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Vascular Innervation in Benign Neurofibromas of Patients with Neurofibromatosis Type 1

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Vascular Innervation in Benign Neurofibromas of Patients with Neurofibromatosis Type 1 ANTICANCER RESEARCH 35: 6509-6516 (2015) Vascular Innervation in Benign Neurofibromas of Patients with Neurofibromatosis Type 1 REINHARD E. FRIEDRICH1*, CHRISTIAN-ALEXANDER BEHRENDT2,3*, MARKUS GLATZEL2 and CHRISTIAN HAGEL2 1Department of Oral and Craniomaxillofacial Surgery, and 2Institute of Neuropathology and 3Department of Vascular Medicine, Heart Center, University Medical Center Hamburg-Eppendorf, University of Hamburg, Hamburg, Germany Abstract. Neurofibroma constitutes a heterogeneous group sub-groups and controls. Vessel density was not significantly of solid tumours occurring sporadically or in association increased in tumours compared to skin biopsies. Within the with syndromes. The aspect of these peripheral nerve sheath tumour sub-groups, diffuse plexiform neurofibroma presented tumours may vary considerably, with disseminated tumours a significantly higher vascular density than atypical covering various parts of the body or nodular/diffuse neurofibroma (p=0.006). Conclusion: Blood vessel density plexiform neurofibroma that can grow to an impressive size. and vascular innervation in the whole cohort of Although neurofibromas have vascular density comparable neurofibromas did not significantly differ from that of to that of normal tissue, they have tendency to bleed upon controls. Thus, the source of prolonged and intense bleeding surgery which is poorly understood. Herein we investigated of neurofibroma during surgical procedures cannot be whether this finding may result from alterations of peripheral explained by increased vessel density or loss of innervation, vasculature innervation. Different types of neurofibroma and but may be attributed to other factors such as alterations in controls were evaluated with special reference to nerve fibre the structure of the vascular wall. topography and vessel density. Materials and Methods: Seventy-six formalin-fixed and paraffin-embedded tissue Neurofibromatosis type 1 (NF1) is one of the most important samples (63 neurofibromas and 13 skin biopsies) were inherited human diseases (1). Penetrance in affected retrieved from the archives of the Institute of Neuropathology, individuals is almost 100% but the phenotype is highly University Medical Center Hamburg-Eppendorf. Nerve fibres variable (1). In 1987, the NF1 gene was discovered on the and blood vessels were differentiated immunohistochemically pericentromeric region of chromosome 17 (2, 3). The on 10-μm-thick tumour slices using antibodies against complete sequence of the gene locus 17q11.2 was published smooth muscle actin (arteries), protein gene product 9.5 three years later (4). The NF1 gene comprises of 350 kb (PGP9.5) and neurofilament (nerve fibres). Skin samples genomic DNA (1) organized into 60 exons which code for served as controls. Nerve fibre and vessel densities were neurofibromin, a protein of 2,485 amino acids (4). The quantified morphometrically. Results: Nerve fibre density protein has a molecular weight of about 220-280 kDa (5) and varied considerably. However, vascular innervation did not acts as a tumour suppressor. It is a negative regulator of rat statistically significantly differ between the different tumour sarcoma (RAS)-GTPase in the RAS pathway (6). Furthermore, neurofibromin stimulates intracellular adenylate cyclase resulting in a decrease of intracellular cAMP (4, 5, *These Authors contributed equally to this study. 7). It was shown that translocation mutation (‘loss of function‘) results in aberrant activation of RAS (1) and Correspondence to: Professor R.E. Friedrich, MD, DMD, Ph.D, functional loss of cell proliferation control (4). While FEBOMFS, Department of Oral and Craniomaxillofacial Surgery, neurofibromin is present in many human cell types, its Eppendorf University Hospital, University of Hamburg, Martinistr. expression is predominantly detected in neurons and glial 52, D-20246 Hamburg, Germany. Tel: +49 40741053259, e-mail: cells, in particular Schwann cells (8). [email protected] A predominant feature of NF1 is the development of Key Words: Nerve fibre density, vessel density, blood vessels, multiple neurofibromas that may present as distinct tumours lymphatic vessels, NF1, neurofibroma, neurofibromatosis, vessel of the skin resembling button-like knots (cutaneous or innervation. dermal neurofibroma) or as tumours arising at various 0250-7005/2015 $2.00+.40 6509 ANTICANCER RESEARCH 35: 6509-6516 (2015) segments of a peripheral nerve arranged like a string of and neurofilament (NF). For this study, the material was pearls (plexiform neurofibroma). Plexiform neurofibroma in independently re-evaluated by two neuropathologists applying NF1 de-differentiates