Endometrial Carcinosarcoma Research Articles

International Federation of Gynecology and Obstetrics (FIGO) staging system revised: what should be considered critically for gynecologic cancer?

International Federation of Gynecology and Obstetrics (FIGO) staging system revised: what should be considered critically for gynecologic cancer?

Combination chemotherapy with carboplatin, paclitaxel and pegylated liposomal doxorubicin for advanced or recurrent carcinosarcoma of the uterus: Clinical experience of a single institution

Objectives The purpose of this study was to evaluate the activity and toxicity of carboplatin, paclitaxel and pegylated liposomal doxorubicin combination in advanced or recurrent of the uterine carcinosarcoma. Methods Twenty-nine eligible patients with measurable disease were treated with carboplatin [area under the curve (AUC) 5], paclitaxel 175mg/m 2 and pegylated liposomal doxorubicin 25 mg/m 2 every 3 weeks for 6–8 cycles. Results There were 10 complete responses (CRs) (34%) and 8 partial responses (PRs) (28%) for an overall response rate (RR) of 62% (95% confidence interval [CI], 43–81%). The median progression-free survival (PFS) was 8.2 months (95% CI, 4.1–12.2 months) and the median overall survival (OS) was 16.4 months (95% CI, 14.7–18.0 months). There was no statistically significant difference between histology and response to therapy. Patients with PS of 0 or 1 had a higher RR than those with worst PS. Toxicity was generally mild except for myelotoxicity. Neutropenia grade 3/4 was recorded in 52% of patients and 10% experienced febrile neutropenia. Anemia grade 3 or 4 developed in 27% of patients and thrombocytopenia grade 3 or 4 in 31% of patients. Three patients (10%) developed grade 3 sensory neuropathy and only 2 patients (8%) grade 3 palmar-plantar erythrodysesthesias. No treatment-related deaths were recorded in our series. Conclusion The combination of carboplatin, paclitaxel and pegylated liposomal doxorubicin appears to have activity in advanced, persistent or recurrent endometrial carcinosarcoma with an acceptable toxicity profile.

Uterine mesenchymal tumors: a review of selected topics

Uterine mesenchymal tumors are unusual neoplasms that frequently give rise to diagnostic difficulties. I have chosen to review the clinical and histopathologic features of three interesting lesions – low-grade endometrial stromal sarcoma, leiomyosarcoma and carcinosarcoma (malignant mixed Mullerian tumor) – and have also provided information about ancillary diagnostic techniques and strategies for sorting between entities featured in the differential diagnosis.

Diagnostic accuracy of the apparent diffusion coefficient in differentiating benign from malignant uterine endometrial cavity lesions: initial results

Our purpose is to evaluate the diagnostic accuracy of apparent diffusion coefficient (ADC) measurement in differentiating malignant from benign uterine endometrial cavity lesions. We retrospectively evaluated 25 uterine endometrial cavity lesions in 25 female patients: endometrial carcinoma (n = 11), carcinosarcoma (n = 2), submucosal leiomyoma (n = 8), and endometrial polyp (n = 4). Diffusion-weighted images were performed at 1.5 T with b factors of 0-1,000/mm(2). The region of interest was defined within the tumor on T2-weighted EPI image and then manually copied to an ADC map. Thereby, the ADC value was obtained. We compared ADC values between malignant and benign lesions using Student's t-test. The mean and standard deviation of ADC values (x10(-3) mm(2)/s) were as follows: endometrial carcinoma, 0.98+/-0.21; carcinosarcoma, 0.97+/-0.02; submucosal leiomyoma, 1.37+/-0.28; and endometrial polyp, 1.58+/-0.45. The ADC values differed significantly between malignant (0.98+/-0.19) and benign lesions (1.44+/-0.34) (P < 0.01). We defined malignant tumors as cases with an ADC value less than 1.15 x 10(-3) mm(2)/s for obtaining the highest accuracy. Sensitivity, specificity, and accuracy were 84.6%, 100%, and 92%, respectively. ADC measurement can provide useful information in differentiating malignant from benign uterine endometrial cavity lesions.

