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Background: Progestin is used for fertility-sparing treatment in cases of endometrial cancer (EC). Progestin can induce hyperprolactinemia by increasing pituitary secretion and endometrial decidualization. However, progestin induces prolactin (PRL) secretion, which stimulates cell proliferation and deleteriously affects treatment. To date, the detrimental effect of PRL, the secretion of which is induced by medroxyprogesterone acetate (MPA) during fertility-sparing treatment, has not yet been fully elucidated. Therefore, we aimed to assess the effects of PRL on EC cells during combined treatment with progestin and metformin., Methods: In total, 71 patients with EC/endometrial atypical hyperplasia who underwent fertility-sparing treatment at our institution from 2009-2019 were enrolled. Serum PRL levels were determined using enzyme immunoassays; mRNA levels in endometrial tissues were determined using quantitative reverse-transcription PCR. To evaluate MPA-induced decidualization, cancer-associated stromal cells were enzymatically released from surgically removed specimens of six patients with EC. To examine PRL-induced cell proliferation, the EC cell lines Ishikawa, HEC1B, and HEC265 were used. In vitro cell proliferation was evaluated using the WST assay; protein levels of signaling molecules were determined using western blotting., Results: MPA administration significantly increased serum PRL levels at 3 and 6 months and upregulated IGFBP-1 and PRL mRNA expression in tissues at 3 months of fertility-sparing treatment. Metformin significantly reduced MPA-induced IGFBP-1 and PRL mRNA expression during fertility-sparing treatment and significantly inhibited the upregulation of IGFBP-1 and PRL mRNA and PRL levels due to decidualization induced by MPA and cAMP treatment in primary cultured EC stromal cells. In vitro, PRL increased cell proliferation and ERK1/2 phosphorylation levels, whereas metformin attenuated these increases., Conclusions: MPA upregulated PRL levels in serum and endometrial tissues during fertility-sparing treatment. Metformin co-administration reduced PRL production and attenuated PRL-induced cell-proliferation activity. This study may provide valuable insights on the application of metformin to improve the outcomes of fertility-sparing treatment., (© 2022. The Author(s).)

Objective: We aimed to evaluate the prevalence of pulmonary embolism (PE) before cancer therapies in patients with ovarian and endometrial cancers with enhanced computed tomography (CT) using D-dimer (DD), and determine the optimal cut-off level of DD., Methods: Since 2009, we have performed preoperative venous thromboembolism (VTE) screening of patients with ovarian and endometrial cancer. For patients with DD levels of more than 1.0 μg/ml, enhanced CT images were obtained from the pulmonary apex to the foot to detect PE and deep venous thrombosis (DVT) simultaneously., Results: Among patients with ovarian cancer, 84 of 413 (20.3%) had VTEs (DVT alone, n = 31 [7.5%]; PE with or without DVT, n = 53 [12.8%]; PE alone, n = 12 [2.9%]). Among patients with endometrial cancer, 50 of 455 (11.0%) had VTEs (DVT alone, n = 19 [4.2%]; PE with or without DVT, n = 31 [6.8%], PE alone, n = 14 [3.1%]). The optimal cut-off level of DD was estimated to be ≥1.5 and ≥1.2 μg/ml in ovarian and endometrial cancers, respectively., Conclusion: Our study revealed a high prevalence of PE before cancer therapies in patients with ovarian and endometrial cancers by enhanced CT using DD., (© 2021 Wiley Periodicals LLC.)

