Gender dimorphism and age of onset in malignant peripheral nerve sheath tumor preclinical models and human patients
© Shurell et al.; licensee BioMed Central Ltd. 2014
Received: 22 July 2013
Accepted: 23 October 2014
Published: 15 November 2014
Gender-based differences in disease onset in murine models of malignant peripheral nerve sheath tumor (MPNST) and in patients with Neurofibromatosis type-1-(NF-1)-associated or spontaneous MPNST has not been well studied.
Forty-three mGFAP-Cre+;Pten loxp/+;LSL-K-ras G12D/+ mice were observed for tumor development and evaluated for gender disparity in age of MPNST onset. Patient data from the prospectively collected UCLA sarcoma database (1974–2011, n = 113 MPNST patients) and 39 published studies on MPNST patients (n = 916) were analyzed for age of onset differences between sexes and between NF-1 and spontaneous MPNST patients.
Our murine model showed gender-based differences in MPNST onset, with males developing MPNST significantly earlier than females (142 vs. 162 days, p = 0.015). In the UCLA patient population, males also developed MPNST earlier than females (median age 35 vs. 39.5 years, p = 0.048). Patients with NF-1-associated MPNST had significantly earlier age of onset compared to spontaneous MPNST (median age 33 vs. 39 years, p = 0.007). However, expanded analysis of 916 published MPNST cases revealed no significant age difference in MPNST onset between males and females. Similar to the UCLA dataset, patients with NF-1 developed MPNST at a significantly younger age than spontaneous MPNST patients (p < 0.0001, median age 28 vs. 41 years) and this disparity was maintained across North American, European, and Asian populations.
Although our preclinical model and single-institution patient cohort show gender dimorphism in MPNST onset, no significant gender disparity was detected in the larger MPNST patient meta-dataset. NF-1 patients develop MPNST 13 years earlier than patients with spontaneous MPNST, with little geographical variance.
KeywordsMPNST Neurofibromatosis Meta-analysis Epidemiology
The significance of gender as a fundamental variable to be studied in the development and progression of disease has been a long standing topic of interest . Men and women differ in their genetic milieu and environmental exposures, which is reflected in overall disease susceptibilities and progression . Epidemiologic studies of cancer patients reveal significant discrepancies in cancer incidence between sexes beyond the typical sex-specific malignancies . For example, gastric, esophageal, brain, liver, head and neck cancers, and non-Hodgkin’s lymphoma occur more often in men than women [3–5].
Mesenchymal glioblastoma multiforme (GBM), which is thought to stem from similar biomolecular pathways as malignant peripheral nerve sheath tumors (MPNST) including loss of neurofibromin (NF1) and TP53 function [6, 7], also shows increased prevalence of disease in men [8, 9]. A murine model of GBM formation developed from NF1 deficient mice expressing a dominant-negative form of p53 (Nf1-/- DNp53) confirmed cell-intrinsic sexual dimorphism in the malignant transformation of astrocytes to GBM, regardless of hormones or tumor environment .
However, gender differences in the development of MPNSTs have not specifically been examined. MPNST is an aggressive soft tissue sarcoma (STS) that accounts for up to 10 percent of all STS [10–12]. It is often associated with the autosomal dominant syndrome of Neurofibromatosis type 1 (NF-1), but arise sporadically as well. MPNSTs carry a particularly poor prognosis, with a 5-year survival of 15-45% in NF-1 patients compared to 43-75% for non-NF-1 patients [10, 13–15].
Although not all gender-based disparities are felt to be based on hormonal differences, there does appear to be a notable association amongst neurofibromas (NF), benign peripheral nerve sheath tumors that are a hallmark of neurofibromatosis, and circulating hormone levels. In NF-1 patients, MPNSTs are often found in the context of a preexisting NF. Although MPNST is felt to more commonly arise from epineural and perineural NFs such as subcutaneous and plexiform NF, the subtype of dermal NF shows considerable hormone responsiveness. Dermal NFs often appear at puberty, reportedly increase in number and size during pregnancy, and may regress after delivery, implicating a possible hormonal influence on tumor growth [16–18]. It has even been suggested that steroid hormones may be involved in the malignant transformation of neurofibroma to MPNST . Investigation of Schwann cell–enriched xenografted NF-1 human dermal NF, plexiform NF, and MPNST samples demonstrated that estrogen and progesterone significantly increased the growth of MPNST in 100% and 66% of samples, respectively, and also increased growth in 25% of dermal NF tested. However, estrogen and progesterone decreased growth in 25% of xenografted plexiform NF with no effect in the remaining plexiform NF samples .
Recently, the development of animal models that recapitulate neurofibroma and MPNST development have allowed for investigation into the mechanisms of tumor development and malignant transformation [21–23]. Interestingly, the N-ethyl-N-nitrosurea (ENU)-induced rat model and the Nf1-/+;Tp53-/+ cis (i.e. B6-NPcis) mouse model have both shown males to develop MPNSTs at an earlier age than females, even while accounting for confounding factors such as parental gender in the B6-NPcis model [21, 24, 25]. This further underscores the possibility of sex-specific differences in MPNST age of onset.
