Berg E, Palmerini E, Smeland S, Picci P, Mertens F, Sveen A, Lothe RA. Transcriptomic subtyping of malignant peripheral nerve sheath tumours highlights immune signatures, genomic profiles, patient survival and therapeutic targets. EBioMedicine 2023; 97:104829. [PMID: 37837931 PMCID: PMC10585232 DOI: 10.1016/j.ebiom.2023.104829] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Revised: 09/26/2023] [Accepted: 09/26/2023] [Indexed: 10/16/2023] Open
Abstract
BACKGROUND Malignant peripheral nerve sheath tumour (MPNST) is an aggressive orphan disease commonly affecting adolescents or young adults. Current knowledge of molecular tumour biology has been insufficient for development of rational treatment strategies. We aimed to discover molecular subtypes of potential clinical relevance. METHODS Fresh frozen samples of MPNSTs (n = 94) and benign neurofibromas (n = 28) from 115 patients in a European multicentre study were analysed by DNA copy number and/or transcriptomic profiling. Unsupervised transcriptomic subtyping was performed and the subtypes characterized for genomic aberrations, clinicopathological associations and patient survival. FINDINGS MPNSTs were classified into two transcriptomic subtypes defined primarily by immune signatures and proliferative processes. "Immune active" MPNSTs (44%) had sustained immune signals relative to neurofibromas, were more frequently low-grade (P = 0.01) and had favourable prognostic associations in a multivariable model of disease-specific survival with clinicopathological factors (hazard ratio 0.25, P = 0.003). "Immune deficient" MPNSTs were more aggressive and characterized by proliferative signatures, high genomic complexity, aberrant TP53 and PRC2 loss, as well as high relative expression of several potential actionable targets (EGFR, ERBB2, EZH2, KIF11, PLK1, RRM2). Integrated gene-wise analyses suggested a DNA copy number-basis for proliferative transcriptomic signatures in particular, and the tumour copy number burden further stratified the transcriptomic subtypes according to patient prognosis (P < 0.01). INTERPRETATION Approximately half of MPNSTs belong to an "immune deficient" transcriptomic subtype associated with an aggressive disease course, PRC2 loss and expression of several potential therapeutic targets, providing a rationale for molecularly-guided intervention trials. FUNDING Research grants from non-profit organizations, as stated in the Acknowledgements.
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Affiliation(s)
- Maren Høland
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Institute for Clinical Medicine, University of Oslo, Oslo, Norway
| | - Kaja C G Berg
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Ina A Eilertsen
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Bodil Bjerkehagen
- Institute for Clinical Medicine, University of Oslo, Oslo, Norway; Division of Laboratory Medicine, Department of Pathology, Oslo University Hospital, Oslo, Norway
| | - Matthias Kolberg
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Kjetil Boye
- Division of Cancer Medicine, Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - Ole Christian Lingjærde
- Department of Informatics, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway
| | - Tormod K Guren
- Division of Cancer Medicine, Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - Nils Mandahl
- Department of Clinical Genetics, University and Regional Laboratories, Lund University, Lund, Sweden
| | - Eva van den Berg
- Department of Genetics, The University Medical Center Groningen, the Netherlands
| | - Emanuela Palmerini
- Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Sigbjørn Smeland
- Institute for Clinical Medicine, University of Oslo, Oslo, Norway; Division of Cancer Medicine, Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - Piero Picci
- Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Fredrik Mertens
- Department of Clinical Genetics, University and Regional Laboratories, Lund University, Lund, Sweden
| | - Anita Sveen
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Institute for Clinical Medicine, University of Oslo, Oslo, Norway
| | - Ragnhild A Lothe
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Institute for Clinical Medicine, University of Oslo, Oslo, Norway.
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12
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Chung MH, Aimaier R, Yu Q, Li H, Li Y, Wei C, Gu Y, Wang W, Guo Z, Long M, Li Q, Wang Z. RRM2 as a novel prognostic and therapeutic target of NF1-associated MPNST. Cell Oncol (Dordr) 2023; 46:1399-1413. [PMID: 37086345 DOI: 10.1007/s13402-023-00819-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/18/2023] [Indexed: 04/23/2023] Open
Abstract
BACKGROUND Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that typically develop in the setting of neurofibromatosis type 1 (NF1) and cause significant morbidity. Conventional therapies are often ineffective for MPNSTs. Ribonucleotide reductase subunit M2 (RRM2) is involved in DNA synthesis and repair, and is overexpressed in multiple cancers. However, its role in NF1-associated MPNSTs remains unknown. Our objective was to determine the therapeutic and prognostic potential of RRM2 in NF1-associated MPNSTs. METHODS Identification of hub genes was performed by using NF1-associated MPNST microarray datasets. We detected RRM2 expression by immunochemical staining in an MPNST tissue microarray, and assessed the clinical and prognostic significance of RRM2 in an MPNST cohort. RRM2 knockdown and the RRM2 inhibitor Triapine were used to assess cell proliferation and apoptosis in NF1-associated MPNST cells in vitro and in vivo. The underlying mechanism of RRM2 in NF1-associated MPNST was revealed by transcriptome analysis. RESULTS RRM2 is a key hub gene and its expression is significantly elevated in NF1-associated MPNST. We revealed that high RRM2 expression accounted for a larger proportion of NF1-associated MPNSTs and confirmed the correlation of high RRM2 expression with poor overall survival. Knockdown of RRM2 inhibited NF1-associated MPNST cell proliferation and promoted apoptosis and S-phase arrest. The RRM2 inhibitor Triapine displayed dose-dependent inhibitory effects in vitro and induced significant tumor growth reduction in vivo in NF1-associated MPNST. Analysis of transcriptomic changes induced by RRM2 knockdown revealed suppression of the AKT-mTOR signaling pathway. Overexpression of RRM2 activates the AKT pathway to promote NF1-associated MPNST cell proliferation. CONCLUSIONS RRM2 expression is significantly elevated in NF1-associated MPNST and that high RRM2 expression correlates with poorer outcomes. RRM2 acts as an integral part in the promotion of NF1-associated MPNST cell proliferation via the AKT-mTOR signaling pathway. Inhibition of RRM2 may be a promising therapeutic strategy for NF1-associated MPNST.
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Affiliation(s)
- Man-Hon Chung
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Rehanguli Aimaier
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Qingxiong Yu
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Haibo Li
- Department of Plastic Surgery, The Third Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Yuehua Li
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Chengjiang Wei
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Yihui Gu
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Wei Wang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Zizhen Guo
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Manmei Long
- Department of Pathology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Qingfeng Li
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
| | - Zhichao Wang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
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13
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González-Muñoz T, Di Giannatale A, García-Silva S, Santos V, Sánchez-Redondo S, Savini C, Graña-Castro O, Blanco-Aparicio C, Fischer S, De Wever O, Creus-Bachiller E, Ortega-Bertran S, Pisapia DJ, Rodríguez-Peralto JL, Fernández-Rodríguez J, Pérez-Portabella CR, Alaggio R, Benassi MS, Pazzaglia L, Scotlandi K, Ratner N, Yohay K, Theuer CP, Peinado H. Endoglin, a Novel Biomarker and Therapeutical Target to Prevent Malignant Peripheral Nerve Sheath Tumor Growth and Metastasis. Clin Cancer Res 2023; 29:3744-3758. [PMID: 37432984 DOI: 10.1158/1078-0432.ccr-22-2462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 10/18/2022] [Accepted: 07/06/2023] [Indexed: 07/13/2023]
Abstract
PURPOSE Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive soft-tissue sarcomas that lack effective treatments, underscoring the urgent need to uncover novel mediators of MPNST pathogenesis that may serve as potential therapeutic targets. Tumor angiogenesis is considered a critical event in MPNST transformation and progression. Here, we have investigated whether endoglin (ENG), a TGFβ coreceptor with a crucial role in angiogenesis, could be a novel therapeutic target in MPNSTs. EXPERIMENTAL DESIGN ENG expression was evaluated in human peripheral nerve sheath tumor tissues and plasma samples. Effects of tumor cell-specific ENG expression on gene expression, signaling pathway activation and in vivo MPNST growth and metastasis, were investigated. The efficacy of ENG targeting in monotherapy or in combination with MEK inhibition was analyzed in xenograft models. RESULTS ENG expression was found to be upregulated in both human MPNST tumor tissues and plasma-circulating small extracellular vesicles. We demonstrated that ENG modulates Smad1/5 and MAPK/ERK pathway activation and pro-angiogenic and pro-metastatic gene expression in MPNST cells and plays an active role in tumor growth and metastasis in vivo. Targeting with ENG-neutralizing antibodies (TRC105/M1043) decreased MPNST growth and metastasis in xenograft models by reducing tumor cell proliferation and angiogenesis. Moreover, combination of anti-ENG therapy with MEK inhibition effectively reduced tumor cell growth and angiogenesis. CONCLUSIONS Our data unveil a tumor-promoting function of ENG in MPNSTs and support the use of this protein as a novel biomarker and a promising therapeutic target for this disease.
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Affiliation(s)
- Teresa González-Muñoz
- Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Angela Di Giannatale
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Susana García-Silva
- Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Vanesa Santos
- Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Sara Sánchez-Redondo
- Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Claudia Savini
- Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
- Patients in Science, Medical Writing and Communication, Valencia, Spain
| | - Osvaldo Graña-Castro
- Bioinformatics Unit, Structural Biology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Carmen Blanco-Aparicio
- Experimental Therapeutics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Suzanne Fischer
- Laboratory of Experimental Cancer Research, Cancer Research Institute Ghent, Ghent, Belgium
- Department of Human Structure and Repair, Ghent University, Ghent, Belgium
| | - Olivier De Wever
- Laboratory of Experimental Cancer Research, Cancer Research Institute Ghent, Ghent, Belgium
- Department of Human Structure and Repair, Ghent University, Ghent, Belgium
| | - Edgar Creus-Bachiller
- Hereditary Cancer Program, Catalan Institute of Oncology, Hospitalet de Llobregat, Barcelona, Spain
- Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
| | - Sara Ortega-Bertran
- Hereditary Cancer Program, Catalan Institute of Oncology, Hospitalet de Llobregat, Barcelona, Spain
- Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
| | - David J Pisapia
- Englander Institute of Precision Medicine, Weill Cornell Medicine, New York, New York
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York
| | - Jose L Rodríguez-Peralto
- Department of Dermatology, 12 de Octubre University Hospital, Complutense University of Madrid, Investigation institute I+12, CIBERONC, Madrid, Spain
| | - Juana Fernández-Rodríguez
- Hereditary Cancer Program, Catalan Institute of Oncology, Hospitalet de Llobregat, Barcelona, Spain
- Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Plataforma Mouse Lab, Servicios Científico-Técnicos, IDIBELL, l'Hospitalet de Llobregat, Barcelona, Spain
| | | | - Rita Alaggio
- Pathology Unit, Department of Laboratories, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
- Department of Medical-Surgical Sciences and Biotechnologies La Sapienza University, Rome, Italy
| | - Maria Serena Benassi
- Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Laura Pazzaglia
- Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Katia Scotlandi
- Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Nancy Ratner
- Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Kaleb Yohay
- New York University Grossman School of Medicine, New York, New York
| | | | - Héctor Peinado
- Microenvironment and Metastasis Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
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14
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Rahouma M, Baudo M, Khairallah S, Dabsha A, Tafuni A, El-Sayed Ahmed MM, Lau C, Iannacone E, Naka Y, Girardi L, Gaudino M, Lorusso R, Mick SL. Primary Cardiac Schwannoma: A Meta-Analysis of Individual Case Reports. J Clin Med 2023; 12:jcm12103356. [PMID: 37240461 DOI: 10.3390/jcm12103356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 04/27/2023] [Accepted: 05/05/2023] [Indexed: 05/28/2023] Open
Abstract
Primary cardiac schwannoma (PCS) is a neurogenic tumor that arises from Schwann cells. Malignant schwannoma (MSh) is an aggressive cancer comprising 2% of all sarcomas. Information on the proper management of these tumors is limited. Four databases were searched for case reports/series of PCS. The primary outcome was overall survival (OS). Secondary outcomes included therapeutic strategies and the corresponding outcomes. Among 439 potentially eligible studies, 53 met the inclusion criteria. The patients included had 43.72 ± 17.76 years and 28.3% were males. Over 50% of patients had MSh, with 9.4% also demonstrating metastases. Schwannoma commonly occurs in the atria (66.0%). Left-sided PCS were more common than right-sided ones. Surgery was performed in almost 90% of the cases; chemotherapy and radiotherapy were used in 16.9% and 15.1% of cases, respectively. Compared to benign cases, MSh occurs at a younger age and is commonly located on the left side. OS of the entire cohort at 1 and 3 years were 60.7%, and 54.0%, respectively. Females and males OS were similar up to 2 years follow-up. Surgery was associated with higher OS (p < 0.01). Surgery is the primary treatment option for both benign and malignant cases and was the only factor associated with a relative improvement in survival.