Introduction: Progestin therapy is the only fertility-sparing treatment option for patients with atypical endometrial hyperplasia (AEH) and endometrial cancer (EC). However, the results of three meta-analyses revealed a high remission rate, as well as an association with a high rate of relapse. We previously conducted a phase II of medroxyprogesterone acetate (MPA) plus metformin as a fertility-sparing treatment for AEH and EC patients, and reported that metformin inhibited disease relapse after remission., Methods and Analysis: A randomised, open, blinded-endpoint design phase IIb dose response trial was planned to commence in July 2019. The trial aims to identify the appropriate dose of metformin to be combined with MPA therapy for fertility - sparing treatment of patients with AEH and EC. The primary endpoint of the trial is the 3-year relapse-free survival (RFS) rate. The secondary endpoints are RFS rate, the overall rate of response to MPA therapy, the conception rate after treatment, the outcome of pregnancy, toxicity evaluation and changes in insulin resistance and body mass index. A total of 120 patients will be enrolled from 15 Japanese institutions within a 2.5-year period and followed up for at least 3 years., Ethics and Dissemination: The protocol was approved by the institutional review board at Chiba University Hospital and boards at 14 other institutions. The trial will be conducted according to the principles of the World Medical Association's Declaration of Helsinki and in accordance with Good Clinical Practice (GCP) standards. The trial findings will be published in a peer-reviewed journal., Trial Registration Number: Japan Registry of Clinical Trials (jRCT2031190065)., Competing Interests: Competing interests: HH has received personal fees from Torii Yakuhin, outside the submitted work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This review seeks to describe new fertility-sparing endometrial cancer (EC) treatment strategies that take into consideration the medical and general health background of patients. We particularly focus on the application of metformin, which is a biguanide widely prescribed for treatment of type 2 diabetes mellitus. Fertility-sparing treatment using progestin is considered a standard treatment option for patients with atypical endometrial hyperplasia (AEH) and EC who desire to conceive. A previous meta-analysis of fertility-sparing treatments revealed a high remission rate; however, high rates of relapse persisted. Most young patients with AEH and EC who are subjected to fertility-sparing treatment have a background of obesity, insulin resistance and abnormal glucose tolerance complicated with polycystic ovary syndrome. Recently, metformin has been attracting more attention in the field of cancer research. Several in vitro and in vivo reports regarding the efficacy of metformin in EC management have accumulated. Thus far, the efficacy of combining metformin with progestin has been revealed in a single phase II study of medroxyprogesterone acetate in combination with metformin as a fertility-sparing treatment for patients with AEH or EC. In addition to improving the metabolic profile of patients with EC having metabolic disorders, metformin supplementation may improve the long-term oncological outcome of these patients. To date, many clinical trials employing progestin and metformin as a fertility-sparing treatment of AEH and EC are ongoing. In the near future, it is expected that the clinical advantage of metformin progestin combination therapy will be clarified., (© 2020 Japan Society of Obstetrics and Gynecology.)

Objective: The present study investigated long-term outcomes of medroxyprogesterone acetate (MPA) plus metformin therapy in terms of control of atypical endometrial hyperplasia (AEH) and endometrial cancer (EC), and post-treatment conception., Methods: We retrospectively analyzed 63 patients (42 with EC; 21 with AEH) who underwent fertility-sparing management using MPA plus metformin. MPA (400 mg/day) and metformin (750-2,250 mg/day) were administered to achieve complete response (CR). Metformin was administered until conception, even after MPA discontinuation., Results: Of the total patients, 48 (76%) had a body mass index (BMI) ≥25 kg/m² and 43 (68%) showed insulin resistance. Sixty-one patients (97%) achieved CR within 18 months. CR rates at 6, 8-9, and 12 months were 60%, 84%, and 90%, respectively. During a median follow-up period of 57 months (range, 13-115 months), relapse occurred in 8 of 61 patients (13.1%) who had achieved CR. Relapse-free survival (RFS) in all patients at 5 years was 84.8%. Upon univariate analysis, patients with BMI ≥25 kg/m² had significantly better prognoses than did those with BMI <25 kg/m² (odds ratio=0.19; 95% confidence interval=0.05-0.66; p=0.009). Overall pregnancy and live birth rates per patient were 61% (19/31) and 45% (14/31), respectively., Conclusions: MPA plus metformin is efficacious in terms of RFS and post treatment conception. Moreover, metformin may be more efficacious for patients with BMI ≥25 kg/m²., Competing Interests: No potential conflict of interest relevant to this article was reported., (Copyright © 2019. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.)

This is a pooled analysis to evaluate the toxicity and efficacy of carbon-ion radiotherapy (C-ion RT) for inoperable endometrial carcinoma. Eligible patients had previously untreated Stage I-III endometrial carcinoma without para-aortic lymph node metastasis. Total dose to the tumor was 62.4-74.4 Gy [relative biological effectiveness (RBE)] in 20 fractions, and the dose to the gastrointestinal tract was limited to <60 Gy (RBE). Intracavitary brachytherapy was not combined in the present study. Fourteen patients with endometrial carcinoma were analyzed. Ten of the 14 patients were judged medically inoperable, and the others refused surgery. The numbers of patients with Stage I, II and III disease were 1, 9 and 4, respectively. Tumor size was 3.8-13.8 cm in maximum diameter. Median follow-up periods for all patients and surviving patients were 50 months (range, 12-218 months) and 78 months (range, 23-218 months), respectively. Two of three patients receiving 62.4-64.8 Gy (RBE) had local recurrence whereas none of 11 patients receiving 68.0 Gy (RBE) or more had local recurrence. Three patients developed distant metastases and one of them also had local recurrence. The 5-year local control, progression-free survival, overall survival, and cause-specific survival rates were 86%, 64%, 68% and 73%, respectively. No patient developed Grade 3 or higher acute or late toxicity. The present study showed that C-ion RT alone could be a safe and curative treatment modality for inoperable endometrial carcinoma.

