Targeted genetic and molecular therapies in neurofibromatosis - A review of present therapeutic options and a glimpse into the future.

Neurofibromatosis type 1, the most common phakomatoses, can present with a host of signs and symptoms, usually involving the skin and the peripheral nervous system. It is characterized by a mutation in the neurofibromatosis type 1 gene on chromosome 17q11.2 that codes for the protein neurofibromin. Neurofibromin acts as a tumor suppressor gene by inhibiting rat sarcoma (Ras) activity and its deficiency leads to increased Ras activity, cellular proliferation and tumor formation. This review was conducted to analyze the various targeted therapies at the genetic and molecular level employed to manage the tumors and other clinical presentations associated with neurofibromatosis type 1. Twenty-eight studies of treatment modalities for the conditions associated with neurofibromatosis and which involved either targeted gene therapy or molecular level therapies, including the latest advances, were included in this review. Mitogen-activated protein kinase kinase inhibition, mammalian target of Rapamycin inhibition and Tyrosine kinase inhibition, represent some of the newer treatment options in this category. Although there are a number of trials for providing therapeutic options at the genetic and molecular level for the various physical and psychological morbidities associated with neurofibromatosis type 1, most of them are in the preclinical stage. Increased clinical trials of the molecules and gene therapies could significantly help in managing the various chronic and sometimes, life-threatening conditions associated with neurofibromatosis 1 and these will probably represent the preferred treatment direction of the future.

High resolution MRI-based radiomic nomogram in predicting perineural invasion in rectal cancer.

BACKGROUND: To establish and validate a high-resolution magnetic resonance imaging (HRMRI)-based radiomic nomogram for prediction of preoperative perineural invasion (PNI) of rectal cancer (RC). METHODS: Our retrospective study included 140 subjects with RC (99 in the training cohort and 41 in the validation cohort) who underwent a preoperative HRMRI scan between December 2016 and December 2019. All subjects underwent radical surgery, and then PNI status was evaluated by a qualified pathologist. A total of 396 radiomic features were extracted from oblique axial T2 weighted images, and optimal features were selected to construct a radiomic signature. A combined nomogram was established by incorporating the radiomic signature, HRMRI findings, and clinical risk factors selected by using multivariable logistic regression. RESULTS: The predictive nomogram of PNI included a radiomic signature, and MRI-reported tumor stage (mT-stage). Clinical risk factors failed to increase the predictive value. Favorable discrimination was achieved between PNI-positive and PNI-negative groups using the radiomic nomogram. The area under the curve (AUC) was 0.81 (95% confidence interval [CI], 0.71-0.91) in the training cohort and 0.75 (95% CI, 0.58-0.92) in the validation cohort. Moreover, our result highlighted that the radiomic nomogram was clinically beneficial, as evidenced by a decision curve analysis. CONCLUSIONS: HRMRI-based radiomic nomogram could be helpful in the prediction of preoperative PNI in RC patients.

Systemic Options for Malignant Peripheral Nerve Sheath Tumors.

OPINION STATEMENT: Malignant peripheral nerve sheath tumors (MPNSTs) are rare mesenchymal neoplasms that represent a profound therapeutic challenge due to their high proclivity for recurrence and metastasis and relatively poor response to systemic therapy regimens. While our understanding of the pathophysiology of MPNST is growing, including loss of the tumor suppressor gene neurofibromin and subsequent activation of the Ras pathway, targeted therapy to modify the poor prognosis seen in MPNST patients has thus far been without success. Correspondingly, MPNST patients are treated as per soft tissue sarcoma treatment algorithms with anthracycline-based therapy as the front-line therapy of choice for patients with unresectable, locally advanced, or metastatic MPNST. Beyond first-line anthracycline-based therapy, other standard cytotoxic chemotherapy agents used in advanced MPNST include the alkylating agent ifosfamide and the topoisomerase II inhibitor etoposide. Notably, soft tissue sarcoma regimens are used in MPNST despite distinct systemic therapy sensitivity and prognosis. This is particularly notable for neurofibromatosis type 1 (NF1)-associated MPNST, which is associated with poorer response to systemic therapy and prognosis than sporadic MPNST. As such, NF1-associated MPNST is a particular area in need of novel therapeutic strategies. Given the lack of benefit in the targeting of unique aspects of MPNST disease biology thus far, pre-clinical studies to identify novel rational therapies are critical to inform future clinical trials.