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Affiliation(s)
- Mohamed Rahouma
- Cardiothoracic Surgery Department, Weill Cornell Medicine, New York, NY 10065, USA
- Surgical Oncology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt
| | - Massimo Baudo
- Cardiothoracic Surgery Department, Weill Cornell Medicine, New York, NY 10065, USA
- Cardiac Surgery Department, Spedali Civili di Brescia, University of Brescia, 25123 Brescia, Italy
| | - Sherif Khairallah
- Cardiothoracic Surgery Department, Weill Cornell Medicine, New York, NY 10065, USA
- Surgical Oncology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt
| | - Anas Dabsha
- Cardiothoracic Surgery Department, Weill Cornell Medicine, New York, NY 10065, USA
- Surgical Oncology Department, National Cancer Institute, Cairo University, Cairo 11796, Egypt
| | - Alessandro Tafuni
- Unit of Pathology, Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
| | - Magdy M El-Sayed Ahmed
- Cardiothoracic Surgery Department, Mayo Clinic, Jacksonville, FL 32224, USA
- Department of Surgery, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Christopher Lau
- Cardiothoracic Surgery Department, Weill Cornell Medicine, New York, NY 10065, USA
| | - Erin Iannacone
- Cardiothoracic Surgery Department, Weill Cornell Medicine, New York, NY 10065, USA
| | - Yoshifumi Naka
- Cardiothoracic Surgery Department, Weill Cornell Medicine, New York, NY 10065, USA
| | - Leonard Girardi
- Cardiothoracic Surgery Department, Weill Cornell Medicine, New York, NY 10065, USA
| | - Mario Gaudino
- Cardiothoracic Surgery Department, Weill Cornell Medicine, New York, NY 10065, USA
| | - Roberto Lorusso
- Department of Cardio-Thoracic Surgery, Maastricht University Medical Centre, Maastricht University, 6202 AZ Maastricht, The Netherlands
- Cardiovascular Research Institute Maastricht, 6229 ER Maastricht, The Netherlands
| | - Stephanie L Mick
- Cardiothoracic Surgery Department, Weill Cornell Medicine, New York, NY 10065, USA
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15
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Dapper H, Diehl C, Knebel C, Mogler C, Borm K, Dobiasch S, Combs SE, Peeken JC. Outcome of patients with soft tissue sarcomas of the extremities and trunk treated by (neo)adjuvant intensity modulated radiation therapy with curative intent. Radiat Oncol 2023; 18:44. [PMID: 36869396 PMCID: PMC9985237 DOI: 10.1186/s13014-023-02238-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 02/25/2023] [Indexed: 03/05/2023] Open
Abstract
BACKGROUND Soft tissue sarcomas (STS) are a relatively rare group of malignant tumors. Currently, there is very little published clinical data, especially in the context of curative multimodal therapy with image-guided, conformal, intensity-modulated radiotherapy. METHODS Patients who received preoperative or postoperative intensity-modulated radiotherapy for STS of the extremities or trunk with curative intent were included in this single centre retrospective analysis. A Kaplan-Meier analysis was performed to evaluate survival endpoints. Multivariable proportional hazard models were used to investigate the association between survival endpoints and tumour-, patient-, and treatment-specific characteristics. RESULTS 86 patients were included in the analysis. The most common histological subtypes were undifferentiated pleomorphic high-grade sarcoma (UPS) (27) and liposarcoma (22). More than two third of the patients received preoperative radiation therapy (72%). During the follow-up period, 39 patients (45%) suffered from some type of relapse, mainly remote (31%). The two-years overall survival rate was 88%. The median DFS was 48 months and the median DMFS was 51 months. Female gender (HR 0.460 (0.217; 0.973)) and histology of liposarcomas compared to UPS proved to be significantly more favorable in terms of DFS (HR 0.327 (0.126; 0.852)). CONCLUSION Conformal, intensity-modulated radiotherapy is an effective treatment modality in the preoperative or postoperative management of STS. Especially for the prevention of distant metastases, the establishment of modern systemic therapies or multimodal therapy approaches is necessary.
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Affiliation(s)
- Hendrik Dapper
- Department of Radiotherapy and Radiation Oncology, Public Hospital of Bielefeld, University Medical Center East Westphalia-Lippe, Bielefeld, Germany. .,Department of Radiation Oncology, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany.
| | - Christian Diehl
- Department of Radiation Oncology, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany
| | - Carolin Knebel
- Department of Orthopaedic Surgery, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany
| | - Carolin Mogler
- Institute of Pathology, Klinikum Rechts der Isar, School of Medicine, Technical University Munich, Munich, Germany
| | - Kai Borm
- Department of Radiation Oncology, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany
| | - Sophie Dobiasch
- Department of Radiation Oncology, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany.,Deutsches Konsortium Für Translationale Krebsforschung (DKTK), Partner Site , Munich, Germany.,Institute for Radiation Medicine (IRM), Helmholtz Zentrum München, Ingolstädter Landstr. 1, Neuherberg, Germany
| | - Stephanie E Combs
- Department of Radiation Oncology, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany.,Deutsches Konsortium Für Translationale Krebsforschung (DKTK), Partner Site , Munich, Germany.,Institute for Radiation Medicine (IRM), Helmholtz Zentrum München, Ingolstädter Landstr. 1, Neuherberg, Germany
| | - Jan C Peeken
- Department of Radiation Oncology, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany.,Deutsches Konsortium Für Translationale Krebsforschung (DKTK), Partner Site , Munich, Germany.,Institute for Radiation Medicine (IRM), Helmholtz Zentrum München, Ingolstädter Landstr. 1, Neuherberg, Germany
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16
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Jayaprakash D, Rathod P, Bhatt S, Sharma A. Unusual Presentation of Malignant Peripheral Nerve Sheath Tumour of Mandible as a Colossal Tumour After Neoadjuvant Chemotherapy. Indian J Otolaryngol Head Neck Surg 2022; 74:5893-5896. [PMID: 36742595 PMCID: PMC9895656 DOI: 10.1007/s12070-021-02477-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 02/16/2021] [Indexed: 02/07/2023] Open
Abstract
The uniqueness of this case is the presentation of malignant peripheral nerve sheath tumors arising from the mandible as a colossal tumor of size of about 28 cm and weight of 1.5 kg after the first cycle of neoadjuvant chemotherapy. Role of neoadjuvant chemotherapy remains controversial and can be avoided if margin negative resection is feasible.
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Affiliation(s)
- Dipin Jayaprakash
- Department Of Surgical Oncology, Gujarat Cancer and Research Institute, Ahmedabad, Gujarat India
| | - Priyank Rathod
- Department Of Surgical Oncology, Gujarat Cancer and Research Institute, Ahmedabad, Gujarat India
| | - Supreet Bhatt
- Department Of Surgical Oncology, Gujarat Cancer and Research Institute, Ahmedabad, Gujarat India
| | - Ankit Sharma
- Department Of Surgical Oncology, Gujarat Cancer and Research Institute, Ahmedabad, Gujarat India
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17
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Bachmann N, Leiser D, Pica A, Bachtiary B, Weber DC. Clinical Outcome After Pencil Beam Scanning Proton Therapy of Patients With Non-Metastatic Malignant and Benign Peripheral Nerve Sheath Tumors. Front Oncol 2022; 12:881665. [PMID: 35832560 PMCID: PMC9271998 DOI: 10.3389/fonc.2022.881665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 05/20/2022] [Indexed: 11/13/2022] Open
Abstract
ObjectivePeripheral nerve sheath tumors (PNSTs) commonly arise from peripheral nerve roots and grow locally invasive. Malignant PNSTs (mPNSTs) represent aggressive sarcomas of neural origin that can originate from PNSTs. Radiation therapy is commonly used as part of the required multimodal treatment. However, both entities tend to occur early in life and are associated with the genetic disorder neurofibromatosis type 1 (NF-1), which is known to cause increased radiosensitivity. Pencil beam scanning proton therapy (PBSPT) allows for a minimization of the dose delivered to organs at risk and the integral dose and, thus, potentially also a reduction of radiation-induced adverse events. We report the clinical outcome and toxicity rates of patients with (m)PNSTs treated with PBSPT.MethodsWe retrospectively reviewed 36 patients who received PBSPT (median dose, 64 GyRBE) with curative intent for (m)PNSTs between 1999 and 2020 at our institute. Twenty-eight (78%) and 8 (22%) patients were treated at diagnosis and for tumor recurrence/progression, respectively. The median age was 32 years (range, 3–75), and 25 (69%) patients were male. mPNST and PNST were diagnosed in 31 (86%) and 5 (14%) patients, respectively. Underlying NF-1 disease was found in 8 (22%) patients. Acute and late toxicities were recorded according to Common Terminology Criteria for Adverse Events, version 4.1 (CTCAE v4.1). Overall survival (OS), local control (LC), and distant control (DC) were estimated using the Kaplan–Meier method.ResultsWith a median follow-up time of 31 months (range, 4–194), 13 (36%) patients died from a progressive disease, 8 (22%) experienced local failure, and 14 (39%) experienced distant failure after PBSPT. Estimated 2-year OS, LC, and DC were 75.5%, 73.5%, and 61.2%, respectively. Acute grade 3 toxicity (dermatitis, mucositis, and pain) was observed in 5 (14%) patients. Late grade 3 cataract and osteonecrosis were both observed in 1 (3%) patient at 34 and 194 months after PBSPT, respectively. There was no late grade >3 toxicity or radiation-induced secondary cancer.ConclusionTo our knowledge, this is the first study to analyze the outcome of (m)PNSTs treated with proton therapy using a PBS delivery paradigm. In our cohort, consisting mainly of patients with mPNSTs, we report reasonable oncological outcomes and low toxicity rates after PBSPT.