Objective: Metformin, an antidiabetic drug, inhibits the endometrial cancer cell growth in vivo by improving the insulin resistance; however, its mechanism of action is not completely understood. Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase associated with insulin resistance and type 2 diabetes, and its inhibition restores the insulin resistance. This study investigated the antitumor effect of metformin on endometrial cancer with a focus on PP2A., Methods: Metformin (1,500-2,250 mg/day) was preoperatively administered to patients with endometrial cancer for 4 to 6 weeks. Expression of the PP2A regulatory subunits, 4 (PPP2R4) and B (PP2A-B), was evaluated using real-time polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) using paired specimens obtained before and after metformin treatment. The effect of PPP2R4 inhibition with small interfering RNA was evaluated in the endometrial cancer cell lines HEC265 and HEC1B. P values of < .05 were considered statistically significant., Results: Preoperative metformin treatment significantly reduced the expression of PP2A-B, as determined using IHC, and the mRNA expression of PPP2R4, as determined using RT-PCR, in the patients with endometrial cancer. However, metformin could not directly alter the PPP2R4 mRNA levels in the endometrial cancer cell lines in vitro. PPP2R4 knockdown reduced the proliferation and induced the apoptosis by activating caspases 3/7 in HEC265 and HEC1B cells., Conclusions: Downregulation of the PP2A-B subunit, including PPP2R4, is an important indirect target of metformin. Inhibition of PP2A may be an option for the treatment of endometrial cancer patients with insulin resistance., Trial Registration: This trial is registered with UMIN-CTR (number UMIN000004852).

We conducted a phase 1/2 study to evaluate the efficacy and safety of carbon ion radiotherapy (C-ion RT) with concurrent chemotherapy for locally advanced uterine cervical adenocarcinoma. Thirty-three patients were enrolled between April 2010 and March 2014. Treatment consisted of C-ion RT with concurrent weekly cisplatin at a dose of 40 mg/m 2 . In the phase 1 component, the total dose was escalated from 68.0 Gy (relative biological effectiveness [RBE]) to 74.4 Gy (RBE) to determine the maximum tolerated dose of C-ion RT. In the phase 2 component, the efficacy and safety of C-ion RT with concurrent chemotherapy were evaluated using the dose determined in the phase 1 component. The median follow-up duration was 30 months. Two patients did not receive chemotherapy because of anemia or leukocytopenia immediately prior to commencing treatment; 31 patients were analyzed. None of the patients developed dose-limiting toxicities. The recommended dose (RD) was determined to be 74.4 Gy (RBE). In the phase 2 component, two patients developed Grade 3-4 toxicities in the gastrointestinal tract, due to repeated laser coagulation or peritonitis caused by appendicitis. In the patients treated with the RD, the 2-year local control, progression-free survival, and overall survival rates were 71%, 56%, and 88%, respectively. C-ion RT with concurrent weekly cisplatin was well tolerated in patients with locally advanced uterine cervical adenocarcinoma. Our findings support further investigations into the efficacy of this strategy., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Obesity and diabetes (DM) are known to increase the risk of endometrial cancer (EC). However, little is known about the prevalence of abnormal glucose metabolism and insulin resistance (IR) in EC patients. We aimed to evaluate the prevalence of abnormal glucose metabolism and IR in EC patients., Methods: We prospectively enrolled atypical endometrial hyperplasia (AEH) and EC patients who had received planned treatment at Chiba University Hospital, Japan. All patients, except those with a confirmed diagnosis of DM, underwent the 75-g oral glucose tolerance test (OGTT) before treatment. We evaluated the prevalence of obesity, defined as body mass index (BMI) ≥25, IR, abnormal glucose metabolism, and the associations between these three factors and the clinical characteristics of AEH and EC patients., Results: We enrolled 279 patients from April 2009 to March 2015. Of these, 56 had a confirmed diagnosis of DM. Abnormal OGTT results, including impaired fasting glucose (n = 7), impaired glucose tolerance (n = 69), and newly identified DM (n = 33), were noted in 109 patients. Obesity, IR, and abnormal glucose metabolism were observed in 49.8, 51.6, and 59.1% of patients, respectively. Abnormal glucose metabolism was significantly associated with age (P < 0.001), body mass index (P = 0.004), and IR status (P < 0.001) in multivariate analysis., Conclusion: Abnormal glucose metabolism, IR, and obesity were highly prevalent in patients with AEH and EC. These results indicate that physicians should consider a patient's metabolic status in the postoperative management of AEH and EC patients.

