Sporadic Neurofibromas Research Articles

MRI features of benign peripheral nerve sheath tumors: how do sporadic and syndromic tumors differ?

To compare MRI features of sporadic and neurofibromatosis syndrome-related localized schwannomas and neurofibromas. In this retrospective study, our pathology database was searched for "neurofibroma" or "schwannoma" from 2014 to 2019. Exclusion criteria were lack of available MRI and intradural or plexiform tumors. Qualitative and quantitative anatomic (location, size, relationship to nerve, signal, muscle denervation) and functional (arterial enhancement, apparent diffusion-weighted coefficient) MRI features of sporadic and syndrome-related tumors were compared. Statistical significance was assumed for p < 0.05. A total of 80 patients with 64 schwannomas (sporadic: 42 (65.6%) v. syndrome-related: 22 (34.4%)) and 19 neurofibromas (sporadic: 7 (36.8%) v. syndrome-related: 12 (41.7%)) were included. Only signal heterogeneity (T2W p=0.001, post-contrast p=0.03) and a diffused-weighted imaging target sign (p=0.04) were more frequent with schwannomas than neurofibromas. Sporadic schwannomas were similar in size to syndrome-related schwannomas (2.9±1.2cm vs. 3.7±3.2 cm, p = 0.6), but with greater heterogeneity (T2W p = 0.02, post-contrast p = 0.01). Sporadic neurofibromas were larger (4.6±1.5cm vs. 3.4±2.4 cm, p = 0.03) than syndrome-related neurofibromas, also with greater heterogeneity (T2W p=0.03, post-contrast p=0.04). Additional tumors along an affected nerve were only observed with syndrome-related tumors). There was no difference in apparent diffusion coefficient values or presence of early perfusion between sporadic and syndrome-related tumors (p > 0.05). Although syndrome-related and sporadic schwannomas and neurofibromas overlap in their anatomic, diffusion and perfusion features, signal heterogeneity and presence of multiple lesions along a nerve are differentiating characteristics of syndrome-related tumors.

Sporadic spinal schwannomas and neurofibromas - a review.

Tumours arising from the spinal nerve roots are more common in men between the third and fourth decades of life, located mainly in the intradural space of the lumbar region. The clinical symptoms of spinal schwannomas and neurofibromas are similar and depend on the location of the tumour and its relationship to the spinal cord and nerve roots. The pain (radiculalgia and/or vertebralgia) is the earliest symptom, followed by sensory deficit, while motor deficits and sphincter disorders are late symptoms. Magnetic resonance imaging is the diagnostic tool of choice and should be performed when the disease is suspected, as early and accurate diagnosis is essential for treatment outcome. The treatment of these lesions is surgical aiming at total tumour resection that promotes neurological recovery and prevents from recurrences. Subtotal removal also provides favourable outcome but at higher recurrence rates. The aim of this literature review was to study some important characteristics of sporadic spinal schwannomas (SSS) and neurofibromas (SSN), i.e. those notassociated with neurofibromatosis type I and II.

Floor of Mouth Neurofibroma: A Rare Presentation

Solitary sporadic neurofibromas are uncommon benign tumours of the neural sheaths of the peripheral nervous system. Solitary sporadic neurofibromas of the oral cavity and floor of mouth are extremely rare. We present the case of a 36-year-old male who presented with a 3-month history of a soft non-tender floor of mouth mass. MRI demonstrated a cystic septated lesion filling the left sublingual space. The lesion was excised via an external approach. Histology and immune assay unexpectedly demonstrated a neurofibroma.

BRAF mutation, TERT promoter mutation, and HER2 amplification in sporadic or neurofibromatosis-related neurofibromas and malignant peripheral nerve sheath tumors: do these molecules have a signature in malignant transformation?