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Affiliation(s)
- Nicolas Bachmann
- Center for Proton Therapy, Paul Scherrer Institute, ETH Domain, Villigen, Switzerland
- Department of Radiation Oncology, Inselspital, Bern University Hospital, Bern, Switzerland
| | - Dominic Leiser
- Center for Proton Therapy, Paul Scherrer Institute, ETH Domain, Villigen, Switzerland
| | - Alessia Pica
- Center for Proton Therapy, Paul Scherrer Institute, ETH Domain, Villigen, Switzerland
| | - Barbara Bachtiary
- Center for Proton Therapy, Paul Scherrer Institute, ETH Domain, Villigen, Switzerland
| | - Damien C. Weber
- Center for Proton Therapy, Paul Scherrer Institute, ETH Domain, Villigen, Switzerland
- Department of Radiation Oncology, Inselspital, Bern University Hospital, Bern, Switzerland
- Department of Radiation Oncology, University Hospital of Zürich, Zürich, Switzerland
- *Correspondence: Damien C. Weber, ;
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18
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Bhalla AD, Landers SM, Singh AK, Landry JP, Yeagley MG, Myerson GSB, Delgado-Baez CB, Dunnand S, Nguyen T, Ma X, Bolshakov S, Menegaz BA, Lamhamedi-Cherradi SE, Mao X, Song X, Lazar AJ, McCutcheon IE, Slopis JM, Ludwig JA, Lev DC, Rai K, Torres KE. Experimental models of undifferentiated pleomorphic sarcoma and malignant peripheral nerve sheath tumor. J Transl Med 2022; 102:658-666. [PMID: 35228656 PMCID: PMC11959861 DOI: 10.1038/s41374-022-00734-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/29/2021] [Accepted: 01/06/2022] [Indexed: 12/19/2022] Open
Abstract
Undifferentiated pleomorphic sarcoma (UPS) and malignant peripheral nerve sheath tumor (MPNST) are aggressive soft tissue sarcomas that do not respond well to current treatment modalities. The limited availability of UPS and MPNST cell lines makes it challenging to identify potential therapeutic targets in a laboratory setting. Understanding the urgent need for improved treatments for these tumors and the limited cellular models available, we generated additional cell lines to study these rare cancers. Patient-derived tumors were used to establish 4 new UPS models, including one radiation-associated UPS-UPS271.1, UPS511, UPS0103, and RIS620, one unclassified spindle cell sarcoma-USC060.1, and 3 new models of MPNST-MPNST007, MPNST3813E, and MPNST4970. This study examined the utility of the new cell lines as sarcoma models by assessing their tumorigenic potential and mutation status for known sarcoma-related genes. All the cell lines formed colonies and migrated in vitro. The in vivo tumorigenic potential of the cell lines and corresponding xenografts was determined by subcutaneous injection or xenograft re-passaging into immunocompromised mice. USC060.1 and UPS511 cells formed tumors in mice upon subcutaneous injection. UPS0103 and RIS620 tumor implants formed tumors in vivo, as did MPNST007 and MPNST3813E tumor implants. Targeted sequencing analysis of a panel of genes frequently mutated in sarcomas identified TP53, RB1, and ATRX mutations in a subset of the cell lines. These new cellular models provide the scientific community with powerful tools for detailed studies of tumorigenesis and for investigating novel therapies for UPS and MPNST.
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Affiliation(s)
- Angela D Bhalla
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sharon M Landers
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anand K Singh
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jace P Landry
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Michelle G Yeagley
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Gabryella S B Myerson
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Cristian B Delgado-Baez
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- University of Puerto Rico-Medical Science Campus, San Juan, PR, USA
- Partnership for Diversity, Sponsored by Women and Minority Faculty Inclusion, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Stephanie Dunnand
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Partnership for Diversity, Sponsored by Women and Minority Faculty Inclusion, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Theresa Nguyen
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xiaoyan Ma
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Svetlana Bolshakov
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Brian A Menegaz
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Xizeng Mao
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xingzhi Song
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Alexander J Lazar
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ian E McCutcheon
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - John M Slopis
- Departments of Pediatrics and Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Joseph A Ludwig
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Dina C Lev
- Department of Surgery, Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel
| | - Kunal Rai
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Keila E Torres
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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19
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Gonzalez-Muñoz T, Kim A, Ratner N, Peinado H. The need for new treatments targeting MPNST: the potential of strategies combining MEK inhibitors with antiangiogenic agents. Clin Cancer Res 2022; 28:3185-3195. [PMID: 35446392 DOI: 10.1158/1078-0432.ccr-21-3760] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 02/01/2022] [Accepted: 04/04/2022] [Indexed: 11/16/2022]
Abstract
Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are aggressive soft tissue sarcomas that represent an important clinical challenge, particularly given their strong tendency to relapse and metastasize, and their relatively poor response to conventional therapies. To date, targeted, non-cytotoxic treatments have demonstrated limited clinical success with MPNSTs, highlighting the need to explore other key pathways in order to find novel, improved therapeutic approaches. Here, we review evidence supporting the crucial role of the RAS/MEK/ERK pathway and angiogenesis in MPNST pathogenesis, and we focus on the potential of therapies targeting these pathways to treat this disease. We also present works suggesting that the combination of MEK inhibitors and anti-angiogenic agents could represent a promising therapeutic strategy to manage MPNSTs. In support of this notion, we discuss the preclinical rational and clinical benefits of this combination therapy in other solid tumor types. Finally, we describe other emerging therapeutic approaches that could improve patient outcomes in MPNSTs, such as immune-based therapies.
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Affiliation(s)
| | - AeRang Kim
- Children's National Hospital, Washington, DC, United States
| | - Nancy Ratner
- Cincinnati Children's Hospital Medical Center, Cincinnati, United States
| | - Héctor Peinado
- Spanish National Cancer Research Centre, Madrid, Madrid, Spain
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20
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Malignant nerve sheath tumor of oculomotor nerve in a pediatric patient. Childs Nerv Syst 2022; 38:807-811. [PMID: 34370084 DOI: 10.1007/s00381-021-05283-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 06/29/2021] [Indexed: 10/20/2022]
Abstract
Malignant nerve sheath tumors are extremely rare pathologies. They tend to occur within peripheral nerves and have close association of neurofibromatosis disease. Here, we present the second case of MNST of oculomotor nerve in literature. The patient was a 2-year-old girl with left sided oculomotor nerve palsy. After resection, the patient immediately had chemotherapy and radiotherapy. One year after surgery disease progressed with extensive intracranial seedings, and she passed away.
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21
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Hirozane T, Nakayama R, Yamaguchi S, Mori T, Asano N, Asakura K, Kikuta K, Kawaida M, Sasaki A, Okita H, Nakatsuka S, Ito T. Recurrent malignant peripheral nerve sheath tumor presenting as an asymptomatic intravenous thrombus extending to the heart: a case report. World J Surg Oncol 2022; 20:8. [PMID: 34996471 PMCID: PMC8742394 DOI: 10.1186/s12957-021-02473-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 12/13/2021] [Indexed: 11/15/2022] Open
Abstract
Background Malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue sarcoma mainly treated via surgical resection. Herein, we report a case of MPNST wherein a massive tumor thrombus extended to the major veins and heart. Case presentation A 39-year-old female with a history of neurofibromatosis type 1 developed MPNST from the right radial nerve. In addition to adjuvant chemotherapy, she underwent wide tumor resection and concomitant radial nerve resection, followed by postoperative radiotherapy. Histological evaluation revealed marked venous invasion. The 2-year follow-up CT revealed an asymptomatic recurrent tumor thrombus extending from the right subclavian vein to the heart. An urgent life-saving operation was performed to ligate the base of the right subclavian vein and remove the entire intravenous thrombus that extended to the right ventricle. The remaining tumor in the right subclavian vein increased in size 3 months after thrombectomy. After confirming the absence of any metastatic lesions, the patient underwent extended forequarter amputation to achieve surgical remission. One year later, a new metastasis to the right diaphragm was safely resected. The patient remains alive without any evidence of disease 2 years after the extended forequarter amputation. Conclusions In cases of a previous history of microscopic venous invasion, recurrence can occur as a massive tumor thrombus that extends to the great vessels. Supplementary Information The online version contains supplementary material available at 10.1186/s12957-021-02473-2.
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Affiliation(s)
- Toru Hirozane
- Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Robert Nakayama
- Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
| | - Sayaka Yamaguchi
- Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Tomoaki Mori
- Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Naofumi Asano
- Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Keisuke Asakura
- Division of Thoracic Surgery, Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Kazutaka Kikuta
- Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.,Division of Musculoskeletal Oncology and Orthopedic Surgery, Tochigi Cancer Center, Tochigi, Japan
| | - Miho Kawaida
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Aya Sasaki
- Department of Pathology, Tokyo Dental College Ichikawa General Hospital, Chiba, Japan
| | - Hajime Okita
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Seishi Nakatsuka
- Department of Radiology, Keio University School of Medicine, Tokyo, Japan
| | - Tsutomu Ito
- Department of Cardiovascular Surgery, Keio University School of Medicine, Tokyo, Japan
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22
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Petković S, Petković S, Tadić-Latinović L, Berendika J, Tubić B, Jungić S. A case report of malignant peripheral nerve sheath tumour of the left thigh and popliteal fossa with lungs, spleen, and brain dissemination related to neurofibromatosis type 1. SCRIPTA MEDICA 2022. [DOI: 10.5937/scriptamed53-32417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
Abstract
A malignant peripheral nerve sheath tumour (MPNST) is a highly aggressive sarcoma. This disease develops in a number of people with neurofibromatosis type 1 (NF1), which is a common genetic disease. The paper presents a patient with typical manifestations of a malignant tumour of the peripheral nerve sheath, in the form of a large tumour of primary localisation in the distal part of the left thigh and left popliteal fossa and with significant dissemination into the lung parenchyma, which was accompanied by respiratory risk. The first operation of the tumour was done four years earlier, after which the patient did not come for regular check-ups. Nine cycles of chemotherapy were performed by Doxorubicin / Ifosfamide / Mesna protocol with clinical improvement and stabilisation, but without a significant impact on the dynamics of the disease and the overall survival was 14 months. It is of utmost importance to early recognise clinical presentation of the malignant form of this tumour and active supervision of a patient with a benign form by experts. In this way, it is possible to apply the optimal treatment modality in a timely manner.
