Malignant Mixed Mesodermal Tumor Research Articles

Cytogenetics of Uterine Sarcomas: Presentation of Eight New Cases and Review of the Literature

Tissue from 14 uterine tumor samples from eight patients—four with endometrial stromal sarcoma (ESS), two with leiomyosarcoma (ULMS), and two with malignant mixed mesodermal tumor (MMMT)—were investigated cytogenetically after short-term culturing. Clonal chromosome aberrations were found in 12 tumors. One ESS showed a recombination between 7p14 and 17q12, a rearrangement characterizing a subset of ESSs. In our series, chromosomes 1, 6, 7, and 16 were involved in structural aberrations most frequently (four cases each). Net loss of 6q material was found in four cases and bands 11q13, 16q13, and 22q13 were each rearranged in four cases. Among 43 uterine sarcomas, including 12 MMTs, now available for evaluation, some differences in breakpoint distribution among different tumor types were found. Rearrangements of bands 1p32, 3p24, and 10q22 were found exclusively in ULMS, whereas aberrations of bands 6p21, 7p21, and 17q12 were found predominantly in ESS.

Cytogenetic Findings in Malignant Mixed Mesodermal Tumors of the Uterus

Cytogenetic analyses of four malignant mixed mesodermal tumors (MMMT) of the uterus are reported, of which one was of the homologous type and three of the heterologous type. Karyotypic analyses were obtained in two cases from original tumors and in two cases from tumors xenotransplanted into nude mice. The karyotype of the homologous MMMT was normal in three different passages of a nude mice xenograft line established from the primary tumor. The heterologous tumors showed normal karyotype in one case and hyperdiploid and near triploid range with extensive numerical and structural rearrangements in two cases. Deletion of chromosome 1 at p32, and deletion of chromosome 11 at q13 were common markers in anomalous cases. The chromosomes most often involved in structural rearrangements were chromosomes 1, 9, 11, 12, 17, and 19. Double minutes, homogeneously staining regions, and telomeric association were also seen.

Parity as an Independent Prognostic Factor in Malignant Mixed Mesodermal Tumors of the Endometrium

Malignant mixed mesodermal tumors (MMMT) are the most malignant neoplasms known to occur in the uterus. The most important prognostic factors are the extent of tumor at diagnosis, depth of myometrial invasion, and, as regarded by some authors, the sarcomatous component. We report on a retrospective analysis in 83 patients with MMMT. By univariate analysis survival was dependent on stage, depth of myometrial invasion, kind of therapy, age at menopause, and parity. However, the sarcomatous component did not significantly influence survival. Using the multivariate Cox regression analysis stage and parity or depth of myometrial invasion and parity were found to independently predict prognosis. Despite an interval of more than 20 years from the last childbirth to tumor appearance a beneficial influence of parity on the prognosis of MMMT was identified. This is unique in oncology. Especially patients with more than three children formed a subgroup of long-term survivors. It is interesting to note that parity was found by means of a Cox regression analysis to be statistically independent, and no correlation with other classical prognostic factors was detected.

Endometrial Carcinomas - Flow Cytometric DNA Content and S-phase Values

The purpose of the investigation was to determine the DNA content and S-phase value in a large material of fresh tumour tissue from endometrial carcinomas and to correlate these parameters to tumour type, grade of differentiation, depth of myometrial invasion and stage. The prospective study consisted of 290 unselected cases of endometrial carcinomas, FIGO stage I-IV where flow cytometry was performed on fresh tumour tissue blocks from hysterectomy specimens. 223 cases had more than 10% tumour tissue in tissue blocks taken adjacent to the blocks for flow cytometry. Non-diploidy was defined as 0.9 > or = DNA index > 1.10 and high S-phase value was defined as > 15%. Non-diploidy was found in 46% of the endometrioid adenocarcinoma and in 85% of the non-endometrioid carcinomas (clear cell adenocarcinoma, serous adenocarcinoma and malignant mixed mesodermal tumour) (p < 0.001). S-phase value was > 15% in 39% of the endometrioid adenocarcinoma and in 100% of the non-endometrioid carcinomas (p < 0.0001). In endometrioid adenocarcinoma there was a statistical significant relation between non-diploidy and grade of histological differentiation (p < 0.006), as well as with depth of myometrial invasion (p < 0.05). There was no relation between non-diploidy and the presence of squamous differentiation, whether benign or malignant or to FIGO stage. High S-phase values (> 15%) was related to the grade of differentiation (p < 0.002). No relation was demonstrated between S-phase > 15% and squamous differentiation, depth of myometrial invasion or FIGO stage. In conclusion, 50% of all the endometrial carcinomas were non-diploid and 43% had S-phase value > 15%. Ploidy correlated with histologic tumour types, grade of differentiation and depth on myometrial invasion while S-phase values only correlated with histologic tumour types and grade of differentiation.