To further extend these studies, we examined our genetically engineered murine model of MPNST for gender differences. To evaluate if this model had clinically translatable findings, we conducted an analysis of MPNST patients diagnosed and treated at the University of California, Los Angeles (UCLA) and analyzed a meta-dataset of patients from 39 published clinical MPNST studies. Our study focused on age of MPNST diagnosis, as this data is consistently reported in the published MPNST literature. Evaluation of the interval between NF onset to MPNST development was not assessed, as this data is not routinely recorded. The aims of this study were to evaluate gender dimorphism in MPNST age of onset in the UCLA patient population and in a larger dataset across several geographical populations, and to evaluate differences in age of MPNST onset between NF-1 and spontaneous patients.
Forty-three mGFAP-Cre+;Pten loxp/+;LSL-K-ras G12D/+ MPNST mice were generated as previously described . These mice develop multiple NFs with subsequent progression to MPNST at a reproducible rate with 100% penetrance. These mice were further purposed for MPNST chemotherapy studies (unpublished data), therefore non-invasive methods of tumor detection were used. Given the small tumor size at the time of detection, micro-PET/CT could not reliably distinguish NF from MPNST based on SUVmax (unpublished data), and was therefore not employed in this study. Physical examination was performed daily to detect tumor formation or illness. Mice were thoroughly examined and palpated for tumor formation, which consistently detected tumors as small as 4 mm diameter. We previously showed that our murine model (Gregorian et al. ) consistently progresses from neurofibroma to MPNST two weeks after tumor onset, regardless of gender. Therefore, initial time of palpable tumor development was used as a surrogate for MPNST development. Mice were euthanized per protocol if tumors reached a diameter of 1.5 cm or interfered with feeding, grooming or ambulation, or if the mouse lost >10% of their body weight. Survival times were not evaluated as the mice were purposed for treatment studies (unpublished). Tumors were fixed and embedded in paraffin, then sectioned and stained with hematoxylin and eosin to confirm pathologic diagnosis of MPNST. Animals were housed in a temperature-, humidity-, and light-controlled room (12-h light/dark cycle), and allowed free access to food and water. All experiments were conducted according to the research guidelines of the University of California, Los Angeles (UCLA) Chancellor’s Animal Research Committee.
UCLA data and patient selection
Since 1974, UCLA has prospectively maintained a sarcoma database with complete clinical and pathologic patient data. A protocol detailing the study design and analysis was approved by the UCLA Institutional Review Board. For inclusion, subjects were required to have tissue diagnosis of a MPNST and undergone surgery and treatment at UCLA. 113 UCLA patients were eligible for study. Original surgical specimens were reviewed by a UCLA sarcoma pathologist (S.M.D.) to re-confirm pathologic diagnosis and grading.
External patient database
To validate our findings within a broader dataset, we performed a PubMed search using the following algorithm “(peripheral nerve sheath tumour[Title]) OR peripheral nerve sheath tumor[Title]) OR MPNST[Title]) OR neurogenic sarcoma[Title]) OR malignant schwannoma[Title]) OR atypical neurofibromas[Title]) OR peripheral nerve sheath tumors[Title]) OR peripheral nerve sheath tumours[Title]) NOT case report[Title]” for published articles from 1960–2011. For this study, only references written in the English language were used. Studies evaluating Neurofibromatosis type 2 were excluded. 990 hits were collected, and abstracts browsed to identify relevant articles. The full manuscripts were reviewed to identify studies that listed individual patients with age of diagnosis, NF-1 status, gender, and geographic data. Ten PubMed suggested articles or citations outside of our original search were included, and met the above criteria. A total of 39 published studies with data on 916 patients with MPNST was collected and aggregated to form the meta-dataset (Additional file 1: Table S1). Data was cross-referenced to ensure duplicate patient reports were excluded. Patients were classified by geographic location, gender, and NF-1 disease status for subgroup analysis.
Statistical significance was determined using Wilcoxon rank sum test, with a significance threshold of alpha ≤0.05. Variables assessed were age of diagnosis, gender, and NF-1 status. Analysis of the datasets was performed using STATA 12.0 (StataCorp. 2011) and R software (R-package version 2.13).
