Mitotic Index is an Independent Predictor of Recurrence‐Free Survival in Meningioma

While World Health Organization (WHO) grading of meningioma stratifies patients according to recurrence risk overall, there is substantial within‐grade heterogeneity with respect to recurrence‐free survival (RFS). Most meningiomas are graded according to mitotic counts per unit area on hematoxylin and eosin sections, a method potentially confounded by tumor cellularity, as well as potential limitations of accurate mitotic figure detection on routine histology. To refine mitotic figure assessment, we evaluated 363 meningiomas with phospho‐histone H3 (Ser10) and determined the mitotic index (number of mitoses per 1000 tumor cells). The median mitotic indices among WHO grade I (n = 268), grade II (n = 84) and grade III (n = 11) tumors were 1, 4 and 12. Classification and regression tree analysis to categorize cut‐offs identified three subgroups defined by mitotic indices of 0–2, 3–4 and ≥5, which on univariate analysis were associated with RFS (P < 0.01). In multivariate analysis, mitotic index subgrouped in this manner was significantly associated with RFS (P < 0.01) after adjustment for Simpson grade, WHO grade and MIB‐1 index. Mitotic index was then examined within individual WHO grade, showing that for grade I and grade II meningiomas, mitotic index can add additional information to RFS risk. The results suggest that the use of a robust mitotic marker in meningioma could refine risk stratification.     

Loss of p53 cooperates with K‐ras activation to induce glioma formation in a region‐independent manner

Gliomas are recognized as a heterogeneous group of neoplasms differing in their location and morphological features. These differences, between and within varying grades of gliomas, have not been explained solely on the grounds of an oncogenic stimulus. Interactions with the tumor microenvironment as well as inherent characteristics of the cell of origin are likely a source of this heterogeneity. There is an ongoing debate over the cell of origin of gliomas, where some suggest a progenitor, while others argue for a stem cell origin. Thus, it is presumed that neurogenic regions of the brain such as the subventricular zone (SVZ) containing large numbers of neural stem and progenitor populations are more susceptible to transformation. Our studies demonstrate that K‐ras^G12D cooperates with the loss of p53 to induce gliomas from both the SVZ and cortical region, suggesting that cells in the SVZ are not uniquely gliomagenic. Using combinations of doxycycline‐inducible K‐ras^G12D and p53 loss, we show that tumors induced by the cooperative actions of these genes remain dependent on active K‐ras expression, as deinduction of K‐ras^G12D leads to complete tumor regression despite absence of p53. These results suggest that the interplay between specific combinations of genetic alterations and susceptible cell types, rather than the site of origin, are important determinates of gliomagenesis. Additionally, this model supports the view that, although several genetic events may be necessary to confer traits associated with oncogenic transformation, inactivation of a single oncogenic partner can undermine tumor maintenance, leading to regression and disease remission. GLIA 2013;61:1862–1872     

Leiomyosarcoma of somatic soft tissues: a tumor of vascular origin with multivariate analysis of outcome in 42 cases.

Leiomyosarcomas of the somatic soft tissues (SST) are rare compared with their retroperitoneal and cutaneous counterparts and, therefore, have not been extensively studied. We have analyzed the clinicopathologic features of 42 SST leiomyosarcomas referred in consultation to determine what factors affect outcome. Cutaneous, visceral, retroperitoneal, uterine, gastrointestinal, and major vessel leiomyosarcomas were excluded. By definition all lesions possessed at least focal cytologic atypia and mitotic activity, although the latter varied from <1/10 high power fields to 66/10 high power fields. The patients (21 females and 21 males) ranged in age from 26 to 86 years (mean 60 years); tumors developed in the lower (n = 28) or upper extremity (n = 11) and trunk (n = 3). Most arose in deep (n = 27) as opposed to superficial (n = 15) soft tissue; 39 arose from a small vein. During the follow-up period (mean 47 months, range 9-162 months), 3 of 38 (8%) patients developed local recurrence and 17 of 38 metastasized (45%) mostly to the lungs. In a univariate analysis age >62 years, size >4 cm, extensive necrosis, modified updated French Federation of Cancer Centers (FFCC) grade, and whether the tumor had been "disrupted" by a previous incisional biopsy or incomplete excision were significantly correlated with metastasis. AJCC stage also approached significance (p = 0.096) but could not be reliably tested because of the sparseness of the data. In multivariate analyses the logistic regression model that best predicted metastasis at 36 months incorporated the effects of age, FFCC grade, and disruption and had a sensitivity of 94.1% and a specificity of 95.2%. Disruption was the only significant risk factor for metastasis in a multivariate analysis (relative risk 2.70; p = 0.0001) but was strongly correlated with large size and deep location. Other parameters did not improve the predictive power of the model significantly. We concluded that the majority of SST leiomyosarcomas are actually of vascular origin, an observation that has clinical and possibly biologic ramifications. Our histologic definition of leiomyosarcoma to include atypia and any level of mitotic activity appears warranted by the biologic outcome in our cases. The risk of metastasis can be calculated from a model incorporating age, FFCC grade, and disruption. Because disruption correlates with size and depth, it could represent a surrogate as opposed to causal marker for metastasis. Nevertheless, in view of their vascular origin, the possibility that tumor disruption may facilitate or promote access to the bloodstream merits further study.     

