Immunohistochemical expression of estrogen and progesterone receptors and outcomes in patients with newly diagnosed uterine leiomyosarcoma

Objective

We assessed the IHC expression of ER and PR and their prognostic significance in uterine leiomyosarcoma (LMS).

Methods

We identified 43 “high-grade” uterine LMS cases from 7/82-7/07 for whom ER/PR IHC analysis was performed at initial diagnosis at our institution.

Results

Disease was confined to the uterine body in 20/43 (47%). Eighteen (42%) of 43 were ER(+); 17/42 (41%) were PR(+). At last follow-up, 33 (77%) had recurred or progressed, and 23 (54%) had died. PR expression was associated with improved progression-free survival (PFS; P = 0.002) and overall survival (OS; P = 0.03) overall; ER expression was not. After adjusting for stage, ER expression was associated with PFS (P = 0.01), not OS (P = 0.3), and PR expression maintained a significant association with PFS (P = 0.002) and approached a significant association with OS (P = 0.05). Neither ER nor PR expression was associated with outcome in cases with disease outside the uterine body. In cases with confined disease, median PFS for ER(+) or PR(+) cases was not reached compared to 16.9 months for ER(−) cases (95% CI: 8.1-25.7; P = 0.03) and 13.5 months for PR(−) cases (95% CI: 5.9-21.1; P = 0.001). Only 1/10 PR(+) cases recurred and died; 9/10 PR(−) cases recurred, and 5 died. Two of 9 ER(+) cases recurred and died; 8/11 ER(−) cases recurred, and 4 died.

Conclusion

ER/PR expression is associated with survival outcomes in patients with high-grade uterine LMS confined to the uterine body. PR expression seems capable of identifying cases confined to the uterine body, which have better outcomes.     

Magnetic resonance imaging of uterine leiomyosarcoma

Summary The magnetic resonance imaging (MRI) findings in a patient with uterine leiomyosarcoma are reported. MRI provides higher contrast resolution in soft tissues than ultrasonography or CT, and the MRI findings described in this case report suggest that MRI can be used to help differentiate between leiomyosarcoma from myoma.     

The impact of tumor morcellation during surgery on the prognosis of patients with apparently early uterine leiomyosarcoma

Objective.

Uterine leiomyosarcoma (LMS) is usually diagnosed after surgery for leiomyoma; thus tumor morcellation frequently occurs. We evaluated the impact of tumor morcellation during surgery on the prognosis of patients with apparently early uterine LMS.

Methods.

Outcomes were retrospectively compared between patients who underwent total abdominal hysterectomy without tumor morcellation and those who underwent surgery that included abdominal, vaginal or laparoscopic tumor morcellation.

Results.

We assessed 56 consecutive patients with stage I and II uterine LMS between 1989 and 2010, 25 with and 31 without tumor morcellation. There were no significant between group differences in age, parity, menopausal status, body mass index, stage, mitotic count, tumor grade, lymph node dissection, adjuvant therapy, and follow-up duration. However, tumor size was significantly smaller (9.8 cm vs. 7.3 cm, P = 0.022) and ovarian tissue was more frequently preserved (38.7% vs. 72%, P = 0.013) in patients with tumor morcellation. In univariate analysis, only tumor morcellation was significantly associated with poorer disease-free survival (DFS) (odds ratio [OR], 2.59; 95% confidence interval [CI], 1.03-6.50; P = 0.043), and higher stage (I vs. II; (OR, 19.12; 95% CI, 1.19-307.11; P = 0.037)) and tumor morcellation (OR, 3.07; 95% CI, 1.05-8.93; P = 0.040) were significantly associated with poorer overall survival (OS). In multivariate analysis, higher stage (OR, 20.34; 95% CI, 1.27-325.58; P = 0.033) and tumor morcellation (OR, 3.11; 95% CI, 1.07-9.06; P = 0.038) were significantly associated with poorer OS. The percentage of patients with abdomino-pelvic dissemination, as shown by peritoneal sarcomatosis or vaginal apex recurrence, was significantly greater in patients with than without tumor morcellation (44% vs. 12.9%, P = 0.032).

Conclusion.

Tumor morcellation during surgery increased the rate of abdomino-pelvic dissemination and adversely affected DFS and OS in patients with apparently early uterine LMS.     

Increased risk of secondary uterine leiomyosarcoma in hereditary retinoblastoma

Objective

In the US, second non-ocular malignancies are the primary cause of death in retinoblastoma survivors with the germline RB1 mutation. Soft tissue sarcomas are one of the most likely malignancies to pose a risk to these patients, with leiomyosarcoma (LMS) being the most common subtype. As our cohort is followed for a longer period, we discover new second malignancy risks for these patients.

