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PubMed1987

Cell culture study on neurofibromatosis.

Cells obtained on culture from normal appearing skin (NFns) and from neurofibromas of neurofibromatosis patients (NFnf), and from normal skin of normal donors (Normal) were studied. We measured the growth rate, maximal cell density, radiation sensitivity and resistance to 3-nitrotyrosine of each of the three groups of strains. The growth rate and maximal cell density of fibroblasts derived from neurofibromas of the neurofibromatosis patients were significantly lower than those in normal donors. The neurofibromatosis cells showed no X-ray hypersensitivity, as compared to normal controls. We also did not observe resistance to 3-nitrotyrosine of the cells derived from normal appearing skin of the neurofibromatosis patients. However, cells derived from neurofibromas of the neurofibromatosis patients showed resistance to 3-nitrotyrosine. This phenomenon may explain the slow growth rate of the latter cells.

Cell Count↗
PubMed1999

The Nf1 tumor suppressor regulates mouse skin wound healing, fibroblast proliferation, and collagen deposited by fibroblasts.

Neurofibromatosis type 1 patients develop peripheral nerve tumors (neurofibromas) composed mainly of Schwann cells and fibroblasts, in an abundant collagen matrix produced by fibroblasts. Trauma has been proposed to trigger neurofibroma formation. To test if loss of the neurofibromatosis type 1 gene (Nf1) compromises fibroblast function in vivo following trauma, skin wounding was performed in Nf1 knockout mice. The pattern and amount of collagen-rich granulation bed tissue, manufactured by fibroblasts, was grossly abnormal in 60% of Nf1+/- wounds. Nf1 mutant fibroblasts showed cell autonomous abnormalities in collagen deposition in vitro that were not mimicked by Ras activation in fibroblasts, even though some Nf1 effects are mediated through Ras. Nf1+/- skin wound fibroblasts also proliferated past the normal wound maturation phase; this in vivo effect was potentiated by muscle injury. In vitro, Nf1+/- fibroblasts showed higher proliferation in 10% serum than Nf1+/+ fibroblasts. Macrophage-conditioned media or epidermal growth factor potentiated Nf1+/- fibroblast proliferation in vitro, demonstrating abnormal response of mutant fibroblasts to wound cytokines. Thus Nf1 is a key regulator of fibroblast responses to injury, and Nf1 mutation in mouse fibroblasts causes abnormalities characteristic of human neurofibromas.

Animals↗
PubMed2003

Familial neurofibromatosis-1 and Gilbert syndrome.

BACKGROUND: Neurofibromatosis (NF) is a genetic disorder of the neural sheet, affecting almost all organ systems. METHOD: A family that consisted of the father and his three children, two males and one female, having NF-1 is evaluated in detail for cosmetic purposes. The routine preoperative laboratory examinations, including complete blood counts, serum biochemistries, urinary analysis, extremity and chest roentgenograms, ultrasounds of the abdomen and the affected regions, and pelvic computed tomographies, revealed characteristics of NF-1 and unexpected hyperbilirubinemia. The patients are evaluated further for the cause of hyperbilirubinemia by the fasting test. Variously localized plexiform neurofibromas of the three children are totally excised. RESULTS: The father was affected as a result of a mutation, and his three children had inherited the disease. The father, having subcutaneous neurofibromas, differs from the children, as they have elephantiasis neurofibromatosa. The children had various rare clinical presentations besides disfiguring deformities. Two male patients had retroperitoneal neurofibromas, and one had splenomegaly and osseous changes. Gilbert's disease was diagnosed, interestingly, and coincidentally in the three patients with elephantiasis due to NF-1. DISCUSSION: An interesting diagnosis of NF occurring coincidentally with Gilbert's disease in a family is reported. This clinical study is the first report of Gilbert's disease accompanying familial NF.

Adult↗
PubMed1983

Genetics in neuro-oncology.