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23
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Sin Y, Yoshimatsu Y, Noguchi R, Tsuchiya R, Ono T, Akiyama T, Nakatani F, Sugaya J, Yoshida A, Kawai A, Kondo T. Establishment and characterization of NCC-MPNST6-C1: a novel patient-derived cell line of malignant peripheral nerve sheath tumors. Hum Cell 2022; 35:400-407. [PMID: 34775549 DOI: 10.1007/s13577-021-00643-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 10/31/2021] [Indexed: 10/19/2022]
Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) are a rare subtype of mesenchymal tumors that arise from the sheath of peripheral nerves. MPNSTs exhibit strong metastatic potential, leading to poor clinical outcomes. The clinical utility of radiation therapy and chemotherapy is marginal with respect to overall survival and effective systematic therapies for MPNSTs are still needed to improve patient outcome. Although patient-derived cell lines are an essential tool for the development of novel therapies, only a limited number of cell lines have been reported and are available from cell banks. Thus, we established the novel MPNST cell line, NCC-MPNST6-C1, using surgically resected MPNST tissue. The NCC-MPNST6-C1 cells retained copy-number alterations similar to those of the original tumors and demonstrated constant proliferation, spheroid formation, and invasion capability in vitro, which reflected the malignant features of the original tumor tissue. While the NCC-MPNST6-C1 cells did not exhibit tumorigenesis in nude mice, their use in drug screening resulted in anti-cancer agents with low IC50 values. Hence, we conclude that the NCC-MPNST6-C1 cell line is a useful resource for the study of MPNSTs.
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Affiliation(s)
- Yooksil Sin
- Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Yuki Yoshimatsu
- Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Rei Noguchi
- Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Ryuto Tsuchiya
- Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Takuya Ono
- Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Taro Akiyama
- Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Fumihiko Nakatani
- Department of Musculoskeletal Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Jun Sugaya
- Department of Musculoskeletal Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Akihiko Yoshida
- Department of Diagnostic Pathology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Akira Kawai
- Department of Musculoskeletal Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Tadashi Kondo
- Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
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24
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Survival and NF1 Analysis in a Cohort of Orthopedics Patients with Malignant Peripheral Nerve Sheath Tumors. Sarcoma 2021; 2021:9386823. [PMID: 34646065 PMCID: PMC8505086 DOI: 10.1155/2021/9386823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 09/18/2021] [Indexed: 11/17/2022] Open
Abstract
Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor syndrome in which benign plexiform neurofibromas are at risk of transforming into malignant peripheral nerve sheath tumors (MPNSTs), a very rare soft-tissue sarcoma. The prognosis of patients with MPNSTs is poor, with most studies reporting <50% survival at five years. However, studies evaluating MPNSTs are limited and report heterogeneous results. Because no MPNST-specific evidence-based treatment guideline exists, individual institutional experiences are very informative to the field. The main objective of this study was to investigate and report MPNST prognostic clinical and genetic biomarkers from our institution's Orthopedics service experience treating 20 cases from 1992 to 2017. Most patients were treated with resection and adjuvant radiation. Extended follow-up, averaging 11.4 years (ranging 1.1 to 25.1), revealed excellent five-year survival rates: 70% for overall and 60% for metastatic disease. An S100 B immunonegative tumor phenotype was associated with a significantly worse outcome than MPNSTs with positive S100 B stain. In addition, NF1 gene mutation analysis was performed on 27 families with NF1 in which at least one affected family member developed MPNSTs. Of the 27 NF1 germline mutations, five were large deletions spanning (or nearly spanning) the gene (18.5%), substantially more than such deletions in NF1 in general, consistent with increased risk of MPNSTs in such cases.
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25
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Kajiyama T, Komori M, Iguchi M, Nakashima J, Nagao A, Hyodo M. Laryngeal malignant peripheral nerve sheath tumor mixed with high- and low-grade malignancies. J Surg Case Rep 2021; 2021:rjab373. [PMID: 34476079 PMCID: PMC8407030 DOI: 10.1093/jscr/rjab373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Accepted: 08/04/2021] [Indexed: 11/30/2022] Open
Abstract
Malignant peripheral nerve sheath tumors (MPNSTs), as defined by immunohistochemical evaluation, are identified along a spectrum ranging from atypical neurofibroma to high-grade MPNST because these tumors are similar in terms of cell shape and tissue components on hematoxylin–eosin (HE) staining. The patient was a 57-year-old male referred to our hospital, with a recurrent red tumor at the anterior commissure of the larynx and submucosal swelling of the right vocal fold. A surgical specimen from a right horizontal partial laryngectomy was evaluated immunohistochemically. A high-grade MPNST lesion was included in the submucosal white tumor, whereas a low-grade MPNST lesion was encountered around the high-grade MPNST lesion. This tumor may involve different malignancies even when it is small. Although intra-tumor heterogeneity in cancers has been reported recently, careful immunohistochemical examination can be important and beneficial for eradicating the tumor while preserving vocal function.
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Affiliation(s)
- Taihei Kajiyama
- Department of Otolaryngology, Kochi Medical School, Kochi University, Nankoku, Japan
| | - Masahiro Komori
- Department of Otolaryngology, Kochi Medical School, Kochi University, Nankoku, Japan
| | - Mitsuko Iguchi
- Department of Pathology, Kochi Medical School, Kochi University, Nankoku, Japan
| | - Junko Nakashima
- Department of Pathology, Kochi Medical School, Kochi University, Nankoku, Japan
| | - Asuka Nagao
- Department of Otolaryngology, Kochi Medical School, Kochi University, Nankoku, Japan
| | - Masamitsu Hyodo
- Department of Otolaryngology, Kochi Medical School, Kochi University, Nankoku, Japan
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26
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Guo X, Wu WM, Wang L, Yang Y. Reconstruction of the chest wall after resection of malignant peripheral nerve sheath tumor: A case report. World J Clin Cases 2021; 9:7117-7122. [PMID: 34540967 PMCID: PMC8409185 DOI: 10.12998/wjcc.v9.i24.7117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Revised: 05/27/2021] [Accepted: 07/06/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Malignant peripheral nerve sheath tumors (MPNSTs) are a group of rare and aggressive sarcomas that often arise from major peripheral nerves and represent a notable challenge to efficacious treatment. MPNSTs can occur in any body surface and visceral organs with nerve fiber distribution. The treatment options for MPNSTs include surgery, chemotherapy, and adjuvant radiotherapy.
CASE SUMMARY A 26-year-old female cellist presented with chest pain on her left side when she squatted to lift the cello. One week later, a chest X-ray was performed and revealed fracture of the fourth rib on the left side. Three months later, the patient inadvertently touched a mass on the left side of the chest wall. Chest computed tomography (CT) three-dimensional reconstruction of the ribs revealed bone destruction of the fourth rib on the left side with a soft tissue mass shadow measuring 5.7 cm × 3.7 cm. CT-guided puncture biopsy of the tumor showed that heterotypic cells (spindle cells) tended to be nonepithelial tumor lesions. PET-CT demonstrated bone destruction and a soft tissue mass with avid 18F-fluorodeoxyglucose activity (SUVmax7.5) in the left fourth rib. The tumor of the left chest wall was resected under general anesthesia, and reconstruction of the chest wall was performed. The postoperative pathological report exhibited an MPNST.
CONCLUSION MPNSTs are relatively chemo-insensitive tumors. The mainstay of treatment for MPNSTs remains resection with tumor-free margins.
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Affiliation(s)
- Xiang Guo
- Department of Thoracic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Wei-Ming Wu
- Department of Thoracic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Lei Wang
- Department of Thoracic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Yi Yang
- Department of Thoracic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
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27
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Allison CM, Shumon S, Joshi A, Quaegebeur A, Sinclair G, Surash S. Malignant intracerebral nerve sheath tumor in a patient with Noonan syndrome: illustrative case. JOURNAL OF NEUROSURGERY: CASE LESSONS 2021; 1:CASE21146. [PMID: 35854906 PMCID: PMC9245752 DOI: 10.3171/case21146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 04/29/2021] [Indexed: 12/05/2022]
Abstract
BACKGROUND Malignant peripheral nerve sheath tumors (MPNSTs) within the neuroaxis are rare, usually arising from peripheral and cranial nerves. Even more scarce are cranial subclassifications of MPNSTs termed “malignant intracerebral nerve sheath tumors” (MINSTs). These tumors are aggressive, with a strong tendency for metastasis. With this presentation, alongside resistance to adjunctive therapy, complete excision is the mainstay of treatment, although it is often insufficient, resulting in a high rate of mortality. OBSERVATIONS The authors report the case of an adult patient with a history of Noonan syndrome (NS) presenting with slowly progressive right-sided hemiparesis and right-sided focal motor seizures. Despite initial imaging and histology suggesting a left frontal lobe high-grade intrinsic tumor typical of a glioblastoma, subsequent molecular analysis confirmed a diagnosis of MINST. The patient’s neurological condition improved after gross-total resection and adjuvant chemo-radiation; he remains on follow-up. LESSONS MINSTs are rare neoplasms with a poor prognosis; management options are limited, with surgery being the cornerstone of treatment. Reports on rare tumors such as this will increase awareness of this particular pathology and disclose clinical experience. In this case, the authors were unable to establish a definite cause-and-effect relation between NS and MINST. Nevertheless, it remains the first reported case in the literature.
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Affiliation(s)
- Callum M. Allison
- Departments of Neurosurgery and
- Pathology, Royal Victoria Infirmary, Newcastle Upon Tyne, United Kingdom
| | | | - Abhijit Joshi
- Department of Neurosurgery, Bezmialem Vakif University Hospital, Istanbul, Turkey; and
| | - Annelies Quaegebeur
- Division of Neuropathology, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, United Kingdom
| | - Georges Sinclair
- Newcastle University Medical School, Newcastle Upon Tyne, United Kingdom
- Department of Oncology, James Cook University Hospital, Middlesbrough, United Kingdom
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28
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Liu D, Mu Y, Chen P, Che B, Li Z, Zhao Y, Sun F, Tang K. Rare primary malignant peripheral nerve sheath tumor of the left testis: A case report. Mol Clin Oncol 2021; 15:144. [PMID: 34094542 PMCID: PMC8165690 DOI: 10.3892/mco.2021.2306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Accepted: 04/09/2021] [Indexed: 11/09/2022] Open
Abstract
Malignant peripheral nerve sheath tumor (MPNST) is a rare disease. The present study discusses the case of a 30-year-old male patient who presented with complaints of pain in the left testis and groin over 1 month. Ultrasonography and computed tomography (CT) imaging revealed the presence of a space-occupying lesion localized in the left testis. The mass was completely resected using an open surgical approach and was diagnosed as a primary MPNST of the left testis on postoperative histopathological examination. As this type of tumor is rare, there is currently no standard diagnostic or treatment method for MPNST. Pathological examination, enhanced CT imaging and immunohistochemical investigation are helpful for establishing the diagnosis and surgical resection is considered to be an effective treatment.
