Endometrial cancer with a POLE mutation progresses frequently through the type I pathway despite its high-grade endometrioid morphology: a cohort study at a single institution in Japan.

POLE-mutated endometrial cancer (EC) frequently shows high-grade endometrioid histology, which represents heterogeneity in the dualistic classification of EC. This study aimed to assess the clinicopathology and pathogenesis of POLE-mutated EC due to the scarcity of related information for Asian women. POLE variants were sequenced in tissues of Japanese women with EC. The tumor mutation burden (TMB) was assessed in tissues with a POLE variant of unknown significance. In the POLE-mutated EC tissues, the immunostaining expression of CD8, hormonal receptors, and p53 was evaluated, and the POLE variants in cancer and atypical endometrial hyperplasia (AEH) lesions were assessed by laser-capture microdissection. POLE variants were identified in five patients (3.9%) with high-grade endometrioid carcinoma among 127 patients with EC (S459F in two tissues and P441P in three tissues with a high TMB). The five cancer tissues coexisted with normal endometrium and/or AEH. Both AEH and cancer cells showed hormonal receptor positivity and harbored the same POLE mutation. Two patients showed a subclonal overexpression pattern of p53 in cancer and AEH lesions. In conclusion, POLE-mutated EC progresses through the type I pathway, even though it frequently shows high-grade endometrioid morphology. The common POLE mutation sites in EC might vary among races.

Serum Prolactin Contributes to Enhancing Prolactin Receptor and pJAK2 in Type I Endometrial Cancer Cells in Young Women Without Insulin Resistance.

Elevated levels of serum prolactin and a high expression of prolactin receptor (PRLR) in cancer cells was recently identified in patients with endometrial cancer (EC). However, the impact of prolactin on EC remains unknown. The aim of this study was to elucidate the clinical and immunohistochemical characteristics of hyperprolactinemic patients with EC according to the pathogenetic types, type I and type II. EC patients were retrospectively divided into a high prolactin (HP) group and a low prolactin (LP) group by a serum prolactin level of 20 ng/mL and were compared between 2 groups. The expression of PRLR, phosphorylated Janus-kinase 2 (pJAK2), estrogen receptor-α, progesterone receptor, and PTEN in cancer tissue were evaluated by immunohistochemistry. Ninety-nine patients were identified. In the type I group, HP group was significantly younger (45.2 vs. 52.2, P=0.028) and their insulin resistance was significantly lower (1.6 vs. 2.5, P=0.033) than those in LP group, and the expression of PRLR and pJAK2 in the HP group was significantly higher than that in the LP group (immunoreactive score: 6.8 vs. 3.9, P=0.003; 5.7 vs. 2.6, P<0.001, respectively). In the type 2 group, there were no differences between all the term. In the type I group, the rate of loss of PTEN in the HP group was significantly lower than the LP group (25.0% vs. 60.7%, P=0.024). Prolactin-PRLR signaling may play a crucial role for the progression of type I EC without involving the PTEN mutation in young hyperprolactinemic women without insulin resistance.

Administration of Cabergoline Contributes to Preserving Fertility in Young Hyperprolactinemic Patients With Endometrial Cancer Treated With Medroxyprogesterone Acetate.

BACKGROUND: An association between high levels of serum prolactin and endometrial cancer (EC) has been reported. However, the effect of antiprolactin drugs on hyperprolactinemic patients with EC has not been determined. The aim of this study was to confirm the effect of cabergoline on young hyperprolactinemic patients treated with medroxyprogesterone acetate (MPA) for the preservation of fertility. METHODS: A retrospective observational study was conducted to identify patients with atypical endometrial hyperplasia or early-stage EC aged 40 years or younger who were treated with oral MPA in Kumamoto University Hospital between 1998 and 2016. RESULTS: Thirty-four patients were identified and divided into two groups of 17 patients each, including a nonadministration of cabergoline group (noncabergoline group) and an administration of cabergoline group (cabergoline group). The ratio of pathological diagnoses of EC in the noncabergoline group was significantly lower than that in the cabergoline group (29.4% vs 70.6%, P = 0.016). The mean serum prolactin levels showed a significant decrease after the administration of cabergoline in the cabergoline group (25.2 [24.0] vs 5.2 [4.2] ng/mL, P = 0.003), and this decreased level was also significantly lower than that in the noncabergoline group (5.2 [4.2] vs 12.0 [5.0] ng/mL, P < 0.001). Kaplan-Meier analysis conducted for 150 months revealed that the estimated mean period until hysterectomy in the noncabergoline group was significantly shorter than that in the cabergoline group (83.5 vs 140.8 months, P = 0.007). Significant differences were observed in EC but not atypical endometrial hyperplasia based on histological classification (25.6 vs 138.0 months, P = 0.001). CONCLUSIONS: The administration of cabergoline may contribute to preserving fertility in young hyperprolactinemic patients with EC who were treated with MPA.

Prognostic significance of CD169-positive lymph node sinus macrophages in patients with endometrial carcinoma.

