Original Contribution
PARP-1 expression as a prognostic factor in Desmoid-type fibromatosis

https://doi.org/10.1016/j.anndiagpath.2019.151442Get rights and content

Highlights

  • Hormone receptors are of minor prognostic relevance in this study

  • PARP-1 expression is associated with poorer prognosis, i.e. faster recurrence

  • Relapse tumors recur more frequently, a fact of which clinicans should be aware of

Abstract

Desmoid-type fibromatoses (or desmoid tumors) are entities of intermediate biological potential and are locally invasive. Radical surgery, as state of the art therapy, is frequently limited by incomplete resections. Hormone modifying therapies are promising but further research is required. Poly Adenosine Diphosphate Ribose Polymerase-1 (PARP-1), a DNA repairing enzyme, might be a pathogenetic factor and could become a potential target for therapy as shown by the successful treatment of selected carcinomas and sarcomas by PARP-inhibition. In this study, we investigated the expression of estrogen receptors (ER) α (1) and β (2), progesterone receptor (PR), androgen receptor (AR), as well as PARP-1 via immunohistochemistry and quantitative RT-PCR in 69 tissue samples of desmoid tumors. Immunohistochemistry was quantified using the Immunoreactivity Score (IRS). Overall expression patterns were correlated with clinical-pathologic parameters to determine their value as a prognostic factor. Among the investigated hormone receptors only ERβ showed partial cytoplasmic reactivity. PARP-1 revealed variable nuclear positivity with IRS ranging from 0 to 6. Univariate survival analysis showed that higher expression of estrogen receptor 1 was associated with shorter disease-free survival (p = 0.005). Uni- (p = 0.03) and multivariate (p = 0.003) analyses of mRNA data revealed that higher PARP-1 expression correlated with earlier recurrence. According to this study PARP-1 expression is associated with poorer prognosis, that is faster recurrence, highlighting the possibility of PARP-1-targeting agents as a therapeutic option. Hormone receptors were of minor prognostic relevance in this study.

Introduction

Desmoid-type fibromatoses, also known as desmoid tumors (DT), are non-metastasizing fibroblastic neoplasms with locally invasive growth. DT are rare with an incidence of 5 per million per year in the general population [1]. The exact pathogenesis of DT is unknown. There is, however, broad evidence of WNT signalling in DT [2]. DT are often associated with mutations in the CTNNB1-gene encoding for β-Catenin [3]. Treatment of DT can be challenging [4]. Pharmacologic strategies include non-steroidal anti-inflammatory drugs, tyrosine kinase inhibitors and cytostatic chemotherapy [5]. Tamoxifen, a selective estrogen receptor modulator, has demonstrated some efficacy in the treatment of DT which underlines the implication of steroid hormone receptors in the pathogenesis of DT [6].

In this study, we investigated the expression of hormone receptors, i.e. estrogen receptors (ER, in mRNA analyses: ESR) 1 (α) and 2 (β), androgen receptor (AR) and progesterone receptor (PR, in mRNA analyses: PgR), as well as the expression of the enzyme Poly Adenosine Diphosphate Ribose Polymerase-1 (PARP-1) and the protein Ki-67 in DT. To our knowledge, the expression of PARP-1 in DT has never been analyzed before. Immunohistochemical analyses of steroid hormone receptor expression vary [7,8]. ERβ seems to be more frequently expressed than ERα [[8], [9], [10]]. Nevertheless positive ER expression does not necessarily imply a therapeutic response to antiestrogens [11]. PARP-1 is part of a nuclear enzyme family which is involved in the repair of single-stranded DNA breaks [12]. PARP-1 expression in DT could be promising, as PARP-1 inhibition showed chemotherapy reinforcing effects in the treatment of Ewing-Sarcoma [13].

The purpose of this study was to investigate correlations between expression levels and established clinicopathological factors, i.e. tumor size, tumor localization, sex, age, resection margin and others in terms of a potential predictive or prognostic influence by means of immunohistochemistry (IHC) and quantitative Real-Time-PCR (qRT-PCR).

Section snippets

Study population and histopathological examination

Sixty-nine tissue samples of DT diagnosed at Charité – Universitätsmedizin Berlin, Germany, between 2005 and 2015 were included in this study. These included 50 (72.5%) primary and 19 (27.5%) relapse tumors. Institutional ethics approval for this retrospective analysis was obtained. General handling procedures and storage conditions of the formalin-fixed and parrafin-embedded (FFPE) tissue samples were constant during the study period. Table 1 gives a summarized overview of patient

Expression of hormone receptors, PARP-1 and Ki-67 in IHC

Hormone receptors showed almost no nuclear positivity in IHC. Only ERβ showed heterogeneous cytoplasmic expression (Table 2) with an IRS between 0 and 4. PARP-1 showed stronger nuclear positivity with a nuclear IRS >0 in 57 of 58 stained cases with an IRS of up to 6. Most of the samples showed an IRS of 2 or 3 (47 of 58; 81.0%). There was no cytoplasmic expression. The tumors exhibited a mean proliferation Ki-67 index of 3.2%. Most of the tumors showed a Ki-67 index between 1 and 5% (n = 25;

Discussion

Our study demonstrates the value of PARP-1 expression in DT as an independent prognostic factor. Moreover, relapse tumors recur faster compared to primary tumors. Hormone receptors did not show any prognostic value in this study. To our knowledge, this is the largest study evaluating the expression of various hormone receptor with different methods in DT so far.

Apart from cytoplasmic ERβ expression, which is presumably artifactual, the other hormone receptors, i.e. ERα, PR, and AR, did not

Acknowledgements

The authors thank Ines Koch and Barbara Meyer-Bartell for their excellent technical assistance. We thank Juliana Andrici, MD, for proofreading and language editing.

Patient consent for publication

Not required.

Declaration of competing interest

None declared.

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