Malignant Peripheral Nerve Sheath Tumor Arising From Transplanted Kidney Assessed by 18F-FDG PET/CT.

Malignant peripheral nerve sheath tumor (MPNST) originates from Schwann cells or pluripotent perineural cells, which is an extremely rare tumor that occurs in the kidney. We report a case of MPNST in transplanted kidney that was diagnosed in a 32-year-old man with a history of kidney transplantation. Contrast-enhanced MRI and F-FDG PET/CT features of MPNST are described, which can accurately discriminate MPNST from infection and benign tumors. These features could potentially provide valuable information to distinguish it from other renal malignancies. F-FDG PET/CT may be a useful tool for the primary diagnosis and the initial staging of MPNST.

Analysis of the Causes and Experience in the Diagnosis and Treatment of Intravertebral Mobile Nerve Sheath Tumors-Case Report and Review of the Literature.

BACKGROUND: We sought to analyze the clinical data and imaging features from a rare case presenting an intravertebral mobile nerve sheath tumor of the lumbar spine, review the relevant literature, discuss the imaging features and possible causes of the tumor, and propose preventive measures and solutions. CASE DESCRIPTION: The clinical data and imaging data of a patient with a lumbar spinal canal mobile nerve sheath tumor were retrospectively analyzed in conjunction with the relevant literature. The first preoperative lumbar spine magnetic resonance imaging (MRI) showed the tumor located at level L1-2. Further lumbar spine MRI, which was performed 5 days later, showed the tumor was at level L3-4, with a range of motion of 8 cm. End spinal resection of the tumor was performed under general anesthesia, and a tumor, which was cystic solid, was found to be located at level L3-4. The tumor originated from a distinctly twisted and elongated posterior root of the spinal cord, with complete fusion of the tumor-bearing nerve. Both the tumor and tumor-carrying nerve were removed. Postoperative pathologic examination confirmed that the tumor was a nerve sheath tumor. Lumbar MRI on postoperative day 10 showed complete resection of the tumor in the L3-4 spinal canal. The patient was discharged with normal urination and defecation, normal sensation in both lower extremities, grade 5 muscle strength, normal muscle tone, and normal reflexes in both knee and Achilles tendons. CONCLUSIONS: Intravertebral mobile nerve sheath tumors are rare, and the marked distortion and elongation of the carrier nerve seen on MRI are important imaging features of this disease. The possible causes of tumor movement include tumor texture, location, positional changes, and altered cerebrospinal fluid dynamics. Acute changes in intraabdominal pressure caused by forceful defecation may be a high-risk factor for tumor migration. Multiple preoperative MRIs to localize the tumor are particularly important.

Treatment of neurofibromatosis 1-associated malignant peripheral nerve sheath tumors: a systematic review.

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.

What's new in nerve sheath tumors.

Peripheral nerve sheath tumors are commonly encountered and frequently pose challenges to the pathologist and the clinician. This review discusses the wide range of entities with an emphasis on new discoveries in the past decade. Clinical, histologic, immunohistochemical, and pathogenetic findings are discussed with an emphasis on clinical implications and differential diagnosis.

Prognostic and predictive markers for perineural and bone invasion of oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is a growing problem worldwide. Several biological and molecular criteria have been established for making a prognosis of OSCC. One of the most important factors affecting the risk of tumor recurrence and overall prognosis is perineural invasion and bone invasion. Perineural invasion is defined as a tumor spreading and the ability of tumor cells to penetrate around or through the nerve tissue. Perineural invasion can cause the tumor to spread to distant areas from the primary tumor location. One possible explanation for this is the formation of microenvironment in the perineural space which may contain cellular factors that act on both nerve tissue and some types of tumor tissues. Bone invasion by OSCC has major implications for tumor staging, choice of treatment, outcome and quality of life. Oral SCCs invade the mandibular or maxillary bone through an erosive, infiltrative or mixed pattern that correlates with clinical behavior. Bone resorption by osteoclasts is an important step in the process of bone invasion by oral SCCs. Some cytokines (e.g. TNFα and PTHrP) lead to receptor activator of NF-κB ligand (RANKL) expression or osteoprotegerin (OPG) suppression in oral SCC cells and in cancer stromal cells to induce osteoclastogenesis. Oral SCCs provide a suitable microenvironment for osteoclastogenesis to regulate the balance of RANKL and OPG. A more molecular-based clinical staging and tailor-made therapy would benefit patients with bone invasion by OSCC.

