Expression von EphA2 in metastasierten und nicht metastasierten primären uvealen Melanomen

Zusammenfassung

Hintergrund: Bisher ist die genaue Expression des Ephrin-Typ-A2-Rezeptors (EphA2) im Hinblick auf dessen Bedeutung während der Zell-Zell-Adhäsion, Zellmigration, Angiogenese und der Formation von VM-Kanälen (VM: Vasculogenic Mimicry) in uvealen Melanomen unter Berücksichtigung der Metastasierungsrate unklar. Material und Methoden: Paraffinschnitte von 50 histopathologisch gut charakterisierten Fällen primärer uvealer Melanome (durchschnittlicher Tumordurchmesser: 16,3 mm) wurden hinsichtlich ihrer Expression von EphA2 evaluiert. Bei 29 Patienten traten systemische Metastasen auf. Die verbleibenden 21 Patienten hatten einen durchschnittlichen Nachuntersuchungszeitraum von 10 Jahren. Zusätzlich wurde die Tumorangiogenese mittels Endoglin-Expression (CD105), das mature Gefäßsystem (Von-Willebrand-Faktor, vWF) und das Vorhandensein von VM (CD31/PAS-Färbung) untersucht. Ergebnisse: Alle uvealen Melanome exprimierten EphA2 mit einer durchschnittlichen Anzahl positiver Zellen von 95,93 % (± Standardabweichung: 6,3 %). Es war zwar keine signifikante objektive Assoziation von EphA2 und der Metastasierungsrate (p = 0,196) bzw. der Endoglin-Expression (p = 0,652), VM (p = 0,267) oder weiteren klinischen oder histopathologischen Prognosefaktoren (p < 0,05) nachweisbar, jedoch zeigte sich eine signifikante Hochregulation von EphA2 im Bereich des Zellkerns in der Subgruppe der metastasierten uvealen Melanome, während eine zytoplasmatische Lokalisation mit einer besseren Prognose assoziiert war (p = 0,006). Zusätzlich wiesen verschiedene okuläre Gewebe wie z. B. bestimmte Netzhautschichten, das Ziliarkörper- und Hornhautepithel bzw. das choroidale oder korneale Endothel eine milde EphA2-Expression auf. Schlussfolgerung: Während eine nukleäre Expression von EphA2 in dieser Serie großer Tumoren signifikant mit einer erhöhten Metastasierungsrate assoziiert war, zeigt eine zytoplasmatische Lokalisation eine bessere Prognose. Da keine Korrelation der EphA2-Expression mit der Angiogenese, dem maturen Gefäßsystem oder dem VM nachgewiesen werden konnte, scheint die regulative Bedeutung von EphA2 für die Ausbildung blutzuführender Systeme möglicherweise in den fortgeschrittenen Stadien in den Hintergrund zu treten.

Abstract

Background: Little is known about how the expression of Ephrin type-A receptor 2 (EphA2) influences cell-cell adhesion, migration, angiogenesis, and the formation of vasculogenic mimicry (VM) channels in uveal melanomas or how this may be related to the rate of metastasis. Material and Methods: Paraffin embedded sections of 50 histopathologically well characterised primary uveal melanomas (mean largest tumour diameter: 16.3 mm) were evaluated with respect to the expression of EphA2. Systemic metastasis was detected in 29 patients. The remaining 21 patients were followed for a mean of 10 years. Tumour angiogensis was analysed by endoglin expression (CD105), the activity of the mature vascular system (von Willebrand factor) and the presence of VM (CD31/PAS staining). Results: All uveal melanomas expressed EphA2, with a mean of 95.93 % positive cells ± SD: 6.3 %. There was no significant association between EphA2 and the rate of metastases (p = 0.196), endoglin expression (p = 0.652), VM (p = 0.267) or with any other clinical or histopathological factors (p < 0.05). However, there was significant up-regulation of EphA2 in the nucleus of the metastatic uveal melanoma subgroup, while cytoplasmatic localisation in the subgroup was associated with better prognosis (p = 0.006). There were low levels of EphA2 expression in the specific retinal layers, the ciliary and corneal epithelium, and the choroidal and corneal endothelium. Conclusion: Nuclear expression of EphA2 in this series of large tumours was significantly associated with an increased rate of metastasis. On the other hand, cytoplasmic localisation was associated with a better prognosis. As there was no correlation between EphA2 expression and angiogenesis, the mature vasculature or VM, EphA2 appears to become less important in the advanced stages of the disease.

Schlüsselwörter

okuläre Tumoren - Pathologie - Chorioidea

Key words

ocular tumours - pathology - choroid

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