Can recurrences be predicted in craniopharyngiomas? β-catenin coexisting with stem cells markers and p-ATM in a clinicopathologic study of 45cases

Abstract

Background: Recurrence is a common feature of craniopharyngiomas, benign tumors that origin from squamous epithelial remnants of Rathke's pouch- arising at any segment of its whole course. There are two histotypes, showing different morphology and clinical behavior: adamantinomatous(adaCP) and papillary (papCP). An univocal strategy of management has not yet been defined, being considered the combination of surgery and radiotherapy the most effective, especially in case of incomplete resection. Therefore, the identification of factors influencing the biological and clinical behaviour is of paramount importance. β-catenin is a cell-cell adhesion protein, whose nuclear localization has been linked to the pathogenesis of adaCP: its nuclear accumulation is associated to the presence of a tumor stem cell subpopulation. The latter is made of cells capable of self-renewal, hence believed to be responsible of recurrence, metastases and resistance to therapy in all tumors. ATM is a kinase activated by autophosphorylation (p-ATM) upon DNA double-strand breaks. It is involved not only in DNA repair, but also in tumor migration and invasiveness. Its expression may have prognostic implications in many neoplastic diseases.

Methods: In this study, we measured the immunohistochemical expression of β-catenin, stem cell markers (CD133, CD166), Ki67 and pATMin 45 craniopharyngiomas and correlated it with clinicopathologic features.

Results: Statistical analysis revealed strong correlation of β-catenin with recurrence (p = 0.0039), Ki67 (p = 0.0011, r = 0.4903) and CD166 (p = 0.0002, r = 0.6218). A slight tendency to a higher expression of β-catenin was recorded for adaCP rather than papCP (p = 0.0895).Fisher's exact test showed that CD166 was significantlyrelated with recurrence (p = 0.0040). Furthermore, cytoplasmic pATM was more expressed in adaCPs (p = 0.0470), compared to papCPs that displayed a more evident nuclear signal (p = 0.0313) instead.

Conclusions: Backing upon these data, we could weigh in on the need of identifying β-catenin and CD166 as prognostic markersthat could be useful in predicting thebiologicalbehavior, as recurrence risk incraniopharyngiomas. The final goal is to drew up a prognostic algorithm to be of aid in the planning of an appropriate treatment strategy. Furthermore, our findings demonstrate that pATM could be used as additional distinction-marker between the two histotypes.

Keywords: CD166; Craniopharyngiomas; Recurrence; β-catenin.

Fig. 1

45 cases were examined with β-catenin, Ki67 and pATM antibodies, 30 cases with CD133 and 31 cases with CD166. (a-c) β-catenin immunostaining score: moderateand strong nuclear signal in <10% (a, adaCPnr23of Table 1) and in 10–50% (b, adaCPnr40) of neoplastic cells, respectively. The signal was more represented in cells forming “whirl-like” structures (c, adaCPnr7). d-f CD166immunostaining score: strong membranous signal observed in <10% of neoplastic cells (d, adaCPnr8); moderate signal observed in 10–50% of cells (e, adaCPnr27), sparing the “whirl-like” structures (*). Strong reactivity in >50% of neoplastic cells (f, adaCPnr31). g-i CD133immunostaining score: signal with moderate intensity observed in 10–50% of neoplastic cells in papCP (g, papCPnr14) and in adaCP (h, adaCPnr44); strong and diffuse (51–80% of neoplastic cells) immunoreactivity in papCP (i, papCPnr13). L-n Ki67 Labeling index: low proliferative index Ki67 (<5%) (l, adaCPnr3); high Ki67 L.I sparing cells forming “whirl-like” clusters (*) (m, adaCPnr15); Ki67 L.I. calculated as 25% (n, adaCPnr7). All pictures were captured at 40× magnification

Fig. 2

Cytoplasmic signal observed in adamantinomatoushistotype (a); mainly nuclear signal in papCPs. CpATM was significantly more expressed in adaCPs (p = 0.0470) (c), while NpATM was more present in papCPs (p = 0.0313) (d)