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Uterine Sarcoma

Uterine sarcoma is a rare kind of cancer in which the cells in the muscles or other supporting tissues of the uterus become cancerous, and represents 1% of gynaecological cancers overall. This is very different to endometrial (uterus) cancer - see above. There are two main histological sub-types; leiomyosarcoma, and stromal sarcoma. A known risk factor for developing uterine sarcoma is prior radiotherapy to the pelvic area, this is estimated to account for between 10% to 25% of cases.

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    MeSH term: Uterine Neoplasms
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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Hayashi T, Kawano M, Ichimura T, et al.
Molecular Pathology and Novel Clinical Therapy for Uterine Leiomyosarcoma.
Anticancer Res. 2016; 36(10):4997-5007 [PubMed] Related Publications
Patients with uterine leiomyosarcoma (LMS) typically present with vaginal bleeding, pain, and a pelvic mass, with atypical presentations of hypercalcemia and eosinophilia also being reported. Radiographic evaluation with combined positron-emission tomography/computed tomography may assist in diagnosis and surveillance in women with uterine LMS; these are commonly used with stage and tumour grade as prognostic indicators and a recently developed risk-assessment index to predict disease-specific survival. Recent studies have shown that the addition of adjuvant therapy after surgical management does not seem to improve survival, and ovarian preservation does not appear to negatively impact outcome. Experimentally, it is noteworthy that proteasome subunit beta 9 (PSMB9)/β1i-deficient mice exhibit spontaneous development of uterine LMS, with a disease prevalence of ~37% by 12 months of age. Furthermore, a recent report showed the loss of ability to induce PSMB9/β1i expression, that is up-regulated by interferon-γ (IFNγ), in human uterine LMS tissues. Here, we reviewed human uterine LMS for genetic mutations in the IFNγ signal cascade, and found serious mutations in three genes, Janus activated kinase 1 (JAK1), signal transducer and activator of transcription 1 (STAT1) and PSMB9/β1i promoter regions. Moreover, molecular experiments demonstrated differential expression of cyclin E and P27/KIP1, that regulate cell-cycle G1 arrest via PSMB9/β1i expression. The discovery of this mutational activation of a key cell-signalling pathway may provide new targets for diagnostic approaches and therapeutic intervention.

Boban M, Tomic S, Sulic M, Vrdoljak E
Three radiation-induced metachronous pelvic tumors in a patient who underwent radiotherapy for cervical cancer: a case report.
Tumori. 2016; 102(Suppl. 2) [PubMed] Related Publications
INTRODUCTION: Patients treated with radiotherapy are under increased long-term risk of developing radiation-induced tumors. In this report we present an exceptionally rare case of a patient who, following radiotherapy for cervical cancer, developed 3 radiation-induced metachronous pelvic tumors.
CASE PRESENTATION: In 1997, a 37-year-old patient with cervical adenocarcinoma (FIGO stage IB2) was subjected to adjuvant conventionally fractionated external-beam radiation therapy and brachytherapy following surgical treatment. Eleven, 14 and 15 years later, 3 radiation-induced malignant tumors developed: a leiomyosarcoma of the gluteus and 2 separate carcinomas of the rectum.
DISCUSSION AND CONCLUSION: Radiotherapy for cervical carcinoma increases the standardized incidence ratios for rectal cancer and soft tissue sarcoma. Unfortunately, the current guidelines on contraindications to radiotherapy appear insufficient as they take into account a very limited number of clinical states and associated conditions, which is in disproportion to the rather high risk of radiation-induced malignancies of 0.45%. Information on the molecular characteristics of human radiation-induced tumors is still of no relevance for everyday clinical practice. Although radiotherapy is one of the most important modalities of oncological treatment, it should be judiciously used in cases where the benefits clearly outweigh the risk of serious untoward effects. In the case of patients undergoing pelvic irradiation, careful follow-up is needed for years.

Artioli G, Borgato L, Calamelli S, Azzarello G
Unusual cardiac metastasis of uterine leiomyosarcoma: case report and literature review.
Tumori. 2016; 102(Suppl. 2) [PubMed] Related Publications
BACKGROUND: Uterine leiomyosarcoma (LMS) is a rare malignancy of mesenchymal tissues and in advanced stages its prognosis is very poor. Surgery followed by radiotherapy and/or chemotherapy is the treatment of choice for advanced disease. Cardiac metastases are very uncommon and only a few cases have been described to date.
CASE: A 55-year-old woman was referred to our center for a uterine LMS with lung metastases at diagnosis. After 3 lines of chemotherapy for persistent lung disease, CT scan showed suspected thrombosis in the right pulmonary vein, along with disease progression in the lungs. The patient started treatment with low-molecular-weight heparin and a fourth line of chemotherapy. After 3 months of therapy, a new CT scan showed a larger thrombus and she underwent a cardiology visit that revealed an intracardiac mass. Submitting the patient to palliative surgery or radiation therapy was not possible because of the aggressiveness of the lung metastases, so she continued chemotherapy, resulting in disease stabilization.
CONCLUSIONS: Surgery is the best option for intracardiac dissemination of uterine LMS, but when this is not possible based on the performance status of the patient and spread of the disease, the combination of chemotherapy and radiotherapy seems to be the best option according to the literature. In our case we treated the patient only with chemotherapy.

Skorstad M, Kent A, Lieng M
Preoperative evaluation in women with uterine leiomyosarcoma. A nationwide cohort study.
Acta Obstet Gynecol Scand. 2016; 95(11):1228-1234 [PubMed] Related Publications
INTRODUCTION: The goal of this study was to assess the sensitivity of different preoperative diagnostic tools used in women with uterine leiomyosarcomas.
MATERIAL AND METHODS: Retrospective cohort study of all women with verified uterine leiomyosarcoma in Norway in the period 2000 to 2012. Data were collected from the Cancer Registry of Norway and medical records.
RESULTS: There were 212 women diagnosed with uterine leiomyosarcoma in the 13-year period. Histopathological examinations by fractional curettage or endometrial biopsies verified malignancy in 55/142 (38.7%). MRI suggested malignancy in 45/55 (81%) of the examinations. CT evaluations indicated suspected malignancy in 64/107 women (59.8%). Biomarkers had low sensitivity for leiomyosarcoma, but suggested more advanced stage disease when high values were detected. Stage IV disease was present in 53.1% versus 25.5% (p = 0.01) of women with CA 125 values above 35 kU/L, compared with women with normal CA 125 values. In 115/212 (54.2%), leiomyosarcoma was only diagnosed postoperatively by histopathological examination of the removed specimen.
CONCLUSIONS: Preoperative diagnostic modalities appear to have low sensitivity for differentiating leiomyosarcoma from fibroids. In Norway, approximately 54% of uterine leiomyosarcoma are unidentified before surgery. MRI evaluation was the imaging modality with the greatest sensitivity in identifying leiomyosarcoma preoperatively.

