Non-Autogenous Innovative Reconstruction Method Following Mandibulectomy.

BACKGROUND: Plexiform ameloblastoma is a locally aggressive odontogenic tumor, rare in the anterior mandible. The treatment of choice is resection with 1-3 cm free margins. In most of reported cases, the affected mandible is reconstructed by autogenic bone graft or osseocutaneous microvascular free flap in order to return function and esthetics. CASE DESCRIPTION: A 2 cm diameter exophytic ameloblastoma, located in the anterior mandible of a 50-year-old male was resected and reconstructed in a unique manner-allogenic bone block, recombinant human bone morphogenetic protein (rhBMP) and xenograft particles via transcutaneous submental approach. After bone maturation, dental implants were placed and restored by fixed prosthetics. PRACTICAL IMPLICATIONS: Mandible reconstruction modalities have a crucial influence on patient quality of life, function and esthetics. Allogenic bone block combined with rhBMP and xenograft particles can replace the traditional autogenous bone in certain circumstances. A submental transcutaneous "tent pole" approach can improve the success rate of the reconstruction procedure.

Cardiac overload resolved by resection of a large plexiform neurofibroma on both the buttocks and upper posterior thighs in a patient with neurofibromatosis type I: a case report.

BACKGROUND: A large plexiform neurofibroma in patients with neurofibromatosis type I can be life threatening due to possible massive bleeding within the lesion. Although the literature includes many reports that describe the plexiform neurofibroma size and weight or strategies for their surgical treatment, few have discussed their possible physical or mental benefits, such as reducing cardiac stress. In addition, resection of these large tumors can result in impaired wound healing, partly due to massive blood loss during surgery. CASE PRESENTATION: A 24-year-old man was diagnosed with neurofibromatosis type I and burdened with a large plexiform neurofibroma on the buttocks and upper posterior thighs. The patient was 159 cm in height and 70.0 kg in weight at the first visit. Cardiac overload was indicated by an echocardiography before surgery. His cardiac output was 5.2 L/min with mild tricuspid regurgitation. After embolism of the arteries feeding the tumor, the patient underwent surgery to remove the neurofibroma, followed by skin grafting. Follow-up echocardiography, performed 6 months after the final surgery, indicated a decreased cardiac output (3.6 L/min) with improvement of tricuspid regurgitation. Because the blood loss during the first surgery was over 3.8 L, malnutrition with albuminemia was induced and half of the skin graft did not attach. Nutritional support to improve the albuminemia produced better results following a second surgery to repair the skin wound. CONCLUSION: Cardiac overload may be latent in patients with neurofibromatosis type I with large plexiform neurofibromas. As in pregnancy, the body may compensate for this burden. In these patients, one stage total excision may improve quality of life and reduce cardiac overload. In addition, nutritional support is likely needed following a major surgery that results in either an extensive skin wound or excessive blood loss during treatment.

Periportal Plexiform Neurofibromatosis; a rare intra-abdominal manifestation of NF1.

Periportal Plexiform Neurofibromatosis (PPNF) is a rare visceral manifestation of Neurofibromatosis Type 1 (NF1) or Von Recklinghausen disease. Neurofibromas are the most common lesions in NF1. We present a case of a young female diagnosed with NF1 who initially presented with hard abdominal mass. Contrast enhanced CT revealed the unusual lintrahepatic periportal plexiform neurofibromatosis in addition to a typical large retroperitoneal lumbar neurofibroma.

Spatiotemporal Loss of NF1 in Schwann Cell Lineage Leads to Different Types of Cutaneous Neurofibroma Susceptible to Modification by the Hippo Pathway.

