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1.
Cancer Med ; 8(3): 972-981, 2019 03.
Article in English | MEDLINE | ID: mdl-30735009

ABSTRACT

Malignant peripheral nerve sheath tumors (MPNSTs) are rare and aggressive soft tissue sarcomas with a significant susceptibility to metastasize early in their course. Pathogenesis is yet to be fully elucidated. Recently, the essential role of mast cells in the tumor onset of neurofibromatosis type 1 (NF1)-associated neurofibromas and MPNSTs was confirmed in both experimental and human studies. In this study, we investigate mast cell density (MCD), microvascular density (MVD), and proliferation index (Ki-67) in MPNST. A secondary aim was to correlate histological staining to clinical data and survival in patients with and without NF1. In total, 34 formalin-fixed paraffin-embedded MPNST tissues from 29 patients were eligible. MCD, MVD, and Ki-67 labeling index (LI) were analyzed in all stained tissues by a computer-based quantitative algorithm (Aperio ImageScope). In addition, chart review was performed for clinical data and survival analysis. Overall, MCD, MVD, and Ki-67 LI were evenly distributed throughout tumor tissue. There was a negative correlation of NF1 status (affected, P = 0.037), tumor size (>10 cm, P = 0.023), and MVD in the tumor periphery (higher tercile, P = 0.002) to survival. Multivariate analysis confirmed the association of MVD in the tumor periphery (higher tercile, P = 0.019) with a decreased overall survival. Diverse mast cell and microvascular distributions suggest that angiogenesis in MPNST occurs independently. The role of mast cells in tumor progression is unclear and lacks prognostic value. Higher MVD has prognostic significance with possible therapeutic implications in MPNST.


Subject(s)
Mast Cells/pathology , Nerve Sheath Neoplasms/blood supply , Nerve Sheath Neoplasms/pathology , Neurofibromatosis 1/pathology , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Microvessels/pathology , Middle Aged , Prognosis , Retrospective Studies , Survival Rate , Tumor Burden , Young Adult
2.
Anticancer Res ; 35(9): 4713-22, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26254361

ABSTRACT

BACKGROUND/AIM: Peripheral nerve sheath (PNS) tumors constitute a heterogeneous group of solid tumors. Neurofibroma and schwannoma are the most frequently diagnosed entities. Both tumor types occur sporadically and are associated with syndromes. Current strategies to fight PNS progression by means of pharmaceuticals aim to specifically interfere with vascular growth factors identified in PNS. Furthermore, malignant transformation of PNS tumors is known to be associated with a change in vascularization. The aim of the study was to investigate vascularization of different PNS tumors with respect to sporadic or syndromal state of the entities. MATERIALS AND METHODS: One hundred and thirty-two formalin-fixed and paraffin-embedded PNS tissue samples were retrieved from the archives of the Institute of Neuropathology, Eppendorf University Hospital. Lymphatic and blood vessels were immunohistochemically identified and morphometrically analyzed in PNS and controls. RESULTS: Blood vessel density in malignant tumors was significantly higher than in benign lesions (30.8/mm(2) vs. 13.46/mm(2)). In the latter, the vessel density resembled that of control tissue. Lymphatic vessel supply was significantly higher in cutaneous neurofibroma and diffuse plexiform neurofibroma (PNF) than in intra-neural localized tumors (schwannoma, nodular PNF). Lymphatic vessels showed no marked differences with respect to tumor entity. Prevalence of mast cells differed markedly between tumor types. CONCLUSION: Different vascularization of PNS may contribute to diverging tumor response following application of anti-neoplastic drugs. Mast cells may have an impact during formation and growth of neurofibroma but are unlikely to be involved in the process of de-differentiation.


Subject(s)
Blood Vessels/pathology , Mast Cells/pathology , Nerve Sheath Neoplasms/blood supply , Nerve Sheath Neoplasms/pathology , Adult , Cell Count , Female , Humans , Lymphatic Vessels/pathology , Male , Neurilemmoma/pathology , Neurofibroma/pathology , Neurofibromatosis 1/diagnosis , Neurofibromatosis 1/pathology , Syndrome
3.
Int J Clin Exp Pathol ; 7(7): 4032-8, 2014.
Article in English | MEDLINE | ID: mdl-25120781

ABSTRACT

Schwannomas or neurilemmoma are benign peripheral nerve sheath tumors, which most frequently occur at the cerebellopontine angle. This morphologic study examines vascular alterations in these tumors, comparing them to other benign spindle cell neoplasms of the nervous system, while correlating these findings with evidence of vascular permeability. Thirty-four nervous system spindle cell neoplasms, sixteen schwannomas, nine fibroblastic/transitional meningiomas and nine peripheral neurofibromas were stained with H&E, Prussian-blue stain, and immunoreacted for factor VIII-related antigen and interstitial albumin. Schwannomas had focal clusters of vascular proliferation including groups of small thin-walled vessels, as well as larger vessels with extensive hyalinization. Neurofibromas and meningiomas almost uniformly had modest numbers of well-defined, thin walled individual vessels. Free hemosiderin and hemosiderin-laden macrophages were frequently identified in schwannomas. Prussian-blue stain for iron revealed focal or fairly widespread positivity in almost all schwannomas, only one meningioma and none of the neurofibromas. Immunoreaction for albumin demonstrated leakage of vascular proteins into the interstitium confirming tumor vessel permeability in schwannomas. Neither neurofibromas nor meningiomas displayed any detectable interstitial albumin. The above findings confirm a degree of reactive proliferation of vessels in schwannoma along with functional deficits in their vascular integrity with permeability to protein and blood. The presence of hyalinized vessels, hemosiderin, both free and within macrophages, and more readily evident Prussian blue staining, may provide an additional diagnostic clue in discriminating between histologically similar spindle cell lesions. The study however raises the possibility that these changes likely precede or facilitate the degenerative 'ancient change' seen in some schwannoma.