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Affiliation(s)
- Dongdong Liu
- Department of Urology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Yi Mu
- Department of Urology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Pan Chen
- Department of Urology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Bangwei Che
- Department of Urology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Zheming Li
- Department of Urology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Yili Zhao
- Department of Urology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Fa Sun
- Department of Urology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
| | - Kaifa Tang
- Department of Urology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China.,Institute of Medical Science of Guizhou Medical University, Guiyang, Guizhou 550004, P.R. China
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29
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Jones KE, Patel A, Kunesh MG, Thuro BA. Malignant peripheral nerve sheath tumor of the orbit: a case report and review of the literature. Orbit 2021; 41:642-646. [PMID: 33926355 DOI: 10.1080/01676830.2021.1918178] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Malignant peripheral nerve sheath tumor is a rare tumor which infrequently involves the orbit. They occur most often in the setting of neurofibromatosis 1 (NF1), and therefore the involvement of the orbit without a history of NF1 is even less common. Management of this tumor is fraught with a high rate of recurrences and metastases, with a high mortality rate. Primary surgical excision with tumor-free margins remains the primary treatment, while adjuvant modalities such as radiation and chemotherapy play a more minor role.
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Affiliation(s)
- Kara E Jones
- School of Medicine, West Virginia University, Charleston, West Virginia, USA
| | - Ami Patel
- School of Medicine, West Virginia University, Charleston, West Virginia, USA
| | - Mary G Kunesh
- Department of Ophthalmology and Visual Sciences, West Virginia University, Morgantown, West Virginia, USA
| | - Bradley A Thuro
- Department of Ophthalmology and Visual Sciences, West Virginia University, Morgantown, West Virginia, USA
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Wang T, Wang J, Zhao J, Yuan D, Yao W. Repetitive syncope caused by a rare massive sporadic malignant peripheral nerve sheath tumor involving carotid arteries: A case report. Medicine (Baltimore) 2021; 100:e24386. [PMID: 33592886 PMCID: PMC7870201 DOI: 10.1097/md.0000000000024386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 12/29/2020] [Indexed: 02/05/2023] Open
Abstract
RATIONALE Malignant peripheral nerve sheath tumors (MPNSTs) are rare sarcomas arising from peripheral nerves. MPNSTs are uncommon in the head and neck, and various clinical manifestation often make the diagnosis challenging. PATIENT CONCERNS A 67-year-old female was referred for evaluation of repetitive syncope with a massive mass in the neck. Preoperative evaluation revealed potential neuroendocrine activity of the mass and enhanced computed tomography showed carotid artery was involved. DIAGNOSIS According to the preoperative imaging, intraoperative finding and postoperative pathological examination, the diagnosis of left neck MPNST involving left carotid arteries was made. INTERVENTIONS Volume expansion therapy with phenoxybenzamine started one week before surgery. Complete surgical resection of the mass was performed and pathological analysis suggested the diagnosis of MPNST. The postoperative radiotherapy was not given due to her poor nutrition. OUTCOMES This patient recovered well after surgery and no sign of recurrence was noted at 2-year follow-up. LESSONS Though the involvement of carotid artery with neuroendocrine activity is rare in sporadic MPNST, preoperative scanning of blood and urine catecholamine is crucial for intraoperative hemodynamic stability, especially when carotid artery is involved.
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Affiliation(s)
| | | | | | | | - Wenqing Yao
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
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Marickar YMF, Abraham B. Malignant peripheral nerve sheath tumour - A long story: Case report. Int J Surg Case Rep 2020; 77:618-623. [PMID: 33395859 PMCID: PMC7708871 DOI: 10.1016/j.ijscr.2020.11.061] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 11/11/2020] [Accepted: 11/11/2020] [Indexed: 11/23/2022] Open
Abstract
INTRODUCTION We present a rare case of Malignant Peripheral Nerve Sheath Tumour (MPNST) of the upper limb, which was excised thirteen times in thirteen years and ultimately ended in above elbow amputation. PRESENTING COMPLAINT AND INVESTIGATIONS A 48 year old female presented initially with a localised swelling of 2 cms diameter in the front of the left elbow in 2007, which was excised. It recurred repeatedly and was excised. In the earlier presentations, the swellings were firm, mobile and not fixed to bone. In the last stage alone, bone fixity was identified. All the fourteen surgeries were performed by the primary author from 2007 to 2020, as the patient was particular. THE MAIN CLINICAL DIAGNOSES: had been neurofibroma and fibrosarcoma. There was no evidence of distant metastasis all these years. She did not respond to radiation or chemotherapy. Initially it was single, but later multiple. She had no clinical features of Neurofibromatosis 1 (NF1) or any family history. As the history progressed, the swellings became muscle deep and later encircled the radial nerve. The radial nerve was salvaged on three occasions. On the last three occasions, the tumour had to be shaved off from the humerus. The final amputation specimen showed a single tumour infiltrating the humerus and x-ray revealed bone destruction and tumour calcification. Final diagnosis was aided by immunohistochemistry (IHC) and cytogenetic study (FISH). CONCLUSION The case is presented for the rarity of the presentation and the trust and dependence of the patient on her personal surgeon.
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Burks SS, Puffer RC, Cajigas I, Valdivia D, Rosenberg AE, Spinner RJ, Levi AD. Synovial Sarcoma of the Nerve-Clinical and Pathological Features: Case Series and Systematic Review. Neurosurgery 2020; 85:E975-E991. [PMID: 31435657 DOI: 10.1093/neuros/nyz321] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 05/18/2019] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Synovial sarcoma of the nerve is a rare entity with several cases and case series reported in the literature. Despite an improved understanding of the biology, the clinical course is difficult to predict. OBJECTIVE To compile a series of patients with synovial sarcoma of the peripheral nerve (SSPN) and assess clinical and pathological factors and their contribution to survival and recurrence. METHODS Cases from 2 institutions collected in patients undergoing surgical intervention for SSPN. Systematic review including PubMed and Scopus databases were searched for related articles published from 1970 to December 2018. Eligibility criteria: (1) case reports or case series reporting on SSPN, (2) clinical course and/or pathological features of the tumor reported, and (3) articles published in English. RESULTS From patients treated at our institutions (13) the average follow-up period was 3.2 yr. Tumor recurrence was seen in 4 cases and death in 3. Systematic review of the literature yielded 44 additional cases with an average follow-up period of 3.6 yr. From pooled data, there were 10 recurrences and 7 deaths (20% and 14%, respectively). Adjuvant treatment used in 62.5% of cases. Immunohistochemical markers used in diagnosis varied widely; the most common are the following: Epithelial membrane antigen (EMA), cytokeratin, vimentin, cluster of differentiation (CD34), and transducin-like enhancer of split 1 (TLE1). Statistical analysis illustrated tumor size and use of chemotherapy to be negative predictors of survival. No other factors, clinically or from pathologist review, were correlated with recurrence or survival. CONCLUSION By combining cases from our institution with historical data and performing statistical analysis we show correlation between tumor size and death.
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Affiliation(s)
- Stephen Shelby Burks
- Miami Project to Cure Paralysis, Department of Neurological Surgery, Miller School of Medicine, University of Miami, Miami, Florida
| | - Ross C Puffer
- Department of Neurosurgery, Mayo Clinic, Rochester, Minnesota
| | - Iahn Cajigas
- Miami Project to Cure Paralysis, Department of Neurological Surgery, Miller School of Medicine, University of Miami, Miami, Florida
| | - David Valdivia
- Miami Project to Cure Paralysis, Department of Neurological Surgery, Miller School of Medicine, University of Miami, Miami, Florida
| | - Andrew E Rosenberg
- Department of Pathology and Laboratory Medicine, Miller School of Medicine, University of Miami, Miami, Florida
| | | | - Allan D Levi
- Miami Project to Cure Paralysis, Department of Neurological Surgery, Miller School of Medicine, University of Miami, Miami, Florida
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Martin E, Coert JH, Flucke UE, Slooff WBM, van de Sande MAJ, van Noesel MM, Grünhagen DJ, Wijnen MHWA, Verhoef C. Neurofibromatosis-associated malignant peripheral nerve sheath tumors in children have a worse prognosis: A nationwide cohort study. Pediatr Blood Cancer 2020; 67:e28138. [PMID: 31889416 DOI: 10.1002/pbc.28138] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 11/29/2019] [Accepted: 12/09/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Malignant peripheral nerve sheath tumors (MPNST) are rare and aggressive non-rhabdomyoblastic soft-tissue sarcomas (NRSTS) in children. This study set out to investigate clinical presentation, treatment modalities, and factors associated with survival in pediatric MPNST using Dutch nationwide databases. METHODS Data were obtained from the Netherlands Cancer Registry (NCR) and the Dutch Pathology Database (PALGA) from 1989 to 2017. All primary MPNSTs were collected. Demographic differences were analyzed between adult and pediatric (age ≤18 years) MPNST. In children, demographic and treatment differences between neurofibromatosis type 1 (NF1) and non-NF1 were analyzed. A Cox proportional hazard model was constructed for localized pediatric MPNSTs. RESULTS A total of 70/784 MPNST patients were children (37.1% NF1). Children did not present differently from adults. In NF1 children, tumor size was more commonly large (> 5 cm, 92.3% vs 59.1%). Localized disease was primarily resected in 90.6%, and radiotherapy was administered in 37.5%. Non-NF1 children tended to receive chemotherapy more commonly (39.5% vs 26.9%). Overall, estimated five-year survival rates of localized NF1-MPNST was 52.4% (SE: 10.1%) compared with 75.8% (SE: 7.1%) in non-NF1 patients. The multivariate model showed worse survival in NF1 patients (HR: 2.98; 95% CI, 1.17-7.60, P = 0.02) and increased survival in patients diagnosed after 2005 (HR: 0.20; 95% CI, 0.06-0.69, P = 0.01). No treatment factors were independently associated with survival. CONCLUSION Pediatric MPNSTs have presentations similar to adult MPNSTs. In children, NF1 patients present with larger tumors, but are treated similarly to non-NF1 MPNSTs. In localized pediatric MPNST, NF1 is associated with worse survival. Promisingly, survival has increased for pediatric MPNSTs after 2005.
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Affiliation(s)
- Enrico Martin
- Department of Plastic and Reconstructive Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
| | - J Henk Coert
- Department of Plastic and Reconstructive Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Uta E Flucke
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.,Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands.,Diagnostic Laboratory and Pathology, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Willem-Bart M Slooff
- Department of Neurosurgery, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Michiel A J van de Sande
- Department of Orthopedic Surgery, Leiden University Medical Center, Leiden, The Netherlands.,Department of Solid Tumors, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Max M van Noesel
- Department of Solid Tumors, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Dirk J Grünhagen
- Department of Surgical Oncology, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands
| | - Marc H W A Wijnen
- Department of Solid Tumors, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - Cornelis Verhoef
- Department of Surgical Oncology, Erasmus Medical Center Cancer Institute, Rotterdam, The Netherlands
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Bajaj G, Tirumani H, Whisman MK, Srivastava S, Ram R, Jambhekar K, Gardner JM, Pandey T. Comprehensive Review of Abdominopelvic Mesenchymal Tumors With Radiologic Pathologic Correlation and Update on Current Treatment Guidelines-Part 2. Semin Ultrasound CT MR 2020; 41:239-259. [PMID: 32446434 DOI: 10.1053/j.sult.2020.03.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Soft-tissue sarcomas are a diverse group of rare mesenchymal malignancies accounting for only 1% of all solid adult malignancies. These have been categorized in 12 broad groups by the World Health Organization (WHO) with their recent update in 2013. Majority of them lack specific imaging features serving as imaging conundrums for a radiologist. These are often large masses at presentation as they are asymptomatic or cause vague clinical symptoms. These tumors are challenging for surgeons as well as they find it difficult to achieve complete resection because of complex intra-abdominal anatomy and their close relationship with critical structures. Often, a multidisciplinary approach is required to decide on the most appropriate management for these complex cases so as to provide optimal patient care. Knowledge of the WHO classification, pathologic features, and treatment options available helps the radiologist make a meaningful contribution in multidisciplinary discussions of such cases and overall patient care. Liposarcoma (well-differentiated and dedifferentiated liposarcomas), leiomyosarcoma, and gastrointestinal stromal tumor are the 3 most common primary intra-abdominal sarcomas. In part 1 of this article, general features of soft-tissue sarcomas and some of the common tumors from WHO category 1-4 found in abdomen and pelvis are discussed. Part 2 will focus on common tumors from remainder of the WHO categories.