Peripheral nerve sheath tumors may occur sporadically or related to neurofibromatosis (NF). Unless the mechanisms of tumorigenesis in NF related malignant peripheral nerve sheath tumors (MPNST) are better understood, it remained unclear in sporadic cases. We aimed to investigate the genetic route for malignancy in both individuals with NF-1 and sporadic ones to open a way for targeted therapies in the future. We investigated the role of HER2 with Dual ISH DNA Probe Cocktail test, BRAF mutation (exon 15) and TERT promoter mutation frequency with Sanger sequencing method in respectively 25 sporadic neurofibromas, 25 NF-1 related neurofibromas and 25 MPNST cases from two institutes. Categorical data were analyzed and summarized as frequency and percentage. Statistical analysis was done with SPSS v.22 statistical package, and the statistical significance level was considered as 0.05. We identified TERT promoter mutation only in one sporadic MPNST (4%) and no BRAF mutation in any case. HER2 amplification is found in 10/25 (40%) MPNST cases. No mutations or gene amplification detected in neurofibromas (p < 0.001). MPNSTs are sarcomas with poor prognosis and limited treatment options. TERT promoter mutations and HER2 amplification may play a putative role in therapeutic purposes.

Sporadic Neurofibroma of the Tongue Unassociated with Neurofibromatosis Type I: A Clinicopathologic Study of Ten Cases.

Neurofibromas rarely occur within the oral cavity and infrequently involve the tongue. The majority of lingual neurofibromas arise in patients affected by neurofibromatosis type 1 (NF1). Neurofibromas of the tongue unassociated with this disorder are exceedingly uncommon. The clinical and pathologic features of 10 cases of sporadic lingual neurofibromas, unassociated with NF1, were evaluated. The patients included six females and four males ranging in age from 30 to 69years (mean 59years; median 63years). An asymptomatic or slowly enlarging lingual mass was the most common clinical presentation. None of the patients were documented to have NF1. Histologically, the tumors were unencapsulated and situated beneath an intact squamous mucosa. The tumors arecomprised ofspindle cells with wavy nuclei within a collagenous to myxoid stroma. One tumor was characterized by a plexiform growth pattern. The lesional cells were positive for S-100 protein. Clinical follow up, available for all patients, showed no recurrences and no subsequent development of additional clinical manifestations of NF1. Lingual neurofibromas should be distinguished from other peripheral nerve sheath tumors that can affect this anatomic site. This series of cases confirms that sporadic neurofibromas of the tongue may be rarely encountered in patients having no other features of NF1.

Prevalence and clinicopathological characteristics of lipomatous neurofibromas in neurofibromatosis 1: An investigation of 229 cutaneous neurofibromas and a systematic review of the literature.

Lipomatous neurofibroma (Lnf) is a histopathological variant with adipocytes noted among cells of cutaneous neurofibromas. We aimed to investigate the prevalence and clinicopathological features of Lnfs of neurofibromatosis 1 (NF1)-associated cutaneous neurofibromas and to review the literature systematically. We also evaluated the expression of leptin (a hormone involved in lipid metabolism) in neurofibromas to better understand the pathogenesis of Lnfs. A prospective histologic study was conducted on 229 cutaneous neurofibromas from 85 NF1 individuals. Leptin expression was immunohistochemically evaluated in 111 cutaneous neurofibromas. To systematically review the literature, two authors independently performed literature searches without year restriction. Forty (17.5%) neurofibromas were lipomatous. Lnfs were significantly larger lesions and associated with females. Eighteen (7.9%) of all neurofibromas had multinucleated floret-like giant cells, and these were associated with Lnfs. All neurofibromas expressed leptin. We systematically reviewed 13 articles. Three large studies investigated Lnfs mainly in sporadic neurofibromas and suggested that 0.3% to 8.0% of tumors (NF1 and sporadic) are Lnfs. In NF1, Lnfs are common, mainly in larger tumors and women. All cutaneous NF1-neurofibromas express leptin. It is unknown if the expression of leptin accounts for the lipomatous variant, but it may have a role in the pathogenesis of cutaneous neurofibroma.

Expression of the BRAF L597Q mutation in sporadic neurofibromas of the upper extremity

The pathogenesis of neurofibromas is poorly understood outside of neurofibromatosis (NF). The BRAF proto-oncogene has been implicated in malignant peripheral nerve sheath tumors (PNSTs), however its role in neurofibromas has not been described. In this study, we identify a BRAF mutation in a 61-year old non-NF patient with a history of sporadic and recurrent neurofibromas localized to the right upper extremity. Despite repeat resections to establish local control, he developed median nerve neuropathy secondary to a 13×4cm plexiform neurofibroma. Genetic sequencing of the neurofibroma revealed the expression of a novel BRAF L597Q mutation. This study is the first to describe the BRAF L597Q mutation in PNSTs and the first to implicate a BRAF mutation in neurofibroma biology. We hypothesize that BRAF mutations may identify a molecularly-distinct subset of recurrent neurofibromas and may provide potential for targeted therapeutics.