into malignant peripheral nerve sheath current WHO criteria (20) to diagnose peripheral nerve sheath tumours (MG, CH). Following these procedures, 10-μm-thick section tumours (MPNST) with a lifetime risk of 8-13% (9). were cut from the blocks for immunohistochemical detection of MPNST are highly vascularized (10, 11). neurofilament, PGP9.5 and smooth muscle actin (SMA) (Table III). The therapy of choice in NF1 is surgical resection of tumours. During ablative surgery for neurofibroma, an Pre-treatment of slides. SuperFrost Plus® slides (Menzel Gläser, increased blood loss from the surgical site is well known Braunschweig, Germany) were coated with poly-L-lysine-solution for (12). It was shown that neurofibroma Schwann cells have 5 minutes, dried for 60 min at 60˚C and stored dust-free until usage. angiogenic properties and that NF1 haploinsufficiency Preparation of slices. Slices 10-μm-thick were cut from the tissue augments angiogenesis (13, 14). blocks omitting ice-cooling of the block prior to cutting. Cuts were Spontaneous bleeding in elephantiasis neurofibromatosa stretched in a water bath at 60˚C and drawn onto poly-L-lysine pre- is well-known (15-17). Heavy bleeding during surgical treated slides. A rubber roller was used to slightly press the slices procedures may result from higher vessel density in tumours onto the slides. After adhering to the slides, the specimen were compared to unaffected skin regions, or alternatively, stored at 60˚C for 120 min. increased blood flow could lead to the same phenomenon. Previous studies have shown no increased vascular density Immunhistochemical double staining of NF and SMA. All reagents were freshly prepared and rapidly used. Two specimens of normal of cutaneous and plexiform neurofibroma compared to nerves (biopsy) were added as controls in every staining passage. normal human skin (18), but increased vascularization of Briefly, 10-μm tissue sections were de-waxed for 120 min at 65˚C malignant peripheral nerve sheath tumours is well- in a dry cabinet followed by 8 h in xylol. Then blocking of documented (10, 11). A hypothesized increased blood flow endogenous peroxidase in 3% H2O2 for 90 min in 100% ethanol was in benign tumours without apparently increased vessel perfomed followed by a descending series of ethanolic solutions and density could result from a larger vessel diameter, in antigen de-masking for 90 min in citrate buffer (pH 6.0) at 85˚C in particular in resistant vessels. Neural and endocrine factors closed cuvette in a water-bath. Tissues were cooled to room temperature in citrate buffer for about 45 min, then rinsed in Tris- have a huge impact on the actual diameter of vessels via buffered saline (TBS). Nonspecific antibody binding was blocked interaction with vascular smooth muscles. with 10% goat serum in TBS buffer for 30 min at room temperature In neurofibroma, tumorous growth of Schwann cells can in a humid chamber. For incubation with 200 μl diluted NF antibody lead to degeneration of nerve fibres (18). Discontinuation of solution (1:400) was added for 18 h at room temperature. Secondary functional sympathetic nerve fibres in neurofibroma might antibody (Histofine® Simple Stain MAX PO-Multi, Nichirei, Tokyo, result in denervation of associated blood vessels and Japan) was applied for 3 h at room temperature and bound consequently in permanent vessel dilatation. This would antibodies were visualized with 3’3-diaminobenzidine- tetrahydrochloride (DAB) for 15 min. After thorough rinsing in predominantly affect resistance vessels. To assess this TBS, SMA antibodies were applied (1:2,000) for 18 h at room hypothesis, we investigated the vascularization and nerve temperature. Histofine® Simple Stain MAX PO-Multi AP was supply of arterioles in NF1-associated neurofibroma and applied for 3 h as secondary antibody and bound SMA antibodies control tissue. were visualized with Fast-Red Chromogen for 15 min. Materials and Methods Immunhistochemical double staining of SMA and PGP9.5. Double staining of tissue sections with PGP9.5 and SMA was performed Patients. All patients fulfilled updated clinical diagnostic criteria for with fully automated staining equipment (BenchMark XT; Ventana NF1 of the US National Institutes of Health given in Table I (19). Medical Systems, Tucson, AZ, USA). The automat performed all Skin samples from patients who did not show NF1 served as necessary staining steps on up to 30 slides in one run. In order to controls. All data were anonymized prior to the study. The mean age achieve representative results in 10-μm-thick slices, tissues were de- of patients was 35.05±18.09 years (minimum 2 years, maximum 80 waxed with xylene for 8 h and incubated in 3% H2O2 for 2 h prior years) at the time of tissue excision. to starting the staining procedure. Tissue samples. Seventy-six formalin-fixed and paraffin-embedded Measurement of tissue nerve fibre
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