Radiation-induced and neurofibromatosis-associated malignant peripheral nerve sheath tumors (MPNST) have worse outcomes than sporadic MPNST.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNST) may be sporadic or associated with neurofibromatosis or prior radiation. MPNST may behave aggressively with a high rate of local recurrence and distant metastasis. METHODS: In an IRB approved protocol, we reviewed the clinical characteristics, treatment, and outcomes of 280 patients treated for MPNST at Massachusetts General Hospital (MGH) between 1960 and 2016. RESULTS: There were 138 men and 142 women with a median age of 41 (range: 3-95) years. Tumors were classified as neurofibromatosis-associated (nfMPNST, n = 77), radiation-induced (rMPNST, n = 21), or sporadic (sMPNST, n = 182) MPNST. The median time to development of rMPNST from prior radiation was 15 years. With a median follow-up of 43.1 months, the median overall survival (OS) was 65.3 months. Older age, nfMPNST, rMPNST, increased tumor size, lymph node involvement, metastatic disease, intermediate to high grade, radiotherapy alone, and R2 resection were related to worse OS, whereas surgery with radiotherapy was associated with improved OS. Among the 251 patients without metastasis, nfMPNST, rMPNST, and increased tumor size were correlated with worse metastasis-free survival; nfMPNST, radiotherapy alone, and R1/R2 resection were associated with local recurrence, whereas surgery with adjuvant radiotherapy was related to improved local control in patients with R1/R2 resection. CONCLUSIONS: Both radiation-induced and neurofibromatosis-associated MPNSTs have poorer prognosis than sporadic MPNSTs. Complete resection of the tumor is a significant prognostic factor for MPNST. The addition of radiotherapy after surgery should be considered especially when the surgical margins are positive.

Differentiation of peripheral nerve sheath tumors in patients with neurofibromatosis type 1 using diffusion-weighted magnetic resonance imaging.

BACKGROUND: We sought to determine the value of diffusion-weighted (DW) magnetic resonance imaging (MRI) for characterization of benign and malignant peripheral nerve sheath tumors (PNSTs) in patients with neurofibromatosis type 1 (NF1). METHODS: Twenty-six patients with NF1 and suspicion of malignant transformation of PNSTs were prospectively enrolled and underwent DW MRI at 3T. For a set of benign (n = 55) and malignant (n = 12) PNSTs, functional MRI parameters were derived from both biexponential intravoxel incoherent motion (diffusion coefficient D and perfusion fraction f) and monoexponential data analysis (apparent diffusion coefficients [ADCs]). A panel of morphological MRI features was evaluated using T1- and T2-weighted imaging. Mann-Whitney U-test, Fisher's exact test, and receiver operating characteristic (ROC) analyses were applied to assess the diagnostic accuracy of quantitative and qualitative MRI. Cohen's kappa was used to determine interrater reliability. RESULTS: Malignant PNSTs demonstrated significantly lower diffusivity (P < 0.0001) compared with benign PNSTs. The perfusion fraction f was significantly higher in malignant PNSTs (P < 0.001). In ROC analysis, functional MRI parameters showed high diagnostic accuracy for differentiation of PNSTs (eg, ADCmean, 92% sensitivity with 98% specificity, AUC 0.98; Dmean, 92% sensitivity with 98% specificity, AUC 0.98). By contrast, morphological imaging features had only limited sensitivity (18-94%) and specificity (18-82%) for identification of malignancy. Interrater reliability was higher for monoexponential data analysis. CONCLUSION: DW imaging shows better diagnostic performance than morphological features and allows accurate differentiation of benign and malignant peripheral nerve sheath tumors in NF1.

Human stem cell modeling in neurofibromatosis type 1 (NF1).