Genetically engineered murine model of MPNST demonstrates gender dimorphism in disease onset
UCLA patients demonstrate gender dimorphism in age of MPNST onset
Meta-dataset fails to show gender dimorphism in MPNST onset
UCLA and meta-dataset analysis shows significantly earlier age of MPNST onset in NF-1 patients compared to spontaneous MPNST patients
Male median age (n)
Female median age (n)
Male vs. female Wilcox p value
Overall median age (n)
NF-1 vs. spont. Wilcox p value
31 yrs (19)
39 yrs (11)
33 yrs (30)
37 yrs (42)
40 yrs (41)
39 yrs (83)
29 yrs (230)
27 yrs (266)
28 yrs (496)
43 yrs (221)
39 yrs (199)
41 yrs (420)
NF-1 associated MPNST patients develop MPNST at a significantly earlier age than spontaneous MPNST patients
Further analysis of the UCLA dataset revealed that patients with NF-1-associated MPNST had a significantly earlier age of onset compared to patients with spontaneous MPNST (Figure 2; median age 33 years vs. 39 years, p = 0.007). In the UCLA dataset, patients with NF-1 developed MPNST an average of 10.3 years earlier than patients without NF-1.Similar to the UCLA dataset, the meta-dataset indicated that patients with NF-1 developed MPNST at a significantly younger age than patients without NF-1 (median 28 vs. 41 years old, p < 0.0001). Evaluation of the overall distribution of male and female age of onset (Figure 3A) revealed distinct peaks for NF-1 associated MPNST onset, as compared to the more broad distribution seen in spontaneous MPNST diagnosis.The data was then analyzed by geographical regions of North America, Europe, and Asia. In the North American population, the median age of NF-1 patient MPNST diagnosis was 28 (n = 218) compared to the age of 40 in spontaneous MPNST patients (n = 236) (Figure 3B). In the European population, the median age of diagnosis in NF-1 patients was 27.9 (n = 250) compared to the spontaneous MPNST patient age of 41 (n = 157) (Figure 3C). Asian populations showed a larger disparity in age of diagnosis; however the size of this cohort was considerably smaller than the others. In Asian populations, the median age of diagnosis in NF-1 patients was 33.5 years (n = 28), compared to a median age of diagnosis of 45 years in the spontaneous MPNST population (p = 0.23) (Figure 3D).
Our genetically engineered murine model of MPNST showed significant gender dimorphism in age of MPNST onset. To see if this was clinically translatable, we investigated gender differences in age of MPNST onset first in our UCLA patient cohort and second in a larger meta-analysis of 916 published MPNST patients. The distribution of MPNST age of onset in our UCLA patient cohort mirrored the gender dimorphism found in our pre-clinical model, with men diagnosed with MPNST at an earlier age, however this finding was not reflected in the larger meta-analysis. The interrogation of gender in our murine model (castration, hormonal manipulation, etc.) was not pursued further as it was not replicated in the larger patient meta-dataset. The gender disparity in the UCLA patient population is likely due to the relative rarity of MPNST, as our MPNST patient population was relatively small (n = 113). The limitation of this initial result underscores the need for collaborative effort in the study of STS subtypes. In rare cancers, such as sarcoma, collective pursuits of clinical research should be encouraged to increase the power and effect-size of the analysis. When our initial result was tested in a larger “meta-dataset” cohort, we believe a clearer picture of MPNST onset was revealed and gender-based differences were not observed.
Additionally, recent literature supports multidisciplinary management of patients with STS at a nationally recognized sarcoma center. Age of diagnosis is likely influenced by non-clinical factors such as adherence to guidelines, referral pathways, and time to referral to a sarcoma center, which were not analyzed in this study. Earlier age of MPNST diagnosis is likely favored by prompt referral to a sarcoma center, and should therefore be encouraged in patients with suspicious tumors.
Analysis of the meta-dataset from 39 published studies on MPNST revealed a 13 year difference in median age of diagnosis between NF-1 and spontaneous MPNST patients. Using a larger multinational meta-dataset of 916 patients, we were able to confirm the findings of earlier reports on smaller cohorts [10, 27]. Given the rarity of MPNST, it is important to study clinicopathologic disease characteristics in larger, adequately powered cohorts when possible. The earlier reports of age of onset differences were based on geographically localized, single-institutional, small populations whose results had the potential to be skewed by institutional differences in monitoring and diagnosis protocols [10, 27]. The disparity in age of onset in our meta-dataset was maintained in North American, European, and Asian populations. In the combined meta-dataset, the age of onset for the NF-1 associated MPNST patients was centered around a distinct peak, which differed significantly from the broad distribution of age at diagnosis for spontaneous cases that spans decades. This wide variance in spontaneous cases suggests that the underlying genetic cause of spontaneous MPNST formation may be the accumulation of a wide assortment of genetic aberrations over time, in contrast to NF-1 MPNST formation which may be due to a few specific genetic mutations.