Lützen U, Zhao Y, Lucht K, et al.
Pioglitazone induces cell growth arrest and activates mitochondrial apoptosis in human uterine leiomyosarcoma cells by a peroxisome proliferator-activated receptor γ-independent mechanism.
Naunyn Schmiedebergs Arch Pharmacol. 2017; 390(1):37-48 [PubMed] Related Publications
The peroxisome proliferator-activated receptor γ (PPARγ) agonists, thiazolidinediones, including pioglitazone (PIO) exhibit anti-tumour activities in cancer cells. The present study investigates the effects of PIO on cell proliferation and apoptosis in SK-UT-1 cells, a human uterine leiomyosarcoma cell line, and human uterine smooth muscle cells (HUtSMC). The proliferation and viability of SK-UT-1 cells treated with vehicle or PIO were assessed by cell counting and WST-1 assay. The activity of MEK/ERK and p38 MAPK signalling pathways and the expression of p53, the cyclin-dependent kinase inhibitor, p21, Bax, Bad and Bim proteins and cleaved caspase-3 were analysed by Western blotting. Quiescent SK-UT-1 cells intensively proliferate and display high levels of phosphorylated, activated MEK1/2, ERK1/2 and p38 MAPK. PIO (10 or 25 μM) induced time- and dose-dependently cell-growth arrest, reduced the cell numbers and effectively suppressed the over-activated MEK/ERK and p38 MAPK signalling pathways as evidenced by the abolished levels of phosphorylated MEK1/2, ERK1/2 and p38 MAPK. PIO activated the intrinsic apoptotic pathway, i.e. up-regulated the p53, p21, Bax and Bad proteins and cleaved caspase-3. PIO also reduced cell numbers of highly proliferative SK-UT-1 cells cultured in growth medium. The anti-proliferative and pro-apoptotic actions of PIO were not PPARγ dependent and exclusive for SK-UT-1 cells as PIO did not interfere with the proliferation of HUtSMC. The pronounced anti-tumorigenic effects of PIO in SK-UT-1 cells address an important issue about the relevance of the PPARγ agonist in the treatment of the human uterine leiomyosarcoma.

Srettabunjong S, Chuangsuwanich T
Inferior Vena Cava Tumor Thrombosis Secondary to Metastatic Uterine Cancer: A Rare Cause of Sudden Unexpected Death.
J Forensic Sci. 2016; 61(2):555-8 [PubMed] Related Publications
Pulmonary tumor thromboembolus (PTTE) secondary to uterine cancer is a rare cause of sudden unexpected deaths in the elderly population. Additionally, tumor extension to the inferior vena cava (IVC) makes it rarer. No such cases have been previously reported in the forensic literature. We report this phenomenon in a previously healthy 70-year-old woman with no other known risk factors for the development of deep vein thrombosis. The deceased was found dead while watching television with her relatives. Autopsy examination revealed that her death was attributed to a saddle embolus lodged in the main pulmonary arteries. A uterine tumor was discovered, and microscopic examination revealed low-grade endometrial stromal sarcoma with angiolymphatic invasion. The tumor cells were also found in the embolus and the remnant thrombosis attached to the inner wall of the IVC. This case demonstrates a sudden unexpected death caused by acute PTTE following seeding of uterine cancer into the IVC and raises awareness of such events.

Holzmann C, Löning T, Bullerdiek J
Hyperhaploid uterine mesenchymal tumors-a novel genetic subgroup?
Cancer Genet. 2016; 209(6):278-81 [PubMed] Related Publications
Hyperhaploid karyotypes have been described to occur in subsets of various solid tumors and leukemias. In these cases, monosomy is noted for most of the chromosomes while a few chromosomes still remain disomic. Evidence has emerged that at least in some tumor entities these remaining chromosomes are non-randomly selected. In addition, structural alterations can accompany the reduced chromosome number and secondary duplication of the chromosome complement is also a frequent finding. In this report, we describe hyperhaploidy in a case of an endometrial stromal nodule of a 50 year old woman who underwent hysterectomy because of symptomatic uterine fibroids. In addition, we review two other recently described cases of uterine mesenchymal tumors with that type of genetic alteration. Despite some histologic differences, striking similarities between these three cases exist with respect to the chromosomes were retained as disomic. Thus, the question arises if hyperhaploidy defines a novel genetic subgroup of uterine mesenchymal tumors.