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Affiliation(s)
- Gitanjali Bajaj
- Department of Radiology, University of Arkansas for Medical Sciences, Little Rock, AR.
| | - Harika Tirumani
- Department of Radiology, University of Arkansas for Medical Sciences, Little Rock, AR
| | - Michella K Whisman
- Department of Pathology, University of Michigan, Ann Arbor, MI; MSK/MRI-Body Imaging, University of Arkansas for Medical Sciences, Little Rock, AR
| | - Shweta Srivastava
- Department of Radiology, University of Arkansas for Medical Sciences, Little Rock, AR
| | - Roopa Ram
- Department of Radiology, University of Arkansas for Medical Sciences, Little Rock, AR
| | - Kedar Jambhekar
- MSK/MRI-Body Imaging, University of Arkansas for Medical Sciences, Little Rock, AR; Department of Radiology and Orthopedics, University of Arkansas for Medical Sciences, Little Rock, AR
| | - Jerad M Gardner
- Departments of Pathology and Dermatology, University of Arkansas for Medical Sciences, Little Rock, AR
| | - Tarun Pandey
- Department of Radiology and Orthopedics, University of Arkansas for Medical Sciences, Little Rock, AR; University of Arkansas for Medical Sciences, Little Rock, AR
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Oncological Treatment Considerations Differ across Surgical Subspecialties Treating Malignant Peripheral Nerve Sheath Tumors: An International Survey. Sarcoma 2020; 2020:6406439. [PMID: 32189989 PMCID: PMC7064831 DOI: 10.1155/2020/6406439] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 01/15/2020] [Accepted: 01/24/2020] [Indexed: 12/18/2022] Open
Abstract
Background Malignant peripheral nerve sheath tumors (MPNSTs) are rare and aggressive soft tissue sarcomas (STS) that, because of their origin, are operated by several surgical subspecialties. This may cause differences in oncologic treatment recommendations based on presentation. This study investigated these differences both within and between subspecialties. Methods A survey was distributed among several (inter)national surgical societies. Differences within and between subspecialties were analyzed by χ2-tests. Results In total, 30 surgical oncologists, 30 neurosurgeons, 85 plastic surgeons, and 29 “others” filled out the survey. Annual caseload, tumor sites operated, and fellowship training differed significantly between subspecialties. While most surgeons agreed upon preoperative use of MRI, the use of radiological staging and FDG-PET use differed between subspecialties. Surgical oncologists agreed upon core needle biopsies as an ideal type of biopsy while other subspecialties differed in opinion. On average, 53% of surgeons always consider preservation of function preoperatively, but 42% would never perform less extensive resections for function preservation. Respondents agreed that radiotherapy should be considered in tumor sizes >10 cm, microscopic, and macroscopic positive margins. A preferred sequence of radiotherapy administration differed between subspecialties. There was no consensus on indications and sequence of administration of chemotherapy in localized disease. Conclusion Surgical oncologists generally agree on preoperative diagnostics; other subspecialties do not. Considering the preservation of function differed among all subspecialties. Surgeons do agree on some indications for radiotherapy, yet the use of chemotherapy in localized MPNSTs lacks consensus. A preferred sequence of multimodal therapy differs between and within surgical subspecialties, but surgical oncologists prefer neoadjuvant radiotherapy.
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Özdemir BC, Bohanes P, Bisig B, Missiaglia E, Tsantoulis P, Coukos G, Montemurro M, Homicsko K, Michielin O. Deep Response to Anti-PD-1 Therapy of Metastatic Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumor With CD274/PD-L1 Amplification. JCO Precis Oncol 2019; 3:1-6. [DOI: 10.1200/po.18.00375] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Affiliation(s)
- Berna C. Özdemir
- Lausanne University Hospital, Lausanne, Switzerland
- International Cancer Prevention Institute, Lausanne, Switzerland
| | | | | | | | | | - George Coukos
- Lausanne University Hospital, Lausanne, Switzerland
- Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | | | - Krisztian Homicsko
- Lausanne University Hospital, Lausanne, Switzerland
- Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Olivier Michielin
- Lausanne University Hospital, Lausanne, Switzerland
- Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
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Martin E, Coert JH, Flucke UE, Slooff WBM, Ho VKY, van der Graaf WT, van Dalen T, van de Sande MAJ, van Houdt WJ, Grünhagen DJ, Verhoef C. A nationwide cohort study on treatment and survival in patients with malignant peripheral nerve sheath tumours. Eur J Cancer 2019; 124:77-87. [PMID: 31760312 DOI: 10.1016/j.ejca.2019.10.014] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 10/01/2019] [Accepted: 10/06/2019] [Indexed: 01/13/2023]
Abstract
BACKGROUND Despite curative intents of treatment in localized malignant peripheral nerve sheath tumours (MPNSTs), prognosis remains poor. This study investigated survival and prognostic factors for overall survival in non-retroperitoneal and retroperitoneal MPNSTs in the Netherlands. METHODS Data were obtained from the Netherlands Cancer Registry and the Dutch Pathology Database. All primary MPNSTs were collected. Paediatric cases (age ≤18 years) and synchronous metastases were excluded from analyses. Separate Cox proportional hazard models were made for retroperitoneal and non-retroperitoneal MPNSTs. RESULTS A total of 629 localized adult MPNSTs (35 retroperitoneal cases, 5.5%) were included for analysis. In surgically resected patients (88.1%), radiotherapy and chemotherapy were administered in 44.2% and 6.7%, respectively. In retroperitoneal cases, significantly less radiotherapy and more chemotherapy were applied. In non-retroperitoneal MPNSTs, older age (60+), presence of NF1, size >5 cm, and deep-seated tumours were independently associated with worse survival. In retroperitoneal MPNSTs, male sex and age of 60+ years were independently associated with worse survival. Survival of R1 and that of R0 resections were similar for any location, whereas R2 resections were associated with worse outcomes. Radiotherapy and chemotherapy administrations were not associated with survival. CONCLUSION In localized MPNSTs, risk stratification for survival can be done using several patient- and tumour-specific characteristics. Resectability is the most important predictor for survival in MPNSTs. No difference is present between R1 and R0 resections in both retroperitoneal and non-retroperitoneal MPNSTs. The added value of radiotherapy and chemotherapy is unclear.
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Affiliation(s)
- Enrico Martin
- Department of Plastic and Reconstructive Surgery, University Medical Center Utrecht, the Netherlands.
| | - J Henk Coert
- Department of Plastic and Reconstructive Surgery, University Medical Center Utrecht, the Netherlands
| | - Uta E Flucke
- Department of Pathology, University Medical Center Utrecht, the Netherlands; Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands; Diagnostic Laboratory and Pathology, Princess Máxima Center for pediatric oncology, Utrecht, the Netherlands
| | | | - Vincent K Y Ho
- Departments of Registry and Research, Netherlands Comprehensive Cancer Organization (IKNL), Utrecht, the Netherlands
| | - Winette T van der Graaf
- Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Thijs van Dalen
- Department of Surgical Oncology, University Medical Center Utrecht, the Netherlands; Department of Surgical Oncology, Diakonessenhuis Utrecht, the Netherlands
| | - Michiel A J van de Sande
- Department of Orthopedic Surgery, Leiden University Medical Center, the Netherlands; Department of Solid Tumors, Princess Máxima Center for pediatric oncology, Utrecht, the Netherlands
| | - Winan J van Houdt
- Department of Surgical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Dirk J Grünhagen
- Department of Surgical Oncology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands
| | - Cornelis Verhoef
- Department of Surgical Oncology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands
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Brandt ZJ, North PN, Link BA. Somatic Mutations of lats2 Cause Peripheral Nerve Sheath Tumors in Zebrafish. Cells 2019; 8:E972. [PMID: 31450674 PMCID: PMC6770745 DOI: 10.3390/cells8090972] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 08/15/2019] [Accepted: 08/22/2019] [Indexed: 02/06/2023] Open
Abstract
The cellular signaling pathways underlying peripheral nerve sheath tumor (PNST) formation are poorly understood. Hippo signaling has been recently implicated in the biology of various cancers, and is thought to function downstream of mutations in the known PNST driver, NF2. Utilizing CRISPR-Cas9 gene editing, we targeted the canonical Hippo signaling kinase Lats2. We show that, while germline deletion leads to early lethality, targeted somatic mutations of zebrafish lats2 leads to peripheral nerve sheath tumor formation. These peripheral nerve sheath tumors exhibit high levels of Hippo effectors Yap and Taz, suggesting that dysregulation of these transcriptional co-factors drives PNST formation in this model. These data indicate that somatic lats2 deletion in zebrafish can serve as a powerful experimental platform to probe the mechanisms of PNST formation and progression.
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Affiliation(s)
- Zachary J Brandt
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Paula N North
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Brian A Link
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
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Tora MS, Xenos D, Texakalidis P, Boulis NM. Treatment of neurofibromatosis 1-associated malignant peripheral nerve sheath tumors: a systematic review. Neurosurg Rev 2019; 43:1039-1046. [PMID: 31209658 DOI: 10.1007/s10143-019-01135-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 05/07/2019] [Accepted: 06/10/2019] [Indexed: 12/24/2022]
Abstract
Malignant peripheral nerve sheath tumors (MPNST) are a rare and aggressive group of tumors that are challenging to treat. Neurofibromatosis type 1 (NF-1)-associated MPNSTs have been associated with poorer clinical outcomes. The treatment options for NF-1-associated MPNSTs broadly include surgery (SG), chemotherapy (CT), and adjuvant radiotherapy (RT). Overall, the role and efficacy of CT and RT are unclear. Examination of existing literature for studies reporting on NF-1-associated MPNSTs and respective treatment-related outcomes was conducted. We conducted a systematic review according to PRISMA guidelines in PubMed/Medline and Cochrane databases of studies which reported treatment-specific outcomes in NF-1-associated MPNSTs. The literature search found 444 records after removal of duplicates. The present study included 50 patients across 12 observational studies. All of the included studies reported data on overall survival (OS 52%, n = 26/50) but mean follow-up in months among the studies and among patients varied widely, between 10.85 (SD, ± 10.38) and 192 (SD, ± 98.22). From the included studies, patients underwent either SG alone (n = 21), SG + CT (n = 10), SG + RT (n = 7), or SG + CT + RT (n = 12). The quality of evidence in the literature regarding optimal treatment options for NF-1-associated MPNSTs remains tenuous. Future retrospective and prospective comparative trials should consider adherence to a set of reporting guidelines to improve the quality of evidence in the literature with respect to individual treatment-related outcomes. The need for prospective multi-institutional efforts cannot be overstated.