This disparity between NF-1 and spontaneous patients may also reflect the earlier and increased frequency of routine physical exams and surveillance for MPNSTs in NF-1 patients. Clinical manifestations of malignant transformation classically rely on reported symptoms of new neurological deficits, rapid increase in size, change in palpated density from soft to hard, and unremitting pain. Patients with NF-1 and clinicians who treat them are often aware of the 10% lifetime risk of MPNST, and might be more apt to notice these changes. The malignant transformation event, whereby a NF degenerates into a MPNST, is distinct from the time at which a patient is formally diagnosed with MPNST. The interval between MPNST development and diagnosis can be shortened with the use of FDG-PET, as it has emerged as an accurate method to distinguish NF from MPNST based on the glycolytic phenotype . Using quantitative SUVmax measurements, the gap in time between actual MPNST development and formal diagnosis can be truncated.
Limitations of this study are ones inherent in studying a rare disease. First, patient diagnosis from both our UCLA and meta-datasets spans decades, covering a time period in which the diagnostic tools for MPNST detection were greatly improved. Improved detection through computerized tomography and magnetic resonance imaging has likely led to earlier detection of MPNST. However, for the same time period, this would affect patients of either sex equally, and affect both NF-associated and spontaneous MPNST patients equally. Second, there may be reporting bias, as most datasets were from surgically-resected patients only, and exclude patients with biopsy-proved but unresectable MPNST.
This study focused on MPNST age of onset only, and did not include analysis of clinical factors such as age of NF-1 diagnosis or disease stage at MPNST diagnosis, due to lack of data reporting in the majority of the studies used in the meta-analysis. Patient gender may influence the development and progression of MPNST, however reports are conflicting. A recent analysis by Kolberg et al. , found no survival advantage between males and females (in 117 spontaneous patients and 62 NF-1 patients) . However, a separate study by Ingham et al.  found a significant difference in survival between male and female MPNST patients, with men having worse survival (n = 52, p = 0.05) . Given these contradictory findings, any gender-specific survival advantage remains to be determined, and should be investigated within a larger cohort.
In conclusion, the difference in age of onset between MPNST formation in NF-1 associated cases and spontaneous cases is reflected in both the actual age of onset and in the population age distribution. This suggests that the two branches of MPNST development are likely rooted in distinct and separate origins, influenced by different genetic and environmental factors.
In addition to the acknowledgement of all authors contributing to this paper, we would like to express our gratitude to the patients and families of those included in this study. E.S. and L.M.T. were partially supported by the University of California post-doctoral Tumor Biology Program, National Institutes of Health T32 CA009056; J.N. was partially supported by the California Institute of Regenerative Medicine pre-doctoral training fellowship and K.B.S. was partially supported by the University of California Los Angeles pre-doctoral Tumor Biology Program, National Institutes of Health T32 CA009056, and a University of California Graduate Division Dissertation Year Fellowship; This work is supported in part by seed grants from University of California Los Angeles Institute for Molecular Medicine, Jonsson Comprehensive Cancer Center Sarcoma Clinical / Translational Research Fund, and a grant from National Institutes of Health (P50 CA086306 to H.W. and F.C.E). The funding institutions did not have any role in the study design, data collection, or analysis.
- Exploring the Biological Contributions to Human Health: Does Sex Matter?. 2001, Washington, DC: The National Academies PressGoogle Scholar