This review provides a framework for the neurosurgeon in understanding the increasingly important role of genetics in the study of nervous system tumors. The three tumors discussed (retinoblastoma, meningioma, and neurofibroma) are neither the most common nor the most clinically devastating tumors faced by neurosurgeons. Rather, the studies on these tumors are presented because of the important lessons each provides. Studies of retinoblastoma demonstrate the ability of a gene which is recessive at the cellular level to require a second mutation for tumorigenesis and therein to appear as a dominantly inherited disorder at the level of the organism. This "multi-hit" theory could easily be applied to other nervous system tumors which have both sporadic solitary tumors and familial multiple tumors. In this group we should include acoustic neuromas, meningiomas, gliomas, neurofibromas, paragangliomas (glomus and carotid body tumors), and the pituitary tumors (and others) associated with the multiple endocrine neoplasia syndromes. The limits of this review do not allow a separate discussion of the neurosurgical aspect of these lesions; for this, the reader is referred elsewhere (18, 19). Meningiomas are discussed because it appears that two separate lines of inquiry may eventually be related at a cellular level. These directions of study are the demonstration that a common karyotypic abnormality (monosomy 22) is associated with a female preponderance of meningiomas and the demonstration of sex hormone binding in meningiomas. Future studies should be aimed at showing an in vitro biologic response of these tumors to exogenously added hormones or to their blocking agents. Moreover, one would hope that this response would correlate with a specific chromosomal abnormality. It is possible that some portion of the DNA which has been deleted or altered in these tumors plays an essential role in the regulation of the sex steroid regulatory system. If this segment of the genome could be identified and studied in the meningioma, the findings could be important not only in the treatment of patients with this tumor but also in the treatment of tumors of other hormonally modulated tissues such as breast and uterus. Finally, neurofibromatosis was chosen as the most common of the phakomatoses and as one which can offer significant insights into many areas of neuro-oncology. The NF gene occurs in at least two forms (VRNF, BANF), and it can be associated with virtually all of the tumors known to neurosurgeons--gliomas, neurofibromas, schwannomas, and meningiomas.(ABSTRACT TRUNCATED AT 400 WORDS)

Chromosome Banding↗
PubMed1997

Nevus spilus (speckled lentiginous nevus) associated with a nodular neurotized nevus.

We report a case of nevus spilus with neurotized nevus studied by immunohistochemical methods using S-100, leu-6, glial fibrillary acid protein (GFAP), and myelin basic protein (MBP). Histologic findings of the speckled lesion showed irregular rete ridge elongation, increased epidermal melanocytes and melanin in the epidermis, and scattered nevus cell nests in the upper dermis, but showed neurotized nevus in the deep dermis, which has many features of neurofibroma. Diffuse expression of S-100 protein and MBP, focal staining with GFAP, and lack of staining with leu-7 were observed, Leu-7, positive only in neurofibromas and not in neurotized nevus, appears to be the more pertinent method for distinguishing neurotized nevus from neurofibroma.

CD57 Antigens↗
PubMed2001

Positron emission tomography in the detection and management of sarcomatous transformation in neurofibromatosis.

Benign neurofibromas undergo sarcomatous transformation in approximately 5% of patients with neurofibromatosis type I. The clinical and radiologic diagnosis of sarcomatous change remains difficult. Positron emission tomography with F-18 fluorodeoxyglucose is a method to assess increased glucose metabolism in malignant tissue such as sarcomas. In this case report, positron emission tomography accurately distinguished malignant from benign neurofibromas. The technique may be useful as a noninvasive screening tool for malignant transformation of neurofibromas.

Adult↗
PubMedDate not supplied

CT and MR of neurofibromatosis of the bladder.

Neurofibromatosis of the genitourinary system is rare. We present the CT and MR findings of neurofibromas of the bladder in three patients with von Recklinghausen disease (neurofibromatosis, Type 1). In one case, genitourinary involvement was the primary presentation of the disease. Both CT and MR imaging revealed diffuse and nodular bladder wall involvement, along with pelvic sidewall and adjacent soft tissue abnormalities. The CT attenuation coefficients measured near soft tissue density. On T1-weighted spin echo MR images the tumors revealed signal intensity slightly greater than that of skeletal muscle. Neurofibromas showed markedly increased signal intensity on T2-weighted images relative to the surrounding soft tissues, with marked enhancement in two cases imaged following Gd-DTPA administration. Obstructive hydronephrosis was present in all cases, presumably due to neurofibromas involving the trigonal region. Pelvic sidewall tumors were visualized as rounded, nodular masses extending into the obturator foramina. In the evaluation of patients with von Recklinghausen disease, MR imaging, compared with CT, more clearly defined tumor extent within the bladder, pelvic sidewalls, and surrounding soft tissues.

Adolescent↗
PubMed2001

An unusual cause of biliary stricture in a patient with neurofibromatosis type 1.

