Hysteroscopic treatment assisted by photodynamic diagnosis for atypical polypoid adenomyoma: A report of two cases.

Atypical polypoid adenomyoma (APA) is an intrauterine tumor for which hysteroscopic tumor resection allows for fertility preservation. Complete resection is important because of the high recurrence rate of APA, but is difficult due to the lack of characteristic hysteroscopic findings. We previously reported a case in which photodynamic diagnosis (PDD) was useful for detection of APA. Here, we report two additional cases of APA treated by hysteroscopic resection with PDD. The procedure was approved by the ethical committee. Case 1: A 35-year-old female who underwent hysteroscopic surgery for a submucosal tumor suspected to be APA with hypermenorrhea. Case 2: A 37-year-old female in whom hysteroscopic surgery was performed for a residual APA lesion after hormone therapy. In Case 1, PDD identified the tumor borders and this enabled as complete resection as possible. In Case 2, lesions could not be identified clearly under white light, but some areas were PDD-positive and were excised. Among 19 specimens from these two cases and the previously reported case, all PDD-positive specimens were pathologically diagnosed as APA. The sensitivity and specificity of PDD for APA were 76.9% and 100%, respectively. These results suggest that PDD can contribute to identification of APA.

Alleviation of Symptoms and Improvement of Endometrial Receptivity Following Laparoscopic Adenomyoma Excision and Secondary Therapy with the Levonorgestrel-releasing Intrauterine System.

To assess the treatment efficacy of adenomyoma and improvement in implantation receptivity associated with the levonorgestrel-releasing intrauterine system (LNG-IUS) combined with adenomyoma resection. Fifty subjects (control group) underwent laparoscopic adenomyoma excision and received gonadotropin-releasing hormone (GnRH) agonists, and 201 subjects (experimental group) underwent laparoscopic adenomyoma resection and received GnRH agonists combined with the LNG-IUS. Pipelle endometrial biopsies were obtained in the mid-luteal phase, before the operation, and 19 months after the operation. Menstrual blood loss was measured using a pictorial blood loss assessment chart. Pain intensity during menstruation was evaluated on a 10-point visual analog scale (VAS). The volume of uterus was measured through ultrasound. Quantification of HOXA10 promoter methylation was performed through bisulfite sequencing polymerase chain reaction (BSP). Real-time polymerase chain reaction analyzed the expression levels of endometrial HOXA10-mRNA and leukemia inhibitory factor (LIF)-mRNA. After surgery, the scores for dysmenorrhea and menorrhagia were significantly improved, and the volume of the uterus was obviously reduced (all p < 0.01). The mean number of methylated CpG sites, level of endometrial HOXA10-mRNA, and level of endometrial LIF-mRNA were 5.6 ± 1.7 versus 3.9 ± 1.3, 0.8 ± 0.2 versus 0.9 ± 0.3, and 0.8 ± 0.2 versus 1.0 ± 0.2, respectively, in the control group versus the experimental group at 19 months after surgery, and significant improvements were observed in the experimental group (p < 0.001, p = 0.034, p < 0.001). Laparoscopic adenomyoma excision and GnRH agonists can alleviate the symptoms, reduce the number of methylated CpG sites in HOXA10, and improve endometrial HOXA10-mRNA and endometrial LIF-mRNA levels. When combined with subsequent use of the LNG-IUS, better efficacy can be achieved.

Atypical polypoid adenomyoma treated by hysteroscopy with photodynamic diagnosis using 5-aminolevulinic acid: A case report.

Surgical resection for atypical polypoid adenomyoma (APA) is an option for fertility preservation. Due to the high recurrence rate of APA, studies have been conducted to improve total resection of tumors. Photodynamic diagnosis (PDD) using 5-aminolevulinic acid (5-ALA) improves tumor resection, but this has not been applied for APA. The patient was 35-year-old. After initial treatment, the APA lesion did not disappear. We performed hysteroscopic tumor resection using 5-ALA-PDD. Only one PDD-positive lesion was found and histopathologically diagnosed as APA. Other areas were PDD-negative and showed no histopathologic APA or malignant findings. This is the first report of hysteroscopic 5-ALA-PDD for APA. This method makes it easy to identify morbid lesions, and may lead to improved total resection and decreased recurrence.