Background: Metformin, widely used in the treatment of type 2 diabetes mellitus, reduces the risk of cancer and relapse after treatment. Fertility-sparing treatment for endometrial cancer (EC) with progestin is associated with a high chance of disease regression, and the high relapse rate continues to be a problem. We assessed the efficacy of metformin in preventing recurrence after medroxyprogesterone acetate (MPA) as fertility-sparing treatment for atypical endometrial hyperplasia (AEH) and EC., Patients and Methods: This phase II study enrolled 17 patients with AEH and 19 patients with EC limited to the endometrium (age, 20-40 years). MPA (400 mg/day) and metformin (750-2250 mg/day) were administered for 24-36 weeks to achieve a complete response (CR). Metformin was administered until conception, even after MPA discontinuation. The primary end point was relapse-free survival (RFS) after remission. We analyzed all efficacy end points in the full analysis set., Results: The body mass index was ≥25 kg/m(2) in 27 patients (mean, 31 kg/m(2); range, 19-51 kg/m(2)), and the homeostasis model assessment for insulin resistance index was ≥2.5 in 24 patients (mean, 4.7; range, 0.7-21). Two patients showed progression at 12 weeks [6%; 95% confidence interval (CI) 2-18]. At 36 weeks, 29 (81%; 95% CI 65-90) patients achieved CR, and 5 (14%; 95% CI 6-29) patients achieved partial response. During a median follow-up of 38 months (range, 9-66 months) after remission, relapse was confirmed in three of the patients who had achieved CR (relapse rate, 10%). The 3-year estimated RFS rate was 89%. No patients experienced severe toxicity., Conclusions: Metformin inhibited disease relapse after MPA therapy. The combination of metformin and MPA in EC treatment should be studied further., Trial Registration Number: UMIN 000002210., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: To achieve optimal cytoreduction for advanced-stage ovarian cancer, modified posterior exenteration is the most frequently performed bowel surgery. We assessed the extents of tumor spreading in the rectosigmoid wall and pelvic side wall in modified posterior exenteration specimens during primary debulking surgery (PDS) and interval debulking surgery (IDS) following neoadjuvant chemotherapy, and compared the validity of selecting this surgical procedure in the patients undergoing PDS with that in the patients undergoing IDS., Methods: Clinicopathological data from consecutive patients who had undergone a modified posterior exenteration for primary ovarian, tubal, and peritoneal cancer at our institution between April 2008 and March 2013 was retrospectively reviewed., Results: A total of 75 patients (38 in PDS and 37 in IDS) were included in this study. Tumor involvement of the rectosigmoid was histopathologically confirmed in 65% of the specimens. Though the extent of tumor spreading in the rectosigmoid was deeper in PDS than in IDS, the frequency of tumor involvement of the rectosigmoid in patients who had undergone modified posterior exenteration during PDS was equivalent to that in the IDS group. Lateral tumor spreading to the side wall(s) was histopathologically confirmed in 53% of the patients in whom a pelvic side wall resection had been performed., Conclusions: During both PDS and IDS for ovarian cancer presenting with tumor involvement of the cul-de-sac, close inspection and palpation by gynecologic oncologists may enable the extent of tumor spreading in the pelvis to be estimated, enabling valid decisions as to whether an en bloc resection of the pelvic tumors together with the rectosigmoid and the pelvic side wall might or might not be appropriate.