Nestin-Positive Stem Cells in Neurofibromas From Patients With Neurofibromatosis Type 1-Tumorigenic or Incidental?

Recently, we found discrete foci of melanin deposits but diffuse positivity with MART-1/MelanA in a neurofibroma from a patient with neurofibromatosis type 1 (NF1). To ascertain the frequency of cells that had the capacity for melanogenesis in neurofibromas from patients with NF1. Given that nestin-positive mammalian neural crest cells are potentially capable of forming neurons and Schwann cells, an additional aim was to assess the proportion of nestin-positive cells to test our hypothesis that the frequency of melanogenic cells is a direct function of the stem cell population harbored. Antibodies used included MART-1/MelanA, a transmembrane protein that is present in normal melanocytes and nestin, a type VI intermediate filament protein present in neuronal precursor cells. Seventy-two neurofibromas from 18 patients (10 with multiple and 8 with single) with NF1 were studied. The control group included solitary sporadic neurofibromas from 24 patients. Expression of markers was as follows: MART-1/MelanA staining in 5/72 cases (7%) from neurofibromas from 2/18 patients with NF1 versus 0/24 (0%) in the sporadic neurofibroma group (P = 0.33) and nestin in 33/72 cases (49%) from neurofibromas from 9/18 patients with NF1 versus 3/24 (12.5%) in the sporadic neurofibroma group (P = 0.003). All 5 cases of neurofibroma that were MART-1/MelanA positive also demonstrated positive staining with nestin. Although we found no difference in melanogenic cells in neurofibromas from patients with NF1 relative to the sporadic group, we did find a significant population of nestin-positive progenitor cells in neurofibromas from patients with NF1. In light of recent evidence linking formation of neural neoplasms such as neurofibroma to alterations in the self-renewal program of stem/progenitor cells, our findings reinforce the potentially tumorigenic role of nestin-positive progenitor cells in neurofibromas from patients with NF1.

Cellular Neurofibroma with Atypia Mimics Sarcoma: Report of a Case with Immunohistochemical Staining Pattern Analysis and Literature Review

A case of two sporadic cellular neurofibromas with atypia and one widespread hyalinization neurofibroma of the lumbar spine in a 51-year-old man without evidence of neurofibromatosis-1 is reported. Cellular neurofibroma with atypia is an unusual variant. The definite criteria for low-grade and high-grade malignant peripheral nerve sheath tumors as well as cellular neurofibroma are not well defined in the literature. The clinical significance of atypical cellular neurofibroma has rarely been systematically studied. To our knowledge, the concomitance of cellular architecture and cytologic atypia is rarely documented, and this is a rare report of atypical cellular neurofibroma. The recognition of this entity is of great importance to both pathologists and clinicians because atypical cellular neurofibroma is clever at masquerading both histologically and cytologically as a sarcoma; therefore, a precise diagnosis of this variant is essential because of the differences in treatment and clinical behavior between benignancy and malignancy. We also examined the immunohistochemical characteristics of CD34 positive cells and focal high expression of p53 up to 73% encountered in our case. To our knowledge, seldom have series or case reports elucidated this phenomenon.

