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Although relatively rare, neurofibromas have been described in many different sites. We present the unusual case of an 8-year-old girl with a plexiform neurofibroma situated deep to the sternomastoid muscle, and review the current literature with particular regard to the pathology and site of neurofibromas.
Primary solitary neurofibroma of the chest wall is rare. We present a 38-year-old man with this disease. The patient was admitted to our hospital because of an abnormal shadow of the left lung in chest roentgenograms. Chest CT scanning showed an extrapleural tumor, 4 x 5 cm in size, which was homogenous and sharply demarcated. The tumor was resected with video-assisted thoracoscopic surgery. The pathohistological diagnosis was neurofibroma originating from the 5th intercostal nerve. His postoperative course was uneventful. Neurofibroma commonly occurs in posterior mediastinum but rarely in the chest wall.
Right outflow tract obstruction due to neurofibroma is rare, with only four cases identified in the world literature. Obstruction due to a pedunculated neurofibroma has never been reported. A 36-year-old woman with no known heart disease presenting with dyspnea, palpitations and chest pain was shown on echocardiogram to have a mobile right ventricular mass. Cardiac catheterization revealed normal coronary arteries and right ventricular outflow tract obstruction by a pedunculated mass, which was surgically removed and histologically proven to be a benign neurofibroma. Following surgery the patient's symptoms disappeared, with no recurrence three years postoperatively.
Among primary nerve sheath tumors, schwannomas and neurinomas are the most common. While the schwannomas (neurilemomas) originate in schwann cells, neurofibromas arise from all the constitutive parts of the nerve. The behavior of each tumor is quite different and only neurofibromas may present malignant transformation, especially when arising in patients with Von Recklinghausen disease (NF1 with multiple neurofibromas).
Tracheal involvement is an extremely rare manifestation in patients with neurofibromatosis type 1 (NF-1). We present a 33-year-old women with NF-1 suffering from progressive dyspnea. Multislice spiral CT revealed a neurofibroma located within the trachea with intratracheal extension. To our knowledge, this is the first report of an intratracheal neurofibroma which has been documented by CT. This indicates that multislice spiral CT allows accurate demonstration of localization and extent of this rare manifestation of neurofibromas.
The close association of neurofibromatosis type 1 (NF1) with gliomas raises the question of whether the NF1 gene may be involved in the pathogenesis of sporadic astrocytic brain tumors. However, no frequent mutations within NF1 have been described in these tumors. Recent data on a limited series of gliomas indicate that NF1 expression may even be increased, thereby questioning the role of NF1 as a tumor suppressor in astrocytomas. In the present study, we examined the expression of NF1 in a series of 96 tumors including astrocytomas, meningiomas and plexiform neurofibromas. NF1 RNA transcription levels were compared to those of the reference genes B2M, ACTB and GAPD. The expression of OMGP, which is interposed in the NF1 gene, served as an additional control. NF1 expression did not significantly diverge among different malignancy stages of astrocytomas. As expected, the plexiform neurofibromas showed only very low NF1 expression. A striking finding was the highly variable expression of those genes selected to serve as references. While B2M and ACTB exhibited comparable levels of expression within different grades of astrocytomas and meningiomas, GAPD showed an inverse pattern in these tumors. In conclusion, NF1 expression is strongly reduced in NF1-associated plexiform neurofibromas but not in astrocytic tumors. The significant differences between B2M, ACTB and GAPD transcript levels brings into question the common practice of defining gene expression as a ratio between the transcripts of interest and those of these reference genes.
We present a case of plexiform neurofibroma of the pelvis in a patient with neurofibromatosis using magnetic resonance imaging (MRI) with computed tomography (CT) correlation. We discovered an extensive pelvic mass with a slightly greater signal intensity than muscle in T1-weighted images and a marked increased signal intensity in T2-weighted images. Multiple hypointense septations were identified throughout the tumor, particularly in the T2-weighted images. The MR appearance of pelvic plexiform neurofibroma is identical to those found in spinal and paraspinal locations. In the presence of an extensive pelvic mass in a patient with neurofibromatosis, MRI is recommended in evaluating and diagnosing plexiform neurofibroma. Since the MRI appearance of this tumor is characteristic, other lesions can possibly be ruled out. In addition, MRI's multiplanar capability is ideally suited to demonstrate the extension of these large tumors.