Shu CA, Pike MC, Jotwani AR, et al.
Uterine Cancer After Risk-Reducing Salpingo-oophorectomy Without Hysterectomy in Women With BRCA Mutations.
JAMA Oncol. 2016; 2(11):1434-1440 [PubMed] Related Publications
Importance: The link between BRCA mutations and uterine cancer is unclear. Therefore, although risk-reducing salpingo-oophorectomy (RRSO) is standard treatment among women with BRCA mutations (BRCA+ women), the role of concomitant hysterectomy is controversial.
Objective: To determine the risk for uterine cancer and distribution of specific histologic subtypes in BRCA+ women after RRSO without hysterectomy.
Design, Setting, and Participants: This multicenter prospective cohort study included 1083 women with a deleterious BRCA1 or BRCA2 mutation identified from January 1, 1995, to December 31, 2011, at 9 academic medical centers in the United States and the United Kingdom who underwent RRSO without a prior or concomitant hysterectomy. Of these, 627 participants were BRCA1+; 453, BRCA2+; and 3, both. Participants were prospectively followed up for a median 5.1 (interquartile range [IQR], 3.0-8.4) years after ascertainment, BRCA testing, or RRSO (whichever occurred last). Follow up data available through October 14, 2014, were included in the analyses. Censoring occurred at uterine cancer diagnosis, hysterectomy, last follow-up, or death. New cancers were categorized by histologic subtype, and available tumors were analyzed for loss of the wild-type BRCA gene and/or protein expression.
Main Outcomes and Measures: Incidence of uterine corpus cancer in BRCA+ women who underwent RRSO without hysterectomy compared with rates expected from the Surveillance, Epidemiology, and End Results database.
Results: Among the 1083 women women who underwent RRSO without hysterectomy at a median age 45.6 (IQR: 40.9 - 52.5), 8 incident uterine cancers were observed (4.3 expected; observed to expected [O:E] ratio, 1.9; 95% CI, 0.8-3.7; P = .09). No increased risk for endometrioid endometrial carcinoma or sarcoma was found after stratifying by subtype. Five serous and/or serous-like (serous/serous-like) endometrial carcinomas were observed (4 BRCA1+ and 1 BRCA2+) 7.2 to 12.9 years after RRSO (BRCA1: 0.18 expected [O:E ratio, 22.2; 95% CI, 6.1-56.9; P < .001]; BRCA2: 0.16 expected [O:E ratio, 6.4; 95% CI, 0.2-35.5; P = .15]). Tumor analyses confirmed loss of the wild-type BRCA1 gene and/or protein expression in all 3 available serous/serous-like BRCA1+ tumors.
Conclusions and Relevance: Although the overall risk for uterine cancer after RRSO was not increased, the risk for serous/serous-like endometrial carcinoma was increased in BRCA1+ women. This risk should be considered when discussing the advantages and risks of hysterectomy at the time of RRSO in BRCA1+ women.

Prueksaritanond N, Chantape W
Comparative Survival Outcomes of Uterine Papillary Serous Carcinoma, Clear Cell Carcinoma, Grade 3 Endometrioid Adenocarcinoma, and Carcinosarcoma of Endometrial Cancer in Rajavithi Hospital.
J Med Assoc Thai. 2016; 99 Suppl 2:S75-83 [PubMed] Related Publications
BACKGROUND: Uterine papillary serous carcinoma (UPSC), clear cell carcinoma (CC), grade 3 endometrioid adenocarcinoma (G3EC), and carcinosarcoma (CS) have been identified as high-grade endometrial cancers and account for the majority of uterine cancer deaths.
OBJECTIVE: To compare survival outcomes of patients with UPSC, CC, G3EC and CS in Rajavithi Hospital.
MATERIAL AND METHOD: A retrospective review was performed of all patients with FIGO stage I-IV endometrial cancer in Rajavithi Hospital between 1 January 2007 and 31 December 2012. Kaplan-Meier estimates were made of overall survival (OS) and progression-free survival (PFS), and log-rank tests were used to compare survival distributions between histological subtypes. Cox regression was used to estimate hazard ratios for histological subtypes, adjusted for other significant prognostic factors.
RESULTS: One hundred sixty-three patients had confirmed diagnosis of high-grade endometrial cancer: 45 had UPSC, 30 had CC; 58 had G3EC; and 30 had CS. The median age distribution of the four groups of patients was approximately 60 years. The body mass index, underlying disease, and parity were similar in each group. All patients underwent a hysterectomy and surgical staging procedure. The 2-year progression-free survival was poorest in the CS cases (79.4%), followed by CC (87.2%), G3EC (92.2%), and UPSC cases (95.5%), and these figures were statistically significantly different among the groups (p = 0.015). The 2-year overall survival was poorest in the CC cases (70.0%), followed by CS (76.7%), UPSC (86.7%), and G3EC (87.9%); however, there were no significant differences among the groups (p = 0.071). In multivariate analysis for OS, advanced stage and suboptimal surgery were significantly associated with increased risk of death. For PFS, advanced stage and positive peritoneal cytology were significantly associated with increased risk of recurrence.
CONCLUSION: CS patients had a significantly lower rate of progression-free survival than other subtypes. These findings should be taken into account when considering counseling, primary treatment and appropriate adjuvant treatment in order to improve survival outcomes in these high-risk patients.

Skorstad M, Kent A, Lieng M
Uterine leiomyosarcoma - incidence, treatment, and the impact of morcellation. A nationwide cohort study.
Acta Obstet Gynecol Scand. 2016; 95(9):984-90 [PubMed] Related Publications
INTRODUCTION: The risk of morcellation of occult uterine leiomyosarcomas (LMS) during laparoscopic procedures has been under scrutiny over recent years. The objective of this study was to assess the operative treatment performed in women with uterine LMS in Norway in 2000-2012, including the number of morcellated LMS.
MATERIAL AND METHODS: Retrospective nationwide cohort study. The study participants were all women with histopathologically verified uterine LMS in Norway during 2000-2012. The data were collected from the Cancer Registry of Norway, National Patient Registry and medical records.
RESULTS: There were 212 women diagnosed with uterine LMS in Norway in 2000-2012. Mean age at time of diagnosis was 58.1 years (SD ± 12.5). The most frequent symptom in women suffering from LMS was abnormal uterine bleeding [110/212 (51.9%)]. LMS was histopathologically verified in 49/212 (23.1%) preoperatively. In 48/212 (22.6%), a malignant condition was suspected and they were treated accordingly. In 115/212 (54.2%), malignancy was not suspected at time of surgery and the women were treated according to the treatment protocol for fibroids. In only four patients was tissue retrieval by power morcellation conducted, accounting for 1.9% of all LMS cases.
CONCLUSIONS: In more than 50% of women suffering from LMS, a malignant diagnosis was not confirmed or suspected prior to surgery. In our material, power morcellation of LMS has not lead to reduced survival. We suggest that power morcellators may be used in surgical treatment of selected cases of premenopausal women with symptomatic, presumed benign uterine leiomyomas.

