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PubMed2005

Superficial neurofibroma: a lesion with unique MRI characteristics in patients with neurofibromatosis type 1.

OBJECTIVE: Our aim was to test the hypothesis that in neurofibromatosis type 1 (NF1), superficial plexiform neurofibromas have different MRI characteristics than deep plexiform neurofibromas. SUBJECTS AND METHODS: Sixty-six patients (median age, 15 years) with superficial plexiform neurofibromas were compared with 56 patients with deep plexiform neurofibromas (median age, 12 years). All patients underwent axial STIR and coronal or sagittal STIR images. RESULTS: Superficial neurofibromas were more likely to be asymmetric (p = 0.004) and extend to the skin surface (p < 0.001). Lesion borders were poorly defined with similar frequency in both superficial and deep groups (77% vs 68%, p = 0.31). The morphology of superficial neurofibromas was more likely diffuse (64% vs 11%, p < 0.001), whereas deep neurofibromas were more likely nodular or fascicular. Of neurofibromas that were nodular or fascicular in morphology, superficial lesions had a smaller maximal fascicle-nodule diameter (mean, 10.3 mm) than deep lesions (mean, 13.4 mm) (p = 0.013). Signal characteristics of deep neurofibromas were more likely to be targetlike (75%) compared with superficial neurofibromas (21%) (p < 0.001). Superficial neurofibromas had a smaller mean volume than deep neurofibromas (180 vs 444 cm(3), p = 0.002). CONCLUSION: Unlike the typical targetlike lesions along the course of major nerves seen in deep plexiform lesions, superficial plexiform neurofibromas in NF1 tend to be asymmetric, have nontargetlike signal intensity, lack nodular or fascicular morphology, and are likely to involve skin.

Adolescent↗
PubMed2004

Molecular profiles of neurofibromatosis type 1-associated plexiform neurofibromas: identification of a gene expression signature of poor prognosis.

PURPOSE: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with a complex variety of clinical symptoms. The hallmark of NF1 is the development of heterogeneous benign neurofibromas, which may appear as dermal neurofibromas or plexiform neurofibromas. NF1 patients with plexiform neurofibromas are at risk of developing malignant peripheral nerve sheath tumors. EXPERIMENTAL DESIGN: To obtain additional insight into the molecular pathogenesis of plexiform neurofibromas, we used real-time quantitative reverse transcription-PCR assays to quantify the mRNA expression of 349 selected genes in plexiform neurofibromas in comparison with dermal neurofibromas and patient-matched malignant peripheral nerve sheath tumors. RESULTS: Thirty genes were significantly up-regulated in plexiform neurofibromas compared with dermal neurofibromas. None were down-regulated. The up-regulated genes mainly encoded transcription factors and growth factors and secreted proteins, cytokines, and their receptors, pointing to a role of paracrine and autocrine signaling defects in the genesis of plexiform neurofibromas. We also identified a gene expression profile, based on MMP9, FLT4/VEGFR3, TNFRSF10B/TRAILR2, SHH, and GLI1, which discriminated those plexiform neurofibromas most likely to undergo malignant transformation. CONCLUSION: Our study has identified a limited number of signaling pathways that could be involved, when altered, in plexiform neurofibroma development. Some of the up-regulated genes could be useful diagnostic or prognostic markers or form the basis of novel therapeutic strategies.

Adolescent↗
PubMed2003

Identification of growth hormone receptor in localised neurofibromas of patients with neurofibromatosis type 1.

BACKGROUND: The hallmark of neurofibromatosis type 1 (NF1) is the development of multiple neurofibromas. Solitary neurofibroma may occur in an individual who does not have NF1, but multiple neurofibromas tend to develop only in those with NF1. It has been suggested that hormones may influence the neurofibromas of patients with NF1. The evidence that hormones may influence the growth of neurofibromas comes mainly from the observation that localised neurofibromas of patients with NF1 commonly grow during puberty and pregnancy. Because growth hormone (GH) concentrations increase during puberty, it is possible that GH influences the growth of these tumours. AIMS: To investigate the presence of GH receptors (GHRs) in neurofibromas. METHODS: By means of immunohistochemistry, the presence of GHRs was investigated in two groups of patients: 16 patients without NF1 with solitary neurofibromas (group A) and 10 patients with NF1 with localised neurofibromas (group B). RESULTS: Six of the 16 patients in group A had neurofibromas that were immunopositive for GHR, whereas nine of the 10 patients in group B were immunopositive. CONCLUSIONS: Most patients with NF1 have localised neurofibromas that express GHR. This suggests that GH may play some role in the development of localised neurofibromas in patients with NF1.