Successful laparotomy tumor resection and levonorgestrel-releasing intrauterine system for atypical polypoid adenomyoma.

Hysteroscopic transcervical resection (TCR) is often performed as fertility sparing treatment for atypical polypoid adenomyoma (APA) patients. However, TCR has the risk of uterine wall perforation, especially when the tumor extends deeply into the uterine muscle layer. We report an APA patient in whom it was impossible to completely resect the tumor by TCR, but laparotomy tumor resection followed by levonorgestrel-releasing intrauterine system (LNG-IUS) was successful. The patient was a 35-year-old nulligravida woman. We performed laparotomy tumor resection and inserted the LNG-IUS into uterine cavity just after surgery. Microscopic residual tumor was suspected based on histopathological findings. However, the patient has not relapsed for 26 months, even though the LNG-IUS was removed after 6 months. Laparotomy tumor resection may be one fertility sparing treatment option for APA patients. Furthermore, it may be effective to use the LNG-IUS after surgery for two purposes that are adhesion prevention and tumor disappearance.

Postoperative maintenance levonorgestrel-releasing intrauterine system for symptomatic uterine adenomyoma.

OBJECTIVE: To evaluate whether a maintenance levonorgestrel-releasing intrauterine system is effective for preventing the recurrence of postoperative adenomyosis-related symptoms. MATERIALS AND METHODS: From January 2005 through December 2014, a retrospective study including 133 patients with symptomatic adenomyosis undergoing conservative uterine-sparing surgery followed by gonadotropin-releasing hormone agonist treatment was conducted. We excluded the 18 patients who did not meet the inclusion criteria. The patients of intervention group (n = 54) received a levonorgestrel-releasing intrauterine system (LNG-IUS), which was inserted after surgery. The patients without LNG-IUS insertion were enrolled in the control group (n = 61). The primary outcome was improvement of adenomyosis-related dysmenorrhea, which was evaluated by the visual analog scale (VAS) and by hemoglobin (Hgb) and CA-125 levels. RESULTS: Over a 12-month follow-up, the intervention group exhibited a greater reduction in dysmenorrhea as assessed with a VAS score (mean ± SD: 6.5 ± 2.5 vs 4.1 ± 3.6, p = 0.001) and a greater elevation in the Hgb level (2.1 ± 1.9 vs 1.0 ± 1.7, p = 0.008) than the control group. At the end of the 24-month follow-up period, the intervention group also exhibited a greater reduction in dysmenorrhea as assessed with a VAS score (mean ± SD 6.1 ± 2.7 vs 3.7 ± 3.7, p = 0.002) and a greater elevation in the Hgb level (1.9 ± 2.1 vs 0.7 ± 1.8, p = 0.022) than the control group. The CA-125 level was significantly lower in the intervention group during the postoperative follow up (12th month follow-up, intervention vs control, 24.5 ± 28.8 vs 50.1 ± 44.0, p = 0.005; 24th month follow-up, 28.6 ± 26.2 vs 75.4 ± 68.5, p = 0.002). CONCLUSION: The maintenance therapy of LNG-IUS is effective and well accepted for long-term therapy after conservative surgery for patients with adenomyosis.

Maintenance hormonal therapy after treatment with medroxyprogesterone acetate for patients with atypical polypoid adenomyoma.

BACKGROUND: As atypical polypoid adenomyoma (APA) has been reported to be a hormone-related tumor, we aimed to analyze the efficacy and safety of maintenance hormonal therapy after fertility-preserving treatment of these patients with medroxyprogesterone acetate (MPA). METHODS: Data were retrospectively analyzed from patients with APA who were treated with a fertility-preserving regimen including MPA between October 2001 and December 2011. Eighteen patients were treated with MPA and 14 (77.8%) achieved either a complete or a partial response after the planned treatment. Five patients took progestin for maintenance therapy. RESULTS: Eighteen patients were treated for a mean observation period of 96.7 months. While taking the maintenance therapy, no patient had APA relapse. One patient developed well-differentiated endometrioid adenocarcinoma 18 months after she stopped taking maintenance progestin. Eleven patients without maintenance therapy underwent hysterectomy, andnine of them developed well-differentiated endometrial cancer. Through univariate analysis, there was a significant difference in time to hysterectomy between patients with and without maintenance therapy (P = 0.015). Through multivariate analysis, body mass index (BMI), menstrual status before protocol therapy, maintenance treatment, and pregnancy were found to be significantly associated with a lower risk of hysterectomy. No patient had a recurrence of APA after hysterectomy during the observation period (median, 54 months; range, 2-148 months). CONCLUSION: No patient showed progression while receiving hormonal therapy, including initial protocol therapy. Maintenance hormonal therapy after treatment with MPA was highly effective and safe, particularly in patients with BMI ≧24 kg/m2 and irregular menstruation cycle.

