Petros M. Pavlopoulos

Hypoxia-inducible factor 1α/vascular endothelial growth factor axis in astrocytomas. Associations with microvessel morphometry, proliferation and prognosis

Hypoxia‐inducible factor (HIF)‐1α is a transcription factor that promotes ischaemia‐driven angiogenesis. The aim of this study was to determine the relation of HIF‐1α to vascular endothelial growth factor (VEGF; an important angiogenic molecule in brain tumours), p53 expression, angiogenesis, proliferative potential and clinical outcome in a large series of diffuse astrocytomas. Expression of HIF‐1α, VEGF, Ki‐67 (a proliferation‐associated marker) and p53 was determined immunohistochemically in 83 adult patients with supratentorial diffuse astrocytomas. Microvessels, highlighted by means of anti‐CD34 immunohistochemistry, were enumerated with computer‐assisted image analysis. Although HIF‐1α and VEGF were expressed in the majority of cases, their levels increased significantly with increasing grade and proliferative potential. HIF‐1α positively correlated with microvessel counts and VEGF with total vascular area and the presence of rounder vessel sections. There was a positive correlation of VEGF with p53 expression in astrocytomas and anaplastic astrocytomas. In univariate analysis, both VEGF and HIF‐1α were associated with shortened survival in the entire cohort, but lost significance when grades II/III and grade IV were analysed separately. Multivariate analysis revealed that the combination of HIF‐1α with grade was a significant prognostic indicator. HIF‐1α expression may be used to refine the prognostic information provided by grade in patients with diffuse astrocytomas. Its adverse prognostic effect is most likely mediated by hypoxia, the driving force for HIF‐1α accumulation.

Prognostic implications of microvessel morphometry in diffuse astrocytic neoplasms

Astrocytic brain tumours, particularly malignant astrocytomas, are recognized to be highly vascular neoplasms with potent angiogenic activity. Recent research has shown that quantification of microvessel density (MVD), as a measure of the degree of angiogenesis, constitutes a strong prognostic indicator in patients with astrocytomas. However, the significance of other morphometric aspects of microvessel network has not been tested so far. In this report, histological sections from 70 astrocytomas (grades II to IV), immunostained for CD34, were evaluated by image analysis for the quantification of MVD, total vascular area (TVA), and microvascular branching, as well as several morphometric parameters related to vessel size or shape. Minor axis length increased with grade (P = 0.045) but MVD and TVA presented a peak in grade III (P = 0.033 and P < 0.001, respectively). Size and shape related parameters affected survival in univariate analysis of grade IV and grades II/III, respectively. In multivariate analysis, only branching counts, along with age and grade, were the independent predictors of survival. Although MVD, TVA and branching counts were adversely related to disease‐free survival in grades II and III (univariate analysis), only TVA remained statistically significant in multivariate analysis. It is concluded that TVA and branching counts are prognostically more informative than MVD for patients with diffuse astrocytic tumours.

Clinical significance of nuclear factor (NF)-κB levels in urothelial carcinoma of the urinary bladder

Nuclear factor (NF)-κB has been reported to be constitutively activated in various human neoplasms. However, its clinical significance in bladder urothelial carcinoma (UC) remains an unresolved issue. We conducted this study trying to elucidate the role of NFκB in bladder UC and its potential prognostic significance, by quantifying immunohistochemically the levels of p65/RelA expression in paraffin-embedded tissue from 116 patients. Some of the cases had previously been stained for cellular FLICE-like inhibitory protein (c-FLIP) and bcl-2. Seventy-four cases displayed concurrent cytoplasmic and nuclear immunoreactivity, whereas 18 only nuclear immunoexpression and 21 only cytoplasmic immunoexpression, and the remaining three cases were negative for p65/RelA. Nuclear p65/RelA expression was positively associated with tumour grade and T-category (p = 0.0001 in both cases). In addition, cytoplasmic p65/RelA expression was lower in advanced T-category (p = 0.0030). Moreover, p65/RelA nuclear expression was positively correlated with c-FLIP (p = 0.0109) and bcl-2 (p = 0.0452). p65/RelA nuclear expression adversely affected survival in both univariate and multivariate analysis in superficial (Ta–T1; p = 0.0010 and p = 0.0008) as well as in muscle-invasive carcinomas (T2–T4; p = 0.0004 and p = 0.0003). Our results demonstrate that NF-κB nuclear expression is correlated with histologic grade and T category in bladder UC. Moreover, NF-κB nuclear expression emerges as an independent prognosticator of adverse significance, conveying information beyond that obtained by standard clinicopathological prognosticators.