Adolescent↗
PubMed2005

Cutaneous lipomatous neurofibroma: characterization and frequency.

BACKGROUND: There are numerous variants of cutaneous neurofibroma reflecting its manner of growth and histologic composition. Lipomatous neurofibroma is the latest described variant with only eight cases reported. METHODS: A systematic study based on 320 consecutive specimens diagnosed of cutaneous neurofibroma was carried out. Conventional microscopy, immunohistochemistry, and statistical methods were used to determine the presence of fat cells, their amount, distribution, and frequency. RESULTS: Intratumoral fat was observed in 22 (6.9%) neurofibromas. All these were dermal neurofibromas. Intraneoplastic fat was divided into two groups: focal and diffuse (regularly interspersed). Eighteen tumors (5.6%) presented adipocytes focally intermingled with the spindle cells. There were four (1.3%) neurofibromas showing spindle cell proliferation with regularly scattered adipocytes. Lipomatous neurofibroma was more frequent located on head and neck than non-lipomatous neurofibroma ( p = 0.04). Neurofibromas without mature adipocytes were more frequently immunoreactive for CD34 compared with tumors showing intratumoral fat ( p = 0.02). CONCLUSIONS: We suggest that both metaplasia and aberrant adipose differentiation from multipotential cells may result in lipomatous neurofibroma. Focal presence of adipose cells may be attributable to metaplasia as the pathogenic mechanism. The fatty tissue being intrinsic to the tumor structure in its diffuse form, the lesion represents a distinctive tumor of the peripheral nerve sheath.

Adipose Tissue↗
PubMed1990

Neurofibromas and neurotized melanocytic nevi are immunohistochemically distinct neoplasms.

Neurofibromas are often clinically, as well as histologically, indistinguishable from completely neurotized melanocytic nevi. We tested the hypothesis that immunologic markers would differentiate the perineural fibroblasts and Schwann cells of neurofibromas from the neurotized cells of melanocytic origin. We examined eight partially neurotized acquired melanocytic nevi, three partially neurotized congenital melanocytic nevi, and five neurofibromas, with antibodies directed against S-100 protein, Leu-7(HNK-1), glial fibrillary acid protein (GFAP), and myelin-basic protein (MBP). A histologic diagnosis of neurofibroma was based on identification of a dermal proliferation of spindle-shaped cells with wavy nuclei, in a background of loose reticulated collagen. Neurotized nevi were diagnosed upon recognition of scattered nests of type A or B nevus cells, surrounded by basement membrane, present in the papillary dermis of lesions otherwise indistinguishable from neurofibromas. The congenital nevi were all large melanocytic nevi known to be present at birth. S-100 stained the majority of neoplastic cells in all neurofibromas, neurotized acquired nevi, and neurotized congenital nevi. Neurofibromas showed focal staining for Leu-7, GFAP, and MBP. In contrast, neurotized acquired and congenital nevi failed to express these markers. We believe that Leu-7, GFAP, and MBP may be helpful in differentiating neurofibromas from completely neurotized melanocytic nevi. The differences in the immunohistochemical profiles of neurofibromas and neurotized nevi support the concept that these neoplasms are histogenically distinct, despite their similar histologic appearance.

Antigens, Differentiation↗
PubMed2005

Vacuolated cells in neurofibroma: an immunohistochemical study.

BACKGROUND: Vacuolated cells could be encountered in neurofibroma. OBJECTIVES: Frequency and immunohistochemical feature of vacuolated cells in neurofibroma. METHODS: Sixty-two lesions of neurofibroma including five plexiform neurofibromas were re-evaluated for the search of vacuolated cells. Immunohistochemical analysis was performed for cases with vacuolated cells. RESULTS: In five cases of plexiform neurofibroma and four cases of sporadic neurofibroma with endoneurial component, presence of vacuolated cells in the endoneurial mucoid area was noted. They were immunoreactive both with S-100 protein and CD34, mostly negative for factor XIIIa and negative for epithelial membrane antigen. Vacuolated cells were found neither in the diffuse portion of plexiform neurofibroma nor in sporadic diffuse neurofibroma. CONCLUSION: Presence of vacuolated cells is a highly characteristic feature of endoneurial portion of neurofibroma. Considering immunoreactivity both with S-100 protein and CD34 in the majority of vacuolated cells, they could be regarded as to represent endoneurial precursor cells in a certain stage of differentiation to Schwann cells.