Pregnant outcomes of atypical polypoid adenomyoma treated with progestin therapy.

AIM: We aimed to investigate the long-term clinical and pregnancy outcome in patients with atypical polypoid adenomyoma (APA) after hysteroscopic excision. METHODS: We analyzed the clinicopathological features, including pregnancy outcomes, in 10 APA patients who had been treated with hysteroscopic excision of the lesion and progesterone therapy. RESULTS: The patients were all nulliparous, and nine had been clinically diagnosed as infertile. There were five patients with complex endometrial hyperplasia at the time of initial diagnosis, two of them had had recurrence of complex hyperplasia, and there was another one who had had complex hyperplasia 18 months after initial diagnosis. The patients had been treated with polypectomy under hysteroscopy and a long-term progestin therapy. They had achieved complete regression, but four had a recurrent or persistent disease. Two patients had eventually undergone hysterectomy due to endometrial carcinoma at 102 months (patient 2) or persisting complex atypical hyperplasia at 131 months (patient 5) after initial diagnosis. All patients were alive with no evidence of disease during a follow-up period of 19-145 months. Seven patients had succeeded in pregnancy with nine live births. Three pregnancies had been achieved by in vitro fertilization and embryo transfer. CONCLUSION: Fertility-sparing surgery under hysteroscopy with progesterone therapy and appropriate assistant reproduction technology is an alternative option for young APA patients. However, close follow-up is required for these patients.

Neoplasia in Turner syndrome. The importance of clinical and screening practices during follow-up.

AIM OF THE STUDY: Turmer syndrome (TS) patients show increased morbidity due to metabolic, autoimmune and cardiovascular disorders. A risk of neoplasia is also reported. Here, we review the prevalence of neoplasia in a cohort of Turner patients. METHODS: We retrospectively evaluated 87 TS women. Follow-up included periodic ultrasound of the neck, abdominal and pelvic organs, dermatologic evaluation and fecal occult blood test. Karyotype was 45,X in 46 patients. During follow-up, 63 girls were treated with growth hormone, 65 with estro-progestin replacement therapy and 20 with L-thyroxine. Autoimmune diseases were present in 29 TS. RESULTS: A total of 17 neoplasms in 14 out of 87 patients were found. Six skin neoplasia, 3 central nervous system tumors, 3 gonadal neoplasia, 2 breast tumors, 1 hepatocarcinoma, 1 carcinoma of the pancreas and 1 follicular thyroid cancer were detected. Age at tumor diagnosis was higher in 45,X pts than in those with other karyotypes (p = 0.003). Adenomioma gallbladdder (AG) was detected in 15.3% of the patients, with a lower age in girls at diagnosis with an associated neoplasia in comparison with TS without tumors (p = 0.017). No correlation between genetic make up, treatment, associated autoimmune diseases and neoplastia was found. CONCLUSION: In our TS population an increased neoplasia prevalence was reported. A high prevalence of AG was also noted and it might be indicative of a predisposition to neoplasia. Further studies are needed to define the overall risk for neoplasia, and to determine the role of the loss of the X-chromosome and hormonal therapies.

Long-term outcomes of fertility-sparing treatment of atypical polypoid adenomyoma with medroxyprogesterone acetate.