Potikul C, Tangjitgamol S, Khunnarong J, et al.
Uterine Sarcoma: Clinical Presentation, Treatment and Survival Outcomes in Thailand.
Asian Pac J Cancer Prev. 2016; 17(4):1759-67 [PubMed] Related Publications
BACKGROUND: Uterine sarcoma is a group of rare gynecologic tumors with various natures, and different lines of treatment. Most have a poor treatment outcome. This study targeted clinical characteristics, treatment, overall survival (OS), progression-free survival (PFS), and prognostic factors in uterine sarcoma patients in one tertiary center for cancer care.
MATERIALS AND METHODS: Uterine sarcoma patients who were treated at the Department of Obstetrics and Gynecology, Faculty of Medicine Vajira Hospital between January 1994 and December 2014 were identified. Clinico-pathological data were analyzed. Prognostic outcomes were examined by Kaplan-Meier curves and Cox regression analysis.
RESULTS: We identified 46 uterine sarcoma patients: 25 carcinosarcoma (CS) (54.3%), 15 leiomyosarcoma (LMS) (32.6%), and 6 undifferentiated uterine sarcoma (UUS) (13.1%) cases. Mean age was 54.0±11.9 years (range 25-82 years). Abnormal uterine bleeding was the most common presenting symptom (63.0%). Among 33 patients (71.7%) who had pre-operative tissue collected, diagnosis of malignancy was correct in 29 (87.9%). All patients received primary surgery and retroperitoneal lymph nodes were resected in 34 (73.9%). After surgery, 5 (10.9%) had gross residual tumors. Stage I disease was most commonly found (56.5%). Adjuvant treatment was given to 27 (58.7%), most commonly chemotherapy. After a median follow-up of 16.0 months (range 0.8-187.4 months), recurrence was encountered in 22 patients (47.8%). Median time to recurrence was 5.8 months (range1.0-105.5 months). Distant metastasis was more common than local or loco- regional failure. The 2-year PFS was 45.2% (95% confidence interval [CI], 30.6%-59.7%) and the 2-year OS was 48.3% (95% CI, 33.3%-60.7%). Multivariable analyses found residual disease after surgery as a significant factor only for PFS.
CONCLUSIONS: Uterine sarcoma is a rare tumor entity. Even with multimodalities of treatment, the prognosis is still poor. Successful cytoreductive surgery is a key factor for a good survival outcome.

Abu-Khalaf MM, Raza MA, Hatzis C, et al.
Efficacy and tolerability of combination cisplatin and ifosfamide chemotherapy with vaginal cuff brachytherapy in the first line treatment of uterine carcinosarcoma.
Eur J Gynaecol Oncol. 2016; 37(2):199-203 [PubMed] Related Publications
PURPOSE OF INVESTIGATION: A retrospective study to evaluate six cycles of cisplatin 40 mg/m2 on day 1 and ifosfamide 1,200 mg/m2 daily on days 1 to 4 with Mesna every four weeks as first line treatment for 29 patients with a diagnosis of uterine carcinosarcoma.
MATERIALS AND METHODS: A total of 23 of 29 patients received high dose rate intracavitary vaginal cuff brachytherapy (VCBT) with two fractions of seven Gy each. Median age was 65 years (range 40-82); 13 (44.8%) had Stage I disease, three (10.3%) had Stage II, eight (27.6%) had Stage III, and five (17.2%) patients had Stage IV disease.
RESULTS: Most common toxicities were anemia grade 1 (35%)/grade 2 (45%), and neutropenia grade 3 (17%)/grade 4 (6.9%). Eleven dose modifications, four treatment discontinuations, and one patient withdrawal occurred. At a median follow up of 45 months (range 9 to 144), Progression free survival (PFS) was 20% and overall survival (OS) was 40% for Stage IV, PFS 75% and OS 62.5% for Stage III, compared to a PFS 75% and OS 72.2% for Stages I-II. Median OS for the entire group was 12.43 years (95% CI 3.69 to inf); for Stage I-III 12.4 years (6.1 to inf), and for Stage IV 15.6 months (95% CI 9.4 to inf).
CONCLUSIONS: Cisplatin and ifosfamide chemotherapy with VCBT was well tolerated and has promising activity in uterine carcinosarcoma.

Karadayi K, Yildiz C, Karakus S, et al.
Cytoreductive surgery and perioperative intraperitoneal chemotherapy for gynecological malignancies: a single center experience.
Eur J Gynaecol Oncol. 2016; 37(2):194-8 [PubMed] Related Publications
INTRODUCTION: The objective of this study was to assess the outcome of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) plus early postoperative intraperitoneal chemotherapy (EPIC) in patients with advanced gynecological malignancies.
MATERIALS AND METHODS: A retrospective series of 51 patients with advanced gynecologic cancer, evaluated between May 2008 to February 2014. Peritoneal Cancer Index (PCI) and Completeness of Cytoreduction (CCR) score were used in the study group. The study group consisted of the cancers of ovarian, fallopian tube, endometrial, and uterine sarcomas.
RESULTS: Mean PCI score of the study group was 18, and the postoperative complications were similar with the literature. Patients were followed in a period of 15 days to 64 months and the mean survival time was 22.8 months. Fifty-two percent of the patients were alive without evidence of the disease and overall one-year survival was found 56%.
CONCLUSIONS: The authors concluded that CRS, HIPEC, EPIC, and peritonectomy are a crucial options in patients with advanced gynecological cancers.

Davidson B, Kjæreng ML, Førsund M, et al.
Progesterone Receptor Expression Is an Independent Prognosticator in FIGO Stage I Uterine Leiomyosarcoma.
Am J Clin Pathol. 2016; 145(4):449-58 [PubMed] Related Publications
OBJECTIVES: To analyze the clinical role of hormone receptors in a large uterine sarcomas series with long-term follow-up.
METHODS: Protein expression of estrogen receptor (ER) and progesterone receptor (PR) by immunohistochemistry was studied in tissue microarrays from 294 patients diagnosed with uterine sarcoma in Norway from 1970 to 2000 and analyzed for an association with clinicopathologic parameters and outcome.
RESULTS: ER and PR were detected in 136 of 291 and 184 of 291 tumors (three noninformative cases each), respectively. Expression was unrelated to histology, patient age, tumor diameter, the degree of atypia, the presence of necrosis or vascular invasion, or mitotic counts. ER and PR expression was unrelated to survival in the analysis of the entire cohort. When survival analysis was confined to stage I leiomyosarcoma (n = 147), higher PR score was significantly related to longer overall survival (OS) (P = .042). Clinicopathologic prognosticators in this group were age (P = .041), tumor diameter (P = .001), and mitotic count (P = .007), with a trend for atypia (P = .087). In Cox multivariate analysis, PR score (P = .019), tumor diameter (P = .013), and mitotic count (P = .002) were independent prognosticators of OS.
CONCLUSIONS: Hormone receptor expression is not informative of outcome in the analysis of uterine sarcomas of all stages and histologic types. PR expression identifies patients with longer survival in stage I leiomyosarcoma.