Antigens, CD34↗
PubMed2000

Long-term culture and characterization of human neurofibroma-derived Schwann cells.

Neurofibromas are benign tumors arising from the peripheral nerve sheath and are a typical finding in neurofibromatosis type 1 (NF1). Schwann cells are the predominant cell type in neurofibromas and thus are supposed to play a major role in the pathogenesis of these tumors. It is not known, however, if NF1 mutations in Schwann cells result in an altered phenotype that subsequently leads to tumor formation. To characterize the biological properties of neurofibroma-derived Schwann cells we developed cell culture techniques that enabled us to isolate Schwann cells from neurofibromas and grow them in vitro for several weeks without significant fibroblast contamination. Neurofibroma-derived Schwann cells were characterized by altered morphology, heterogeneous growth behavior, and increased expression of the P0 antigen while several other features of normal human Schwann cells were retained. We conclude that neurofibroma-derived Schwann cells exhibit a distinct phenotype in vitro but that the observed abnormalities by themselves are insufficient to explain neurofibroma formation. Application of our improved culture conditions makes neurofibroma-derived Schwann cells readily available for further studies to define their role in tumorigenesis in neurofibromatosis type 1.

Adolescent↗
PubMed1985

Tissue culture studies of neurofibromatosis: effects of axolemmal fragments and cyclic adenosine 3',5'-monophosphate analogues on proliferation of Schwann-like and fibroblast-like neurofibroma cells.

Six dermal neurofibromas obtained from 5 patients with neurofibromatosis were dissociated and the cells were plated on polylysine-coated glass. Two principal cell types were observed in the cultures: elongated and bipolar Schwann-like cells (SLCs), and polymorphic flattened fibroblast-like cells (FLCs). Indirect immunofluorescence demonstrated that SLCs expressed surface laminin but not surface fibronectin; FLCs expressed surface fibronectin but were only weakly positive for surface laminin. Tritiated thymidine autoradiography demonstrated that cultured SLCs proliferated slowly (labeling index, 0.7 to 4.0%), whereas FLCs divided more rapidly (labeling index, 7.5 to 26.4%). Axolemmal fragments prepared from human or rat central nervous system specimens adhered to SLCs derived from each of the 6 neurofibromas, but not to FLCs. Axolemmal fragments induced a marked proliferative response of SLCs from 2 of the 6 neurofibromas but had no effect on proliferation of SLCs from the other 4 neurofibromas or FLCs from any of the 6 neurofibromas. In one patient from whom 2 neurofibromas were obtained, SLCs from one neurofibroma responded to axolemmal fragments, while SLCs from the other did not. Treatment of the cultures with 0.1 mM cyclic adenosine 3'5'-monophosphate (cAMP) analogue, 8-bromo cAMP, caused marked inhibition of proliferation of both SLCs and FLCs derived from all 6 neurofibromas. The same concentration of another cAMP analogue, dibutyryl cAMP, inhibited proliferation of SLCs but not of FLCs.

Adult↗
PubMed1998

Analysis of vascularity of human neurofibromas.

BACKGROUND: A common misperception is that the vascularity of a tumor can be determined by its gross appearance. Neurofibromas are grossly white in appearance. The degree of vascularity of neurofibromas has not been determined. OBJECTIVE: The purpose of this study was to determine the extent of neovascularization of neurofibromas. METHODS: Neurofibromas from patients with neurofibromatosis-1 or spontaneous neurofibromas were stained with antibodies against von Willebrand factor (factor VIII-related antigen) and vascular endothelial growth factor (VEGF). RESULTS: Neurofibromas, both spontaneous and congenital, exhibit a high degree of vascularity. In addition, perivascular cells in neurofibromas stain with antibodies to VEGF, an angiogenic factor. CONCLUSION: Neurofibromas, despite their gross appearance, are highly vascular. Their vascularity may be mediated, in part, through the angiogenic factor VEGF.

Endothelial Growth Factors↗
PubMed2002

Plexiform neurofibromas in NF1: toward biologic-based therapy.