The future of precision medicine is heavily reliant on the use of human tissues to identify the key determinants that account for differences between individuals with the same disorder. This need is exemplified by the neurofibromatosis type 1 (NF1) neurogenetic condition. As such, individuals with NF1 are born with a germline mutation in the NF1 gene, but may develop numerous distinct neurological problems, ranging from autism and attention deficit to brain and peripheral nerve sheath tumors. Coupled with accurate preclinical mouse models, the availability of NF1 patient-derived induced pluripotent stem cells (iPSCs) provides new opportunities to define the critical factors that underlie NF1-associated nervous system disease pathogenesis and progression. In this review, we discuss the generation and potential applications of iPSC technology to the study of NF1.

Pilomatrixoma of the Neck/Shoulder Region Mimicking a Rapidly Growing Neoplasm of Peripheral Nerve Sheath Origin in Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is an autosomal dominant hereditary disorder. Neurofibroma is the most common neoplasm of this disease. This lesion is characterized by circumscribed soft or knotty skin tumors derived from peripheral nerve sheath cells. Numerous other neoplasms have been described for this tumor predisposition syndrome. This case report adds the diagnostic and therapeutic procedures in the case of an NF1 patient in whom the rapidly growing, nodular, subcutaneous tumor initially led to the suspicion of a malignant neoplasm. The tumor proved to be pilomatrixoma, which closely adhered to a neurofibroma.

Radiation-Induced Glandular Malignant Peripheral Nerve Sheath Tumor.

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft-tissue tumors. They can occur in patients with neurofibromatosis type-1 (NF-1) or as sporadic tumors. Only 10% of MPNSTs are radiation induced. Divergent differentiation in MPNSTs can occur in 15% of cases and may include cartilage, bone, skeletal muscle, blood vessels, and very rarely well-formed glands, the latter typically described in NF-1-associated MPNSTs. We report an exceedingly rare case of radiation induced glandular MPNST arising in a neurofibroma of the femoral nerve in a patient previously irradiated for endometrial carcinoma.

Overweight, obesity and height as risk factors for meningioma, glioma, pituitary adenoma and nerve sheath tumor: a large population-based prospective cohort study.

BACKGROUND: In 2016, the International Agency for Research on Cancer (IARC) has announced that avoiding body fatness (i.e. overweight and obesity) contributes to prevent meningioma occurrence, but considered the available evidence for glioma inadequate. The association of body fatness with other CNS tumor subgroups is largely unknown. OBJECTIVES: To assess whether body fatness or body height are associated with risk for meningioma, glioma, pituitary adenoma (PA) or nerve sheath tumor (NST) in a large population-based Norwegian cohort. METHODS: In this prospective cohort study of 1.8 million Norwegian residents, weight and height were measured at baseline and incident intracranial tumors were subsequently identified by linkage to the Cancer Registry of Norway. Cox regression analyses were performed to estimate risk for each tumor subgroup in relation to anthropometric measures, stratified by sex and in different age groups. RESULTS: During 54 million person-years of follow-up 3335 meningiomas, 4382 gliomas, 1071 PAs and 759 NSTs were diagnosed. Obesity (BMI ≥30 kg/m2) was not associated with risk for meningioma or glioma, but was significantly associated with risk for PA (HR 1.43; 95% CI 1.09-1.88) compared with the reference group (BMI 20-24.9 kg/m2). For intracranial NSTs, obesity was associated with reduced tumor risk (HR 0.68; 95% CI 0.46-0.99). Body height was associated with increased risk for all four tumor subgroups. CONCLUSIONS: This study does not confirm overweight or obesity as risk factors for meningioma. Additionally, overweight and obesity can be quite confidently excluded as risk factors for glioma. However, this study indicates that body fatness increases the risk for PA, while it reduces the risk for NST.

Radiation-Induced Schwannomas and Neurofibromas: A Systematic Review.