Baek MH, Park JY, Rhim CC, et al.
Immunohistochemical Characterization of Histone Deacetylase as a Potential Prognostic Marker and Therapeutic Target in Endometrial Stromal Sarcoma.
Anticancer Res. 2016; 36(5):2527-34 [PubMed] Related Publications
AIM: Endometrial stromal sarcoma (ESS) is a rare tumor with limited treatment options. Histone deacetylase (HDAC) is a potential therapeutic target in ESS showing a good rate of response in laboratory studies. In this study we investigated the expression of HDAC enzymes in 41 ESS patients.
MATERIALS AND METHODS: Immunohistochemical expression of HDACs was analyzed by tissue microarrays.
RESULTS: Strong positive immunoreactivity was observed in 32 (78.0%), 23 (56.1%), 8 (19.5%), 36 (87.8%), 7 (17.1%), 30 (73.2%), 31 (75.6%), and 33 (80.5%) for HDACs 1-8, respectively. Although not statistically significant, HDAC 1, 4, 6, 7, and 8 exhibited a high frequency of strong immunoreactivity linked to a lower 10-year DFS (100.0% vs. 81.3%, p=0.202; 100.0% vs. 83.3%, p=0.393; 90.9% vs. 83.3%, p=0.579; 90.0% vs. 83.9%; and 100.0% vs. 81.8%, p=0.207; respectively).
CONCLUSION: HDACs 1, 4, 6, 7, and 8, that showed an especially high frequency of strong immunoreactivity, may represent potential therapeutic targets for ESS.

Ebina Y, Katabuchi H, Mikami M, et al.
Japan Society of Gynecologic Oncology guidelines 2013 for the treatment of uterine body neoplasms.
Int J Clin Oncol. 2016; 21(3):419-34 [PubMed] Related Publications
The third version of the Japan Society of Gynecologic Oncology guidelines for the treatment of uterine body neoplasms was published in 2013. The guidelines comprise nine chapters and nine algorithms. Each chapter includes a clinical question, recommendations, background, objectives, explanations, and references. This revision was intended to collect up-to-date international evidence. The highlights of this revision are to (1) newly specify costs and conflicts of interest; (2) describe the clinical significance of pelvic lymph node dissection and para-aortic lymphadenectomy, including variant histologic types; (3) describe more clearly the indications for laparoscopic surgery as the standard treatment; (4) provide guidelines for post-treatment hormone replacement therapy; (5) clearly differentiate treatment of advanced or recurrent cancer between the initial treatment and the treatment carried out after the primary operation; (6) collectively describe fertility-sparing therapy for both atypical endometrial hyperplasia and endometrioid adenocarcinoma (corresponding to G1) and newly describe relapse therapy after fertility-preserving treatment; and (7) newly describe the treatment of trophoblastic disease. Overall, the objective of these guidelines is to clearly delineate the standard of care for uterine body neoplasms in Japan with the goal of ensuring a high standard of care for all Japanese women diagnosed with uterine body neoplasms.

Terek MC, Akman L, Hursitoglu BS, et al.
The retrospective analysis of patients with uterine sarcomas: A single-center experience.
J Cancer Res Ther. 2016 Jan-Mar; 12(1):309-13 [PubMed] Related Publications
BACKGROUND: Uterine sarcomas are rare, malignant, gynecological tumors and show diverse histopathological features. Therefore, there is no consensus on risk factors for poor outcome and optimal treatment. The aim of this retrospective analysis is to report the clinical outcome of patients with uterine sarcoma treated at a single center.
MATERIALS AND METHODS: The data was obtained regarding the patient's demographic characteristics, pathological results, treatments given, survival, and complications of all uterine sarcoma patients treated in a single center between the years 2000 and 2012. The 80.month overall survival. (OS) was determined with respect to prognostic factors including age, stage of disease, histopathological type, and adjuvant treatment.
RESULTS: A total of 57 case records are retrieved for this retrospective analysis. The mean age of the patients is 62.5 ± 11.2 years. International Federation of Gynecology and Obstetrics (FIGO) stage distribution is stage I: 29; stage II: 13; stage III: 9; stage IV: 6. Fifty-seven patients underwent surgery, 33 received postoperative radiotherapy (PORT), and 32 received chemotherapy. Median follow-up period was 25 months (range 2-85 months). The 80-month OS for the entire group of patients was 36.7%. The significant prognostic factors for survival are age under 50 years, stage of disease, and adjuvant chemotherapy.
CONCLUSION: Although limited by small sample size and retrospective nature, age under 50 years, stage of disease, and adjuvant chemotherapy are significant prognostic factors for survival for uterine sarcomas.

Zhiqiang L, Bin S, Min F, Yufang L
Leiomyosarcoma of cervical stump following subtotal hysterectomy: a case report and review of literature.
Eur J Gynaecol Oncol. 2016; 37(1):148-51 [PubMed] Related Publications
BACKGROUND: Leiomyosarcoma that arises in the uterine cervix stump after subtotal hysterectomy is exceedingly rare. Only one case has been documented. The authors report an unusual case of leiomyosarcoma that arose in the cervix stump.
CASE PRESENTATION: A 46-year-old female presented with a one-month history of vaginal bleeding. Vaginal and ultrasonography examination revealed a mass in the cervix. The patient underwent radical resection of the cervix, bilateral salpingo-oophorectomy, and pelvic lymphadenectomy. Chemotherapy and radiotherapy was given after the operation. The patient suffered from severe menopausal symptoms and received hormone replacement therapy. She eventually committed suicide.
CONCLUSION: Given the rarity of cases of leiomyosarcoma of cervical stump, its proper treatment remains to be determined. In dealing with benign uterus diseases, we should pay adequate attention in retaining the cervix. If the cervix is retained, patients require appropriate follow-up. The authors hope that this work will benefit the fields of gynecology and oncology.