In developed countries, endometrial cancer (EC) is the most common malignancy among women. Unopposed estrogen therapy, obesity, nulliparity, diabetes mellitus and arterial hypertension have been linked to an increased risk of EC. However, the molecular mechanisms of EC oncogenesis and metastasis have not yet been fully elucidated. Our recent studies of microRNA (miRNA) expression signatures revealed that the microRNA-1/133a (miR‑1/133a) cluster is frequently downregulated in various types of human cancers. However, the functional role of the miR‑1/133a cluster in EC cells is still unknown. Thus, the aim of this study was to investigate the functional significance of the miR‑1/133a cluster and its regulated molecular targets, with an emphasis on the contributions of miR‑1/133a to EC oncogenesis and metastasis. We found that the expression levels of miR‑1 and miR‑133a were significantly reduced in EC tissues. Moreover, restoration of mature miR‑1 or miR‑133a miRNAs significantly inhibited cancer cell migration and invasion, suggesting that these clustered miRNAs act as tumor suppressors. Prediction of miRNA targets revealed that phosphodiesterase 7A (PDE7A) was a potential target gene regulated by both miR‑1 and miR‑133a. PDE7A was confirmed to be overexpressed in EC clinical specimens and silencing of PDE7A significantly inhibited cancer cell migration and invasion. Our data demonstrated that downregulation of the miR‑1/133a cluster promoted cancer cell migration and invasion via overexpression of PDE7A in EC cells. Elucidation of the molecular networks regulated by tumor-suppressive miRNAs will provide insights into the molecular mechanisms of EC oncogenesis and metastasis.

Metformin is a diabetes drug with anticancer properties. Several studies have investigated the effects of metformin combined with chemotherapeutic agents, with controversial results. This study evaluated the efficacy of combined metformin/cisplatin treatment in an endometrial cancer cell line. Ishikawa cells were treated with metformin, cisplatin or both types of treatment. Cell proliferation was evaluated by quantification and colorimetric and thymidine incorporation assays, cell cycle progression was assessed by flow cytometry, and apoptosis by the caspase-3 activity assay. The effects of metformin and cisplatin used in combination were assessed under normoxic (21% O2) and hypoxic (1% O2) conditions. Mitochondrial morphology was examined using the MitoTracker dye, while function was assayed by lactate production. Discrepant results were obtained from the different assays of cell proliferation, with the value obtained from the colorimetric assay being higher than that from cell counts after drug treatment. Combined treatment with metformin (≥2 mM) and cisplatin (1 µM) had additive anti-proliferative effects on cells under normoxic conditions. However, the additive effect of metformin was attenuated under hypoxia. Metformin caused morphological and functional changes in mitochondria, which appeared shortened after exposure to metformin, while the connections between individual mitochondria appeared weaker. Additionally, decreased MitoTracker staining was observed after an 8-h exposure to metformin. The colorimetric assay did not accurately determine the effects of metformin and cisplatin on cell proliferation. The additive effects of metformin on cisplatin-induced inhibition of cell proliferation were attenuated under hypoxic conditions, while metformin compromised mitochondrial structure and function. Additional studies are needed to determine the efficacy of this drug combination in vivo.

Background: Metformin, an antidiabetic drug, decreases the incidence of various cancers in diabetic patients. Metformin-induced inhibition of cancer cell proliferation has been confirmed in vitro but not in humans. Because endometrial cancer is associated with insulin resistance, the authors investigated whether a diabetes-therapeutic metformin dose inhibits cancer cell growth in patients with endometrial cancer., Methods: A dose of metaformin was administered (1500-2250 mg/day) to 31 patients with endometrial cancer preoperatively for 4 to 6 weeks. Cell proliferation was assessed in patient tissues using immunohistochemical and Western blot analyses and DNA synthesis was measured in serum using a thymidine uptake assay. All statistical tests were 2-sided. P values of < .05 were considered statistically significant., Results: Preoperative metformin treatment decreased DNA synthesis in sera and significantly reduced the Ki-67 (mean proportional decrease, 44.2%; 95% confidence interval [95% CI], 35.4-53.0 [P < .001]) and topoisomerase IIα (mean proportional decrease, 36.4%; 95% CI, 26.7-46.0 [P < .001]) labeling indices. Levels of phospho-ribosomal protein S6 and phospho-extracellular signal-regulated kinase 1/2 (ERK1/2) were found to be significantly decreased and phospho-adenosine monophosphate-activated protein kinase and p27 levels were significantly increased. Preoperative metformin use caused significant decreases in circulating factors, including insulin, glucose, insulin-like growth factor 1, and leptin. DNA synthesis-stimulating activity in patient sera was significantly decreased during metformin administration., Conclusions: An antidiabetic dose of metformin inhibited endometrial cancer cell growth in vivo, an effect likely due to its effect on humoral factor(s). This translational study provides considerable rationale to initiate large clinical trials., (© 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)