- Benigni R: Social sexual inequality and sex difference in cancer incidence. Environ Res. 2007, 104 (1): 128-134.View ArticlePubMedGoogle Scholar
- Cook MB, Dawsey SM, Freedman ND, Inskip PD, Wichner SM, Quraishi SM, Devesa SS, McGlynn KA: Sex disparities in cancer incidence by period and age. Cancer Epidemiol Biomarkers Prev. 2009, 18 (4): 1174-1182.View ArticlePubMedPubMed CentralGoogle Scholar
- McCann J: Gender differences in cancer that don't make sense–or do they?. J Natl Cancer Inst. 2000, 92 (19): 1560-1562.View ArticlePubMedGoogle Scholar
- Sun T, Warrington NM, Rubin JB: Why does Jack, and not Jill, break his crown? Sex disparity in brain tumors. Biol Sex Differ. 2012, 3: 3-View ArticlePubMedPubMed CentralGoogle Scholar
- Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, Alexe G, Lawrence M, O'Kelly M, Tamayo P, Weir BA, Gabriel S, Winckler W, Gupta S, Jakkula L, Feiler HS, Hodgson JG, James CD, Sarkaria JN, Brennan C, Kahn A, Spellman PT, Wilson RK, Speed TP, Gray JW, Meyerson M, et al: Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010, 17 (1): 98-110.View ArticlePubMedPubMed CentralGoogle Scholar
- Yang J, Du X: Genomic and molecular aberrations in malignant peripheral nerve sheath tumor and their roles in personalized target therapy. Surg Oncol. 2013, 22 (3): e53-57.View ArticlePubMedGoogle Scholar
- Dubrow R, Darefsky AS: Demographic variation in incidence of adult glioma by subtype, United States, 1992-2007. BMC Cancer. 2011, 11: 325-View ArticlePubMedPubMed CentralGoogle Scholar
- Sun T, Warrington NM, Luo J, Brooks MD, Dahiya S, Snyder SC, Sengupta R, Rubin JB: Sexually dimorphic RB inactivation underlies mesenchymal glioblastoma prevalence in males. J Clin Invest. 2014Google Scholar
- Ducatman BS, Scheithauer BW, Piepgras DG, Reiman HM, Ilstrup DM: Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases. Cancer. 1986, 57 (10): 2006-2021.View ArticlePubMedGoogle Scholar
- McGaughran JM, Harris DI, Donnai D, Teare D, MacLeod R, Westerbeek R, Kingston H, Super M, Harris R, Evans DG: A clinical study of type 1 neurofibromatosis in north west England. J Med Genet. 1999, 36 (3): 197-203.PubMedPubMed CentralGoogle Scholar
- Vauthey JN, Woodruff JM, Brennan MF: Extremity malignant peripheral nerve sheath tumors (neurogenic sarcomas): a 10-year experience. Ann Surg Oncol. 1995, 2 (2): 126-131.View ArticlePubMedGoogle Scholar
- Ghosh BC, Ghosh L, Huvos AG, Fortner JG: Malignant schwannoma. A Clinicopathologic Study Cancer. 1973, 31 (1): 184-190.PubMedGoogle Scholar
- Kolberg M, Holand M, Agesen TH, Brekke HR, Liestol K, Hall KS, Mertens F, Picci P, Smeland S, Lothe RA: Survival meta-analyses for >1800 malignant peripheral nerve sheath tumor patients with and without neurofibromatosis type 1. Neuro-Oncology. 2013, 15 (2): 135-147.View ArticlePubMedGoogle Scholar
- Guccion JG, Enzinger FM: Malignant Schwannoma associated with von Recklinghausen's neurofibromatosis. Virchows Archiv A, Pathol Anatomy Histol. 1979, 383 (1): 43-57.View ArticleGoogle Scholar
- Swapp GH, Main RA: Neurofibromatosis in pregnancy. Brit J Dermatol. 1973, 88 (5): 431-435.View ArticleGoogle Scholar
- Sharpe JCaY RH: Recklinghausen's neurofibromatosis: clinical manifestations in thirty-one cases. Arch Intern Med. 1937, 59 (2): 299-328.View ArticleGoogle Scholar
- Roth TM, Petty EM, Barald KF: The role of steroid hormones in the NF1 phenotype: focus on pregnancy. Am J Med Genet A. 2008, 146A (12): 1624-1633.View ArticlePubMedGoogle Scholar
- Fishbein L, Zhang X, Fisher LB, Li H, Campbell-Thompson M, Yachnis A, Rubenstein A, Muir D, Wallace MR: In vitro studies of steroid hormones in neurofibromatosis 1 tumors and Schwann cells. Mol Carcinog. 2007, 46 (7): 512-523.View ArticlePubMedGoogle Scholar
- Li H, Zhang X, Fishbein L, Kweh F, Campbell-Thompson M, Perrin GQ, Muir D, Wallace M: Analysis of steroid hormone effects on xenografted human NF1 tumor schwann cells. Cancer Biol Ther. 2010, 10 (8): 758-764.View ArticlePubMedPubMed CentralGoogle Scholar
- Gregorian C, Nakashima J, Dry SM, Nghiemphu PL, Smith KB, Ao Y, Dang J, Lawson G, Mellinghoff IK, Mischel PS, Phelps M, Parada LF, Liu X, Sofroniew MV, Eilber FC, Wu H: PTEN dosage is essential for neurofibroma development and malignant transformation. Proc Natl Acad Sci U S A. 2009, 106 (46): 19479-19484.View ArticlePubMedPubMed CentralGoogle Scholar