Pulcinelli FM, Catalano A, Malle G, et al.
A uterus soaked in blood with low haemoglobin in a case of unrecognized uterine sarcoma.
Eur J Gynaecol Oncol. 2016; 37(1):122-5 [PubMed] Related Publications
INTRODUCTION: Uterine sarcomas are rare and aggressive tumors. In some cases they can cause rupture of the uterus with or without clinical and radiological symptoms. Therefore, it is important to observe patients with clinical and/or radiological suspicion of sarcoma, even when there are no clinical manifestations.
CASE REPORT: A 71-year old woman, who was under the authors' observation for pain in the right iliac fossa. The US and the CT scan showed an abdominal-pelvic mass.Laboratory tests showed a slight but progressive reduction of haemoglobin, which could not be explained by the clinical symptoms and by the results of the imaging tests. During the surgical intervention, a small amount of peritoneal fluid, an increased uterine volume, and a subverted anatomy were observed A haematoma was found in the uterus and this could explain the progressive reduction of haemoglobin and the very low presence of peritoneal effusion.
CONCLUSION: The rupture of the uterus could not have been suspected as the patient did not have any type of symptoms, except for the slow and progressive reduction in the haemoglobin value. Therefore, it is important to observe patients with clinical and/or radiological suspicion of sarcoma, even when there are no clinical manifestations.

Prueksaritanond N, Cheanpracha P, Yanaranop M
Association of Serum HE4 with Primary Tumor Diameter and Depth of Myometrial Invasion in Endometrial Cancer Patients at Rajavithi Hospital.
Asian Pac J Cancer Prev. 2016; 17(3):1489-92 [PubMed] Related Publications
BACKGROUND: Although there are no biomarkers that are routinely used in endometrial cancer (EC) management, many studies have found that serum human epididymis protein 4 (HE4) is superior to cancer antigen 125 (CA125) in the detection of EC. The correlation of HE4 with two prognostic factors for EC, primary tumor diameter (PTD) and depth of myometrial invasion (DMI) may be useful in identifying EC patients at high risk of lymphatic dissemination.
OBJECTIVE: To evaluate the correlation of serum HE4 with PTD and DMI in patients with EC.
MATERIALS AND METHODS: A cross-sectional study was conducted on 70 EC patients who were scheduled for elective surgery at Rajavithi Hospital between 1st September 2013 and 30th May 2014. Preoperative serum levels of HE4 and CA125 were investigated, and then gross measurement of PTD was taken and postoperative pathologic slides were reviewed for DMI including histologic types, grading and staging.
RESULTS: Preoperative serum HE4 levels were strongly correlated with PTD (r=0.65, p<0.001) and moderately correlated with DMI (r=0.46, p<0.001). Moreover, serum HE4 levels were significantly elevated in EC patients with PTD >2 cm (p<0.001) and DMI > 50% (p=0.004). The performance of serum HE4 in identifying EC patients at low risk and high risk of lymph node metastasis was significantly better than that of CA125 (AUC 0.88 vs. 0.65, p=0.003). At an optimal cut-off value of 70 pM/L, serum HE4 had a sensitivity of 83.3% and a specificity of 80.0%.
CONCLUSIONS: In EC patients, preoperative serum HE4 is significantly correlated with PTD and DMI. Serum HE4 levels could be useful in identifying endometrial cancer patients at high risk of lymphatic spread who would benefit from systemic lymphadenectomy at the cut-off value of 70 pM/L.

Hembree TN, Teer JK, Hakam A, Chiappori AA
Genetic Investigation of Uterine Carcinosarcoma: Case Report and Cohort Analysis.
Cancer Control. 2016; 23(1):61-6 [PubMed] Related Publications
BACKGROUND: Uterine carcinosarcoma, a rare gynecological malignancy, often presents at the advanced stage with a poor prognosis because current therapies have not improved rates of survival. Genetic characterization of this tumor may lead to novel, specifically targeted drug targets to provide better treatment options for patients with this malignancy.
METHODS: We present a case of a woman aged 61 years with uterine carcinosarcoma and retrospectively analyzed 100 study patients with uterine carcinosarcoma. From this group, 9 study patients underwent targeted sequencing of 1,321 genes.
RESULTS: All 9 study patients had at least 1 mutation in JAK2, KRAS, PIK3CA, CTNNB1, PTEN, FBXW7, TP53, and ERBB2; of these, TP53 was the most frequently mutated gene (6/9). In addition, ARID1A and KMT2C, which have been described and identified as part of a set of chromatin-remodeling genes, were also found in our analyses. From our 100-person cohort clinical analyses, study patients with stage 1 cancer had a median survival rate of 33 months (95% confidence interval, 19-109) compared with a median survival rate of 6 months (95% confidence interval, 3-12) in those with stage 4 disease.
CONCLUSIONS: Disease stage alone predicted the rate of clinical survival. Up to 50% in the study group were identified at having early stage disease (stage 1/2), indicating improved rates of overall detection compared with previously reported data. Our mutational analysis findings add to the number of tumors in which these mutations have been found and suggest that chromatin-remodeling dysregulation may play a role in the tumorigenesis of carcinosarcoma.

Garcia N, Bozzini N, Baiocchi G, et al.
May Sonic Hedgehog proteins be markers for malignancy in uterine smooth muscle tumors?
Hum Pathol. 2016; 50:43-50 [PubMed] Related Publications
Several studies have demonstrated that the Sonic Hedgehog signaling pathway (SHH) plays an important role in tumorigenesis and cellular differentiation. We analyzed the protein expression of SHH pathway components and evaluated whether their profile could be useful for the diagnosis, prognosis, or prediction of the risk of malignancy for uterine smooth muscle tumors (USMTs). A total of 176 samples (20 myometrium, 119 variants of leiomyoma, and 37 leiomyosarcoma) were evaluated for the protein expression of the SHH signaling components, HHIP1 (SHH inhibitor), and BMP4 (SHH target) by immunohistochemistry. Western blot analysis was performed to verify the specificity of the antibodies. We grouped leiomyoma samples into conventional leiomyomas and unusual leiomyomas that comprise atypical, cellular, mitotically active leiomyomas and uterine smooth muscle tumors of uncertain malignant potential. Immunohistochemical analysis showed that SMO, SUFU, GLI1, GLI3, and BMP4 expression gradually increased depending on to the histologic tissue type. The protein expression of SMO, SUFU, and GLI1 was increased in unusual leiomyoma and leiomyosarcoma samples compared to normal myometrium. The inhibitor HHIP1 showed higher expression in myometrium, whereas only negative or basal expression of SMO, SUFU, GLI1, and GLI3 was detected in these samples. Strong expression of SHH was associated with poorer overall survival. Our data suggest that the expression of SHH proteins can be useful for evaluating the potential risk of malignancy for USMTs. Moreover, GLI1 and SMO may serve as future therapeutic targets for women with USMTs.