Role of Ang1 and its interaction with VEGF-A in astrocytomas

Angiopoietins (Ang1 and Ang2) modulate the activity of the endothelial cell (EC)-specific receptor tyrosine kinase Tie2, which together with vascular endothelial growth factor (VEGF-A) and its EC-specific receptors, VEGFR1 and VEGFR2, regulate normal physiological vessel development. The functional role of angiopoietins in tumor angiogenesis, in particular astrocytoma angiogenesis, remains unclear. In this study, we focus on the specific contribution of Ang1 to the vascular growth of glioblastoma multiforme (GBM) and its interactive role with VEGF-A. Subcutaneous and intracranial GBM xenografts were generated using 3 established astrocytoma cell lines (U87, U373, and U343) that were transfected to stably over-express Ang1. GBM xenografts were also generated to express low levels of VEGF-A and high Angl. We found that Ang1 increases the vascular growth of both subcutaneous and intracranial xenografts of GBM by approximately 3-fold. However, the increased vascular growth was only seen in xenografts with concurrent VEGF-A elevation, since decreasing VEGF-A expression resulted in a loss of the pro-angiogenic growth advantage seen with Ang1. Collectively, our data suggest that Ang1 regulates GBM vascularity in a VEGF-A dependent manner, synergizing the initial pro-angiogenic response that is triggered by VEGF-A and promoting the vascular growth of GBM.     

The use of fine-needle aspiration cytology and core biopsy in the assessment of highly suspicious mammographic microcalcifications: analysis of outcome for 182 lesions detected in the setting of a population-based breast cancer screening program

BACKGROUND: Fine-needle aspiration biopsy (FNAB) is used as the first-line diagnostic test for lesions that require morphologic assessment in the authors' breast cancer screening program. A positive cytologic diagnosis is an indication to proceed to definitive surgery. Core biopsy is used if FNAB is not diagnostic. In the context of increased use of core biopsy at other centers, the authors reviewed their experience with the cytologic assessment of highly suspicious microcalcifications. METHODS: Between January 1996 and June 2000, the dominant radiologic abnormality was classified prospectively as high-grade microcalcifications in 182 lesions. Data were recorded on patient demographics, radiologic features, and the findings of FNAB and core biopsy, if performed. The results of the screening assessment were then compared with the final histologic findings. RESULTS: Overall, 15.6% of all radiologically high-grade lesions were microcalcifications. The mean patient age was 58.76 years. The lesions had a mean size of 38.49 mm (range, 5-200 mm), and 92.31% of high-grade microcalcifications proved to be malignant. Among the cases evaluated by FNAB, a positive cytologic diagnosis of malignancy was made in 70.93% of lesions, without any false-positive diagnoses and obviating the need for diagnostic core biopsy. FNAB had a sensitivity of 77.22% and a positive predictive value (PPV) of 100%. When core biopsy was performed due to the absence of a positive cytologic diagnosis, it averted the need for open biopsy in 76% of lesions. CONCLUSIONS: Where there is access to skilled cytopathologists, FNAB can provide a highly accurate, rapid, and cost-effective means of triage of patients who would benefit most from the more expensive core biopsy.     

Molecular regulators of angiogenesis in the developing nervous system and adult brain tumors (review)

Angiogenesis involves a highly regulated and coordinated interaction of multiple angiogenic factors and is critical for both embryonal development and physiological vessel formation in adults. Angiogenesis is also proven to significantly contribute to the progression of various disease processes. Pathological angiogenesis is thought to recapitulate physiological angiogenesis, however the precise molecular mechanisms are not understood. Various angiogenic genes and gene products have been isolated, purified, and cloned from both neoplastic and normal tissues that contribute to the angiogenic process. In this review we summarize the role of the main angiogenic factors in both normal embryonal vascularization of the embryonal nervous system together with the main brain tumors seen in adults.