Neurofibromatosis type 1 (NF1) is one of the most common neurogenetic diseases affecting adults and children. Neurofibromas are one of the most common of the protean manifestations of NF1. Plexiform neurofibromas, which will frequently cause cosmetic abnormalities, pain, and neurologic deficits, are composed of "neoplastic" Schwann cells accompanied by other participating cellular and noncellular components. There is increasing evidence that loss of NF1 expression in neoplastic Schwann cells is associated with elevated levels of activated RAS, supporting the notion that the NF1 gene product, neurofibromin, acts as a growth regulator by inhibiting ras growth-promoting activity. In addition, there is increasing evidence that other cooperating events, which may be under cytokine modulation, are important for neurofibroma development and growth. Treatment of plexiform neurofibromas has been empiric, with surgery being the primary option for those with progressive lesions causing a major degree of morbidity. The efficacy of alternative treatment approaches, including the use of antihistamines, maturation agents, and antiangiogenic drugs, has been questionable. More recently, biologic-based therapeutic approaches, using drugs that target the molecular genetic underpinnings of plexiform neurofibromas or cytokines believed important in tumor growth, have been initiated. Evaluation of such trials is hindered by the unpredictable natural history of plexiform neurofibromas and difficulties in determining objective response in tumors that are notoriously large and irregular in shape. Innovative neuroimaging techniques and the incorporation of quality-of-life scales may be helpful in evaluation of therapeutic interventions. The ability to design more rational therapies for NF1-associated neurofibromas is heavily predicated on an improved understanding of the molecular and cellular biology of the cells involved in neurofibroma formation and growth.

Biological Therapy↗
PubMed2004

Extraaxial neurofibromas versus neurilemmomas: discrimination with MRI.

OBJECTIVE: The purpose of our study was to evaluate whether MRI can discriminate between extraaxial neurofibromas and neurilemmomas. MATERIALS AND METHODS: MR images of 52 patients with a pathologically proven extraaxial neurofibroma or neurilemmoma were retrospectively reviewed by observers who were unaware of the surgical results, regarding the presence or absence of individual imaging criteria. MRI findings in 12 patients with a localized neurofibroma and 40 patients with a neurilemmoma were compared using the chi-square test or Fisher's exact test. RESULTS: MRI findings suggestive of neurofibroma (p < 0.05) were a target sign on T2-weighted images (58% in neurofibromas vs 15% in neurilemmomas), central enhancement (75% vs 8%), and a combination of both findings (63% vs 3%). MRI findings suggestive of a neurilemmoma (p < 0.05) were a fascicular appearance on T2-weighted images (25% vs 63%), a thin hyperintense rim on T2-weighted images (8% vs 58%), a combination of both findings (8% vs 48%), and diffuse enhancement (13% vs 67%). No significant difference was seen between neurofibromas and neurilemmomas for a centrally entering and exiting nerve (42% in neurofibromas vs 23% in neurilemmomas), a peripherally entering and exiting nerve (58% vs 77%), a cystic area (38% vs 64%), a low-signal margin (100% vs 100%), peripheral enhancement (13% vs 26%), or a target sign on contrast-enhanced images (11% vs 31%). CONCLUSION: MRI shows features helpful for differentiating extraaxial neurofibromas from neurilemmomas; however, no single finding or combination of findings allows definitive differentiation.

Adolescent↗
PubMed2003

Progesterone receptor expression in neurofibromas.

Neurofibromas are benign tumors of the peripheral nerve sheath, which occur sporadically and in association with the common familial cancer syndrome, neurofibromatosis type 1. There are intriguing links between the growth of neurofibromas and levels of circulating hormones: neurofibromas often first appear around the time of puberty, increase in number and size during pregnancy, and shrink after giving birth. We examined 59 human neurofibromas for the expression of estrogen and progesterone receptors (PRs), because their ligands, estrogen and progesterone, were attractive candidate hormones. The majority (75%) of neurofibromas expressed PR, whereas only a minority (5%) of neurofibromas expressed estrogen receptor. Within neurofibromas, PR was expressed by non-neoplastic tumor-associated cells and not by neoplastic Schwann cells. We hypothesize that progesterone may play an important role in neurofibroma growth and suggest that antiprogestins may be useful in the treatment of this tumor.

Humans↗
PubMedDate not supplied

Ki-67 proliferation-index (MIB-1) of neurofibromas in neurofibromatosis type 1 patients.