Neurofibromatosis type 1 (NF1) is a common autosomal dominant condition associated with germline mutations of the NF1 gene located at chromosome band 17q11.2. Molecular analysis of a number of NF1-specific tumors has shown the inactivation of both NF1 alleles during tumorigenesis, supporting the tumor suppressor hypothesis for the NF1 gene. Using interphase dual-color fluorescence in situ hybridization (FISH) technique on paraffin-embedded tissues, we studied 11 plexiform, 4 cutaneous, and 6 subcutaneous neurofibromas. Cytogenetic analysis was conducted using two probes, one specific for the NF1 region (RP11-229K15) and one for the centromeric region of chromosome 17 as control. No large somatic deletions were found. Only in one of the plexiform neurofibromas loss of a whole chromosome 17 was observed. If we assume that dual-color FISH analysis is sensitive enough to detect the majority of large somatic deletions present, then other mutational mechanisms affecting the NF1 gene are probably involved in neurofibroma formation, and other tumor suppressor genes may play an important role in NF1 tumorigenesis.
Damselfish neurofibromatosis (DNF) is a neoplastic disease affecting bicolor damselfish (Stegastes partitus Poey) on Florida reefs. Previous studies have demonstrated high densities of eosinophilic granule containing cells (EGC), the proposed equivalent of mast cells in fishes, in neurofibromas and malignant peripheral nerve sheath tumors (mpnst) in DNF. These lesions are similar to those in the disease neurofibromatosis type 1 (NF1) in humans, which contain large numbers of mast cells. In the present study, experiments were conducted to measure the response of EGC in these tumors as well as in the submucosa of the digestive tract to the mast cell degranulating agent compound 48/80. Degranulation of these cells was visible by light microscopy and characterized by conspicuous swelling of granules and often by the presence of free granules adjacent to the EGC. Degranulation occurred by release of intact granules (diacytosis), as reported in other fishes, rather than by fusion of granules with the cell membrane (exocytosis) as reported in mast cells in mammals. Baseline levels of EGC exhibiting degranulation ranged from 20-26% in the submucosa to 30% in tumors. Within 1-2h of exposure to compound 48/80, significant increases in average levels of degranulation were observed, to 67% in the gut and 72% in tumors. Degranulation was significantly more extensive in the tumors than in the gut. The outermost edges of the tumors contained significantly higher densities of EGC but these cells exhibited lower rates of degranulation than those in the inner regions of tumors. These observations support the hypothesis that the EGC present in neurofibromas and mpnst in DNF are equivalent to the mast cell component in neurofibromas in NF1.
Pacinian neurofibromas are unusual tumors with components that resemble Vater-Pacini corpuscles and are probably a variant of nerve-sheath myxoma. Lesions composed predominantly of these structures have occurred on or near the buttocks in three previously reported cases; however, all were solitary and congenital. Two of these patients, with lesions that closely resembled mature Vater-Pacini corpuscles, had underlying skeletal anomalies. Our patient had multiple hairy pacinian neurofibromas (nerve-sheath myxomas) on the buttocks that were not associated with radiographic evidence of and underlying skeletal anomaly. Skeletal anomalies may be associated with "sacrococcygeal paciniomas" but probably not with true pacinian neurofibromas.
Collagen components in neurofibroma tissue from patients with von Recklinghausen disease were investigated, in comparison with those in normal skin and peripheral nerve tissue. Biochemical analysis of collagen isolated from the tissues by limited pepsin digestion indicated that the neurofibroma tissue contained type I collagen as the major constituent and increased amounts of types III and V collagen. The relative ratios of alpha 1(III)/alpha 1(I) and alpha 1(V) + alpha 2(V)/alpha 1(I) in the tissue were 0.87-0.92 and 0.16-0.17, respectively, while in normal skin, these ratios were 0.36-0.45 and less than 0.024, respectively. Amino acid analysis and circular dichroism studies of types I, III and V collagen purified from the tissue showed that these collagens were essentially the same as the corresponding types of collagen isolated from fetal human skin and placenta. The increased deposition of types III and V collagen suggested that alternation of collagen metabolism had occurred in the neurofibroma tissue.
Spinal neurofibromas are found in up to 38% of NF1 patients. However, they cause clinical implications only in about 5% of the patients. In contrast, multiple symptomatic spinal neurofibromas are the main clinical finding in patients with familial spinal neurofibromatosis. Familial spinal neurofibromatosis has been considered to be a distinct clinical form of neurofibromatosis. Linkage analysis in two families and identification of a NF1 gene mutation in a third family strongly associate spinal neurofibromatosis with the NF1 gene. We describe a NF1 patient who satisfies the NIH diagnostic criteria and has severe spinal involvement with bilateral spinal root neurofibromas at every level. A recurrent splice site mutation (IVS19b-3C>G) was identified in the NF1 gene in the patient. We discuss the possibility that the clinical picture of this patient represents an additional example of spinal neurofibromatosis. By comparison of the clinical expression of NF1 in this patient and that in another patient with the identical mutation the hypothesis that spinal neurofibromatosis is associated with a particular mutation is highly unlikely. The involvement of other genes linked to the NF1 gene or modifying genes is currently the most likely explanation for the clinical phenotype of spinal neurofibromatosis.