OBJECTIVE: Radiation-induced benign peripheral nerve sheath tumors are uncommon late complications of irradiation. We conducted the largest systematic review of individual patient data. METHODS: We performed a systematic search of PubMed databases and compiled a comprehensive literature review. Kaplan-Meier analysis was used to investigate survival, and statistical significance was assessed with a log-rank test. RESULTS: We analyzed 40 cases of radiation-induced benign peripheral nerve sheath tumors. The histologic distributions were 28 schwannomas, 11 neurofibromas, and 1 ganglioneuroma. The average age of radiation exposure for development of primary lesions was 14.9 ± 15.5 years, and the latency period between radiotherapy to the onset of secondary tumors was 24.5 ± 12.7 years. The average irradiation dose delivered was 26.3 ± 20.3 Gy. The median overall survival for all cases was not reached (95% confidence interval, 22-not reached) months, with 10-year survival rates of 65.2%. Surgical negative margin was a positive prognostic factor for radiation-induced benign peripheral nerve sheath tumors. CONCLUSIONS: The risk of incidence of secondary benign peripheral nerve sheath tumors in patients treated with radiotherapy should be considered in long-term follow-up periods. At present, complete surgical resection is the main stay for the treatment of radiation-induced benign peripheral nerve sheath tumors.

Hybrid peripheral nerve sheath tumors: report of five cases and detailed review of literature.

BACKGROUND: Hybrid peripheral nerve sheath tumors (PNSTs) have been recognized recently and were first included in the 4th edition of World Health Organization (WHO) Classification of Tumors of Soft tissue and Bone, published in 2013. These tumors show combined features of more than one type of conventional benign peripheral nerve sheath tumors. The most common combinations are those of schwannoma/perineurioma followed by combinations of neurofibroma/schwannoma and neurofibroma/perineurioma. A detailed literature review of published cases is presented. We have discussed the types and etiology, epidemiology and sites of localization, gross and microscopic appearances and immunohistochemical features of hybrid PNSTs and association of these tumors with tumor syndromes. CASE PRESENTATION: We have included five cases which were diagnosed in our department as we believe that publication of these new cases is relevant for the improved understanding of these specific tumors. Four of our five patients were males, mean age was 24 years. There was wide variation in the location of these tumors. Mean size of excised tumors was 5.5 cms in the greatest dimensions. Three out of five cases represented hybrid schwannoma/perineurioma histologically. No significant nuclear atypia, mitotic activity or necrosis seen. All five cases were completely excised. All five patients are alive and well at the time of writing with no recurrence. CONCLUSION: Hybrid PNSTs are distinct tumors and are usually benign. However, rare case reports have described local recurrence and at least two recent case reports have described malignant transformation in these tumors. Further studies on large number of cases are required to determine the exact pathogenetic basis of these tumors.

Spontaneous spinal plexiform perineurioma in a juvenile chicken ( Gallus domesticus).

A 2-mo-old pet chicken ( Gallus domesticus) was presented because of lameness and a hind limb mass of 1 mo duration. Radiographs revealed a soft tissue mass extending from the mid-femur into the body wall. Cytology of a sample obtained from a fine-needle aspirate was unremarkable. The bird was prepared for surgical investigation of the mass but died acutely at the time of pre-medication. Autopsy revealed an extradural mesenchymal neoplasm that focally compressed the lumbar spinal cord, extended into and along the adjacent nerve structures, and displaced the kidneys, skeletal muscle, and body wall. Histopathology was consistent with a perineurioma, which was positive for alcian blue and negative for S100, GLUT1, and neurofilament proteins on immunohistochemistry. PCR testing of tumor tissue was negative for gallid herpesvirus 2 (Marek's disease virus) and avian leukosis virus. Although the etiology of the mass was not determined, our case highlights a severe manifestation of an uncommonly diagnosed tumor in the chicken. Though uncommon, perineurioma should be considered a differential diagnosis for lameness in the chicken.

Low-Grade Sinonasal Sarcoma With Neural and Myogenic Features: A Recently Discovered Entity With Unique Features and Diagnostic Challenge.

Low-grade sinonasal sarcoma with neural and myogenic features is an entity recently described in the literature. Little is known about its etiopathogenesis, natural history, or optimal treatment. In fact, it has relatively unique findings: it has a distinctive cytogenetic signature, and it expresses both smooth muscle actin and S100 protein. However, its diagnosis is challenging on biopsies showing negative staining for these 2 markers. The differential diagnoses include fibrosarcoma, malignant peripheral nerve sheath tumors, and other benign and malignant lesions. A complete resection, with or without radiotherapy, is required because this lesion appears to be locally aggressive. However, the clinical outcome seems to be good. Low-grade sinonasal sarcoma with neural and myogenic features merits classification as an independent tumor in the next World Health Organization classification of head and neck tumors. Reports of additional cases are required to support its unique classification.