PURPOSE: Our objective was to analyze the long-term oncologic outcomes of fertility-preserving hormonal treatment with medroxyprogesterone acetate (MPA) in patients with APA. METHODS: In a retrospective chart review, we identified patients with APA who were treated with MPA for fertility preservation at our hospital between 2001 and 2011. Eighteen patients with histologically diagnosed APA were identified. Clinical data including treatment, obstetrical, and oncologic outcomes were recorded. RESULTS: The mean observation period was 77.6 months (median 73.5, range 22-142), and the mean age was 33.6 years. Four patients also developed well-differentiated endometrial carcinoma. After the treatment, 14 patients (77.8 %) achieved either a complete response or partial response. Eight patients experienced recurrence, while four experienced persistent disease. Ten patients (55.6 %) eventually underwent hysterectomy. The median time to hysterectomy was 40.3 months (range 24-68). Nine patients progressed to endometrial cancer, and one experienced persistent APA. Among younger patients (<35 years of age), four out of five patients who were married could have children. Seven patients (38.9 %) showed no evidence of the disease during the observation period (median 60 months, range 22-117 months). No one died because of the disease during the observation period. CONCLUSIONS: MPA yields a high response rate in APA, and if only younger patients are considered, a favorable pregnancy rate can be obtained. However, because recurrence rate is high, long-term follow-up under supervision of a trained gynecologic oncologist is required. To confirm MPA's utility, multi-center collaboration would be warranted.

Medical treatment for adenomyosis and/or adenomyoma.

Uterine adenomyosis and/or adenomyoma is characterized by the presence of heterotopic endometrial glands and stroma within the myometrium, >2.5 mm in depth in the myometrium or more than one microscopic field at 10 times magnification from the endometrium-myometrium junction, and a variable degree of adjacent myometrial hyperplasia, causing globular and cystic enlargement of the myometrium, with some cysts filled with extravasated, hemolyzed red blood cells, and siderophages. Hysterectomy is a "gold standard" and definitive therapy for uterine adenomyosis, and many cases of adenomyosis have been diagnosed by pathological review retrospectively. As such, the diagnosis of adenomyosis is difficult, and this subsequently results in difficulty in the management of these patients, especially those who are symptomatic but have a strong desire to preserve their uterus. In our previous review, we found that the use of uterine-sparing surgery in the management of uterine adenomyosis and/or adenomyoma is still controversial, although some data support its feasibility. Conservative treatment is still needed in the group of patients that requires preservation of fertility and improvement of quality of life. However, studies focusing on the topic of medical treatment for adenomyosis are rare. In this article, current knowledge regarding the use of medical therapy for uterine adenomyosis, partly based on the understanding of endometriosis, is reviewed.

Adenomyoma associated with high level of CA 125 and CA 19-9: case report.

PURPOSE OF INVESTIGATION: A rare case of increasing CA 125 and CA 19-9 levels increasing in a woman with adenomyoma is described. METHODS: A 39-year-old nullipara woman with CA 125 = 1,796 U/ml and CA 19-9 = 177 U/ml was submitted to abdominal and pelvic MRI, gastric endoscopy, colonoscopy, hysteroscopy, pelvic Doppler and PET scan. None of the exams revealed any apparent malignant disease. RESULTS: Six months of gonadotropin releasing hormone agonist treatment reduced CA 125 and CA 19-9 levels. However, after contraceptive pill use the markers were again elevated, and a laparoscopic hysterectomy was performed, and normal CA 125 and CA 19-9 levels were achieved. CONCLUSIONS: Adenomyoma may be associated with high levels of CA 125 and CA 19-9.

Comparison of surgery alone and combined surgical-medical treatment in the management of symptomatic uterine adenomyoma.

OBJECTIVE: To compare the efficacy of surgical-medical treatment and surgery alone in the treatment of uterine symptomatic adenomyoma. DESIGN: Prospective nonrandomized study. SETTING: Medical centers. PATIENT(S): One hundred sixty-five women treated with conservative adenomyomectomy. INTERVENTION(S): Surgery followed by six-course treatment (n = 114, surgical-medical group) or no treatment (n = 51, surgery-alone group) with a gonadotropin-releasing hormone (GnRH) agonist regimen. MAIN OUTCOME MEASURE(S): Symptom relief (scale: 0, no symptoms, to 5, worst symptoms) and relapse (when any one scale was > or =2 after treatment) during the 2-year follow-up period. RESULT(S): The general characteristics of the patients were similar in both groups, except for the diameter of the adenomyoma and age. Patients in both groups had statistically significant symptom relief, and all symptom scores declined from a mean of 3 or 4 to a mean of 1 or less at the end of the 2-year follow-up period. The symptom-relapse rates in the surgical-medical group were statistically significantly lower than those in the surgery alone group (n = 32, 28.1% vs. n = 25, 49.0%, respectively). CONCLUSION(S): Conservative surgery, regardless of GnRH agonist treatment, may be acceptable for management of a selected population with severe symptomatic adenomyoma. However, surgical-medical treatment provided more effective symptom control (a lower symptom relapse rate) than surgery alone during the 2-year follow-up period.