- Winzen B, Koelsch B, Fischer C, Kindler-Rohrborn A: Genetic basis of sex-specific resistance to neuro-oncogenesis in (BDIX x BDIV) F(2) rats. Mamm Genome. 2009, 20 (11–12): 741-748.View ArticlePubMedGoogle Scholar
- Koelsch BU, Fischer C, Neibecker M, Schmitt N, Schmidt O, Rajewsky MF, Kindler-Rohrborn A: Gender-specific polygenic control of ethylnitrosourea-induced oncogenesis in the rat peripheral nervous system. Int J Cancer J Int Du Cancer. 2006, 118 (1): 108-114.View ArticleGoogle Scholar
- Koelsch B, Winzen-Reichert B, Fischer C, Kutritz A, van den Berg L, Kindler-Rohrborn A: Sex-biased suppression of chemically induced neural carcinogenesis in congenic BDIX.BDIV-Mss4a rats. Physiol Genomics. 2011, 43 (10): 631-639.View ArticlePubMedGoogle Scholar
- Walrath JC, Fox K, Truffer E, Gregory Alvord W, Quinones OA, Reilly KM: Chr 19(A/J) modifies tumor resistance in a sex- and parent-of-origin-specific manner. Mamm Genome. 2009, 20 (4): 214-223.View ArticlePubMedPubMed CentralGoogle Scholar
- Benz MR, Czernin J, Dry SM, Tap WD, Allen-Auerbach MS, Elashoff D, Phelps ME, Weber WA, Eilber FC: Quantitative F18-fluorodeoxyglucose positron emission tomography accurately characterizes peripheral nerve sheath tumors as malignant or benign. Cancer. 2010, 116 (2): 451-458.View ArticlePubMedPubMed CentralGoogle Scholar
- Hruban RH, Shiu MH, Senie RT, Woodruff JM: Malignant peripheral nerve sheath tumors of the buttock and lower extremity. A study of 43 cases. Cancer. 1990, 66 (6): 1253-1265.View ArticlePubMedGoogle Scholar
- Ingham SHS, Moran A, Wylie J, Leahy M, Evans DG: Malignant peripheral nerve sheath tumours in NF1: improved survival in women and in recent years. Eur J Cancer. 2011, 47 (18): 2723-2728.View ArticlePubMedGoogle Scholar
- D'Agostino AN, Soule EH, Miller RH: Primary malignant neoplasms of nerves (malignant neurilemomas) in patients without manifestations of multiple neurofibromatosis (Von Recklinghausen's disease). Cancer. 1963, 16: 1003-1014.View ArticlePubMedGoogle Scholar
- D'Agostino AN, Soule EH, Miller RH: Sarcomas of the peripheral nerves and somatic soft tissue associated with multiple neurofibromatosis (Von Recklinghausen's disease). Cancer. 1963, 16: 1015-1027.View ArticlePubMedGoogle Scholar
- White HR: Survival in malignant schwannoma. An 18-year study. Cancer. 1971, 27 (3): 720-729.View ArticlePubMedGoogle Scholar
- Trojanowski JQ, Kleinman GM, Proppe KH: Malignant tumors of nerve sheath origin. Cancer. 1980, 46 (5): 1202-1212.View ArticlePubMedGoogle Scholar
- Arpornchayanon O, Hirota T, Itabashi M, Nakajima T, Fukuma H, Beppu Y, Nishikawa K: Malignant peripheral nerve tumors: a clinicopathological and electron microscopic study. Jpn J Clin Oncol. 1984, 14 (1): 57-74.PubMedGoogle Scholar
- Bojsen-Moller M, Myhre-Jensen O: A consecutive series of 30 malignant schwannomas. Survival in relation to clinico-pathological parameters and treatment. Acta Pathol Microbiol Immunol Scand A. 1984, 92 (3): 147-155.PubMedGoogle Scholar
- Ducatman BS, Scheithauer BW: Malignant peripheral nerve sheath tumors with divergent differentiation. Cancer. 1984, 54 (6): 1049-1057.View ArticlePubMedGoogle Scholar
- Daimaru Y, Hashimoto H, Enjoji M: Malignant peripheral nerve-sheath tumors (malignant schwannomas). An immunohistochemical study of 29 cases. Am J Surg Pathol. 1985, 9 (6): 434-444.View ArticlePubMedGoogle Scholar
- Bailet JW, Abemayor E, Andrews JC, Rowland JP, Fu YS, Dawson DE: Malignant nerve sheath tumors of the head and neck: a combined experience from two university hospitals. Laryngoscope. 1991, 101 (10): 1044-1049.View ArticlePubMedGoogle Scholar
- de Cou JM, Rao BN, Parham DM, Lobe TE, Bowman L, Pappo AS, Fontanesi J: Malignant peripheral nerve sheath tumors: the St. Jude Children's Research Hospital experience. Ann Surg Oncol. 1995, 2 (6): 524-529.View ArticleGoogle Scholar
- Kunisada T, Kawai A, Ozaki T, Sugihara S, Taguchi K, Inoue H: A clinical analysis of malignant schwannoma. Acta Med Okayama. 1997, 51 (2): 87-92.PubMedGoogle Scholar