Gagliato Dde M, Linck RD, Bezerra RO, et al.
An uncommon response to metronomic therapy in a heavily pretreated patient with metastatic carcinosarcoma: a case report.
J Med Case Rep. 2016; 10:60 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Uterine carcinosarcoma is well known for its aggressive behavior. There is little evidence regarding the gold standard combination chemotherapy in metastatic or locally advanced carcinosarcoma, due to poor survival outcomes obtained with conventional scheduled chemotherapy. This case report represents the first-ever reported objective response to a metronomic chemotherapy regimen and adds to the current literature.
CASE PRESENTATION: We describe a case of a Caucasian woman diagnosed with metastatic carcinosarcoma that had already been treated with multiple lines of conventional chemotherapy, with progressive disease. This patient had a surprising clinical and imaging response when treated with oral metronomic cyclophosphamide.
CONCLUSIONS: We reviewed the mechanism of action implicated in metronomic chemotherapy, and correlated it with the biology of disease in carcinosarcoma. This information may add to the current literature, providing important insights to future clinical trials in this patient population.

Pinto A, Howitt B
Uterine Adenosarcoma.
Arch Pathol Lab Med. 2016; 140(3):286-90 [PubMed] Related Publications
Müllerian adenosarcoma is an uncommon biphasic tumor composed of malignant stromal and benign epithelial components. Morphologically, adenosarcoma is characterized by a broad leaflike architecture, reminiscent of phyllodes tumors of the breast. Periglandular cuffing of the stromal cells around the compressed or cystically dilated glands is characteristic. The mesenchymal component is typically a low-grade spindle cell sarcoma, whereas the epithelial counterpart is commonly endometrioid with frequent squamous or mucinous metaplasia and may, in some circumstances, show mild to moderate atypia. In all cases, it is important to assess for the presence of sarcomatous overgrowth and myometrial invasion, which are the prognostic factors. In this brief review, we present the clinical, histopathologic, and immunohistochemical features of adenosarcoma, as well as updates on the molecular biology of this neoplasm.

Visnovsky J, Kudela E, Slavik P, et al.
Survival and risk factors associated with uterine sarcomas and carcinosarcomas in stage I and II.
Neuro Endocrinol Lett. 2015; 36(8):750-7 [PubMed] Related Publications
OBJECTIVE: Uterine sarcomas are rare mesodermal malignant tumors with an incidence between 0.5 and 3.3 cases per 100,000 females per year. Most sarcomas are aggressive tumors leading to poor overall survival rates and only limited therapeutic options. The aim of this study was to evaluate the risk factors for uterine sarcomas and carcinosarcomas, and to identify the factors influencing the survival rate.
SUBJECTS AND METHODS: We conducted a retrospective study with twenty-nine patients who were diagnosed with uterine sarcoma and thirty-four patients with carcinosarcoma between the years 1990 and 2006 at the Oncogynecologic center at the University Hospital in Martin, Slovakia. We focused on the analysis of the risk factors and survival rate of early stages I and II.
RESULTS: We confirmed highly statistically significant values for the inverse correlation between survival and tumor size, positive lymph nodes, high mitotic activity, vascular invasion, positive peritoneal cytology, elevated CA-125, smoking and BMI in sarcoma and carcinosarcoma group (p<0.001 for all factors). The use of lymphadenectomy had no effect on survival of all patients.
DISCUSSION: Sarcomas and carcinosarcomas are aggressive tumors leading to poor overall survival rates and only limited therapeutic options. As there is no consensus on specific treatment, an individual approach based on evaluation of known risk factors is essential.

Hasahya OT, Berggren V, Sematimba D, et al.
Beliefs, perceptions and health-seeking behaviours in relation to cervical cancer: a qualitative study among women in Uganda following completion of an HPV vaccination campaign.
Glob Health Action. 2016; 9:29336 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cervical cancer remains a leading cause of morbidity and mortality in Uganda. Despite earlier information campaigns to introduce human papilloma virus (HPV) vaccination, which also targeted cervical cancer, misinterpretation and misunderstanding of the subject remain high. Women in Uganda present with cervical cancer at an advanced stage due to poor health-seeking behaviours, with an associated high mortality rate. This project explored beliefs, attitudes, perceptions, and health-seeking behaviours in relation to cervical cancer among women in Uganda after an HPV vaccination project had been rolled out.
DESIGN: A qualitative study design was used, with six focus group discussions (FGDs) that included 36 women, aged 25-49 years, with no previous history of cervical cancer symptoms or diagnosis. The women were interviewed in February and March 2013. The transcribed data was analysed using content analysis.
RESULTS: Three themes emerged: feeling unprotected and unsafe, misbelief and wondering about cervical cancer, and fear of the testing procedure. Participating women had heard of cervical cancer but preferred to wait to access cervical cancer screening until symptom debut.
CONCLUSIONS: There are still barriers to cervical cancer screening among women in Uganda, where there is a need for culture-specific, sensitive information and interventions to address the issues of improving the cervical cancer screening uptake among these women. Societal context needs to be taken into account when implementing community-based health education.