Neurofibromatosis type 1 (NF1) is a cancer predisposition disorder that results from inactivation of the tumor suppressor neurofibromin, a negative regulator of RAS signaling. Patients with NF1 present with a wide range of clinical manifestations, and the tumor with highest prevalence is cutaneous neurofibroma (cNF). Most patients harboring cNF suffer greatly from the burden of those tumors, which have no effective medical treatment. Ironically, none of the numerous NF1 mouse models developed so far recapitulate cNF. Here, we discovered that HOXB7 serves as a lineage marker to trace the developmental origin of cNF neoplastic cells. Ablating Nf1 in the HOXB7 lineage faithfully recapitulates both human cutaneous and plexiform neurofibroma. In addition, we discovered that modulation of the Hippo pathway acts as a "modifier" for neurofibroma tumorigenesis. This mouse model opens the doors for deciphering the evolution of cNF to identify effective therapies, where none exist today. SIGNIFICANCE: This study provides insights into the developmental origin of cNF, the most common tumor in NF1, and generates the first mouse model that faithfully recapitulates both human cutaneous and plexiform neurofibroma. The study also demonstrates that the Hippo pathway can modify neurofibromagenesis, suggesting that dampening the Hippo pathway could be an attractive therapeutic target.This article is highlighted in the In This Issue feature, p. 1.

Lifespan Development: Symptoms Experienced by Individuals with Neurofibromatosis Type 1 Associated Plexiform Neurofibromas from Childhood into Adulthood.

This secondary data analysis qualitatively identified salient concerns reported by individuals with Neurofibromatosis Type 1 (NF1)-associated plexiform neurofibromas (pNFs) at different stages of development. Past literature has focused on overall symptomatology, but has not examined nuances in how these symptoms are experienced across developmental phases. Therefore, we aimed to identify commonalities and differences in symptom experiences across age groups to better assist individuals to adjust to symptoms across the lifespan. Thirty-one children, adolescents, and adults (age ≥ 5 years old) and 15 parents participated in semi-structured interviews. Analyses focused on the following symptom categories: pain, social functioning, physical function impact, and stigma. Aspects of pain endorsed by all age groups included localized brief pain on contact with pNF and abnormal sensations; however, only adolescents and adults reported chronic pain and change in pain over time. Social functioning themes of limited activity participation, role limitations, and relationship impact were endorsed by all age groups, but differences emerged across age groups in the types of activity and role limitations, the type of relationship impact, and family planning concerns. All age groups described difficulty with mobility, but only parents reported problems with coordination and physical developmental milestones. While all age groups reported external stigma, internalized stigma was predominately endorsed by adults. While individuals in all age groups described pNF concerns related to pain, social function, physical function, and stigma, specific aspects of these symptoms differed across the developmental continuum. These findings can help assist individuals with pNF better transition to the next developmental phases.

Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation.

PURPOSE: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. METHODS: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. RESULTS: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del. CONCLUSION: We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.

Contributions of inflammation and tumor microenvironment to neurofibroma tumorigenesis.

Neurofibromatosis type 1 associates with multiple neoplasms, and the Schwann cell tumor neurofibroma is the most prevalent. A hallmark feature of neurofibroma is mast cell infiltration, which is recruited by chemoattractant stem cell factor (SCF) and has been suggested to sustain neurofibroma tumorigenesis. In the present study, we use new, genetically engineered Scf mice to decipher the contributions of tumor-derived SCF and mast cells to neurofibroma development. We demonstrate that mast cell infiltration is dependent on SCF from tumor Schwann cells. However, removal of mast cells by depleting the main SCF source only slightly affects neurofibroma progression. Other inflammation signatures show that all neurofibromas are associated with high levels of macrophages regardless of Scf status. These findings suggest an active inflammation in neurofibromas and partly explain why mast cell removal alone is not sufficient to relieve tumor burden in this experimental neurofibroma model. Furthermore, we show that plexiform neurofibromas are highly associated with injury-prone spinal nerves that are close to flexible vertebras. In summary, our study details the role of inflammation in neurofibromagenesis. Our data indicate that prevention of inflammation and possibly also nerve injury at the observed tumor locations are therapeutic approaches for neurofibroma prophylaxis and that such treatment should be explored.

Sleep and pulmonary outcomes for clinical trials of airway plexiform neurofibromas in NF1.