The majority of biliary strictures occur as a consequence of iatrogenic injury to the extrahepatic biliary tract, with more than 80% following cholecystectomy. The laparoscopic era has led to heightened awareness of this problem. The occurrence of an iatrogenic stricture can be particularly devastating to both patient and surgeon. The literature highlights a number of factors involved in the aetiology of such traumatic stricture formation. We report an unusual case of a Bismuth 2 stricture of the proximal common hepatic duct,occurring in a patient with type 1 neurofibromatosis, following an iatrogenic bile duct injury that occurred during a laparoscopic cholecystectomy. Histological examination of the strictured region of bile duct removed at surgery demonstrated multiple neurofibromas of varying sizes present in the submucosa. Neurofibromatosis type 1 (von Recklinghausen disease) affects the gastrointestinal tract in up to 25% of cases, and in such cases is characterized by multiple submucosal neurofibromas. We believe this is the first reported case of a biliary stricture in a patient with neurofibromatosis type 1, which appeared to be as a consequence of neurofibromas in the submucosa of the bile duct.

Adult↗
PubMed2005

Expression and function of somatostatin receptors in peripheral nerve sheath tumors.

Although somatostatin receptors have been detected in many normal and neoplastic tissues, little is known of their expression and function in peripheral nerve tumors. In the present study, we examined the expression of all 5 somatostatin receptor subtypes (sst1-5) in 3 normal peripheral nerves, 3 traumatic neuromas, 27 schwannomas, 18 neurofibromas, and 177 malignant peripheral nerve sheath tumors (MPNSTs) by immunohistochemistry as well as by Western blot and reverse transcriptase-polymerase chain reaction investigations in 2 normal peripheral nerves, one neurofibroma, 5 schwannomas, and 5 MPNSTs. Immunoreactive somatostatin receptors were not detectable in normal peripheral nerve and in nonneoplastic Schwann cell proliferations. In contrast, sst2A mRNA and protein was present in 89% of schwannomas. This receptor subtype was less frequently detected in neurofibromas (22%) and MPNSTs (15%). Interestingly, sst4 was seen in 32% of MPNSTs and was almost exclusively expressed in this malignant tumor type. In support of a role in Schwann cell tumor growth control by somatostatin was the observation of induced internalization of sst2A and inhibition of cell proliferation in an NF1-associated MPNST cell line. Moreover, administration of an sst2A-selective agonist resulted in induction of MPNST cell apoptosis. We conclude that peripheral nerve sheath tumors often express at least one functional somatostatin receptor. Furthermore, our findings suggest a potential clinical role for somatostatin receptor agonists in tumor imaging and/or treatment of schwannomas and MPNSTs.

Animals↗
PubMed2003

Immunohistochemical demonstration of EMA/Glut1-positive perineurial cells and CD34-positive fibroblastic cells in peripheral nerve sheath tumors.

To clarify the cellular composition of various peripheral nerve tumorous lesions (traumatic neuroma, 5 cases; schwannoma, 10 cases; neurofibroma, 14 cases; perineurioma, 3 cases; conventional malignant peripheral nerve sheath tumor (MPNST), 7 cases; perineurial MPNST, 4 cases), expression of several markers specific to nerve sheath cells, including glucose transporter protein 1 (Glut1) and CD34, were immunohistochemically investigated with highly sensitive detection methods. In normal nerves and neuromas, perineuriums were positive for Glut1 as well as for epithelial membrane antigen (EMA), and there were some CD34-positive fibroblast-like cells in the endoneurium. Schwannomas consisted principally of S-100 protein-positive Schwann cells, whereas a few CD34-positive fibroblastic cells were present in Antoni B areas. Neurofibromas and conventional MPNST exhibited a mixed proliferation of S-100 protein-, EMA/Glut1-, and CD34-positive cells, indicating a heterogeneous composition of the constituents. The catalyzed signal amplification (CSA) system demonstrated more numerous EMA-positive perineurial cells in neurofibromas than did the ENVISION+ method. Perineurial cell tumors (benign and malignant) were composed of EMA/Glut1-positive and S-100 protein-negative tumor cells. The present study confirmed the characteristic cellular composition to each nerve sheath tumor immunohistochemically and showed the usefulness of the nerve sheath cell markers. Glut1 as well as EMA are specific to perineurial cells, and CD34 seems to be immunoreactive to endoneurial fibroblasts.

Antigens, CD34↗
PubMed2003

Inhibition of the proliferation of a malignant peripheral nerve sheath tumor cell line by gamma interferon gene transfection.