Methods

We estimated the risk for uterine leiomyosarcoma (ULMS) in a cohort of 1854 patients with retinoblastoma who were diagnosed at two US institutions from 1914 through 1996. The standardized incidence ratio and excess absolute risk were calculated by comparison with population data from the Connecticut Tumor Registry or from National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database. The cumulative risk at 50 years of age was also calculated.

Results

Seven of 525 female hereditary retinoblastoma patients developed ULMS. Five of these patients were used in the risk analysis, resulting in an excess risk of 3.87 per 10,000 women. Among hereditary patients who developed ULMS the excess risk increases dramatically with age: to 20/10,000 for female hereditary retinoblastoma patients aged between 30 and 39 years, and to 27/10,000 for patients aged 40 + years.

Conclusion

There is a substantial excess risk of ULMS in female hereditary retinoblastoma patients. As more patients survive into their thirties, this number is likely to increase. These findings raise the question of early childbearing, screening and prophylactic measures in hereditary retinoblastoma patients: all issues that would benefit from confirmation from other retinoblastoma cohorts, to allow for better guided counsel of these patients.     

Array comparative genomic hybridization analysis of uterine leiomyosarcoma

PURPOSE: Using a genome-wide array-based comparative genomic hybridization (array-CGH), DNA copy number changes in uterine leiomyosarcoma were analyzed. MATERIALS AND METHODS: We analyzed 4 cases of uterine leiomyoma and 7 cases of uterine leiomyosarcoma. The paraffin-fixed tissue samples were microdissected under microscope and DNA was extracted. Array-based CGH and fluorescence in situ hybridization (FISH) were carried out with Genome database (Gene Ontology). RESULTS: Uterine leiomyoma showed no genetic alterations, while all of 7 cases of uterine leiomyosarcoma showed specific gains and losses. The percentage of average gains and losses were 4.86% and 15.1%, respectively. The regions of high level of gain were 7q36.3, 7q33-q35, 12q13-12q15, and 12q23.3. And the regions of homozygous loss were 1p21.1, 2p22.2, 6p11.2, 9p21.1, 9p21.3, 9p22.1, 14q32.33, and 14q32.33 qter. There were no recurrent regions of gain, but recurrent regions of loss were 1p21.1-p21.2, 1p22.3-p31.1, 9p21.2-p22.2, 10q25-q25.2, 11q24.2-q25, 13q12-q12.13, 14q31.1-q31.3, 14q32.32-q32.33, 15q11-q12, 15q13-q14, 18q12.1-q12.2, 18q22.1-q22.3, 20p12.1, and 21q22.12-q22.13. In the high level of gain regions, BAC clones encoded HMGIC, SAS, MDM2, TIM1 genes. Frequently gained BAC clone-encoded genes were TIM1, PDGFR-beta, REC Q4, VAV2, FGF4, KLK2, PNUTL1, GDNF, FLG, EXT1, WISP1, HER-2, and SOX18. The genes encoded by frequently lost BAC clones were LEU1, ERCC5, THBS1, DCC, MBD2, SCCA1, FVT1, CYB5, and ETS2/E2. A subset of cellular processes from each gene was clustered by Gene Ontology database. CONCLUSION: Using array-CGH, chromosomal aberrations related to uterine leiomyosarcoma were identified. The high resolution of array-CGH combined with human genome database would give a chance to find out possible target genes present in the gained or lost clones.     

The role of cytoreductive surgery for newly diagnosed advanced-stage uterine carcinosarcoma

Objectives

Uterine carcinosarcoma (CS) is a rare but aggressive malignancy frequently associated with extrauterine metastasis at the time of diagnosis. The objective of this study was to assess the role of cytoreductive surgery in patients with stage IIIC-IVB uterine CS.

Methods

We conducted a retrospective review of all patients with uterine CS treated at our institution from 1990 to 2009. Clinicopathologic factors, surgical procedures, adjuvant therapy, and survival outcomes were collected for all patients. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Factors predictive of survival outcomes were compared using the log-rank test and Cox regression analysis.

Results

An analysis of 44 patients was performed (stage IIIC, n = 14; stage IVB, n = 30). Complete gross resection was achieved in 57% of patients. PFS and OS for the entire cohort were 8.6 months and 18.5 months, respectively. Complete gross resection was associated with a median OS of 52.3 months versus 8.6 months in patients with gross residual disease (P < 0.0001). Stage IIIC disease was associated with a median OS of 52.3 months versus 17.5 months for patients with stage IVB disease. In patients who received adjuvant therapy, OS was 30.1 months versus 4.7 months in patients who did not receive adjuvant therapy (P < 0.001). On multivariate analysis, only complete gross resection and the ability to receive adjuvant therapy were independently associated with OS.