OBJECTIVE: Plexiform neurofibromas (PNs) are complex, benign nerve sheath tumors that occur in approximately 25%-50% of individuals with neurofibromatosis type 1 (NF1). PNs that cause airway compromise or pulmonary dysfunction are uncommon but clinically important. Because improvement in sleep quality or airway function represents direct clinical benefit, measures of sleep and pulmonary function may be more meaningful than tumor size as endpoints in therapeutic clinical trials targeting airway PN. METHODS: The Response Evaluation in Neurofibromatosis and Schwannomatosis functional outcomes group reviewed currently available endpoints for sleep and pulmonary outcomes and developed consensus recommendations for response evaluation in NF clinical trials. RESULTS: For patients with airway PNs, polysomnography, impulse oscillometry, and spirometry should be performed to identify abnormal function that will be targeted by the agent under clinical investigation. The functional group endorsed the use of the apnea hypopnea index (AHI) as the primary sleep endpoint, and pulmonary resistance at 10 Hz (R10) or forced expiratory volume in 1 or 0.75 seconds (FEV1 or FEV0.75) as primary pulmonary endpoints. The group defined minimum changes in AHI, R10, and FEV1 or FEV0.75 for response criteria. Secondary sleep outcomes include desaturation and hypercapnia during sleep and arousal index. Secondary pulmonary outcomes include pulmonary resistance and reactance measurements at 5, 10, and 20 Hz; forced vital capacity; peak expiratory flow; and forced expiratory flows. CONCLUSIONS: These recommended sleep and pulmonary evaluations are intended to provide researchers with a standardized set of clinically meaningful endpoints for response evaluation in trials of NF1-related airway PNs.

Visual outcomes in children with neurofibromatosis type 1 and orbitotemporal plexiform neurofibromas.

PURPOSE: To describe the visual outcomes and volumetric magnetic resonance imaging (3D MRI) in children with neurofibromatosis type 1 (NF1) and orbitotemporal plexiform neurofibromas. DESIGN: Multicenter retrospective case series. METHODS: Two institutions with dedicated NF1 clinical research programs queried their established clinical databases for children with orbitotemporal plexiform neurofibromas. Visual acuity, refractive error, ambylopia, and treatment history were abstracted. Extent of orbitotemporal plexiform neurofibroma involvement was assessed clinically and with 3D MRI analysis. Children with optic pathway gliomas or ocular causes of decreased visual acuity (ie, cataracts, glaucoma) other than strabismus or anisometropia were excluded. RESULTS: Twenty-one children met inclusion criteria (median age 8 years, range 0.33-23 years). Orbitotemporal plexiform neurofibroma location was classified as isolated eyelid (n = 6), eyelid and orbit (n = 7), orbit and temporal region (n = 7), or diffuse orbit (n = 1). Three subjects had bilateral orbital involvement. Amblyopia secondary to the orbitotemporal plexiform neurofibroma was present in 13 subjects (62%) and was caused by strabismus (n = 2, 10%), occlusion from ptosis (n = 9, 43%), or anisometropia (n = 9, 43%), or a combination of factors (n = 6, 29%). MRI-derived volumes were measured in 19 subjects (median 41.8 mL, range 2.7-754 mL). All subjects with amblyopia had orbitotemporal plexiform neurofibroma volumes greater than 10 mL. CONCLUSION: In our series, amblyopia occurs in more than half of NF1 children with orbitotemporal plexiform neurofibromas, most commonly because of ptosis and anisometropia. The 3D MRI analysis allowed for sensitive measurement of orbitotemporal plexiform neurofibroma size, and larger volumes were associated with development of amblyopia.

Bone mineral density in children and young adults with neurofibromatosis type 1.

Concern for impaired bone health in children with neurofibromatosis type 1 (NF-1) has led to increased interest in bone densitometry in this population. Our study assessed bone mineral apparent density (BMAD) and whole-body bone mineral content (BMC)/height in pediatric patients with NF-1 with a high plexiform neurofibroma burden. Sixty-nine patients with NF-1 (age range 5.2-24.8; mean 13.7 ± 4.8 years) were studied. Hologic dual-energy X-ray absorptiometry scans (Hologic, Inc., Bedford, MA, USA) were performed on all patients. BMD was normalized to derive a reference volume by correcting for height through the use of the BMAD, as well as the BMC. BMAD of the lumbar spine (LS 2-4), femoral neck (FN), and total body BMC/height were measured and Z-scores were calculated. Impaired bone mineral density was defined as a Z-score ≤-2. Forty-seven percent of patients exhibited impaired bone mineral density at any bone site, with 36% at the LS, 18% at the FN, and 20% total BMC/height. BMAD Z-scores of the LS (-1.60 ± 1.26) were more impaired compared with both the FN (-0.54 ± 1.58; P=0.0003) and the whole-body BMC/height Z-scores (-1.16 ± 0.90; P=0.036). Plexiform neurofibroma burden was negatively correlated with LS BMAD (r(s)=-0.36, P=0.01). In pediatric and young adult patients with NF-1, LS BMAD was more severely affected than the FN BMAD or whole-body BMC/height.

