Vascular Innervation in Benign Neurofibromas of Patients with Neurofibromatosis Type 1.

UNLABELLED: Neurofibroma constitutes a heterogeneous group of solid tumours occurring sporadically or in association with syndromes. The aspect of these peripheral nerve sheath tumours may vary considerably, with disseminated tumours covering various parts of the body or nodular/diffuse plexiform neurofibroma that can grow to an impressive size. Although neurofibromas have vascular density comparable to that of normal tissue, they have tendency to bleed upon surgery which is poorly understood. Herein we investigated whether this finding may result from alterations of peripheral vasculature innervation. Different types of neurofibroma and controls were evaluated with special reference to nerve fibre topography and vessel density. MATERIALS AND METHODS: Seventy-six formalin-fixed and paraffin-embedded tissue samples (63 neurofibromas and 13 skin biopsies) were retrieved from the archives of the Institute of Neuropathology, University Medical Center Hamburg-Eppendorf. Nerve fibres and blood vessels were differentiated immunohistochemically on 10-µm-thick tumour slices using antibodies against smooth muscle actin (arteries), protein gene product 9.5 (PGP9.5) and neurofilament (nerve fibres). Skin samples served as controls. Nerve fibre and vessel densities were quantified morphometrically. RESULTS: Nerve fibre density varied considerably. However, vascular innervation did not statistically significantly differ between the different tumour sub-groups and controls. Vessel density was not significantly increased in tumours compared to skin biopsies. Within the tumour sub-groups, diffuse plexiform neurofibroma presented a significantly higher vascular density than atypical neurofibroma (p=0.006). CONCLUSION: Blood vessel density and vascular innervation in the whole cohort of neurofibromas did not significantly differ from that of controls. Thus, the source of prolonged and intense bleeding of neurofibroma during surgical procedures cannot be explained by increased vessel density or loss of innervation, but may be attributed to other factors such as alterations in the structure of the vascular wall.

Surgical Management of Giant Scalp Neurofibroma After Ultra-Selective Embolization of Nutrient Artery.

OBJECTIVES: Neurofibroma, a common benign tumor in soft tissue, continues to grow, so it often appears to be giant. Surgical management of giant neurofibroma is a challenge due to the risk of excessive bleeding. Embolization of tumor's nutrient artery may reduce the blood loss in operation. This study introduces the surgical management of giant scalp neurofibroma with preoperative ultra-selective embolization of nutrient artery. METHODS: From January 2006 to December 2013, 9 patients with giant scalp neurofibroma were enrolled into the study. Digital subtraction angiography (DSA) showed tumor's nutrient artery. Ultra-catheter was inserted into the nutrient artery and its branches as close as possible to the tumor. Then ultra-selective embolization was performed with gelatin sponge particles. Surgical removal of tumor was performed in 3 days after embolization. The wound was repaired by skin graft. RESULTS: All of the 9 patients underwent successful DSA and ultra-selective embolization. Among them, occipital artery was embolized in 3 patients (left side in 1 patient and right side in 2 patients). Both occipital artery and superficial temporal artery were embolized in 6 patients (left side in 2 patients, right side in 3 patients, and both side in 1 patient). No complications, such as ectopic embolism, occurred in the patients. All of the tumors were resected completely without blood transfusion. The skin graft survived very well on the wounds. CONCLUSIONS: Preoperative ultra-selective embolization of nutrient artery is a feasible, safe, and effective method to reduce the blood loss in operation and facilitate the surgical management of giant scalp neurofibroma.

Differential expression of angiogenic factors in peripheral nerve sheath tumors.

It is difficult to differentiate some malignant peripheral nerve sheath tumors (MPNST) from benign peripheral nerve sheath tumors (BPNST) histologically, and to predict the clinical outcome of patients with MPNST. In this study, the expression of VEGF and MVD were evaluated immunohistochemically in 22 cases of MPNST, 14 of neurofibroma and 19 of schwannoma and correlation of the staining grade of VEGF or MVD and the various clinical factors were analyzed, and statistically evaluated. Levels of VEGF mRNA expression were also determined with real-time RT-PCR. Statistically higher positive staining for VEGF was observed in MPNST compared to neurofibroma (P=0.004) and schwannoma (P<0.001). Even low grade MPNST showed higher VEGF positive staining than neurofibroma. Moreover, high VEGF expression statistically correlated with the poor prognosis of the patients with MPNST (P=0.015). Although MVD in MPNST was significantly higher than that in neurofibroma (P=0.038) and schwannoma (P<0.001), MVD could not predict the prognosis of the patients with MPNST. Although VEGF mRNA expression tended to be higher in MPNST compared to neurofibroma, the difference was not significant. Levels of VEGF protein expression serve as a novel diagnostic and prognostic tools for peripheral nerve sheath tumors.

Color Doppler sonography of focal lesions of the skin and subcutaneous tissue.

We evaluated with color Doppler sonography 71 visible and palpable nodules of the skin and subcutaneous tissue from 51 patients. The nodules were classified as avascular (type I), hypovascular with a single vascular pole (type II), hypervascular with multiple peripheral poles (type III), and hypervascular with internal vessels (type IV). Of the 32 malignant nodules, 9% showed a type I pattern, 50% had a type III pattern, and 41% had a type IV pattern; of the 39 benign nodules, 86% showed a type I pattern and 14% had a type II pattern. The sensitivity and specificity of hypervascularity in malignant lesions were 90% and 100%, respectively, whereas the sensitivity and specificity of hypovascularity in benign lesions were 100% and 90%, respectively. The authors conclude that color Doppler sonography is able to increase the specificity of ultrasonography in the evaluation of nodular lesions of the skin.

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.