A solitary malignant peripheral nerve sheath tumor was resected, and a tumor cell line was obtained using an explant culture. The morphology of this cell line was quite similar to those of cell lines of dermal neurofibromas of neurofibromatosis 1, except for the fact that the malignant peripheral nerve sheath tumor cell line could be cultured for more than two months. When the tumor cell line was transfected with human gamma interferon gene, the growth rate was remarkably abolished, as previously observed in neurofibroma cell lines transfected with the gamma interferon gene. This new finding suggests the potential for treating either solitary or neurofibroma-related, inoperable, malignant peripheral nerve sheath tumors by local gamma interferon gene transfection in vivo.

Aged↗
PubMed2005

Sclerosing segmental neurofibromatosis.

Segmental neurofibromatosis is a rare disorder characterized by cafe-au-lait macules and/or neurofibromas limited to a single body segment. The neurofibromas in segmental neurofibromatosis are usually soft, non-tender nodules as in other types of neurofibromatosis. Histopathologically, they are usually non-encapsulated, loosely textured dermal tumors. We report a case of sclerosing segmental neurofibromatosis, in which the patient presented with several grouped, erythematous to brownish, firm tender nodules on the left side of the posterior neck. Histopathologically, the stroma was mostly very fibrotic, especially around hair follicles, in addition to the usual features of neurofibroma. The atypical clinical feature, hardness, and tenderness of the lesions may be associated with the fibrosis.

Diagnosis, Differential↗
PubMed2005

Symptoms associated with malignancy of peripheral nerve sheath tumours: a retrospective study of 69 patients with neurofibromatosis 1.

BACKGROUND: Neurofibromatosis 1 (NF1) is a common genetic disorder with variable clinical manifestations and an unpredictable course. Plexiform neurofibromas are common complications of NF1. Their malignant transformation is the main cause of mortality in adult patients with NF1. OBJECTIVES: To identify clinical factors associated with malignant transformation of plexiform neurofibromas. METHODS: Using the database of our neurofibromatosis clinic we included in a retrospective study all patients with NF1 having at least one peripheral nerve sheath tumour for which they underwent surgery or surgical biopsy. Predictive values for malignant transformation of three clinical symptoms, i.e. pain, enlargement of mass and neurological symptoms, were evaluated in association with histological parameters. RESULTS: Of 69 patients studied, 48 had at least one plexiform neurofibroma and 21 had a malignant peripheral nerve sheath tumour. Only enlargement of the tumour had high negative and positive predictive values for malignant transformation: 0.92 and 0.95, respectively. In multivariate analysis, tumour enlargement was independently associated with malignant transformation (odds ratio 167.8, 95% confidence interval 14.0-2012.1). CONCLUSIONS: From a practical point of view, pain, neurological deficit and enlargement of a pre-existing peripheral nerve sheath tumour in NF1 must lead to deep surgical biopsy to rule out malignant transformation.

Adolescent↗
PubMed1998

Coexpression of HGF and c-Met/HGF receptor in human bone and soft tissue tumors.

To understand the interaction between hepatocyte growth factor (HGF) and its receptor c-Met on various bone and soft tissue tumors, their expressions were investigated by western blot analysis, immunohistochemistry and enzyme immunoassay. Western blot analysis revealed that c-Met protein was expressed in 21 (38.8%) of 54 tumors, which detailed to seven (25.9%) of 27 bone tumors and 14 (51.8%) of 27 soft tissue tumors. Most malignant fibrous histiocytomas (MFH) and all neurofibromas expressed c-Met protein. The highest expression of c-Met protein was seen in a case of biphasic synovial sarcoma, where its immunoreactivity was localized only on the epithelial component and not on the sarcomatous component. By enzyme immunoassay for HGF, all but one MFH showed HGF production and the mean level of HGF was the highest among the tumors investigated. Neurofibromas and osteosarcomas had the next highest mean levels of HGF production, respectively. Coexpression of HGF and c-Met was observed in 19 (35.2%) of 54 tumors and was frequently observed in neurofibroma, followed by MFH and synovial sarcoma. Although the mode of interaction between HGF and c-Met varies among the various bone and soft tissue tumors including MFH, their signaling system may play an important role in the development and progression of bone and soft tissue tumors.

Blotting, Western↗
PubMed2005

Neurofibromatosis of atypical presentation.

Neurofibromatosis (NF) is considered to be a heterogeneous neuroectodermal disease clinically defined by the presence of neurofibromas, multiple café-au-lait spots, intertriginous freckles and Lisch nodules. Mosaicism explains atypical presentations of the disease. Early mutations, before tissue differentiation, give rise to generalized disease. We report an atypical presentation of neurofibromatosis with an unusual distribution of neurofibromas, a peculiar, clinically and pathologically, neurofibroma on the trunk and the association with an ovarian serous cystoadenofibroma.