- Angelov L, Davis A, O'Sullivan B, Bell R, Guha A: Neurogenic sarcomas: experience at the University of Toronto. Neurosurgery. 1998, 43 (1): 56-64. discussion 64-55View ArticlePubMedGoogle Scholar
- Kourea HP, Bilsky MH, Leung DH, Lewis JJ, Woodruff JM: Subdiaphragmatic and intrathoracic paraspinal malignant peripheral nerve sheath tumors: a clinicopathologic study of 25 patients and 26 tumors. Cancer. 1998, 82 (11): 2191-2203.View ArticlePubMedGoogle Scholar
- Casanova M, Ferrari A, Spreafico F, Luksch R, Terenziani M, Cefalo G, Massimino M, Gandola L, Lombardi F, Fossati-Bellani F: Malignant peripheral nerve sheath tumors in children: a single-institution twenty-year experience. J Pediatr Hematol Oncol. 1999, 21 (6): 509-513.View ArticlePubMedGoogle Scholar
- Liapis H, Marley EF, Lin Y, Dehner LP: p53 and Ki-67 proliferating cell nuclear antigen in benign and malignant peripheral nerve sheath tumors in children. Pediatr Dev Pathol. 1999, 2 (4): 377-384.View ArticlePubMedGoogle Scholar
- Schmidt H, Taubert H, Meye A, Wurl P, Bache M, Bartel F, Holzhausen HJ, Hinze R: Gains in chromosomes 7, 8q, 15q and 17q are characteristic changes in malignant but not in benign peripheral nerve sheath tumors from patients with Recklinghausen's disease. Cancer Lett. 2000, 155 (2): 181-190.View ArticlePubMedGoogle Scholar
- Schmidt H, Wurl P, Taubert H, Meye A, Bache M, Holzhausen HJ, Hinze R: Genomic imbalances of 7p and 17q in malignant peripheral nerve sheath tumors are clinically relevant. Genes Chromosomes Cancer. 1999, 25 (3): 205-211.View ArticlePubMedGoogle Scholar
- Ferner RE, Lucas JD, O'Doherty MJ, Hughes RA, Smith MA, Cronin BF, Bingham J: Evaluation of (18)fluorodeoxyglucose positron emission tomography ((18)FDG PET) in the detection of malignant peripheral nerve sheath tumours arising from within plexiform neurofibromas in neurofibromatosis 1. J Neurol Neurosurg Psychiatry. 2000, 68 (3): 353-357.View ArticlePubMedPubMed CentralGoogle Scholar
- Mertens F, Dal Cin P, De Wever I, Fletcher CD, Mandahl N, Mitelman F, Rosai J, Rydholm A, Sciot R, Tallini G, van Den Berghe H, Vanni R, Willén H: Cytogenetic characterization of peripheral nerve sheath tumours: a report of the CHAMP study group. J Pathol. 2000, 190 (1): 31-38.View ArticlePubMedGoogle Scholar
- Leroy K, Dumas V, Martin-Garcia N, Falzone MC, Voisin MC, Wechsler J, Revuz J, Creange A, Levy E, Lantieri L, Zeller J, Wolkenstein P: Malignant peripheral nerve sheath tumors associated with neurofibromatosis type 1: a clinicopathologic and molecular study of 17 patients. Arch Dermatol. 2001, 137 (7): 908-913.PubMedGoogle Scholar
- Evans DG, Baser ME, McGaughran J, Sharif S, Howard E, Moran A: Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet. 2002, 39 (5): 311-314.View ArticlePubMedPubMed CentralGoogle Scholar
- Zhou H, Coffin CM, Perkins SL, Tripp SR, Liew M, Viskochil DH: Malignant peripheral nerve sheath tumor: a comparison of grade, immunophenotype, and cell cycle/growth activation marker expression in sporadic and neurofibromatosis 1-related lesions. Am J Surg Pathol. 2003, 27 (10): 1337-1345.View ArticlePubMedGoogle Scholar
- Watson MA, Perry A, Tihan T, Prayson RA, Guha A, Bridge J, Ferner R, Gutmann DH: Gene expression profiling reveals unique molecular subtypes of Neurofibromatosis Type I-associated and sporadic malignant peripheral nerve sheath tumors. Brain Pathol. 2004, 14 (3): 297-303.View ArticlePubMedGoogle Scholar
- Tucker T, Wolkenstein P, Revuz J, Zeller J, Friedman JM: Association between benign and malignant peripheral nerve sheath tumors in NF1. Neurology. 2005, 65 (2): 205-211.View ArticlePubMedGoogle Scholar
- Brenner W, Friedrich RE, Gawad KA, Hagel C, von Deimling A, de Wit M, Buchert R, Clausen M, Mautner VF: Prognostic relevance of FDG PET in patients with neurofibromatosis type-1 and malignant peripheral nerve sheath tumours. Eur J Nucl Med Mol Imaging. 2006, 33 (4): 428-432.View ArticlePubMedGoogle Scholar
- Upadhyaya M, Spurlock G, Majounie E, Griffiths S, Forrester N, Baser M, Huson SM, Gareth Evans D, Ferner R: The heterogeneous nature of germline mutations in NF1 patients with malignant peripheral serve sheath tumours (MPNSTs). Hum Mutat. 2006, 27 (7): 716-View ArticlePubMedGoogle Scholar