The role of angiogenesis in the transformation of plexiform neurofibroma into malignant peripheral nerve sheath tumors in children with neurofibromatosis type 1.

PURPOSE: The role of angiogenesis in the transformation of peripheral neurofibroma (PNF) to malignant peripheral nerve sheath tumor (MPNST) in neurofibromatosis type 1 (NF1) remains elusive and forms the objective of this study. EXPERIMENTAL DESIGN: Archival tissue from 5 children with NF1 and PNF, who developed MPNST between the ages of 8 and 15 years were analyzed for differences in microvasculature. The role of proangiogenic growth factors such as Vascular Endothelial Growth Factor (VEGF), and its receptors Flk-1 and Flt-1, and vessel maturity, defined as von Willebrand factor (vWf), α-smooth muscle actin+ (SMA+), were evaluated by immuno-histochemistry. RESULTS: A qualitative evaluation of the vasculature showed predominantly α-SMA+/vWf+ more stable vessels in PNF, and an irregular meshwork of α-SMA-/vWf+ endothelial cells structures in MPNST. In NF and PNF tumor cells were VEGF-, in contrast to VEGF+ tumor cells in MPNST. If present, the VEGF stain was confined mainly to the perivascular spaces in PNF, unlike the mainly stromal VEGF stain in MPNST. VEGF receptors also manifested a tumor stage-specific pattern. Flk-1 and Flt-1 were restricted to the mature, well-formed vasculature in PNF, but exhibited a diffuse pattern in MPNST. CONCLUSION: Our study provides a rare opportunity to document consistent and histologically detectable differences in the vascular organization of PNF and MPNST. It permits a pair-wise evaluation of the malignant conversion of benign PNF into its malignant counterpart, in the same patients. The phenotypic variations and characteristics of the vessels in these tumors are consistent with the idea that a strong proangiogenic drive contributes to the progressive growth in MPNST.

[18F]2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) as a diagnostic tool for neurofibromatosis 1 (NF1) associated malignant peripheral nerve sheath tumours (MPNSTs): a long-term clinical study.

BACKGROUND: Malignant peripheral nerve sheath tumours (MPNSTs) are difficult to detect in neurofibromatosis 1 (NF1) individuals. The purpose was to evaluate [(18)F]2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) and PET computed tomography (CT) as a diagnostic tool for MPNST in NF1 patients with symptomatic plexiform neurofibromas and to verify the diagnosis by pathology and clinical follow-up. PATIENTS AND METHODS: NF1 individuals with symptomatic plexiform neurofibromas underwent clinical evaluation and magnetic resonance imaging. Qualitative FDG PET and PET CT associated with semi-quantitative maximum standard uptake value (SUVmax) assessed possible malignant change. Excision/biopsy verified the diagnosis when possible and clinical follow-up was undertaken in all patients. RESULTS: In all, 116 lesions were detected in 105 patients aged 5-71 years, including 80 plexiform neurofibromas, five atypical neurofibromas, 29 MPNST and two other cancers. Biopsy confirmed the findings in 59 tumours and no MPNST was diagnosed on clinical follow-up of 23 lesions diagnosed as benign on FDG PET and PET CT. FDG PET and PET CT diagnosed NF1-associated tumours with a sensitivity of 0.89 [95% confidence interval (CI) 0.76-0.96] and a specificity of 0.95 (CI 0.88-0.98), but the SUVmax level did not predict tumour grade. CONCLUSION: FDG PET and PET CT is a sensitive and specific diagnostic tool for NF1-associated MPNST. Other PET tracers will be required to solve the problem of predicting tumour grade.

Neurofibromatosis 1 and neurofibromatosis 2: a twenty first century perspective.