Melanocytic nevi are associated with neurofibromas in neurofibromatosis, type I, but not sporadic neurofibromas. A study of 226 cases*

Neurofibromatosis, type 1, is associated with cutaneous melanin pigmentation, but an association with ordinary melanocytic nevi has not been described. This retrospective case-control study was designed to see if neurofibromas in patients with neurofibromatosis, type 1 (NF-1) differ from sporadic neurofibromas (SN) in their incidence of associated melanocytic nevi and other histologic features. Slides from 114 NF-1 were compared with 112 SN and 300 intradermal melanocytic nevi (IDN). Small lentiginous melanocytic nevi were identified over 13 NF-1 (11%) but no SN (P=0.0002). Compared with other NF-1, NF-1 with nevi were more frequently associated with melanocytic hyperplasia, giant melanosomes and diffuse neurofibroma (P<0.03). Compared with SN, NF-1 were also more frequently associated with melanocytic hyperplasia, lentigo simplex-like changes, diffuse neurofibroma and plexiform neurofibroma (P<0.001). Sebaceous hyperplasia (14%), dermal elastosis (9%), lipomatous change (8%), epithelial cysts (4%) and keratin granulomas or folliculitis (3%) were not significantly different in prevalence between NF-1, SN and the control group of IDN. This study suggests that there is a difference in the potential for melanocytic proliferation in NF-1 compared with SN. NF-1, SN and IDN are associated with a similar range of incidental histologic changes. Ball NJ, Kho GT. Melanocytic nevi are associated with neurofibromas in neurofibromatosis, type 1, but not sporadic neurofibromas. A study of 226 cases.

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.

A series of 397 peripheral neural sheath tumors: 30-year experience at Louisiana State University Health Sciences Center

This is a retrospective review of 397 benign and malignant peripheral neural sheath tumors (PNSTs) that were surgically treated between 1969 and 1999 at the Louisiana State University Health Sciences Center (LSUHSC). The surgical techniques and adjunctive treatments are presented, the tumors are classified with respect to type and prevalence at each neuroanatomical location, and the management of malignant PNSTs is reviewed. There were 361 benign PNSTs (91%). One hundred forty-one benign lesions were brachial plexus tumors: 54 schwannomas (38%) and 87 neurofibromas (62%), of which 55 (63%) were solitary neurofibromas and 32 (37%) were neurofibromatosis Type 1 (NF1)-associated neurofibromas. Among the brachial plexus lesions supraclavicular tumors predominated with 37 (69%) of 54 schwannomas; 34 (62%) of 55 solitary neurofibromas; and 19 (59%) of 32 NF1-associated neurofibromas. One hundred ten upper-extremity benign PNSTs consisted of 32 schwannomas (29%) and 78 neurofibromas (71%), of which 45 (58%) were sporadic neurofibromas and 33 (42%) were NF1-associated neurofibromas. Twenty-five benign PNSTs were removed from the pelvic plexus. Lower-extremity PNSTs included 32 schwannomas (38%) and 53 neurofibromas (62%), of which 31 were solitary neurofibromas and 22 were NF1-associated neurofibromas. There were 36 malignant PNSTs: 28 neurogenic sarcomas and eight other sarcomas (fibro-, spindle cell, synovial, and perineurial sarcomas). The majority of tumors were benign PNSTs from the brachial plexus region. Most of the benign PNSTs in all locations were neurofibromas, with sporadic neurofibromas predominating. Similar numbers of schwannomas were found in the upper and lower extremities, whereas neurofibromas were more prevalent in the upper extremities. Despite aggressive limb-ablation or limb-sparing surgery plus adjunctive therapy, malignant PNSTs continue to be associated with high morbidity and mortality rates.

The Histologic Differences Between Neurofibromas in Patients With Neurofibromatosis, Type I and Sporadic Neurofibromas

Neurofibromatosis is associated with cutaneous melanin pigmentation, but an association with ordinary melanocytic nevi has not been described. This retrospective case‐control study was designed to see if neurofibromas in patients with Neurofibromatosis, Type I (NF‐1) differ from sporadic neurofibromas (SN) in their incidence of associated melanocytic nevi and other histologic features. Slides from 114 NF‐1 were compared with 112 SN. Lentiginous melanocytic nevi were identified over 13 NF‐1 (11%) but no SN (p = 0.00019, Fisher’s test). Compared with other NF‐1, NF‐1 with nevi were more frequently associated with melanocytic hyperplasia, honeycomb infiltration of the subcutis (p &lt; 0.03, Fisher’s test), and a greater number of biopsies (p = 0.04, t‐test). Compared with SN, NF‐1 were more frequently associated with melanocytic hyperplasia, lentigo simplex‐like changes, honeycomb infiltration of the subcutis (p &lt; 0.001, Chi squared test), plexiform neurofibroma and epidermolytic hyperkeratosis (p &lt; 0.03, Fisher’s test). SN more frequently presented as a polyp or papule (p &lt; 0.009). Sebaceous hyperplasia (present in 14% of cases), dermal elastosis (9%), lipomatous neurofibroma (8%), epithelial cysts (4%), and keratin granulomas or folliculitis (3%) were equally common in NF‐1 and SN. This study suggests that there may be a fundamental difference in the potential for melanocytic proliferation in NF‐1 compared with SN.