Conclusions

Cytoreductive surgery, with a goal of achieving a complete gross resection, is associated with an improvement in OS among patients with advanced uterine CS.     

Epithelioid leiomyosarcoma of the uterine cervix: a case report and review of the literature

BACKGROUND: Epithelioid leiomyosarcomas arising from the uterine cervix are extremely rare neoplasms, with only three cases reported in the English literature. CASE: A 53-year-old Japanese woman was admitted to our university hospital due to massive vaginal bleeding from a cervical tumor. A total hysterectomy with bilateral salpingo-oophorectomy was performed. Histological findings, including immunohistochemical study using desmin, SMA, cytokeratin, S-100, HMB-45, vimentin, melan-A, and CD68, led to a diagnosis of epithelioid leiomyosarcoma of the uterine cervix. The patient underwent adjuvant chemotherapy and has been disease-free for over 20 months. CONCLUSION: Immunohistochemical studies may be needed to differentiate among the alternative diagnoses of malignant melanoma, metastatic carcinoma, and epithelioid sarcoma. Additional cases are needed to develop optimal management strategies and to predict prognosis.     

Clinical outcome of metastatic uterine leiomyosarcoma and carcinosarcoma in a single institute

AIM: To investigate the clinical outcome of uterine sarcomas, particularly in patients with pulmonary and abdominal metastasis, treated at a single institute. METHODS: We identified five patients with uterine leiomyosarcoma (LMS), one patient with endometrial stromal sarcoma (ESS), and three patients with carcinosarcoma (CS) between 2003 and 2006. RESULTS: All patients underwent at least hysterectomy and bilateral adnectomy. All five LMS cases (two patients in International Federation of Obstetrics and Gynecology stage I and three in stage III) recurred: one patient showed metastasis to the lung and four patients showed metastasis to the abdomen 16.6 months (mean) after hysterectomy. Two of three (66.7%) CS recurred: one patient showed metastasis to the lung and the other to the abdomen 5 months (mean) after hysterectomy. The ESS (stage I) patient showed metastasis to the lung 11 months after hysterectomy. Five patients with metastases received surgical interventions (two pulmonary resections and three abdominal resections), and all of these patients are currently alive 1.1-5.1 years postoperatively. Two patients with CS (stage I) and one patient with LMS (stage III) died of sarcoma dissemination, but neither of these three patients had undergone surgical intervention after hysterectomy (one for pulmonary and two for abdominal metastases). CONCLUSIONS: Resection of lung and abdominal metastases in uterine LMS and CS is beneficial to improve patient survival.     

A phase II trial of thalidomide in patients with refractory leiomyosarcoma of the uterus and correlation with biomarkers of angiogenesis: a gynecologic oncology group study

OBJECTIVES: To evaluate the efficacy and adverse events (AEs) of thalidomide in previously treated, measurable, persistent or recurrent leiomyosarcoma (LMS) of the uterus, and to explore associations between angiogenic markers and treatment or clinical outcome. METHODS: Eligible, consenting patients were treated until disease progression or toxicity intervened with daily starting dose of 200 mg thalidomide/day that was increased by 200 mg every 2 weeks to a target dose of 1000 mg/day. End-points included progression-free survival (PFS)>or=6 months, toxicity, response, PFS and survival. Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and soluble endothelial protein C receptor (sEPCR) were evaluated in pre- and post-treatment serum and plasma. RESULTS: Of 30 enrolled patients, one was ineligible (wrong histology). Median age was 56 years. Among 29 eligible patients, seven reached the target dose and only two received more than 4 cycles. Two patients (7%) experienced PFS>or=6 months. There were no objective responses, seven (24%) had stable disease, 19 (66%) progressed and 3 (10%) were not evaluable for response. Median PFS was 1.9 months and median overall survival was 8.3 months. Grade 4 AEs were not observed. The most common grade 3 AEs were neurologic (6), pulmonary (4) and constitutional (3). Treatment with thalidomide was associated with a significant decrease in plasma bFGF (p=0.008) and serum sEPCR (p=0.006), but not in plasma VEGF. Plasma VEGF was associated with increased risk of progression (hazard ratio [HR]=3.5; 95% confidence interval (CI)=1.5-7.8; p=0.003) and death (HR=4.7; 95% CI=1.6-13.8; p=0.005) after adjusting for GOG performance status. CONCLUSIONS: Thalidomide was not active in patients with uterine LMS and did not alter VEGF concentration. The association between pretreatment VEGF and prognosis in this population supports further evaluation of anti-angiogenic therapies in uterine LMS.     