Historically, neurofibromatosis 1 (NF1) has been inextricably linked with neurofibromatosis 2 (NF2). Both are inherited autosomal-dominant neurocutaneous disorders that have high de novo mutation rates and carry a high risk of tumour formation. However, they are clinically and genetically distinct diseases and should be considered as seperate entities. NF1 is a common disease that mainly affects the skin and peripheral nervous system and causes characteristic bony dysplasia. By contrast, NF2 is a rare disorder with a relative paucity of skin manifestations and high-grade malignancy is unusual. Neurological symptoms are the predominant problem and the cardinal sign is bilateral vestibular schwannomas. In this Review, I discuss the pertinent diagnostic, clinical, and genetic symptoms of NF1 and NF2. I also examine the current views on the pathogenesis of these neurocutaneous disorders in the wake of advances in molecular genetics and the development of mouse models of disease.

Association between benign and malignant peripheral nerve sheath tumors in NF1.

OBJECTIVE: People with neurofibromatosis type 1 (NF1) have a 10% lifetime risk of developing a malignant peripheral nerve sheath tumor (MPNST). MPNSTs are often metastatic and are a frequent cause of death among people with NF1. Clinical evidence suggests that most MPNSTs in people with NF1 develop from preexisting plexiform neurofibromas. However, it is not known whether an individual's risk of developing an MPNST is associated with the burden of benign neurofibromas. The authors conducted a study to determine whether people with NF1 who have benign neurofibromas of various kinds are at greater risk of developing MPNSTs than patients with NF1 who lack these benign tumors. METHODS: Clinical information on 476 NF1 probands in the Henri Mondor Database was analyzed by logistic regression to examine associations between MPNSTs and internal plexiform, superficial plexiform, subcutaneous, and cutaneous neurofibromas. RESULTS: Individuals with subcutaneous neurofibromas were approximately three times more likely to have internal plexiform neurofibromas or MPNSTs than individuals without subcutaneous neurofibromas. Individuals with internal plexiform neurofibromas were 20 times more likely to have MPNSTs than individuals without internal plexiform neurofibromas. When this analysis was done with both subcutaneous and internal plexiform neurofibromas as explanatory variables, only the association of MPNSTs with internal plexiform neurofibromas remained significant. CONCLUSIONS: The observation that malignant peripheral nerve sheath tumors are strongly associated with internal plexiform neurofibromas suggests that patients with neurofibromatosis type 1 with these benign tumors warrant increased surveillance for malignancy.

April 2002: 35-year-old healthy man with enlarging right parotid mass.

The April 2002 Case of the Month (COM). 35-year-old healthy man developed a mass in the right parotid gland. A superifical parotidectomy was performed for a 4.5 x 1.5 x 1.5 cm mass involving the intraparotid facial nerve. Grossly the tumor was multinodular, smooth and yellow with normal surrounding salivary gland. Microscopically, the tumor showed expanding nodules composed of proliferating fibroblasts, Schwann cells, and perineural-like cells in a myxoid stroma. Normal peripheral nerve twigs were identified in the periphery of the tumor. There was no increased mitotic activity, cellularity or nuclear pleomorphism. S-100 immunohistochemical stain was positive. The tumor was diagnosed as a solitary plexiform neurofibroma. Plexiform neurofibromas in this area have been described in children with von Recklinghausen's disease or neurofibromatosis 1 (NF 1). Plexiform neurofibromas typically involve deep seated nerve trunks and is considered pathognomonic for NF 1. This unusual case represents a solitary variant of plexiform neurofibroma presenting as a parotid mass in an adult patient without a personal stigmata or family history of NF 1.

Foot drop in a long-distance runner. An unusual presentation of neurofibromatosis.

An athletic patient presented with a nontraumatic peroneal neuropathy that failed to resolve after a period of rest. A magnetic resonance image (MRI) showed a multilobulated mass in the course of the common peroneal nerve consistent with a plexiform neurofibroma. Surgical exploration revealed a mass, which coursed from the midthigh to the fibular neck, that was intimately involved with the fibers of the nerve bundle and had cystic degeneration with vesicles along its length. The authors recommend MRI as highly accurate in diagnosing unusual causes of peroneal neuropathy.