Expression of apoptotic and proliferation markers in meningiomas

Fifty‐two intracranial, totally excised meningiomas were immunohistochemically analysed for the expression of bcl‐2 and p53 proteins, in parallel with the assessment of the proliferating cell nuclear antigen labelling index (PCNA LI) and the mitotic index (MI). bcl‐2 was expressed in 26·8 per cent and p53 in 32·6 per cent of the tumours, exhibiting a similar staining pattern, with low levels of immunoreactive cells. The bcl‐2‐positive/p53‐negative subgroup showed a significant association with a benign histological pattern. Expression of bcl‐2 appeared to have no influence on the rate of recurrence; p53 expression was the only factor with prognostic significance for recurrence (p =0·10). There was no interaction between bcl‐2 and p53 expression. The PCNA LI was correlated with the MI and the grade of malignancy, proving to be a useful proliferation marker and an additional indicator of the more anaplastic histological patterns in meningiomas. Proliferation indices appeared to have no correlation with the recurrence rate of totally resected tumours. Meningiomas expressing the bcl‐2 protein presented a high proportion of proliferating cells in S phase. In contrast, all the tumours which recurred had a minimal S‐fraction of proliferating nuclei. These findings may improve our understanding of the interaction between cell proliferation, expression of apoptotic markers, and recurrence in meningiomas.Copyright

Association of single umbilical artery with congenital malformations of vascular etiology.

ABSTRACT The possible association of a single umbilical artery (SUA) with malformations of vascular etiology is investigated in this study. Four hundred twelve fetal and embryonic autopsies showing one or more congenital malformations, collected over 7 years, were reviewed. Microscopic confirmation of a SUA was evident in 20 cases (4.85%). The two subgroups with 2 (nA = 20) or 3 umbilical vessels (nB = 392) were compared with each other, in relation to the frequency of malformations per organ system. In the group of fetuses with congenital malformations, no association was observed between SUA and the incidence of CNS, cardiac, pulmonary, or genital malformations. However, there was a significantly higher incidence of atresia of hollow organs (P = 0.003), renal aplasia (P = 0.034), and limb reduction defects (LRD) (P = 0.0383) when only a single umbilical artery was present. This suggests a possible etiopathogenetic association of SUA with congenital malformations of vascular etiology. Furthermore, the findings of our study suggest that prenatal identification of a SUA warrants a thorough search for atresias, renal aplasia, and LRD-type malformations.

Prognostic significance of replication protein A (RPA) expression levels in bladder urothelial carcinoma

What’s known on the subject? and What does the study add?

Vascular fractal dimension and total vascular area in the study of oral cancer.

Microvessel quantification has been studied extensively as a factor reflecting angiogenesis in various malignant tumors. The aim of our study was to evaluate the vascular fractal dimension and the immunohistochemically positive total vascular area in oral cavity carcinomas in order to assess their potential value as factors reflecting angiogenesis.

Malignant Peripheral Nerve Sheath Tumor of the Urinary Bladder in von Recklinghausen Disease

A case of malignant peripheral nerve sheath tumor of the bladder in a 57-year-old man with multiple neurofibromatosis type 1 is presented. The patient had a recent history of a transurethrally resected bladder ganglioneuroma. A probable histogenetic association between these two extremely rare neoplasms is proposed.

Cell proliferation rate and nuclear morphometry in Roberts syndrome

Roberts syndrome (RS) is a rare autosomal recessive disorder characterized primarily by symmetric reduction anomalies of all limbs, growth retardation and craniofacial abnormalities. Most RS patients are reported to present a typical abnormality of their constitutive heterochromatin, accompanied by abnormal cytological growth characteristics. We present an extremely severe case of an RS fetus, karyotypically documented, with a clinical presentation including growth deficiency, tetraphocomelia, frontal meningocele, craniofacial abnormalities and penile enlargement with hypospadias. Nuclear morphometrical analysis in tissues of various organs revealed a reduced nuclear size in RS as compared to normal controls, and statistically significant differences in morphometric parameters related to the nuclear shape. Immunohistochemical study of the same organs showed a reduced expression of proliferating cell nuclear antigen in the presented case, thus indicating a decreased cell proliferation rate in RS. Our results reconfirm previously reported findings in cultured fibroblasts of RS cases, thereby reinforcing on a histologic level, the hypothesis that reduced cell proliferation may be involved in the growth retardation and the reduction abnormalities observed in RS.

Primary Sjögren's syndrome complicated by hemolytic uremic syndrome.

We describe a case of primary Sjögrens syndrome complicated by hemolytic uremic syndrome (HUS), possibly the first report of this association. The immunohistochemical findings suggest that immune complexes may have contributed to the endothelial injury and the pathogenesis of HUS in this case.