Subject(s)
Nerve Sheath Neoplasms/blood supply , Nerve Sheath Neoplasms/pathology , Neurilemmoma/blood supply , Neurilemmoma/pathology , Biomarkers, Tumor/analysis , Humans
4.
Kyobu Geka ; 67(5): 423-5, 2014 May.
Article in Japanese | MEDLINE | ID: mdl-24917293

ABSTRACT

We herein report a case of malignant peripheral nerve sheath tumor that caused a hemothorax. A 39-year-old male was found to have an abnormal shadow on a chest X-ray. Chest computed tomography showed a 60-mm tumor in the right posterior mediastinum. Fourteen months earlier, he underwent drainage of a hemothorax with a medaistinal tumor but refused to undergo further examinations. We performed a tumor resection combined with the right lower lobectomy and the partial resection of the pericardium because of invasion. The histological examination confirmed the diagnosis of a malignant peripheral nerve sheath tumor. Postoperative radiotherapy was performed. The patient has been well without recurrence for 9 months.


Subject(s)
Hemothorax/etiology , Lung Neoplasms/surgery , Nerve Sheath Neoplasms/surgery , Adult , Hemothorax/diagnostic imaging , Humans , Lung Neoplasms/blood supply , Lung Neoplasms/complications , Lung Neoplasms/pathology , Male , Neoplasm Invasiveness , Nerve Sheath Neoplasms/blood supply , Nerve Sheath Neoplasms/complications , Nerve Sheath Neoplasms/diagnostic imaging , Pneumonectomy , Tomography, X-Ray Computed
5.
J Pediatr Hematol Oncol ; 32(7): 548-53, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20686424

ABSTRACT

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.


Subject(s)
Cell Transformation, Neoplastic , Neovascularization, Pathologic/physiopathology , Nerve Sheath Neoplasms/physiopathology , Neurofibroma, Plexiform/physiopathology , Neurofibromatosis 1/physiopathology , Actins/metabolism , Adolescent , Child , Female , Humans , Male , Microcirculation/physiology , Neovascularization, Pathologic/pathology , Nerve Sheath Neoplasms/blood supply , Nerve Sheath Neoplasms/pathology , Neurofibroma, Plexiform/blood supply , Neurofibroma, Plexiform/pathology , Neurofibromatosis 1/pathology , Tissue Banks , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor Receptor-1/metabolism , Vascular Endothelial Growth Factor Receptor-2/metabolism , von Willebrand Factor/metabolism
6.
Clin Exp Metastasis ; 25(7): 819-25, 2008.
Article in English | MEDLINE | ID: mdl-18679811

ABSTRACT

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.


Subject(s)
Nerve Sheath Neoplasms/chemistry , Vascular Endothelial Growth Factor A/analysis , Adolescent , Adult , Aged , Aged, 80 and over , Child , Female , Humans , Immunohistochemistry , Male , Middle Aged , Nerve Sheath Neoplasms/blood supply , Neurilemmoma/blood supply , Neurilemmoma/chemistry , Neurofibroma/blood supply , Neurofibroma/chemistry , RNA, Messenger/analysis , Vascular Endothelial Growth Factor A/genetics
7.
Lab Invest ; 87(11): 1092-102, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17876295

ABSTRACT

Malignant peripheral nerve sheath tumors (MPNST) are the most aggressive cancers associated with neurofibromatosis type 1 (NF1). Here we report a practical and reproducible model of intraneural NF1 MPNST, by orthotopic xenograft of an immortal human NF1 tumor-derived Schwann cell line into the sciatic nerves of female scid mice. Intraneural injection of the cell line sNF96.2 consistently produced MPNST-like tumors that were highly cellular and showed extensive intraneural growth. These xenografts had a high proliferative index, were angiogenic, had significant mast cell infiltration and rapidly dominated the host nerve. The histopathology of engrafted intraneural tumors was consistent with that of human NF1 MPNST. Xenograft tumors were readily examined by magnetic resonance imaging, which also was used to assess tumor vascularity. In addition, the intraneural proliferation of sNF96.2 cell tumors was decreased in ovariectomized mice, while replacement of estrogen or progesterone restored tumor cell proliferation. This suggests a potential role for steroid hormones in supporting tumor cell growth of this MPNST cell line in vivo. The controlled orthotopic implantation of sNF96.2 cells provides for the precise initiation of intraneural MPNST-like tumors in a model system suitable for therapeutic interventions, including inhibitors of angiogenesis and further study of steroid hormone effects on tumor cell growth.


Subject(s)
Cell Proliferation , Estrogens/physiology , Nerve Sheath Neoplasms/metabolism , Neurofibromatosis 1/metabolism , Neurofibromin 1/physiology , Peripheral Nervous System Neoplasms/metabolism , Progesterone/physiology , Animals , Cell Line, Tumor , Female , Humans , Magnetic Resonance Imaging , Mast Cells , Mice , Mice, SCID , Neoplasm Transplantation , Neovascularization, Pathologic/metabolism , Nerve Sheath Neoplasms/blood supply , Nerve Sheath Neoplasms/pathology , Neurofibromatosis 1/pathology , Ovariectomy , Peripheral Nervous System Neoplasms/blood supply , Peripheral Nervous System Neoplasms/pathology , Schwann Cells/pathology , Sciatic Nerve/metabolism , Sciatic Nerve/pathology , Transplantation, Heterologous
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