Steroidogenesis in ovarian‐like mesenchymal stroma of hepatic and pancreatic mucinous cystic neoplasms

Abstract

Aim Mucinous cystic neoplasms (MCNs) occur in the ovary, pancreas, and retroperitoneum but very rarely in the liver. Mucinous cystic neoplasms are known to harbor ovarian-like mesenchymal stroma (OLS) expressing progesterone and estrogen receptors. In this study we evaluated steroidogenesis in OLS of 25 hepatic MCNs and 24 pancreatic MCNs. Methods Both steroid receptors and steroidogenic factors were immunohistochemically evaluated using H-scores and results were compared with those in 15 ovarian MCNs and 10 normal ovaries. Results Androgen receptor (AR) H-scores in OLS were significantly higher in hepatic, pancreatic, and ovarian MCN than those in normal ovaries. H-scores of cytochrome P450 17α-hydroxylase/c17-20 lyase (P450c17) and 5α-reductase-1 (5αRED-1) in the stroma were significantly higher in OLS of hepatic and pancreatic MCN than in the stroma of ovarian MCN and normal ovary. In tumor epithelium, AR H-scores were significantly higher in hepatic and pancreatic MCN than in ovarian MCN. In both hepatic and pancreatic MCN, a significant positive correlation was detected between AR H-score in the epithelium and P450c17 H-score in OLS (hepatic MCN: Pearson's r = 0.446, P = 0.025; pancreatic MCN: r = 0.432, P = 0.035). In pancreatic MCN, a significantly positive correlation was detected between AR H-score in the tumor epithelium and 5αRED-1 H-score in OLS (Pearson's r = 0.458, P = 0.024). Conclusions These results indicated that locally produced androgens in OLS could be pivotal for tumorigenesis of both hepatic and pancreatic MCN and influence epithelial cells, possibly in a paracrine fashion, which could represent biological significance of OLS in these neoplasms.

Laparoscopic S7 hepatectomy for hepatic mucinous neoplasm: a case report and literature review

“…Androgens seem to be the key to the occurrence of hepatopancreatic MCN. [ 5 ]. Many women have been diagnosed with MCN.…”

Molecular and Immunohistochemical Analysis of Mucinous Cystic Neoplasm of the Liver

“…Immunohistochemical investigation of mucinous cystic neoplasm of the liver has ascertained that the ovarian-type stroma is positive for progesterone receptor, estrogen receptor, and inhibin-α. 3,[9][10][11] These findings suggest that the stroma of mucinous cystic neoplasm of the liver is potentially hormonally responsive similar to normal ovaries. A study by Westerhoff et al 12 showed that FOXL2, a transcription factor expressed in normal ovaries, is also expressed in the ovarian-type stroma of mucinous cystic neoplasm of the liver; however, the role of FOXL2 in mucinous cystic neoplasm of the liver remained to be elucidated.…”

“…The ovarian-like stroma of pancreatic mucinous cystic neoplasms has been proposed to be hormonally responsive based on estrogen receptor expression by immunohistochemical and gene expression analysis similar to liver mucinous cystic neoplasms. 11,13 Immunohistochemistry-based studies of the ovarian-like stroma of pancreatic and hepatic mucinous cystic neoplasms have also alluded to its potential steroidogenic capability with expression of StAR, CYP17, CYP19, 17β-hydroxysteroid dehydrogenase 1, 3β-hydroxysteroid dehydrogenase, and CYP11. 11,14 However, gene expression analysis of steroidogenic enzymes has never been performed in either pancreatic or hepatic mucinous cystic neoplasms.…”

“…11,13 Immunohistochemistry-based studies of the ovarian-like stroma of pancreatic and hepatic mucinous cystic neoplasms have also alluded to its potential steroidogenic capability with expression of StAR, CYP17, CYP19, 17β-hydroxysteroid dehydrogenase 1, 3β-hydroxysteroid dehydrogenase, and CYP11. 11,14 However, gene expression analysis of steroidogenic enzymes has never been performed in either pancreatic or hepatic mucinous cystic neoplasms. Elucidation of the molecular pathways driving the histogenesis of the ovarian-like stroma in pancreatic mucinous cystic neoplasms have shown overexpression of the WNT/β-catenin pathway based on expression of some members of the WNT/β-catenin pathway such as secreted Frizzled-related protein, WNT1, FZD3, FZD6, and nuclear β-catenin accumulation in the ovarian-like stroma.…”

“…Elucidation of the molecular pathways driving the histogenesis of the ovarian-like stroma in pancreatic mucinous cystic neoplasms have shown overexpression of the WNT/β-catenin pathway based on expression of some members of the WNT/β-catenin pathway such as secreted Frizzled-related protein, WNT1, FZD3, FZD6, and nuclear β-catenin accumulation in the ovarian-like stroma. 11,13,15 Furthermore, some studies have identified inactivating mutations in RNF43, an ubiquitin ligase and a negative regulator of the WNT/β-catenin pathway. 16 The epithelial component of pancreatic mucinous cystic neoplasms has also been investigated by whole-exome sequencing and targeted sequencing demonstrating mutations in KRAS, p53, SMAD4, p16, RNF43, and PIK3CA.…”