Loss of Progesterone Receptor Expression Is an Early Tumorigenesis Event Associated with Tumor Progression and Shorter Survival in Pancreatic Neuroendocrine Tumor Patients

Sung Joo Kim, Soyeon An, Jae Hoon Lee, Joo Young Kim, Ki-Byung Song, Dae Wook Hwang, Song Cheol Kim, Eunsil Yu, Seung-Mo Hong, Sung Joo Kim, Soyeon An, Jae Hoon Lee, Joo Young Kim, Ki-Byung Song, Dae Wook Hwang, Song Cheol Kim, Eunsil Yu, Seung-Mo Hong

Abstract

Background: Pancreatic neuroendocrine tumors (PanNETs) are the second most common pancreatic neoplasms and there is no well-elucidated biomarker to stratify their detection and prognosis. Previous studies have reported that progesterone receptor (PR) expression status was associated with poorer survival in PanNET patients.

Methods: To validate previous studies, PR protein expression was assessed in 21 neuroendocrine microadenomas and 277 PanNETs and compared with clinicopathologic factors including patient survival.

Results: PR expression was gradually decreased from normal islets (49/49 cases, 100%) to neuroendocrine microadenoma (14/21, 66.6%) to PanNETs (60/277, 21.3%; p < .001). PanNETs with loss of PR expression were associated with increased tumor size (p < .001), World Health Organization grade (p = .001), pT classification (p < .001), perineural invasion (p = .028), lymph node metastasis (p = .004), activation of alternative lengthening of telomeres (p = .005), other peptide hormonal expression (p < .001) and ATRX/DAXX expression (p = .015). PanNET patients with loss of PR expression (5-year survival rate, 64.1%) had significantly poorer recurrence-free survival outcomes than those with intact PR expression (90%) by univariate (p = .012) but not multivariate analyses. Similarly, PanNET patients with PR expression loss (5-year survival rate, 76%) had significantly poorer overall survival by univariate (p = .015) but not multivariate analyses.

Conclusions: Loss of PR expression was noted in neuroendocrine microadenomas and was observed in the majority of PanNETs. This was associated with increased grade, tumor size, and advanced pT and pN classification; and was correlated with decreased patient survival time by univariate but not multivariate analyses. Loss of PR expression can provide additional information on shorter disease-free survival in PanNET patients.

Keywords: Neuroendocrine tumors; Pancreas; Receptors, progesterone; Survival.

Conflict of interest statement

Conflicts of Interest

No potential conflict of interest relevant to this article was reported.

Figures

Fig. 1.
Fig. 1.
Representative images of progesterone receptor (PR) labeling in normal pancreas, neuroendocrine microadenoma, and pancreatic neuroendocrine tumor (PanNET). (A) Islets are positive, while acinar and ductal epithelial cells are negative for PR staining in the normal pancreas. Some neuroendocrine microadenomas show intact PR labeling (B), while other neuroendocrine microadenomas demonstrate loss of PR labeling (C). Some PanNETs show intact PR labeling (D), while other PanNETs demonstrate loss of PR labeling (E).
Fig. 2.
Fig. 2.
Progesterone receptor (PR) expression status and the H-score in normal islets, neuroendocrine microadenomas, and pancreatic neuroendocrine tumors (PanNETs). (A) Comparison of PR expression in normal islets, neuroendocrine microadenomas, and PanNETs. (B) The H-score for PR in normal islets, neuroendocrine microadenomas, and PanNETs is 5.1±2.3, 3.0±3.3, and 1.3±2.5, respectively (p<.001>

Fig. 3.

Kaplan-Meier survival analyses of pancreatic…

Fig. 3.

Kaplan-Meier survival analyses of pancreatic neuroendocrine tumor (PanNET) patients according to progesterone receptor…

Fig. 3.
Kaplan-Meier survival analyses of pancreatic neuroendocrine tumor (PanNET) patients according to progesterone receptor (PR) expression. (A) The 100% overall 5-year survival rate for PanNET patients with PR expression is significantly better than that for those without insulin expression (76%, p=.015). (B) The recurrence-free 5-year survival rate for PanNET patients with PR expression (90%) is significantly better than that for those without PR expression (64.1%, p=.012).
Fig. 3.
Fig. 3.
Kaplan-Meier survival analyses of pancreatic neuroendocrine tumor (PanNET) patients according to progesterone receptor (PR) expression. (A) The 100% overall 5-year survival rate for PanNET patients with PR expression is significantly better than that for those without insulin expression (76%, p=.015). (B) The recurrence-free 5-year survival rate for PanNET patients with PR expression (90%) is significantly better than that for those without PR expression (64.1%, p=.012).

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