Prognostic significance of mast cell and microvascular densities in malignant peripheral nerve sheath tumor with and without neurofibromatosis type 1

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.

Prognostic Significance of Immunohistochemical Markers and Genetic Alterations in Malignant Peripheral Nerve Sheath Tumors: A Systematic Review

“…Targeting vascular pathways in MPNSTs may be beneficial, but unfortunately few studies have focused on this. Studies included in this review also showed that increased vascularity, as evidenced by increased microvascular density as well as increased expression of VEGF, may be associated with more aggressive biological behavior ( 57 , 59 ). It seems that many other targets may be of prognostic value as well emphasizing the need for further research into MPNST tumor biology.…”

“…High MVD was associated with worse survival in one/four studies. This association was also significant in multivariable analyses (HR 7.3, 95% CI: 1.4–38.5) ( 57 ). High VEGF staining was associated with worse survival in one/two studies, but this was not studied in a multivariable model ( 59 ).…”

“…Microvascular density (MVD) and vascular epithelial growth factor (VEGF) staining were evaluated as vascularization markers ( Table 2 ) ( 4 , 28 , 30 , 57 , 59 ). High MVD was associated with worse survival in one/four studies.…”

“…Thirteen other immunohistochemical markers were studied, most commonly the proliferation marker Ki67 ( 4 , 7 , 24 , 30 , 31 , 40 – 43 , 48 , 52 , 54 , 57 , 58 , 60 – 62 ). On average a cut-off at 20.9% (range: 5–30%) for high Ki67 staining was used and it was significantly associated with worse survival in 8/12 studies, of which two studies showed an independent association (HR 2.4, 95% CI: 1.1–4.9 and HR 10.2, 95% CI: 3.6–32.1) ( 28 , 30 ).…”

Toward Understanding the Mechanisms of Malignant Peripheral Nerve Sheath Tumor Development

“…However, drastically reducing the number of mast cells does not impair mouse neurofibroma development [66], and therapeutic strategies targeting mast cells in MPNST patients largely failed [67]. A trend toward a lower mast cell count in MPNST [68,69] has been challenged [44]. Thus, the functional role of mast cells in the neurofibroma to MPNST sequence may be marginal.…”