OBJECTIVE: The aim of this study was to analyse the proliferation rate of neurofibromas, in neurofibromatosis type 1 (NF1) patients in order to find out whether tumor growth can be correlated with the different subtypes, size and localisation of tumors, or gender. Large tumors and those localisations that do not allow a complete resection, e.g. the trigeminal branch plexiform neurofibromas, often require repeated surgical interventions. Therefore, the question whether partial resection is associated with alterations of the tumor type and proliferation is of great interest. MATERIALS AND METHODS: We investigated 317 specimens of 96 patients. Twenty-five specimens were identified as local recurrences, all of them being consecutive resections in the previously operated area. All patients were NF 1-affected individuals who fulfilled the US National Institute of Health consensus criteria for defining the disease. The proliferation index (PI) was assessed on formalin-fixed, paraffin-embedded tissue stained with the MIB- 1 antibody (Ki-67 antigen). The PI was evaluated in three high-power fields (0.1 square millimeter) in the area with the highest proliferative activity. The correlations were calculated according to Spearman-Rho. RESULTS: Men were more often surgically treated in the head and neck than women (p < 0.02). Plexiform neurofibromas were more frequently operated on in the head and neck than in other regions (p < 0.01). Older patients were more often treated for the diffuse cutaneous type of neurofibromas (p < 0.0001). The type of tumor did not differ from primaries to recurrent tumors. The MIB- 1 PI showed no association with any of the clinical parameters. In particular, there was no difference of the MIB-1 index between primaries and recurrent tumors. DISCUSSION: This study showed, for the first time, that proliferation in neurofibromas is not enhanced in previously partially resected neurofibromas. Hence, the argument that trauma or surgery for neurofibromas might promote proliferation, especially in the plexiform neurofibroma, is not supported by the results of the present study. Further this analysis demonstrated interdependencies between tumor type, localisation, age and gender indicative of the social difficulties encountered by the NF1 patients which may be helpful for the advising practitioner.

Adolescent↗
PubMed1991

The neurofibroma in von Recklinghausen neurofibromatosis has a unicellular origin.

von Recklinghausen neurofibromatosis (NF1) is the most common hereditary syndrome predisposing to neoplasia. NF1 is an autosomal dominant disease caused by a single gene which maps to chromosome 17q11.2. The most common symptomatic manifestation of NF1 is the benign neurofibroma. Our previous studies of tumors in NF1, studies which detected a loss of heterozygosity for DNA markers from the NF1 region of chromosome 17 in malignant tumors, did not detect a loss in neurofibromas. We report here that a more extensive study, including the analysis of neurofibromas from 19 unrelated NF1 patients by using seven probes, failed to detect a single instance of loss of heterozygosity. This finding suggests that neurofibromas are either polyclonal or monoclonal in origin but arise by a mechanism different from that of NF1 malignancies. In order to investigate the first possibility, we analyzed neurofibromas from female NF1 patients by using an X chromosome-specific probe, from the phosphoglycerokinase (PGK) gene, which detects an RFLP. The detected alleles carry additional recognition sites for the methylation-sensitive enzyme HpaII, so that the allele derived from the active X chromosome is digested by HpaII while the one from the hypermethylated, inactive X chromosome is not. We analyzed neurofibromas from 30 unrelated females with NF1. Eight patients were heterozygous for the PGK RFLP. By this assay, neurofibromas from all eight appeared monoclonal in origin. These results suggest that benign neurofibromas in NF1 arise by a mechanism that is different from that of malignant tumors.(ABSTRACT TRUNCATED AT 250 WORDS)

Blotting, Southern↗
PubMed1997

Confirmation of a double-hit model for the NF1 gene in benign neurofibromas.

Neurofibroma is a benign tumor that arises from small or large nerves. This neoplastic lesion is a common feature of neurofibromatosis type 1 (NF1), one of the most common autosomal dominant disorders. The NF1 gene codes for a protein called "neurofibromin." It possesses a region that shares a high homology with the family of GTPase-activating proteins, which are negative regulators of RAS function and thereby control cell growth and differentiation. The evidence points to the NF1 gene being a tumor-suppressor gene. NF1 patients also have an increased incidence of certain malignant tumors that are believed to follow the "two hit" hypothesis, with one allele constitutionally inactivated and the other somatically mutated. Recently, somatic loss of heterozygosity (LOH) has been described for neurofibromas, and mutations in both copies of the NF1 gene have been reported for a dermal neurofibroma. The aim of our study was the analysis of the NF1 locus in benign neurofibromas in NF1 patients. We performed LOH analysis on 60 neurofibromas belonging to 17 patients, 9 of them with family history of the disease and 8 of them sporadic. We have analyzed five intragenic NF1 markers and six extragenic markers, and we have found LOH in 25% of the neurofibromas (corresponding to 53% of the patients). In addition, we found that in the neurofibromas of patients from familial cases the deletions occurred in the allele that is not transmitted with the disease, indicating that both copies of the NF1 gene were inactivated in these tumors. Therefore, the recent reports mentioned above, together with our findings, strongly support the double inactivation of the NF1 gene in benign neurofibromas.