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Affiliation(s)
- Muhibullah S Tora
- Department of Neurosurgery, School of Medicine, Emory University Hospital, 101 Woodruff Circle, Suite 6204, Atlanta, GA, 30322, USA.
- Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA.
| | - Dimitrios Xenos
- Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Pavlos Texakalidis
- Department of Neurosurgery, School of Medicine, Emory University Hospital, 101 Woodruff Circle, Suite 6204, Atlanta, GA, 30322, USA
| | - Nicholas M Boulis
- Department of Neurosurgery, School of Medicine, Emory University Hospital, 101 Woodruff Circle, Suite 6204, Atlanta, GA, 30322, USA
- Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA
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Non-cytotoxic systemic treatment in malignant peripheral nerve sheath tumors (MPNST): A systematic review from bench to bedside. Crit Rev Oncol Hematol 2019; 138:223-232. [DOI: 10.1016/j.critrevonc.2019.04.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Revised: 03/28/2019] [Accepted: 04/08/2019] [Indexed: 12/19/2022] Open
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Korfhage J, Lombard DB. Malignant Peripheral Nerve Sheath Tumors: From Epigenome to Bedside. Mol Cancer Res 2019; 17:1417-1428. [PMID: 31023785 DOI: 10.1158/1541-7786.mcr-19-0147] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 04/08/2019] [Accepted: 04/16/2019] [Indexed: 01/05/2023]
Abstract
Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas typically developing in the context of neurofibromatosis type 1 (NF-1). With the exception of surgical resection, these tumors are resistant to all current therapies, and unresectable, recurrent, or metastatic tumors are considered incurable. Preclinical studies have identified several novel candidate molecular targets for therapeutic intervention, but, to date, targeted therapies have proven ineffective. Recent studies have identified recurrent mutations in polycomb repressive complex 2 (PRC2) core components, embryonic ectoderm development protein (EED) and suppressor of zeste 12 homolog (SUZ12), in MPNST. These mutations result in global loss of the histone H3 lysine 27 trimethylation epigenetic mark, normally deposited by PRC2, and subsequent gain in acetylation at this residue. This altered chromatin state has been shown to promote MPNST malignancy; however, acetylation at this residue sensitizes MPNSTs to BRD4 and bromodomain and extra-terminal domain inhibition. Interestingly, the catalytic component of PRC2, enhancer of zeste homolog 2 (EZH2), is not mutated in MPNST, hinting that a noncanonical, PRC2-independent function of EZH2 may play a role in this cancer. This review examines the pathobiology of MPNST, the contribution of PRC2 subunits to this process, and the prospects for PRC2-related therapies for this cancer. IMPLICATIONS: Identification of mutations in the PRC2 components EED and SUZ12 in the majority of MPNSTs may imply noncanonical oncogenic activities of the intact component, EZH2, and provide new opportunities for therapeutic intervention.
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Affiliation(s)
- Justin Korfhage
- Department of Pathology and Institute of Gerontology, University of Michigan, Ann Arbor, Michigan
| | - David B Lombard
- Department of Pathology and Institute of Gerontology, University of Michigan, Ann Arbor, Michigan.
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Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) are rare and aggressive soft-tissue sarcomas with dismal prognosis. Complete resection, which is the only known definitive therapy, is not feasible with every tumor, and local recurrence after surgery is another challenge to successful treatment. Treatments used with other sarcoma types have not proven beneficial to MPNST patients. Targeted therapies blocking several signaling pathways known to drive MPNST pathogenesis have also not improved patient outcomes in clinical trials. This review discusses existing therapies and targeted chemotherapeutic options currently being tested clinically, and potential therapeutic avenues identified in preclinical studies that include targeting signaling pathways such as the HIPPO-YAP pathway and epigenetic mechanisms as well as multi-agent strategies.
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Affiliation(s)
- Lai Man Natalie Wu
- Division of Experimental Hematology & Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Qing Richard Lu
- Division of Experimental Hematology & Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
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Høland M, Kolberg M, Danielsen SA, Bjerkehagen B, Eilertsen IA, Hektoen M, Mandahl N, van den Berg E, Smeland S, Mertens F, Sundby Hall K, Picci P, Sveen A, Lothe RA. Inferior survival for patients with malignant peripheral nerve sheath tumors defined by aberrant TP53. Mod Pathol 2018; 31:1694-1707. [PMID: 29946184 DOI: 10.1038/s41379-018-0074-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 04/22/2018] [Accepted: 04/22/2018] [Indexed: 02/06/2023]
Abstract
Malignant peripheral nerve sheath tumor is a rare and aggressive disease with poor treatment response, mainly affecting adolescents and young adults. Few molecular biomarkers are used in the management of this cancer type, and although TP53 is one of few recurrently mutated genes in malignant peripheral nerve sheath tumor, the mutation prevalence and the corresponding clinical value of the TP53 network remains unsettled. We present a multi-level molecular study focused on aberrations in the TP53 network in relation to patient outcome in a series of malignant peripheral nerve sheath tumors from 100 patients and 38 neurofibromas, including TP53 sequencing, high-resolution copy number analyses of TP53 and MDM2, and gene expression profiling. Point mutations in TP53 were accompanied by loss of heterozygosity, resulting in complete loss of protein function in 8.2% of the malignant peripheral nerve sheath tumors. Another 5.5% had MDM2 amplification. TP53 mutation and MDM2 amplification were mutually exclusive and patients with either type of aberration in their tumor had a worse prognosis, compared to those without (hazard ratio for 5-year disease-specific survival 3.5, 95% confidence interval 1.78-6.98). Both aberrations had similar consequences on the gene expression level, as analyzed by a TP53-associated gene signature, a property also shared with the copy number aberrations and/or loss of heterozygosity at the TP53 locus, suggesting a common "TP53-mutated phenotype" in as many as 60% of the tumors. This was a poor prognostic phenotype (hazard ratio = 4.1, confidence interval:1.7-9.8), thus revealing a TP53-non-aberrant patient subgroup with a favorable outcome. The frequency of the "TP53-mutated phenotype" warrants explorative studies of stratified treatment strategies in malignant peripheral nerve sheath tumor.
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Affiliation(s)
- Maren Høland
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.,Institute for Clinical Medicine, University of Oslo, Oslo, Norway
| | - Matthias Kolberg
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Stine Aske Danielsen
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Bodil Bjerkehagen
- Department of Oral Biology, University of Oslo, Oslo, Norway.,Department of Pathology, Division of Laboratory Medicine, Oslo University Hospital, Oslo, Norway
| | - Ina A Eilertsen
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Merete Hektoen
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Nils Mandahl
- Department of Clinical Genetics, University and Regional Laboratories, Lund University, Lund, Sweden
| | - Eva van den Berg
- Department of Genetics, The University Medical Center Groningen, Groningen, The Netherlands
| | - Sigbjørn Smeland
- Institute for Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Oncology, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway
| | - Fredrik Mertens
- Department of Clinical Genetics, University and Regional Laboratories, Lund University, Lund, Sweden
| | - Kirsten Sundby Hall
- Department of Oncology, Division of Cancer Medicine, Oslo University Hospital, Oslo, Norway
| | - Piero Picci
- Laboratory of Experimental Oncology, Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Anita Sveen
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Ragnhild A Lothe
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway. .,Institute for Clinical Medicine, University of Oslo, Oslo, Norway.
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Probst M, Koerdt S, Ritschl LM, Bissinger O, Liesche F, Gempt J, Meyer B, Burian E, Lummel N, Kolk A. Malignant Peripheral Nerve Sheath Tumor in the Course of the Mandibular Nerve. World Neurosurg 2018; 117:e130-e137. [DOI: 10.1016/j.wneu.2018.05.203] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 05/26/2018] [Accepted: 05/28/2018] [Indexed: 11/29/2022]
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Wu LMN, Deng Y, Wang J, Zhao C, Wang J, Rao R, Xu L, Zhou W, Choi K, Rizvi TA, Remke M, Rubin JB, Johnson RL, Carroll TJ, Stemmer-Rachamimov AO, Wu J, Zheng Y, Xin M, Ratner N, Lu QR. Programming of Schwann Cells by Lats1/2-TAZ/YAP Signaling Drives Malignant Peripheral Nerve Sheath Tumorigenesis. Cancer Cell 2018; 33:292-308.e7. [PMID: 29438698 PMCID: PMC5813693 DOI: 10.1016/j.ccell.2018.01.005] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Revised: 10/04/2017] [Accepted: 01/08/2018] [Indexed: 02/07/2023]
Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell (SC)-lineage-derived sarcomas. Molecular events driving SC-to-MPNST transformation are incompletely understood. Here, we show that human MPNSTs exhibit elevated HIPPO-TAZ/YAP expression, and that TAZ/YAP hyperactivity in SCs caused by Lats1/2 loss potently induces high-grade nerve-associated tumors with full penetrance. Lats1/2 deficiency reprograms SCs to a cancerous, progenitor-like phenotype and promotes hyperproliferation. Conversely, disruption of TAZ/YAP activity alleviates tumor burden in Lats1/2-deficient mice and inhibits human MPNST cell proliferation. Moreover, genome-wide profiling reveals that TAZ/YAP-TEAD1 directly activates oncogenic programs, including platelet-derived growth factor receptor (PDGFR) signaling. Co-targeting TAZ/YAP and PDGFR pathways inhibits tumor growth. Thus, our findings establish a previously unrecognized convergence between Lats1/2-TAZ/YAP signaling and MPNST pathogenesis, revealing potential therapeutic targets in these untreatable tumors.
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Affiliation(s)
- Lai Man Natalie Wu
- Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Yaqi Deng
- Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Jincheng Wang
- Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Chuntao Zhao
- Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Jiajia Wang
- Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Rohit Rao
- Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Lingli Xu
- Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai, China
| | - Wenhao Zhou
- Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai, China
| | - Kwangmin Choi
- Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Tilat A Rizvi
- Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Marc Remke
- Departments of Pediatric Oncology, Neuropathology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf 40225, Germany; Department of Pediatric Neuro-Oncogenomics, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Düsseldorf 40225, Germany
| | - Joshua B Rubin
- Departments of Pediatrics and Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Randy L Johnson
- Department of Cancer Biology, MD Anderson Cancer Center, University of Texas, Houston, TX 77054, USA
| | - Thomas J Carroll
- Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Anat O Stemmer-Rachamimov
- Department of Pathology, Massachusetts General Hospital, Dana-Farber/Harvard Cancer Center, Harvard Medical School, Boston, MA 02114, USA
| | - Jianqiang Wu
- Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Yi Zheng
- Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Mei Xin
- Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Nancy Ratner
- Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Q Richard Lu
- Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai, China.