Neurofibromatosis, or von Recklinghausen's disease, is an autosomal dominant disease with multiple neurofibroma and café-au-lait spots. However, neurofibroma in the bladder wall is a rare condition in von Recklinghausen's disease. A 31-year-old man with neurogenic voiding dysfunction due to sacral meningocele and acute urinary retention with neurofibroma of the bladder wall is presented with detailed radiologic evaluation. Patients with von Recklinghausen's disease should be carefully evaluated if urological symptoms exist.
The CO2 laser is presented as a useful tool for the removal of large numbers of neurofibromas, the major source of cosmetic disfigurement in the patient with peripheral neurofibromatosis. Its advantages include high patient satisfaction with the rapid, staged removal of thousands of neurofibromas, with minimal morbidity and an enhanced appearance. The operative technique for each of the forms of neurofibroma, that is, pedunculated, sessile, and subcutaneous, is described. As with all procedures involving a change in appearance, it is essential that the patient be fully aware of the limitations of the procedure and the expected final result. This is easily accomplished in this procedure by the use of a "test treatment."
Various neurofibroma cell lines isolated from either dermal, plexiform, or diffuse neurofibromas were found to respond to human gamma interferon by decreasing proliferation rates in vitro. The cell number decreased to around 40-50% of controls (without gamma interferon) six days after the treatment. The cell lines showed dramatic inhibition of tritium-labeled thymidine uptake one day after the treatment with gamma interferon. Either 100 IU/ml or 1,000 IU/ml of gamma interferon resulted in the same range of inhibition. It is calculated that venous infusion of one vial of commercial recombinant gamma interferon (200 x 10(6) IU/ml) reaches more than 100 IU/ml in the peripheral blood, which means that it may be clinically useful. The cell lines also responded to gamma interferon by initiating expression of CD54. Immunological modulation of neurofibroma cell components by gamma interferon in vivo remains to be studied.
Neurofibromas of neurofibromatosis 1 (NF1) are highly vascular. Because the number of PDGF beta receptors in neurofibroma-derived cultured cells (NF-derived cells) has been reported to be increased, we tested whether platelet-derived growth factor BB (PDGF-BB) could induce expression of vascular endothelial growth factor (VEGF) in NF-derived cells. When analysed by reverse transcription-polymerase chain reaction, VEGF mRNA expression was found to be stimulated by PDGF-BB and TGF-beta1. Those growth factors stimulated the secretion of VEGF from NF-derived cells. PDGF-BB furthermore induced the mitogen-activated protein kinase phosphorylation in NF-derived cells from patients with NF1. In conclusion, PDGF-BB stimulated VEGF secretion in NF-derived cells, and this stimulation is probably important in neurofibroma hypervascularization.
Primarily isolated neurofibroma cell lines and a human dermal fibroblast cell line were transfected with human gamma interferon gene in vitro, and changes in the cell proliferation rates were investigated. The proliferation rates of both cell lines were remarkably suppressed after the gene transfection. In particular, the neurofibroma cell lines almost stopped proliferating five days after gene transfection. The tritium thymidine uptake of the fibroblast cell line was almost abolished three days after gene transfection. The culture media from both of the gene-transfected cell lines contained a measurable gamma interferon concentration as late as five days after transfection, this was detected by an enzyme-linked immunosorbent assay. These data suggest that gamma interferon gene therapy might be a possible treatment for intractable or inoperable neurofibromas in patients with von Recklinghausen's disease in the future.
The effect of platelet-poor plasma from patients with von Recklinghausen's disease (neurofibromatosis, NF) on the cell growth of cultured neurofibroma-derived fibroblast-like cells (NF fibroblast-like cells grown from explant cultures of cutaneous neurofibromas) was examined. Platelet-poor plasma and sera from nine NF patients and nine control individuals were examined. When comparing platelet-poor plasma from patients with NF with control individuals, the former stimulated the proliferation of fibroblast-like cells derived from neurofibromas, not that of normal fibroblasts.