6601 POSTER A pilot study of topotecan in patients with irinotecan-refractory small cell lung cancer

The purpose of this study was to evaluate the activity and toxicity of carboplatin, paclitaxel and pegylated liposomal doxorubicin combination in advanced or recurrent of the uterine carcinosarcoma.Twenty-nine eligible patients with measurable disease were treated with carboplatin [area under the curve (AUC) 5], paclitaxel 175mg/m2 and pegylated liposomal doxorubicin 25 mg/m2 every 3 weeks for 6–8 cycles.There were 10 complete responses (CRs) (34%) and 8 partial responses (PRs) (28%) for an overall response rate (RR) of 62% (95% confidence interval [CI], 43–81%). The median progression-free survival (PFS) was 8.2 months (95% CI, 4.1–12.2 months) and the median overall survival (OS) was 16.4 months (95% CI, 14.7–18.0 months). There was no statistically significant difference between histology and response to therapy. Patients with PS of 0 or 1 had a higher RR than those with worst PS. Toxicity was generally mild except for myelotoxicity. Neutropenia grade 3/4 was recorded in 52% of patients and 10% experienced febrile neutropenia. Anemia grade 3 or 4 developed in 27% of patients and thrombocytopenia grade 3 or 4 in 31% of patients. Three patients (10%) developed grade 3 sensory neuropathy and only 2 patients (8%) grade 3 palmar-plantar erythrodysesthesias. No treatment-related deaths were recorded in our series.The combination of carboplatin, paclitaxel and pegylated liposomal doxorubicin appears to have activity in advanced, persistent or recurrent endometrial carcinosarcoma with an acceptable toxicity profile.

Endometrial carcinosarcoma presenting as a tibial metastasis

Metastasis to a lower-extremity bone is an extremely rare event in patients with endometrial carcinoma. A 64-year-old woman presented with progressive right leg pain but no gynecologic complaints. A diagnostic workup revealed primary endometrial carcinosarcoma with an isolated tibial metastasis. Though the patient received only local irradiation to the tibial lesion, complete resolution of symptoms resulted. Six months after the radiotherapy, the intraabdominal disease progressed and the patient died. We note that tibial metastasis is one of the possible presenting symptoms in patients with endometrial malignant tumors. Irradiation can improve their quality of life and so may be effective in the management of symptomatic tibial metastasis.

Endometrial carcinoma recurring as carcinosarcoma: Report of two cases

Endometrial carcinosarcoma is a rare, aggressive disease, accounting for approximately 3% of all uterine neoplasms. The emergence of sarcomatous elements is considered the evolution of subclones arising from high grade endometrial carcinomas. Here, we report two cases of primary endometrial carcinomas recurring as carcinosarcoma. Case 1. a 58-year-old postmenopausal woman diagnosed to have a poorly differentiated endometrial endometrioid adenocarcinoma (FIGO stage IB) developed an intra-abdominal recurrence of disease after 17 months from diagnosis. Histopathological analysis documented a biphasic neoplasia consisting of an epithelial (grade 3 endometrial endometrioid adenocarcinoma) and a sarcomatous component. Salvage chemotherapy with cisplatin, ifosfamide, epirubicin, and then with taxotere was attempted. The patient died after 2 months. Case 2. A 56-year-old woman with a diagnosis of grade 3 endometrial adenosquamous carcinoma of the endometrium (FIGO stage IIIA) experienced pelvic recurrence after five months from completion of chemotherapy. Definitive histology was malignant mixed mesodermal tumor with focal areas of chondrosarcomatous elements. The patient was triaged to exclusive concomitant chemoradiotherapy and salvage chemotherapy. The patient died after 3 months. We describe two cases of high grade endometrial carcinomas recurring as carcinosarcoma, thus providing evidence that the metaplastic sarcomatous evolution is a very rare event which can occur in patients with anaplastic endometrial cancer.