- Holtkamp N, Atallah I, Okuducu AF, Mucha J, Hartmann C, Mautner VF, Friedrich RE, Mawrin C, von Deimling A: MMP-13 and p53 in the progression of malignant peripheral nerve sheath tumors. Neoplasia. 2007, 9 (8): 671-677.View ArticlePubMedPubMed CentralGoogle Scholar
- Minovi A, Basten O, Hunter B, Draf W, Bockmuhl U: Malignant peripheral nerve sheath tumors of the head and neck: management of 10 cases and literature review. Head Neck. 2007, 29 (5): 439-445.View ArticlePubMedGoogle Scholar
- Tabone-Eglinger S, Bahleda R, Cote JF, Terrier P, Vidaud D, Cayre A, Beauchet A, Theou-Anton N, Terrier-Lacombe MJ, Lemoine A, Penault-Llorca F, Le Cesne A, Emile JF: Frequent EGFR Positivity and Overexpression in High-Grade Areas of Human MPNSTs. Sarcoma. 2008, 2008: 849156-View ArticlePubMedPubMed CentralGoogle Scholar
- Upadhyaya M, Kluwe L, Spurlock G, Monem B, Majounie E, Mantripragada K, Ruggieri M, Chuzhanova N, Evans DG, Ferner R, Thomas N, Guha A, Mautner V: Germline and somatic NF1 gene mutation spectrum in NF1-associated malignant peripheral nerve sheath tumors (MPNSTs). Hum Mutat. 2008, 29 (1): 74-82.View ArticlePubMedGoogle Scholar
- Brekke HR, Kolberg M, Skotheim RI, Hall KS, Bjerkehagen B, Risberg B, Domanski HA, Mandahl N, Liestol K, Smeland S, Danielsen HE, Mertens F, Lothe RA: Identification of p53 as a strong predictor of survival for patients with malignant peripheral nerve sheath tumors. Neuro-Oncology. 2009, 11 (5): 514-528.View ArticlePubMedPubMed CentralGoogle Scholar
- Brekke HR, Ribeiro FR, Kolberg M, Agesen TH, Lind GE, Eknaes M, Hall KS, Bjerkehagen B, van den Berg E, Teixeira MR, Mandahl N, Smeland S, Mertens F, Skotheim RI, Lothe RA: Genomic changes in chromosomes 10, 16, and X in malignant peripheral nerve sheath tumors identify a high-risk patient group. J Clin Oncol. 2010, 28 (9): 1573-1582.View ArticlePubMedGoogle Scholar
- Rekhi B, Ingle A, Kumar R, DeSouza MA, Dikshit R, Jambhekar NA: Malignant peripheral nerve sheath tumors: clinicopathological profile of 63 cases diagnosed at a tertiary cancer referral center in Mumbai. India Indian J Pathol Microbiol. 2010, 53 (4): 611-618.View ArticlePubMedGoogle Scholar
- Subramanian S, Thayanithy V, West RB, Lee CH, Beck AH, Zhu S, Downs-Kelly E, Montgomery K, Goldblum JR, Hogendoorn PC, Corless CL, Oliveira AM, Dry SM, Nielsen TO, Rubin BP, Fletcher JA, Fletcher CD, van de Rijn M: Genome-wide transcriptome analyses reveal p53 inactivation mediated loss of miR-34a expression in malignant peripheral nerve sheath tumours. J Pathol. 2010, 220 (1): 58-70.View ArticlePubMedPubMed CentralGoogle Scholar
- Beert E, Brems H, Daniels B, De Wever I, Van Calenbergh F, Schoenaers J, Debiec-Rychter M, Gevaert O, De Raedt T, Van Den Bruel A, de Ravel T, Cichowski K, Kluwe L, Mautner V, Sciot R, Legius E: Atypical neurofibromas in neurofibromatosis type 1 are premalignant tumors. Genes Chromosomes Cancer. 2011, 50 (12): 1021-1032.View ArticlePubMedGoogle Scholar
- Pryor JG, Brown-Kipphut BA, Iqbal A, Scott GA: Microarray comparative genomic hybridization detection of copy number changes in desmoplastic melanoma and malignant peripheral nerve sheath tumor. Am J Dermatopathol. 2011, 33 (8): 780-785.View ArticlePubMedGoogle Scholar
- Yang J, Ylipaa A, Sun Y, Zheng H, Chen K, Nykter M, Trent J, Ratner N, Lev DC, Zhang W: Genomic and molecular characterization of malignant peripheral nerve sheath tumor identifies the IGF1R pathway as a primary target for treatment. Clin Cancer Res. 2011, 17 (24): 7563-7573.View ArticlePubMedPubMed CentralGoogle Scholar
- Yu J, Deshmukh H, Payton JE, Dunham C, Scheithauer BW, Tihan T, Prayson RA, Guha A, Bridge JA, Ferner RE, Lindberg GM, Gutmann RJ, Emnett RJ, Salavaggione L, Gutmann DH, Nagarajan R, Watson MA, Perry A: Array-based comparative genomic hybridization identifies CDK4 and FOXM1 alterations as independent predictors of survival in malignant peripheral nerve sheath tumor. Clin Cancer Res. 2011, 17 (7): 1924-1934.View ArticlePubMedGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/14/827/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.