[Effect of triptorelin and an extended-interval dosing regimen in the treatment of patients with endometriosis and adenomyoma].

OBJECTIVE: To study the role of triptorelin in the treatment of patients with endometriosis, adenomyoma and fibromyoma and the effect of an extended-interval dosing regimen. METHODS: Seventy patients suffering from endometriosis, adenomyoma and fibromyoma were divided into two groups: extended-interval dosing (group E) and conventional dosing (group C). There were treated with injection of triptorelin 3.75 mg intramuscularly either every 6 weeks of totally four dose regimen (group E) or every 4 weeks of six dose regimen (group C). Comparison was made in improvement of symptoms, size of uterus and volume of tumor, as well as in serum levels of 17beta-estradiol, luteinizing hormone, and follicle-stimulating hormone. RESULTS: In each group, symptoms and tumor growth significantly improved after treatment (P < 0.05). For the patients of both groups E and C, the levels of gonadotropins and gonadal steroids were obviously reduced throughout the treatment period and up to 8 - 10 weeks after the injection of the last dose (P < 0.05). The hormonal profile of group E was similar to group C (P > 0.05). CONCLUSIONS: Gonadotropin-releasing hormone agonist is efficacious in the treatment of endometriosis and adenomyoma through reducing the serum levels of follicle-stimulating hormone, luteinizing hormone and 17beta-estradiol. The curative effect is satisfactory in most patients receiving an extended interval dosing regimen. To reduce the cost of treatment, the extended-interval dosing regimen of triptorelin should be adopted in well-equipped hospitals.

Expression of apoptosis-related proteins in adenomyotic uteri treated with danazol and GnRH agonists.

The biologic properties of adenomyosis and the effects of therapeutic agents on adenomyosis were evaluated with immunohistochemistry, terminal deoxy-nucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method, transmission electron microscopy, and analysis of genomic abnormality. In the adenomyotic endometrium, estrogen receptor (ER) expression was more intense than in the eutopic endometrium during the secretory phase, and bcl-2 was constantly expressed throughout the menstrual cycle. The expression of ER and bcl-2 was weaker in the adenomyotic endometrium treated with danazol than in that treated with gonadotro-pin-releasing hormone agonist (GnRHa), whereas bcl-2 phosphorylated on serine-87 was more intensely expressed in danazol-treated adenomyotic endometrium than in the GnRHa-treated one. The number of TUNEL-positive cells increased in the adenomyotic endometrium treated with danazol or GnRHa. Ultrastructurally, most of the adenomyotic endometrial cells treated with danazol underwent postapoptotic necrosis and formed a cluster of dead cells. In contrast, cells treated with GnRHa underwent typical apoptosis and were sparsely distributed in the adenomyotic endometrium. Analysis of several cancer-related genes showed no microsatellite instability or loss of heterozygosity in adenomyotic tissues. Therefore, we conclude that the occurrence of adenomyosis is correlated to bcl-2 expression regulated by estrogen and ER rather than genetic mutation.

Effects of angiogenesis inhibitor TNP-470 on the development of uterine adenomyosis in mice.