Activity of trabectedin (ET-743, Yondelis) in metastatic uterine leiomyosarcoma

BACKGROUND: The ongoing search for more effective agents in the treatment of uterine leiomyosarcomas is warranted because of the poor prognosis related to these tumors. CASE: A case of advanced, recurrent and refractory uterine leiomyosarcoma is presented that responded to trabectedin (ET-743) 1.2 mg/m2 intravenously over 24 h every 3 weeks after failing four prior regimens. A durable objective response lasting at least 8 months was documented. CONCLUSION: Trabectedin (ET-743) has activity in uterine leiomyosarcoma and warrants further investigation.     

Metastasis of uterine leiomyosarcoma to the pancreas

BACKGROUND: Metastasis of uterine leiomyosarcoma to the pancreas is extremely rare. CASE: A 46-year-old woman presented with hypermenorrhea and dysmenorrhea and underwent surgery. The histologic and immunohistochemical diagnosis was uterine leiomyosarcoma stage I with no metastasis to the ovaries or the pelvic lymph nodes. The mitotic count was very high. Thereafter, recurrences in the lung and subsequently in the pancreas were detected. The lesions in the lung and pancreas were resected and diagnosed as metastases of uterine leiomyosarcoma based on histology and immunohistochemistry. CONCLUSION: We report an extraordinarily rare case of uterine leiomyosarcoma with metastasis to the pancreas following initial metastasis to the lung, both of which were diagnosed using histology and immunohistochemistry of the specimens obtained at surgery.     

Metastatic uterine leiomyosarcoma coexisting with papillary carcinoma of the thyroid gland

Metastatic leiomyosarcoma to the thyroid gland has rarely been described. We report a 54-year-old postmenopausal woman with uterine leiomyosarcoma, who presented with a single "cold" nodule in the right thyroid lobe 3 months after hysterectomy. The lesion was identified as a papillary thyroid carcinoma. In a separate area of the thyroid, a 1.2-mm area of a malignant mesenchymal neoplasm with morphologic and immunohistochemical features of leiomyosarcoma existed. Seven months after thyroidectomy the patient developed micronodular lung disease visible on successive chest computed tomography scans, consistent with metastatic disease from the primary uterine leiomyosarcoma that showed very good and prolonged response to chemotherapy. The thyroid papillary carcinoma was likely the recipient of an early and possibly the first metastasis of the patient's uterine leiomyosarcoma. This is the first report of metastatic leiomyosarcoma coexisting with a primary thyroid carcinoma and supports the possibility of a common pathway connecting thyroid gland neoplasms and sarcomas.     

A phase 2 study of alisertib (MLN8237) in recurrent or persistent uterine leiomyosarcoma: An NRG Oncology/Gynecologic Oncology Group study 0231D

Objective

This two-stage Phase II study assessed the activity of single agent alisertib in patients with recurrent/persistent uterine leiomyosarcoma (uLMS).

A Phase II evaluation of ixabepilone (IND #59699, NSC #710428) in the treatment of recurrent or persistent leiomyosarcoma of the uterus: An NRG Oncology/Gynecologic Oncology Group Study

Objective

The combination of gemcitabine and docetaxel is the standard first-line therapy for recurrent or metastatic uterine leiomyosarcoma. There is no standard second-line therapy. Ixabepilone is a semi-synthetic analog of epothilone B that binds to the same site on beta tubulin as paclitaxel and may be a more potent polymerizer of tubulin. We sought to determine the activity of ixabepilone as a single agent as second-line treatment for patients with metastatic uterine leiomyosarcoma who had received taxane based therapy.

Methods

Eligible women with unresectable uterine leiomyosarcoma progressing after prior cytotoxic therapy containing a taxane were treated with ixabepilone 40 mg/m² on day one of a 21 day cycle. Patients with prior pelvic radiation were treated without dose reduction. Response Evaluation Criteria in Solid Tumors (RECIST) response was assessed by computed tomography (CT).

Results

Twenty-three of 26 women were evaluable (two wrong histology, one never treated) with two of 23 receiving 1 cycle of therapy. There were no complete or partial responses. Stable disease (SD) was seen in four patients (17.4%, median 3.4 months). Seventeen patients (73.9%) had increasing disease (PD) and two patients were inevaluable per RECIST. One patient had SD over 6 cycles of treatment. Median PFS for all 23 patients was 1.4 months and overall survival was 7.0 months. The predominant grade 3 or 4 toxicity was uncomplicated myelosuppression: neutropenia grade 3 (13%), grade 4 (17%), and anemia grade 3 (22%).

Conclusion

Ixabepilone as a single agent is not an active second-line therapy for uterine leiomyosarcoma previously treated with a taxane.