Mäkinen N, Aavikko M, Heikkinen T, et al.
Exome Sequencing of Uterine Leiomyosarcomas Identifies Frequent Mutations in TP53, ATRX, and MED12.
PLoS Genet. 2016; 12(2):e1005850 [PubMed] Free Access to Full Article Related Publications
Uterine leiomyosarcomas (ULMSs) are aggressive smooth muscle tumors associated with poor clinical outcome. Despite previous cytogenetic and molecular studies, their molecular background has remained elusive. To examine somatic variation in ULMS, we performed exome sequencing on 19 tumors. Altogether, 43 genes were mutated in at least two ULMSs. Most frequently mutated genes included tumor protein P53 (TP53; 6/19; 33%), alpha thalassemia/mental retardation syndrome X-linked (ATRX; 5/19; 26%), and mediator complex subunit 12 (MED12; 4/19; 21%). Unlike ATRX mutations, both TP53 and MED12 alterations have repeatedly been associated with ULMSs. All the observed ATRX alterations were either nonsense or frameshift mutations. ATRX protein levels were reliably analyzed by immunohistochemistry in altogether 44 ULMSs, and the majority of tumors (23/44; 52%) showed clearly reduced expression. Loss of ATRX expression has been associated with alternative lengthening of telomeres (ALT), and thus the telomere length was analyzed with telomere-specific fluorescence in situ hybridization. The ALT phenotype was confirmed in all ULMSs showing diminished ATRX expression. Exome data also revealed one nonsense mutation in death-domain associated protein (DAXX), another gene previously associated with ALT, and the tumor showed ALT positivity. In conclusion, exome sequencing revealed that TP53, ATRX, and MED12 are frequently mutated in ULMSs. ALT phenotype was commonly seen in tumors, indicating that ATR inhibitors, which were recently suggested as possible new drugs for ATRX-deficient tumors, could provide a potential novel therapeutic option for ULMS.

Sozen H, Çiftçi R, Vatansever D, et al.
Combination of adjuvant chemotherapy and radiotherapy is associated with improved survival at early stage type II endometrial cancer and carcinosarcoma.
Aust N Z J Obstet Gynaecol. 2016; 56(2):199-206 [PubMed] Related Publications
AIMS: The aim of this study was to describe the impact of postoperative adjuvant treatment modalities and identify risk factors associated with recurrence and survival rates in women diagnosed with early stage type II endometrial cancer and carcinosarcoma.
METHODS: In this retrospective study, patients diagnosed with early stage (stages I-II) carcinosarcoma and type II endometrial cancer were reviewed. All women underwent comprehensive surgical staging. Postoperative treatment options of chemotherapy (CT), radiotherapy (RT), observation (OBS) and chemotherapy-radiotherapy (CT-RT) combination were compared in terms of recurrence and survival outcome.
RESULTS: In CT-RT treatment arm, recurrence rate was found as 12.5% and this result is significantly lower than the other treatment approaches (P = 0.01 CT alone: 33.3%, RT alone: 26.7%, OBS: 62.5%). Three-year disease free survival(DFS) rate and overall survival (OS) rate were statistically higher for the group of women treated with combination of CT-RT (92-95%) compared to the women treated with RT alone (65-72%), treated with CT alone (67-74%) and women who received no adjuvant therapy (38-45%). The multivariate analysis revealed that carcinosarcoma histology was associated with shortened DFS and OS (P = 0.001, P = 0.002). On the other hand, being at stage Ia (P = 0.01, P = 0.04) and receiving adjuvant treatment of CT-RT combination (P = 0.005, P = 0.002) appeared to lead to increased DFS and OS rates.
CONCLUSIONS: We identified that a combination treatment of chemotherapy and radiotherapy is superior compared to other postoperative adjuvant treatment approaches concerning PFS, OS and recurrence rates in stages I-II of type II endometrial cancers and uterine carcinosarcoma.

Lee JW, Heo EJ, Moon SH, et al.
Prognostic value of total lesion glycolysis on preoperative (18)F-FDG PET/CT in patients with uterine carcinosarcoma.
Eur Radiol. 2016; 26(11):4148-4154 [PubMed] Related Publications
OBJECTIVES: To investigate the relationship between functional tumour parameters measured during preoperative (18)F-FDG PET/CT and clinical outcomes in patients with uterine carcinosarcoma.
METHODS: For patients with pathologically proven uterine carcinosarcoma, we determined the maximal and average standardized uptake values, cumulative total lesion glycolysis (TLG) and sum of all metabolic tumour volumes (MTVs). Their predictive value for recurrence and the effects of pretreatment functional tumour activity on patient survival were compared.
RESULTS: Clinicopathological data from 28 eligible patients were reviewed. The median duration of progression-free survival was 18.6 months (range 6.1-84.5 months), and 10 (35.7 %) patients experienced recurrences. Univariate analyses showed significant associations between recurrence and tumour size, lymph node metastasis, high TLG and MTV values, and ovarian invasion. Multivariate analysis identified high TLG value as an independent risk factor for recurrence (p = 0.048, hazard ratio 115.261, 95 % confidence interval 1.041-12,765.483). Kaplan-Meier survival curves showed that progression-free survival significantly differed in groups categorized according to TLG (p = 0.007, log-rank test).
CONCLUSIONS: Preoperative TLG measured with (18)F-FDG PET/CT was statistically significantly associated with uterine carcinosarcoma recurrence. Metabolic parameters can provide useful quantitative criteria for disease prognostication in patients with uterine carcinosarcoma before treatment.
KEY POINTS: • Preoperative TLG was an independent risk factor for recurrence in uterine carcinosarcoma. • Progression-free survival significantly differed in groups categorized by TLG. • Metabolic parameters can provide useful quantitative criteria for disease prognostication.

Monappa V, Kudva R, Hasan R
Uterine malignant mixed Müllerian tumor camouflaging as pelvic sarcoma.
J Cancer Res Ther. 2015 Oct-Dec; 11(4):997-9 [PubMed] Related Publications
Malignant mixed Müllerian tumors (MMMTs) of the uterus are rare, aggressive tumors that present at an advanced stage and are associated with poor prognosis. They arise as a result of divergent carcinomatous and mesenchymal differentiation of tumor stem cells. Rarely one of the components may predominate contributing to diagnostic confusion. We present a rare case of uterine MMMT arising in endometrial adenocarcinoma, camouflaging as pelvic sarcoma with a major sarcomatous component. This case report highlights the importance of thorough tissue sampling and the role of immunohistochemistry (IHC) in arriving at an accurate diagnosis. This case also demonstrates the conversion theory of histogenesis of MMMTs.

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