Lymph node (LN) macrophages play critical roles in anti-tumor immunity, which develops via the activation of cytotoxic T cells (CTL) and NK cells. The present study aims to determine the prognostic significance of CD169(+) LN macrophages in patients with endometrial carcinoma (EC). The number of CD169(+) cells or the CD169(+) -to-CD68(+) macrophage ratio in regional LN (RLN), and the number of CD8(+) CTL or CD57(+) NK cells in tumor tissues were investigated by immunohistochemistry in paraffin-embedded tissue samples from 79 patients with EC. A high density of CD169(+) cells in the RLN of patients with EC was correlated with an early clinical stage or no LN metastasis. A high number of CD169(+) cells and a high CD169(+) -to-CD68(+) macrophage ratio were significantly associated with longer overall survival in EC. We also found that the density of CD169(+) macrophages was positively correlated with the number of CD8(+) CTL and CD57(+) NK cells that infiltrated into tumor tissues. A high density of CD57(+) cells in EC tissues was associated with a better prognosis, while a high density of CD8(+) cells was not linked to an altered prognosis. The present study showed that the density of CD169(+) macrophages in RLN was associated with an improved prognosis in EC patients. CD169(+) macrophages in RLN might represent a useful marker for assessing clinical prognoses and monitoring anti-tumor immunity in patients with EC.

An Ovarian Carcinoid Tumor With Peptide YY-Positive Insular Component: A Case Report and Review of the Literature.

Ovarian carcinoid tumors are uncommon and account for 1% of all carcinoid tumors. The insular type of ovarian carcinoid tumor is common in western countries; in contrast, the strumal and trabecular types seem to be common in Asian countries. Strumal and trabecular types are associated with peptide YY (PYY) production, which may cause constipation. Here, we report the case of a 70-yr-old Japanese woman with chronic constipation who was referred to Kumamoto University Hospital because of a right adnexal mass. Imaging tests suggested that the solid mass might be malignant; therefore, abdominal total hysterectomy, bilateral salpingo-oophorectomy, and omentectomy were performed. A subsequent histopathologic examination confirmed an insular carcinoid tumor with a trabecular component in the right ovary. Both components were positive for PYY but not for serotonin. The patient complained of diarrhea instead of constipation soon after the surgery. Because PYY-positive insular carcinoid tumor in the ovary has not been previously reported, we reviewed 19 reported cases of patients with PYY-positive ovarian carcinoid tumors. The origins, common histologic types and symptoms caused by specific peptides secreted in ovarian carcinoid tumors differ between western and Asian countries.

Long-Term Outcome of Aromatase Inhibitor Therapy With Letrozole in Patients With Advanced Low-Grade Endometrial Stromal Sarcoma.

BACKGROUND: There has been no consensus on the indications for the treatment of advanced low-grade endometrial stromal sarcoma (LGESS), and the possible effects of hormonal treatment including progestins and aromatase inhibitors have been reported. The aim of this study was to investigate the efficacy of aromatase inhibitor therapy with letrozole for patients with residual or recurrent LGESS. METHODS: We retrospectively reviewed the clinical response of patients with advanced LGESS who had been treated with letrozole. We also analyzed the adverse effects after the administration of letrozole. The expression levels of estrogen receptor and aromatase in the tumors were immunohistochemically examined. RESULTS: In 5 patients who had been treated for unresectable LGESS lesions after initial or repeat surgical procedures, residual lesions in 3 patients and recurrence lesions in 2 patients were the indications for hormonal therapy with letrozole. The median duration of letrozole exposure at retrospective analysis was 53 (10-96) months. The clinical outcomes were classified as complete response in 2 patients, partial response in 1 patient, and stable disease in 2 patients. Myalgias, hot flashes, and arthralgias were not observed during the follow-up period in any patients. The median serum levels of estradiol were <5.0 (cutoff value, <0.5-11.8) pg/mL. The median age-matched bone mineral densities were 92% (79%-123%). The LGESS tissues in all 5 patients were positive for estrogen receptor and aromatase expression. CONCLUSIONS: Letrozole as well as progestins could be the first choice of treatment for patients with recurrent or residual LGESS, which is difficult to resect surgically because of its efficacy and minimal adverse effects.

Prolactin Enhances the Proliferation of Proliferative Endometrial Glandular Cells and Endometrial Cancer Cells.

To elucidate the mechanism of endometrial cancer (EC) development in young hyperprolactinemic women, this study assessed the hormonal receptor expression, proliferation, and signaling induced by prolactin in endometrial glands (EG) and EC. Prolactin receptor (PRLR) and estrogen receptor alpha (ER-α) in EG were evaluated during the menstrual cycle by immunohistochemistry. The following parameters were compared between EM-E6/E7/TERT cells, which originated from proliferative EG and Ishikawa cells. The expression levels of PRLR, pJAK2 (phosphorylated Janus Activating Kinase 2), its downstream pathways (MAPK, PI3K, and STAT), and ER-α were assessed after adding prolactin by Western blotting. U0126 was used as a MAPK inhibitor. The proliferation caused by estradiol was also examined by MTS assay after adding prolactin. PRLR expression in the EG was significantly higher in the proliferative phase than in the secretory phase, and it was correlated with ER-α expression during the menstrual cycle. After adding prolactin, the expression of pJAK2, PRLR and ER-α was significantly increased in both cell lines, MAPK was activated after adding prolactin in both cell lines, and PI3K and STAT were activated only in EM-E6/E7/TERT cells. The increased proliferation induced by estradiol was enhanced after adding prolactin in both cell lines. All changes caused by prolactin were inhibited in Ishikawa cells pretreated with U0126. Long-term effects of serum prolactin on persistent proliferative endometrium in the presence of estradiol may induce abnormal proliferation of EG in hyperprolactinemic women. Prolactin-PRLR signaling via MAPK may play a crucial role in the progression of EC in hyperprolactinemic women.