Proliferative activity, angiogenesis, and necrosis in peripheral nerve sheath tumors: a quantitative evaluation for prognosis.

Malignant peripheral nerve sheath tumors (MPNSTs) are distinguished from a control group of typical benign schwannomas and neurofibromas on the basis of a set of quantitatively evaluated parameters, i.e., the cell density; the number of mitoses and apoptotic bodies; the nuclear area and shape; the number and absolute and relative areas of silver-staining nucleolar organizer regions; necrosis; and angiogenesis. Only the extent of tumor necrosis, the mitotic rate, and the parameters related to silver-staining nucleolar organizer regions discriminate between less aggressive MPNSTs (disease-free patients after 4 years of follow-up) and more aggressive MPNSTs (with recurrences or metastases during the first 4 years of follow-up).

Inhibition of angiogenesis and growth of human nerve-sheath tumors by AGM-1470.

The effectiveness of AGM-1470, a potent, fungal-derived inhibitor of angiogenesis, in suppressing the neovascularization and growth of human Schwann cell tumors was tested in six schwannomas, seven neurofibromas, and one neurofibrosarcoma. Tumor fragments from surgical specimens were implanted into the subrenal capsule of 348 nude mice (nu/nu). Seven days after implantation, the tumors were measured and vascularity was graded. The animals were then randomly assigned to one of two groups, to receive either saline (control group) or systemic AGM-1470 treatment. After 2 to 6 weeks of treatment, tumor size and degree of vascularity were recorded. In the six different schwannomas implanted into 138 mice, the average vascular grade in the control group after 2 weeks of treatment increased from 2.2 to 3.2 (+1.0), while in the AGM-1470-treated group it decreased from 2.2 to 1.7 (-0.5) (p < 0.01). In the seven different neurofibromas implanted into 158 mice, the change in the average vascular grade in control and AGM-1470-treated animals was +0.5 and -1.0, respectively (p < 0.01). In the one neurofibrosarcoma implanted into 52 mice, the change in average vascular grade in each group during the 6-week treatment period was +1.9 and -1.0, respectively (p < 0.01). Neurofibrosarcoma growth after 6 weeks of AGM-1470 treatment was only 8.5% of the growth found in the control animals (p < 0.01). This study determined that AGM-1470 is effective in inhibiting angiogenesis and the growth of human nerve-sheath tumors.

Mast cell frequency in soft tissue tumors. Relation to type and grade of malignancy.

A high content of mast cells (MC) is considered characteristic of neurofibromas but not of malignant schwannomas and neurilemmomas. We examined the extent and reliability of this finding by counting MC in 61 peripheral nerve sheath tumors and in 103 non-neurogenic soft tissue sarcomas. We furthermore investigated correlations between the amount of MC and various features of the tumors (e.g. grades of malignancy). Neurofibromas had very high mast cell counts. However, this result only applied to about 70% of these tumors. Malignant schwannomas, malignant fibrous histiocytomas and leiomyosarcomas had remarkably high median values of MC counts with a wide dispersion within the histological groups. Synovial sarcomas were the only group that contained MC in every case, though often in small numbers. In univariate analyses the number of MC was negatively correlated to grades of malignancy, cellularity and mitotic activity of the sarcomas and tended to correlate positively to the amount of myxoid and collagenous connective tissue and lymphocytic infiltrates. Multiple linear regression analysis revealed a significant correlation to the grade of malignancy and the amount of connective tissue.

Vascular changes in cutaneous neurofibromas.

A variety of vascular changes has been associated with neurofibromatosis, and morphological alterations of arteries have been described previously. However, little attention has been paid to structural modifications of the microvasculature in neurofibromas themselves. Small vessels of 10 cutaneous neurofibromas, excised from patients with neurofibromatosis, were studied by using transmission electron microscopy and compared with normal skin vessels. The major alterations were: (1) increased thickness of the cytoplasm of endothelial cells which send numerous long processes to the lumen and, in some instances, obliterate it; (2) larger numbers of endothelial cell processes on the abluminal surface which are apposed to pericyte processes; (3) increased amounts of filaments and free ribosomes in the cytoplasm of endothelial cells, and (4) abundant pericytes with bundles of cytoplasmic filaments and many small subplasmalemmal densities. Mitotic figures were not seen in any of the vascular elements. These changes were interpreted to be the result of a generalized malformative process of blood vessels in neurofibromas rather than a consequence of the action of a tumor angiogenesis factor.

Multiple pulmonary neurofibromas with hypoxemia. Occurrence due to pulmonary arteriovenous shunts within the tumors.

A 62-year-old woman with multiple neurofibromas of the lung was found to have severe hypoxemia due to right-to-left shunting within the tumors. Pulmonary angiograms demonstrated that the major area of shunting was in a large tumor mass in the right lower lobe. Pathologically the neurofibromas were vascular with hyperplastic small arteries and arterioles and large dilated veins. Multiple pulmonary neurofibromas are rare; and, to our knowledge, never previously reported in association with pulmonary arteriovenous shunting.

[Comments on the problem of differential diagnosis of tumours of the nerve sheaths in angiography (author's transl)]. / Zur Problematik der Diff.-Diagnose der Geschwülste der Nervenscheiden im angiographischen Bild.

The article describes the special features governing the assessment of angiographic findings in tumours of the nerve sheaths. Considerations of differential diagnosis, especially between neurinoma and neurofibroma, are discussed. Likewise, the problems of differential diagnosis of such tumours against neoplasms of the tissue of the soft parts, are also discussed. Angiography permits only a limited determination of the degree of malignancy of the neurinoma and neurofibroma. It is always mandatory to correlate these findings with the histological findings. However, angiography does seem to be justified as an additional examination technique, since it supplies fundamental pointers for surgery.