EGFR expression and HER2/neu overexpression/amplification in endometrial carcinosarcoma

EGFR expression and HER2/neu overexpression/amplification in endometrial carcinosarcoma

Thyroid metastasis of endometrial carcinosarcoma associated with Graves' disease

A 54-year-old woman who had undergone total abdominal hysterectomy and bilateral adnexial resection because of endometrial carcinosarcoma presented with thyrotoxicosis, rapidly enlarging neck mass, right cervical tenderness to the ears, palpitation, swelling and heat intolerance, 3 years after the operation. Her serum thyroid hormone levels confirmed hyperthyroidism. Triiodothyronine/thyroxine ratio was 18. The thyroid antibodies were markedly elevated. A thyroid scan showed a cold area corresponding to the thyroid nodule, with high radioiodine uptake in the remaining thyroid tissue. Antithyroid drugs were started to control the hyperthyroidism. In our patient, who had a history of malignancy, the rapidly enlarging neck mass was considered as metastasis to the thyroid gland. The patient underwent bilateral total thyroidectomy. Histopathological examination demonstrated findings compatible with Graves' disease on the left and a carcinosarcoma metastasis on the right thyroid lobe. We suggest that both destructive thyroiditis and Graves' disease contributed to our patient's thyrotoxicosis. Metastatic thyroid carcinoma and destructive thyroiditis should be considered in patients with rapidly enlarging neck mass and a prior history of visceral malignancy.

PDGFR-α as a potential therapeutic target in uterine sarcomas

Uterine sarcomas are a heterogeneous group of tumors with a propensity for metastasis and resistance to conventional therapy. Recent success in the treatment of other solid tumors with the targeted tyrosine kinase inhibitor imatinib mesylate offers new avenues for investigation. The primary target of imatinib is c-kit, but the drug also inhibits PDGFR-alpha and PDGFR-beta. Given the lack of identified molecular targets in endometrial stromal sarcomas, leiomyosarcomas, and carcinosarcomas, the purpose of this study was to determine the protein expression of c-kit, PDGFR-alpha, and PDGFR-beta in these tumors as a preliminary step to determining their susceptibility to directed therapy. A secondary goal was to identify specific gene mutations that might be associated with activation of these proteins in uterine sarcomas. Archived tissue from 42 cases of uterine sarcomas was stained for c-kit, PDGFR-alpha, and PDGFR-beta using immunohistochemistry. Laser-capture microdissected samples of uterine carcinosarcomas, or homogeneous areas of leiomyosarcomas or endometrial stromal sarcomas, were subjected to genetic analysis of PDGFR-alpha exons 12 and 18. The majority (38/42, 90%) of uterine sarcomas lacked c-kit expression and 90% (38/42) demonstrated negative or weak staining for PDGFR-beta. In contrast, 70% (30/42) of cases had strong staining for PDGFR-alpha in the tumor but not in normal myometrium or endometrium. Sequencing results revealed no mutations in exons 12 or 18 of PDGFR-alpha. c-kit and PDGFR-beta are unlikely to represent primary treatment targets in uterine sarcomas. The strong expression of PDGFR-alpha in uterine sarcoma specimens suggests a role for this receptor in tumor development, although its potential as a therapeutic target requires further investigation.