Biopsy, Needle↗
PubMed2005

Pigment cell-related manifestations in neurofibromatosis type 1: an overview.

Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder, affecting approximately 1 in 3500 individuals. The most commonly seen tumors in NF1 patients are the (sub)cutaneous neurofibromas. However, individuals with NF1 typically present in childhood with well-defined pigmentary defects, including cafe-au-lait macules (CALMs), intertriginous freckling and iris Lisch nodules. NF1 is considered a neurocristopathy, primarily affecting tissues derived from the neural crest. Since the pigment producing melanocyte originates in the neural crest, the presence of (hyper)pigmentary lesions in the NF1 phenotype because of changes in melanocyte cell growth and differentiation is to be expected. We want to discuss the pigmentary cutaneous manifestations of NF1 represented by CALMs and intertriginous freckles and the pigmentary non-cutaneous manifestations represented by iris Lisch nodules. Several hypotheses have been suggested in explaining the poorly understood etiopathogenesis of CALMs. Whether other pigmentary manifestations might share similar etiopathogenic mechanisms remains obscure. Additional attention will be drawn to a readily seen phenomenon in NF1: hyperpigmentation overlying (plexiform) neurofibromas, which could suggest common etiopathogenetic-environmental cues or mechanisms underlying CALMs and neurofibromas. Finally, we want to address the relationship between malignant melanoma and NF1.

Cafe-au-Lait Spots↗
PubMed1987

Common pathogenetic mechanism for three tumor types in bilateral acoustic neurofibromatosis.

Bilateral acoustic neurofibromatosis (BANF) is a genetic defect associated with multiple tumors of neural crest origin. Specific loss of alleles from chromosome 22 was detected with polymorphic DNA markers in two acoustic neuromas, two neurofibromas, and one meningioma from BANF patients. This indicates a common pathogenetic mechanism for all three tumor types. The two neurofibromas were among three taken from the same patient, and both showed loss of identical alleles demonstrating that the same chromosome suffered deletion in both tumors. The third neurofibroma from this patient showed no detectable loss of heterozygosity, which suggests the possibility of a more subtle mutational event that affects chromosome 22. In the two acoustic neuromas, only a portion of chromosome 22 was deleted, narrowing the possible chromosomal location of the gene that causes BANF to the region distal to the D22S9 locus in band 22q11. The identification of progressively smaller deletions on chromosome 22 in these tumor types may well provide a means to clone and characterize the defect.

Alleles↗
PubMed2004

Ophthalmological manifestations in segmental neurofibromatosis type 1.

AIMS: To study the ophthalmological manifestations in individuals with the typical features of neurofibromatosis type 1 (NF1) circumscribed to one or more body segments, usually referred to as segmental NF1. METHODS: Visual acuity and colour tests, visual field examination, slit lamp biomicroscopy of the anterior segment, and a detailed examination of the retina by indirect ophthalmoscopy were performed at diagnosis and follow up in 72 consecutive subjects (29 males, 43 females; aged 1-64 years; mean age 14.6 years) seen at the university departments of paediatrics in Catania and Rome, Italy, during years 1990-2003, who had in restricted body areas: (1) typical pigmentary manifestations of NF1 (cafe au lait spots and freckling) only (n = 48); (2) NF1 pigmentary manifestations and neurofibromas alone (n = 2); (3) neurofibromas only (n = 15); and (4) plexiform neurofibromas only (n = 7). RESULTS: None of the 72 patients had Lisch nodules in the iris irrespective of age at eye examination or hypertelorism (a "minor" NF1 feature) and none developed typical associated ophthalmological NF1 complications. An additional child had an isolated optic pathways glioma (OPG), which behaved both biologically and radiographically as an NF1 associated OPG. CONCLUSIONS: This represents the first systematic study reporting on eye involvement in the largest series of individuals at different ages having segmental NF1. As one of the postulated mechanisms to explain segmental NF1 is somatic mosaicism for the NF1 gene (so far demonstrated only in two patients) the present findings could be explained either by the fact that the eye is too far from the mutated area with NF1 lesions in most cases or by the NF1 (or other "predisposing" or "cooperating") gene mutation restricted to too few cellular clones or to tissues embryologically different from the eye.

Adolescent↗