Alleles↗
PubMed2006

Somatic loss of wild type NF1 allele in neurofibromas: Comparison of NF1 microdeletion and non-microdeletion patients.

Neurofibromatosis type I (NF1) is an autosomal dominant familial tumor syndrome characterized by the presence of multiple benign neurofibromas. In 95% of NF1 individuals, a mutation is found in the NF1 gene, and in 5% of the patients, the germline mutation consists of a microdeletion that includes the NF1 gene and several flanking genes. We studied the frequency of loss of heterozygosity (LOH) in the NF1 region as a mechanism of somatic NF1 inactivation in neurofibromas from NF1 patients with and without a microdeletion. There was a statistically significant difference between these two patient groups in the proportion of neurofibromas with LOH. None of the 40 neurofibromas from six different NF1 microdeletion patients showed LOH, whereas LOH was observed in 6/28 neurofibromas from five patients with an intragenic NF1 mutation (P = 0.0034, Fisher's exact). LOH of the NF1 microdeletion region in NF1 microdeletion patients would de facto lead to a nullizygous state of the genes located in the deletion region and might be lethal. The mechanisms leading to LOH were further analyzed in six neurofibromas. In two out of six neurofibromas, a chromosomal microdeletion was found; in three, a mitotic recombination was responsible for the observed LOH; and in one, a chromosome loss with reduplication was present. These data show an important difference in the mechanisms of second hit formation in the 2 NF1 patient groups. We conclude that NF1 is a familial tumor syndrome in which the type of germline mutation influences the type of second hit in the tumors.

Alleles↗
PubMed2005

Biallelic somatic inactivation of the NF1 gene through chromosomal translocations in a sporadic neurofibroma.

Neurofibroma is a benign tumor originating from Schwann cells in peripheral nerve sheaths and may occur as a sporadic tumor or as part of the dominantly inherited tumor syndrome NF1. NF1 is caused by constitutional mutations in the NF1 gene, located in chromosome band 17q11. Whereas the involvement of the NF1 gene in neurofibroma development in NF1 patients has been fairly well characterized, the significance of inactivation of this gene in sporadic neurofibromas remains less well investigated. Inactivation of both copies of NF1 has been described in a few neurofibromas from NF1 patients, and LOH at the same locus has been reported in additional cases. In the present study, we report the cytogenetic and molecular cytogenetic findings in a sporadic neurofibroma that at G-banding analysis showed a translocation between one chromosome 2 and the long arms of both copies of chromosome 17. FISH analysis using a set of 3 BAC clones covering the entire coding region of NF1 revealed the complete loss of one allele and the deletion of the 5' portion of the second allele as a result of 2 translocation events. To the best of our knowledge, this represents the first demonstration of a somatic biallelic inactivation of the NF1 gene in neurofibroma, providing further evidence for the importance of NF1 inactivation also in sporadic neurofibromas.

Adult↗
PubMed2003

Differentially expressed genes in neurofibromatosis 1-associated neurofibromas and malignant peripheral nerve sheath tumors.

Neurofibromas represent one of the hallmarks of neurofibromatosis 1 (NF1) patients. Tumor progression of neurofibromas to malignant peripheral nerve sheath tumors (MPNST) is a frequent and life threatening complication. To learn more about processes involved in malignant transformation, we evaluated differential gene expression in plexiform neurofibroma and MPNST from the same NF1 patient. Suppression subtractive hybridization (SSH) yielded 133 differentially expressed genes confirmed by reverse Northern blotting. Virtual Northern blots were employed to validate 23 genes. To independently verify differential expression, immunohistochemical analyses with antibodies to matrix metalloproteinase 13 (MMP13), platelet-derived growth factor receptor alpha (PDGFRA) and fibronectin (FN1) were performed on 9 dermal and 9 plexiform neurofibromas and 16 MPNST from 19 NF1 patients. All three proteins proved to be up-regulated in MPNST. MMP13 expression was observed in 44% of MPNST but was absent in neurofibromas. PDGFRA was expressed in all tumors, but the number of cells expressing it was below 30% in neurofibromas and over 50% in MPNST. Likewise, FN1 was expressed in all tumors, but less than 30% of the cells in neurofibromas and more than 70% of the cells in MPNST exhibited antibody binding. Our data point to several genes not previously recognized to be differentially expressed, and provide a framework for future studies on progression-associated gene expression in low- and high-grade nerve sheath tumors.

Adult↗