Losses in chromosomes 17, 19, and 22q in neurofibromatosis type 1 and sporadic neurofibromas: a comparative genomic hybridization analysis

Neurofibromatosis type 1 (von Recklinghausen's NF1) is an autosomal dominant disease associated with an increased risk of benign and malignant neoplasia including malignant peripheral nerve sheath tumors (MPNSTs). In this study, we employed comparative genomic hybridization (CGH) to determine changes in the relative chromosome copy number in 24 patients with neurofibromas, including 12 NF1-associated and 12 sporadic cases. Differences in the frequency and distribution of chromosomal imbalances were observed in both NF1-asociated and sporadic neurofibromas. Chromosomal imbalances were more common in NF1-associated tumors than in sporadic neurofibromas. In both groups, the number of losses was higher than the number of gains, suggesting a predominant role of tumor suppressor gene in tumorigenesis. A number of new chromosomal imbalances were noted including chromosomes 17, 19, and chromosome arm 22q, which may be related to oncogenes or tumor suppressor genes in neurofibromas. In NF1-associated neurofibromas, the most frequent losses were found in chromosome 17 (the minimal common regions were 17p11.2→p13 in nine cases and 17q24→q25 in six cases) and 19p (19p13.2 in nine cases). In addition, both NF1-associated and sporadic neurofibromas often exhibited losses at chromosome arms 19q and 22q (in NF1 tumors, the minimal common regions were 19q13.2→qter in seven cases).

Frequent genomic imbalances in chromosomes 17, 19, and 22q in peripheral nerve sheath tumours detected by comparative genomic hybridization analysis.

Comparative genomic hybridization (CGH) was used to detect changes in relative chromosome copy number in 50 cases of peripheral nerve sheath tumour (PNSTs), including nine malignant peripheral nerve sheath tumours (MPNSTs), 27 neurofibromas (with three plexiform neurofibromas) and 14 schwannomas. Chromosome imbalances were frequently detected in benign as well as malignant PNSTs. In both NF1-associated and sporadic MPNSTs, the number of gains was higher than the number of losses, suggesting proto-oncogene activation during MPNST progression. NF1-asociated MPNSTs exhibited gains of chromosomes 17q and X (2/4 cases each), whereas sporadic MPNSTs showed gains of chromosome 4q (3/5 cases). On the other hand, in benign neurofibromas and schwannomas, the number of losses was higher than the number of gains, suggesting a predominant role of tumour suppressor genes in tumourigenesis. Both sporadic and NF1-associated neurofibromas exhibited losses at chromosome 22q in more than 50% of cases. These chromosomal regions may contain common chromosomal abnormalities characteristic of both types of neurofibromas. In NF1-associated neurofibromas, most frequent losses were found in chromosomes 17 [17p11.2-p13 in nine cases (60%); 17q24-25 in 6 cases (40%)] and 19 [19p13.2 in eight cases (53%); 19q13.2-qter in eight cases (53%)], whereas in sporadic neurofibromas and schwannomas losses of chromosomes 17 and 19 were detected in less than 50% of cases. Since this 17p11.2-p13 region is known to contain the tumour suppressor gene TP53, patients with NF1 may be at high risk of malignant neoplasms including MPNSTs. Gains were more frequently detected in plexiform neurofibromas (2/3 cases) than other benign tumours, suggesting proto-oncogene activation in tumourigenesis of plexiform neurofibroma. The significance of the losses of chromosome 19 in these cases is not clear at present, but in NF1-associated neurofibromas, the presence of some as yet unknown tumour suppressor genes on chromosome 19 cannot be ruled out.