EGFR expression and HER2/neu overexpression/amplification in endometrial carcinosarcoma

Objective. Endometrial carcinosarcomas are aggressive biphasic neoplasms traditionally treated as a high-grade uterine sarcoma. Epidermal growth factor receptor (EGFR) and HER2/neu (HER2) tyrosine kinases have been implicated in the development and progression of several human cancers and are targets for therapeutic intervention. The aim of this study was to evaluate for HER2 and EGFR expression in cases of endometrial carcinosarcoma. Methods. Formalin-fixed, paraffin-embedded sections from 55 cases of confirmed endometrial carcinosarcoma were immunostained with commercially available antibodies to EGFR and HER2. Fluorescent in situ hybridization for HER2 gene amplification was performed on all cases showing 2+ or 3+ HER2 staining by immunohistochemistry. HER2 gene amplification and EGFR expression were correlated with several prognostic variables. Results. EGFR expression was identified in the majority of tumors (45/55, 82%). HER2 overexpression (3+) was seen in 14/55 (25%) cases and HER2 gene amplification was seen in 11 (20%) cases. EGFR expression and HER2 gene amplification did not show significant correlation with disease progression, disease-free survival or overall survival. The carcinomatous component of tumors more frequently showed HER2 overexpression as compared to the sarcomatous component (25% vs. 4%, P = 0.008). The sarcomatous component of tumors more frequently showed EGFR overexpression as compared to the carcinomatous component (44% vs. 24%, P = 0.04). Conclusions. EGFR and HER2 appear to play a role in the carcinogenesis of endometrial carcinosarcomas. The carcinomatous and sarcomatous elements of these tumors showed consistent differences in HER2 and EGFR expression patterns supporting biologic differences between these components. Studies evaluating the clinical utility of HER2 or EGFR targeted therapy in these tumors appear warranted.

Endometrial carcinosarcomas have a different prognosis and pattern of spread compared to high-risk epithelial endometrial cancer

Objective The endometrial origin of uterine carcinosarcoma has recently been well established. The current study investigates whether uterine carcinosarcomas can be included in protocols on high-risk endometrial cancer, given the similarities in biologic behavior of both entities. Methods Pathological and surgical notes of patients diagnosed with grade 3 endometrioid, carcinosarcoma, serous and clear cell endometrial cancer subtypes were retrospectively analyzed with special attention to the spread pattern of the different subtypes. Information on site of relapse and time to recurrence was obtained. Results We traced 146 patients of which 9 patients were ineligible. Histological subtypes of the remaining 137 patients were as follows: 50 (37%) grade 3 endometrioid carcinoma, 54 (39%) serous or clear cell carcinoma (non-endometrioid carcinoma), and 33 (24%) carcinosarcomas. Distribution of early stage disease (I and II) was 67, 46, and 78% for grade 3 endometrioid, non-endometrioid, and carcinosarcoma, respectively. Although we could not trace differences in hematogenic and transperitoneal spread among the three subtypes, non-endometrioid and carcinosarcomas were more likely to spread to pelvic and paraaortic lymph nodes ( P < 0.01). Using univariate analysis, both stage ( P < 0.006, Wald statistic) and histological type appear to determine the outcome, whereas lymphovascular space infiltration ( P < 0.25) and age ( P < 0.07) were not significantly different between the three histological subtypes. Cox Regression multivariate analysis on 127 women suffering from the three histological subtypes suggested that both stage III–IV disease ( P < 0.00001) and histological type (carcinosarcoma) ( P < 0.003) were of prognostic significance [hazard ratio (CI 95%) were, respectively, 3.8 (2.1–7.0) and 3.2 (1.7–5.9)]. Analyzing cases limited to stage I–II endometrial cancer, 24/28 (86%) grade 3 endometrioid, 18/24 (75%) non-endometrioid, and 11/25 (44%) carcinosarcomas survived, suggesting a worse outcome for endometrial carcinosarcoma when compared to the other subtypes ( P < 0.008, Log Rank). A higher incidence of pulmonary metastases explained the worse outcome for early stage carcinosarcoma ( P < 0.006), whereas the incidence of liver metastasis, transperitoneal spread, or recurrences in lymph nodes or vagina were comparable between the three pathologic subtypes. Conclusions Although endometrial carcinosarcoma originates from epithelial cancer, the intrinsic more aggressive tumor biology suggests that this subtype should not be incorporated in studies on high-risk epithelial endometrial cancer.