Objective: The purpose of this study was to investigate the diagnostic impact of preoperative serum p53 antibody (S-p53 Ab) in patients with endometrial cancer., Study Design: A hospital-based series of 67 patients, comprising 58 endometrioid adenocarcinomas (EA) and 9 serous adenocarcinomas (SA) between 1998-2002 were included. First, preoperative pathology was compared with final pathology in terms of histologic classification and tumor grade. Second, S-p53 Ab and CA125 were measured using preoperative serum samples, and immunohistochemical staining for p53 protein was assessed using hysterectomy specimens., Results: There were discrepancies between preoperative and final pathology in terms of histologic classification (7%) and tumor grade in EAs (30%); other objective tests, therefore, were needed to minimize the diagnostic problems. S-p53 Ab titers varied from 0.27-786 (mean, 124) in SAs and from 0.1-7.47 (mean, 0.46) U/mL in EAs, respectively, and were positive in 6 (67%) SAs and in 3 (6%) EAs using 1.3 U/mL as cut-off. S-p53 Ab-positive rate was significantly correlated with SA histology and grade 3 EA tumor (odds ratio, 40; P = .005; 95% confidence interval, 3.04-525.43) with higher sensitivity and higher specificity than p53 staining and CA125, respectively., Conclusion: S-p53 Ab could conveniently and specifically identify high-risk endometrial cancer.

Background: There are therapeutic dilemmas regarding conservative management of endometrial cancer in young women., Methods: We planned a prospective study to conservatively treat women aged under 40 years with clinical stage 1A, grade 1 endometrioid adenocarcinoma from 1999 to 2005. There were nine women (aged 28-40) who fulfilled the criteria, and medroxyprogesterone acetate (400 mg/day) was continued for 6 months. Curettage materials were pathologically evaluated according to our criteria including partial response (PR) (a small amount of cancer tissue with remarkable hormonal effects or atypical hyperplasia). To predict complete response (CR) to progestin, immunohistochemical staining for insulin-like growth factor type 1 receptor, phosphatase and tensin homolog deleted on chromosome ten, progesterone receptor (PgR), estrogen receptor and Ki67 were assessed., Results: Seven (78%) and two cases presented complete and PRs, respectively. Two patients developed recurrent disease 10 and 22 months after the last dilatation and curettage, and both had synchronous ovarian cancer. However, all nine patients were alive and disease-free for a mean of 39 months. Of eight married patients, four (50%) conceived and three delivered full-term singletons. CR was related to positive expression of PgR (P=0.008)., Conclusions: Patients with an initial PR can obtain CR after further treatment, and the PgR may be useful in predicting CR to fertility-preserving treatment in young women with endometrial cancer.

Background: Malignant transformation of adenomyosis is a very rare event. Only about 30 cases of this occurrence have been documented till now., Case Presentation: The patient was a 57-year-old woman with a slightly enlarged uterus, who underwent total hysterectomy and unilateral adnexectomy. On gross inspection, the uterine wall displayed a single nodule measuring 5 cm and several small gelatinous lesions. Microscopic examination revealed a common leiomyoma and multiple adenomyotic foci. A few of these glands were transformed into a moderately differentiated adenocarcinoma. The endometrium was completely examined and tumor free. The carcinoma was, therefore, considered to be an endometrioid adenocarcinoma arising from adenomyosis. Four months later, an ultrasound scan revealed enlarged pelvic lymph nodes: a cytological diagnosis of metastatic adenocarcinoma was made. Immunohistochemical studies showed an enhanced positivity of the tumor site together with the neighbouring adenomyotic foci for estrogen receptors, aromatase, p53 and COX-2 expression when compared to the distant adenomyotic glands and the endometrium. We therefore postulate that the neoplastic transformation of adenomyosis implies an early carcinogenic event involving p53 and COX-2; further tumor growth is sustained by an autocrine-paracrine loop, based on a modulation of hormone receptors as well as aromatase and COX-2 local expression., Conclusion: Adenocarcinoma in adenomyosis may be affected by local hormonal influence and, despite its small size, may metastasize.