OBJECTIVE: To investigate the effects of angiogenesis inhibitor TNP-470 on uterine microvessels in mice. Pituitary grafting frequently induced uterine adenomyosis. DESIGN: In vivo experimental study. SETTING: Department of Biological Sciences, University of Tokyo and Medical Research Institute, Tokyo Medical and Dental University. ANIMAL(S): SHN mice, which are known to develop uterine adenomyosis spontaneously, and also very soon after pituitary grafting. INTERVENTION(S): Immunohistochemical study on uterine blood vessels using an antibody to von Willebrand factor in pituitary gland-implanted mice with or without TNP-470. MAIN OUTCOME MEASURE(S): Reduced incidence of uterine adenomyosis. RESULT(S): Twelve of 15 mice developed uterine adenomyosis with dilated blood vessels, but none of the TNP-470-treated mice with shrunken microvessels. The number of bromodeoxyuridine immunoreactive cells and activities of thymidylate synthase and thymidine kinase in uterine tissues were markedly reduced in TNP-470-treated mice. CONCLUSION(S): TNP-470, a potent inhibitor of the development of vascular endothelium, reduced the development of endometrial blood vessels resulting in a lowered incidence of uterine adenomyosis induced by pituitary grafting in mice, and reduced the increase in S-phase cells and enzyme activity for pyrimidine nucleotide synthesis.

Clinical usefulness of urinary CrossLaps as a sensitive marker of bone metabolism.

CrossLaps peptide [Glu-Lys-Ala-His-Asp-Gly-Gly-Arg], a part of the C-telopeptide of the alpha 1-chain of type I collagen of bone, is a recently developed biochemical marker of bone turnover. In this study, the clinical utility of measurement of urinary CrossLaps was investigated in eleven premenopausal women who received a gonadotropin-releasing hormone (GnRH) agonist for 6 months for treatment of adenomyosis (n = 1) or leiomyomas (n = 10). Along with urinary CrossLaps, the levels of various biochemical markers, and serum estradiol, calcitonin and intact parathyroid hormone (i-PTH) were measured, and lumbar spine bone mineral density (BMD) was also monitored before, during, and at the end of the course of GnRH agonist therapy. Apart from CrossLaps, markers of bone resorption tested were urinary pyridinoline, deoxypyridinoline and hydroxyproline. Markers of bone formation tested were serum osteocalcin and bone-specific alkaline phosphatase (B-ALP). Serum estradiol levels decreased to undetectable levels at 2 months of GnRH agonist therapy. The values for all biochemical markers increased significantly throughout the therapy. The degree of an increase in CrossLaps levels was greater than that in all other markers. Mean lumbar spine (L2-L4) BMD was decreased by 7.2% at 6 months of treatment. The percent change in BMD at 6 months of treatment correlated inversely with the percent change in CrossLaps levels from the baseline to 1, 2, and 5 months of treatment. These results indicate that measurement of urinary CrossLaps might be a useful tool to predict the risk of bone loss caused by hypoestrogenism including GnRH agonist therapy.

Laparoscopic bipolar coagulation for the conservative treatment of adenomyomata.

STUDY OBJECTIVE: To assess the effectiveness of treating adenomyomata with laparoscopic bipolar coagulation. DESIGN: Prospective, observational study. Setting. The gynecology department of a community hospital. PATIENTS: Ten women, each with severe dysmenorrhea, chronic menorrhagia, and adenomyomata diagnosed by magnetic resonance imaging. INTERVENTIONS: Laparoscopic bipolar coagulation of adenomyomata. MEASUREMENTS AND MAIN RESULTS: The mean (+/- SEM) total adenomyoma volume before leuprolide acetate administration was 119 +/- 16 cm3 (range 6-190 cm3); after 3 months of therapy this was reduced to 86 +/- 8 cm3 (range 6-162 cm3, p <0. 0001) a 27.7% reduction. Further reduction occurred 7 to 12 months postoperatively to 31 +/- 3.4 cm3 (range 3-155 cm3, p <0.0001), a 73.9% reduction from baseline. Twelve months postoperatively, seven (70.0%, p <0.05) women had continued resolution or significant reduction of dysmenorrhea and resolution of menorrhagia. One woman (10.0%) with unresolved dysmenorrhea and menorrhagia required hysterectomy, and two (20.0%) with recurrent menorrhagia required resection of the endomyometrium; one continued to have menorrhagia but refused further surgical or medical treatment. CONCLUSIONS: Conservative treatment obviated the need for major surgery in 90% of women with adenomyomata, but further evaluation of this technique is necessary to determine its definitive role.