Pathologies of the uterine endometrial cavity: usual and unusual manifestations and pitfalls on magnetic resonance imaging

The endometrial cavity may demonstrate various imaging manifestations such as normal, reactive, inflammatory, and benign and malignant neoplasms. We evaluated usual and unusual magnetic resonance imaging (MRI) findings of the uterine endometrial cavity, and described the diagnostic clues to differential diagnoses. Surgically proven pathologies of the uterine endometrial cavity were evaluated retrospectively with pathologic correlation. The pathologies included benign endometrial neoplasms such as endometrial hyperplasia and polyp, malignant endometrial neoplasms such as endometrial carcinoma and carcinosarcoma, endometrial-myometrial neoplasm such as endometrial stromal sarcoma, pregnancy-related lesions in the endometrial cavity such as gestational trophoblastic diseases (hydatidiform mole, invasive mole and choriocarcinoma) and placental polyp, myometrial lesions simulating endometrial lesions such as submucosal leiomyoma and some adenomyosis, endometrial neoplasms simulating myometrial lesions such as adenomyomatous polyp and endometrial lesions arising in the hemicavity of a septate/bicornate uterus, and fluid collections in the uterine cavity (hydro/hemato/pyometra). It is important to recognize various imaging findings in these diseases, in order to make a correct preoperative diagnosis.

Polycystic ovary syndrome and gynecological cancers: Is there a link?

Polycystic ovary syndrome [PCOS] is the most common endocrinopathy of women in reproductive age. An association between PCOS and type-1 endometrial cancer has often been reported in the literature. The prolonged anovulation with consequent continued secretion of estrogen unopposed by progesterone may enhance the development and growth of this malignancy, particularly in young women. Hypersecretion of luteinizing hormone [LH], chronic hyperinsulinemia and increased serum insulin-like growth factor [IGF]-I levels may represent risk factors for endometrial cancer. However, data available in the literature do not allow a meta-analysis to be carried out to calculate an estimate of the relative risk of endometrial cancer in women with PCOS. Anecdotal cases of low-grade endometrial stromal sarcoma and carcinosarcoma have been reported in association with prolonged unopposed estrogen stimulation, and in particular with PCOS. A few studies have addressed the possibility of an association between PCOS and epithelial ovarian cancer risk, and the results are conflicting but generally reassuring, and similarly the few available data appear to exclude a strong association between PCOS and breast cancer.

Homologous carcinosarcoma of the uterine corpus associated with tamoxifen therapy

A very rare case of homologous carcinosarcoma of the endometrium associated with long-term tamoxifen treatment for breast cancer is reported. A 70-year-old Japanese woman was admitted with atypical genital bleeding. Six years earlier, she had undergone total right mastectomy for breast cancer, and administration of tamoxifen had been started postoperatively. On admission, biopsy revealed a homologous carcinosarcoma of the endometrium with metastasis in the endocervix. The patient underwent a Wertheim's hysterectomy that revealed stage IIIc disease with pelvic lymph node metastasis. She received six courses of adjuvant chemotherapy. Histological examination showed a homologous carcinosarcoma, composed of poorly differentiated adenocarcinoma and anaplastic sarcoma. No heterologous elements; for example, malignant cartilage or rhabdomyoblasts, were seen. Tamoxifen is a possible etiologic factor in the development of endometrial carcinosarcomas.

Loss of IGF-II imprinting in endometrial tumors: overexpression in carcinosarcoma