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Bergamaschi L, Bisogno G, Manzitti C, D'Angelo P, Milano GM, Scagnellato A, Cappelletti M, Chiaravalli S, Dall'Igna P, Alaggio R, Ruggiero A, Di Martino M, Affinita MC, Pierobon M, Garaventa A, Casanova M, Ferrari A. Salvage rates and prognostic factors after relapse in children and adolescents with malignant peripheral nerve sheath tumors. Pediatr Blood Cancer 2018; 65. [PMID: 28926683 DOI: 10.1002/pbc.26816] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2017] [Revised: 08/02/2017] [Accepted: 08/12/2017] [Indexed: 12/30/2022]
Abstract
BACKGROUND Malignant peripheral nerve sheath tumor (MPNST) is one of the most common nonrhabdomyosarcoma soft tissue sarcomas encountered in pediatric age, and it is generally characterized by poor outcome, particularly for relapsing patients. MATERIALS AND METHODS This study considered 73 patients <21 years of age with relapsing MPNST observed among 120 patients enrolled in Italian pediatric protocols from 1979 to 2004. With the aim of possibly establishing a risk-adapted stratification, patients' outcome was examined using univariate and multivariate analysis based on clinical features at onset, first-line treatments, clinical findings at the time of first relapse, and second-line treatments. RESULTS The time to relapse ranged from 1 to 204 months after first diagnosis (median 7 months). The first relapse event was mainly local. At the time of our analysis, nine patients were alive in remission. The median overall survival after first relapse was 11 months, and the survival rates were 39.2% at 1 year and 15.8% at 5 years. The factors revealing the greatest impact on prognosis were as follows: initial tumor invasiveness, time of relapse, and achievement of a secondary complete remission (which was related to the feasibility of radical surgery). CONCLUSIONS Our study confirmed the unsatisfactory prognosis for pediatric patients with relapsing MPNST and pointed to a risk-adapted stratification model for the purposes of deciding second-line treatments. For the time being, an aggressive surgical approach seems to be the only effective salvage treatment and should be recommended. New therapeutic approaches are under evaluation with a view to improving current outcomes.
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Affiliation(s)
- Luca Bergamaschi
- Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy
| | - Gianni Bisogno
- Pediatric Hemathology and Oncology Division, Padova University Hospital, Padova, Italy
| | - Carla Manzitti
- Department of Pediatric Hematology/Oncology, Giannina Gaslini Children's Hospital, Genova, Italy
| | - Paolo D'Angelo
- Pediatric Oncology Unit, G. Di Cristina Children's Hospital, Palermo, Italy
| | - Giuseppe Maria Milano
- Department of Hematology/Oncology, Ospedale Pediatrico Bambino Gesù IRCCS, Roma, Italy
| | - Angela Scagnellato
- Pediatric Hemathology and Oncology Division, Padova University Hospital, Padova, Italy
| | - Mirko Cappelletti
- Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy
| | - Stefano Chiaravalli
- Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy
| | | | - Rita Alaggio
- Pathology Department, Padova University Hospital, Padova, Italy
| | - Antonio Ruggiero
- Division of Pediatric Oncology, Catholic University of Roma, Roma, Italy
| | - Martina Di Martino
- Pediatric Oncology Service, Department of Pediatrics Second University, Napoli, Italy
| | - Maria Carmen Affinita
- Pediatric Hemathology and Oncology Division, Padova University Hospital, Padova, Italy
| | - Marta Pierobon
- Pediatric Hemathology and Oncology Division, Padova University Hospital, Padova, Italy
| | - Alberto Garaventa
- Department of Pediatric Hematology/Oncology, Giannina Gaslini Children's Hospital, Genova, Italy
| | - Michela Casanova
- Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy
| | - Andrea Ferrari
- Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy
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Bao X, Kong X, Yang C, Wu H, Ma W, Wang R. Targeted next-generation sequencing of malignant peripheral nerve sheath tumor of the pterygopalatine fossa with intracranial metastatic recurrence. Medicine (Baltimore) 2018; 97:e9636. [PMID: 29369179 PMCID: PMC5794363 DOI: 10.1097/md.0000000000009636] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Malignant peripheral nerve sheath tumor (MPNST) is an uncommon neoplasm that rarely involves the head and neck region. Intracranial MPNSTs unrelated to cranial nerves are highly malignant tumors with poor overall survival, probably because of infiltrating growth into surrounding brain tissue. The pathogenesis of MPNST remains unclear. There are no conclusive explanations for the mechanisms underlying the initiation, progression, and metastasis of MPNST. In this paper, we describe a case of MPNST in the pterygopalatine fossa with intracranial metastatic recurrence and review related literatures. Meanwhile, targeted next-generation sequencing (NGS) revealed the presence of both a beta-catenin (CTNNB1) missense mutation p.Ser33Phe and a mediator complex subunit 12 (MED12) frameshift mutation p.Tyr1278fs in the recurrent intracranial tumor. Therapies that target CTNNB1 mutation, MED12 mutation, CTNNB1 activation, or Wnt pathway activation are worth future studying.
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Affiliation(s)
| | | | | | - Huanwen Wu
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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SARC006: Phase II Trial of Chemotherapy in Sporadic and Neurofibromatosis Type 1 Associated Chemotherapy-Naive Malignant Peripheral Nerve Sheath Tumors. Sarcoma 2017; 2017:8685638. [PMID: 29138631 PMCID: PMC5613633 DOI: 10.1155/2017/8685638] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Accepted: 08/10/2017] [Indexed: 12/29/2022] Open
Abstract
Background Worse chemotherapy response for neurofibromatosis type 1- (NF1-) associated compared to sporadic malignant peripheral nerve sheath tumors (MPNST) has been reported. Methods We evaluated the objective response (OR) rate of patients with AJCC Stage III/IV chemotherapy-naive NF1 MPNST versus sporadic MPNST after 4 cycles of neoadjuvant chemotherapy, 2 cycles of ifosfamide/doxorubicin, and 2 cycles of ifosfamide/etoposide. A Simon optimal two-stage design was used (target response rate 40%). Results 34 NF1 (median age 33 years) and 14 sporadic (median age 40 years) MPNST patients enrolled. Five of 28 (17.9%) evaluable NF1 MPNST patients had a partial response (PR), as did 4 of 9 (44.4%) patients with sporadic MPNST. Stable disease (SD) was achieved in 22 NF1 and 4 sporadic MPNST patients. In both strata, results in the initial stages met criteria for expansion of enrollment. Only 1 additional PR was observed in the expanded NF1 stratum. Enrollment was slower than expected and the trial closed before full accrual. Conclusions This trial was not powered to detect differences in response rates between NF1 and sporadic MPNST. While the OR rate was lower in NF1 compared to sporadic MPNST, qualitative responses were similar, and disease stabilization was achieved in most patients.
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Kolberg M, Bruun J, Murumägi A, Mpindi JP, Bergsland CH, Høland M, Eilertsen IA, Danielsen SA, Kallioniemi O, Lothe RA. Drug sensitivity and resistance testing identifies PLK1 inhibitors and gemcitabine as potent drugs for malignant peripheral nerve sheath tumors. Mol Oncol 2017; 11:1156-1171. [PMID: 28556483 PMCID: PMC5579334 DOI: 10.1002/1878-0261.12086] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 04/24/2017] [Accepted: 05/16/2017] [Indexed: 12/13/2022] Open
Abstract
Patients with malignant peripheral nerve sheath tumor (MPNST), a rare soft tissue cancer associated with loss of the tumor suppressor neurofibromin (NF1), have poor prognosis and typically respond poorly to adjuvant therapy. We evaluated the effect of 299 clinical and investigational compounds on seven MPNST cell lines, two primary cultures of human Schwann cells, and five normal bone marrow aspirates, to identify potent drugs for MPNST treatment with few side effects. Top hits included Polo-like kinase 1 (PLK1) inhibitors (volasertib and BI2536) and the fluoronucleoside gemcitabine, which were validated in orthogonal assays measuring viability, cytotoxicity, and apoptosis. DNA copy number, gene expression, and protein expression were determined for the cell lines to assess pharmacogenomic relationships. MPNST cells were more sensitive to BI2536 and gemcitabine compared to a reference set of 94 cancer cell lines. PLK1, RRM1, and RRM2 mRNA levels were increased in MPNST compared to benign neurofibroma tissue, and the protein level of PLK1 was increased in the MPNST cell lines compared to normal Schwann cells, indicating an increased dependence on these drug targets in malignant cells. Furthermore, we observed an association between increased mRNA expression of PLK1, RRM1, and RRM2 in patient samples and worse disease outcome, suggesting a selective benefit from inhibition of these genes in the most aggressive tumors.
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Affiliation(s)
- Matthias Kolberg
- Department of Molecular OncologyInstitute for Cancer Researchthe Norwegian Radium HospitalOslo University HospitalNorway
- Centre for Cancer BiomedicineUniversity of OsloNorway
| | - Jarle Bruun
- Department of Molecular OncologyInstitute for Cancer Researchthe Norwegian Radium HospitalOslo University HospitalNorway
- Centre for Cancer BiomedicineUniversity of OsloNorway
| | - Astrid Murumägi
- Institute for Molecular Medicine FinlandFIMMUniversity of HelsinkiFinland
| | - John P. Mpindi
- Institute for Molecular Medicine FinlandFIMMUniversity of HelsinkiFinland
| | - Christian H. Bergsland
- Department of Molecular OncologyInstitute for Cancer Researchthe Norwegian Radium HospitalOslo University HospitalNorway
- Centre for Cancer BiomedicineUniversity of OsloNorway
| | - Maren Høland
- Department of Molecular OncologyInstitute for Cancer Researchthe Norwegian Radium HospitalOslo University HospitalNorway
- Centre for Cancer BiomedicineUniversity of OsloNorway
| | - Ina A. Eilertsen
- Department of Molecular OncologyInstitute for Cancer Researchthe Norwegian Radium HospitalOslo University HospitalNorway
- Centre for Cancer BiomedicineUniversity of OsloNorway
| | - Stine A. Danielsen
- Department of Molecular OncologyInstitute for Cancer Researchthe Norwegian Radium HospitalOslo University HospitalNorway
- Centre for Cancer BiomedicineUniversity of OsloNorway
| | - Olli Kallioniemi
- Institute for Molecular Medicine FinlandFIMMUniversity of HelsinkiFinland
- Science for Life LaboratorySolnaSweden
- Department of Oncology and PathologyKarolinska InstitutetSolnaSweden
| | - Ragnhild A. Lothe
- Department of Molecular OncologyInstitute for Cancer Researchthe Norwegian Radium HospitalOslo University HospitalNorway
- Centre for Cancer BiomedicineUniversity of OsloNorway
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50
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Radiation-Induced Malignant Peripheral Nerve Sheath Tumors: A Systematic Review. World Neurosurg 2017; 105:961-970.e8. [DOI: 10.1016/j.wneu.2017.06.010] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2017] [Revised: 05/31/2017] [Accepted: 06/01/2017] [Indexed: 12/14/2022]
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