The genomic imprinting of the maternal allele defines the monoallelic expression of the IGF-II gene in most human tissues. The loss of imprinting (LOI) leading to biallelic overexpression of IGF-II has been reported in several human malignancies, including uterine leiomyosarcoma. To ascertain if LOI occurs in endometrial malignancies, the allelic expression of the IGF-II gene was examined in samples of normal human endometrium ( n=22) and endometrial tumors ( n=12) by assessing the ApaI polymorphism in cDNA segments amplified by RT-PCR. The biallelic overexpression of IGF-II mRNA, involving activation of all four (P1–P4) promoters, was detected in one normal endometrium and in one endometrial carcinosarcoma. Low level biallelic expression of IGF-II was also detected in two samples of hormone-unresponsive/Type II endometrial carcinomas. The level of IGF-I mRNA in these four samples was low. The IGF-IR mRNA was overexpressed in all endometrial cancers including the carcinosarcoma sample, but not in normal endometrium. These data suggest that LOI associated with overexpression of IGF-II and concomitant overexpression of IGF-IR may play a role in the rare carcinosarcoma of the endometrium.

Endometrial müllerian carcinosarcoma after cessation of tamoxifen therapy for breast cancer

The aim of this report is to draw the attention of clinicians to the possible occurrence of endometrial cancers of rare histological type among women currently undergoing or having in the past undergone tamoxifen therapy, in particular for breast cancer. We report a case of heterologous mixed malignant müllerian tumor occurring in an 80-year-old woman. At 69, she had been diagnosed with breast cancer and received tamoxifen for a total of 55 months over a 6-year period. In the 5th year after cessation of tamoxifen therapy, an endometrial carcinosarcoma was diagnosed. Although the association between tamoxifen use and endometrial cancer is recognized, only a few reports of occurrence long after cessation of therapy exist. We believe ours is the second for this particular histological type. Tamoxifen may have played a role in the occurrence of this tumor although it is also known that this type of tumor may arise de novo in elderly women. The etiologic hypothesis obtained from this case description will now be tested in a formal epidemiological investigation which hopefully will provide more definitive evidence.

Is there an association between long-term tamoxifen treatment and the development of carcinosarcoma (malignant mixed Müllerian tumor) of the uterus?

A cluster of five patients with endometrial carcinosarcoma (malignant mixed Müllerian tumor) occurred at our center during 1993; four of these had been prescribed long-term tamoxifen for breast carcinoma. Searching the archives for the 9-year period 1983-1992 revealed two further cases of uterine carcinosarcoma occurring in patients prescribed tamoxifen, from a total of 16 cases of this tumor. Five of the six patients diagnosed with carcinosarcoma who had been taking tamoxifen had been maintained on the drug for at least 6 years, while the other had a 3-year history of tamoxifen therapy. From these data we raise the question of an association between long-term tamoxifen treatment and development of endometrial carcinosarcoma, following the dramatic increase in the prescribing of this drug after 1984.

Carcinosarcoma of urinary bladder: Report of 5 cases with immunohistologic study

We studied 5 cases of carcinosarcoma of the urinary bladder. Immunoperoxidase studies were performed to identify the nature of the tumor and to establish the diagnosis. We suggest that these tumors represent a transition of epithelial to mesenchymal malignancy. Three of our patients had a history of radiation therapy prior to development of carcinosarcoma; of which 2 had a long interval between exposure to radiatio and tumor development. Radiation is a risk factor for endometrial carcinosarcoma, and in this report we strongly suggest such an association for the urinary bladder.

Carcinosarcoma (Malignant Mixed Mesodermal Tumor) of the Uterus

We report on the pathologic findings in primary tumors and metastases in 203 cases of stage I and II endometrial carcinosarcoma (malignant mixed mesodermal tumor) subjected to hysterectomy and staging laparotomy. Metastases were studied in 40 of these cases, including 34 with positive findings in the pelvic and/or para-aortic lymph nodes. Features of the stromal component of the primary tumors, including grade, mitotic index, and the presence and types of heterologous elements, showed no relation to the presence of metastases at operation. High-grade, serous, and clear cell carcinomatous components, on the other hand, were associated with a higher frequency of metastases, as were deep myometrial invasion, lymphatic or vascular space invasion, and involvement of the isthmus or cervix. The current concepts of histogenesis and differentiation of these tumors are discussed, and the suggestion is made that they might represent metaplastic carcinomas.