The expression of epidermal growth factor receptor, HER-2/Neu, p53, and Ki-67 antigen in uterine malignant mixed mesodermal tumors and adenosarcoma: Swisher E.M.; Gown A.M.; Skelly M.; Ek M.; Tamimi H.K.; Cain J.M.; Greer B.E.; Muntz H.G.; Goff B.A. USA Gynecol Oncol 1996 60/1 (81–88)

The expression of epidermal growth factor receptor, HER-2/Neu, p53, and Ki-67 antigen in uterine malignant mixed mesodermal tumors and adenosarcoma: Swisher E.M.; Gown A.M.; Skelly M.; Ek M.; Tamimi H.K.; Cain J.M.; Greer B.E.; Muntz H.G.; Goff B.A. USA Gynecol Oncol 1996 60/1 (81–88)

Sarcoma of the uterus. A clinical study of 42 patients.

Records of 42 patients with a diagnosis of uterine sarcoma treated between 1974 and 1995 at the Department of Oncology and Radiotherapy, Medical University of Gdańsk have been reviewed. There were 15 cases of leiomyosarcoma, 14 cases of carcinosarcoma (malignant mixed mesodermal tumor) and 13 cases of endometrial stromal sarcoma. There were 24 FIGO stage I patients, 3 stage II patients, 7 stage III patients and 8 stage IV patients. Thirty seven patients had previously been operated on, of whom 33 had undergone total abdominal hysterectomy and bilateral salpingoophorectomy. Adjuvant postoperative treatment was administered in 19 patients and included radiotherapy in 16 patients, chemotherapy in two and chemotherapy and irradiation in one. Out of 31 radically operated patients, 19 (61%) had recurrences, within 2-42 months of primary treatment (median 10 months); nine patients had distant metasases, six patients had local recurrence and four had both local and distant failure. Treatment failure occurred in seven out of 14 patients who received adjuvant radiotherapy and in 12 out of 17 treated without irradiation. Median survival time in both groups was 26 months. The survival for the whole series ranged from 2 months to 19+ years (median 26 months) and was not related to tumor type. Two and five year actuarial survival rates were 54% and 30%, respectively.

Cytogenetic findings in four malignant mixed mesodermal tumors of the ovary

Short-term cultures of four malignant mixed mesodermal tumors of the ovary were cytogenetically analyzed. The primary tumor was examined in three cases, whereas in one case the sample was obtained from a residual tumor mass after chemotherapy. The tumor sampled after cytostatic treatment had a relatively simple karyotype with numerical changes that included pentasomy 12 and an i(1)(q10) as the only structural abnormality. Karyotypic analysis of the three primary tumors revealed extensive structural as well as numerical aberrations, i.e., a picture similar to that seen in the few malignant mixed mesodermal tumors with karyotypic anomalies described previously. Rearrangements of chromosome 1, leading to loss of distal 1p, and homogeneously staining regions have so far been the most frequent cytogenetic changes in this tumor type. Malignant mixed mesodermal tumors of the ovary thus seem to be karyotypically identical to the more numerous mixed mesodermal tumors of uterine origin, and they do not differ substantially in this respect from pure ovarian carcinomas.

The Expression of Epidermal Growth Factor Receptor, HER-2/Neu,p53, and Ki-67 Antigen in Uterine Malignant Mixed Mesodermal Tumors and Adenosarcoma

Uterine malignant mixed mesodermal tumors (MMMT) are highly malignant tumors containing both malignant glands and stroma, while adenosarcomas (AS) are less aggressive tumors composed of malignant stroma and benign glands. Immunohistochemistry was used to grade overexpression of p53 protein, HER-2/neuprotein, epidermal growth factor receptor (EGFR), and Ki-67 antigen in both the glands and stroma of tissue from 20 women with MMMT and 6 women with AS. EGFR was overexpressed in 2 AS and 9 MMMT, and was more commonly found in the sarcomatous component than the carcinomatous component in MMMT (P= 0.03). p53 was not found in any AS samples and was strongly present in 6 MMMT samples with a random distribution between the malignant components. HER-2/neuprotein was not overexpressed in any AS or primary MMMT. Ki-67 antigen, a marker of cell proliferation, was found at higher levels in MMMT than AS samples (P= 0.03) and high Ki-67 antigen expression correlated with a decreased survival in patients with MMMT (P= 0.004). Independent characterization of oncogene proteins in the malignant components of these heterogeneous tumors may provide insight into the histogenesis and behavior of these malignancies.

Endometrioid carcinoma of the ovary with a prominent spindle-cell component, a source of diagnostic confusion. A report of 14 cases.

Fourteen endometrioid carcinomas of the ovary with a prominent component of spindle-shaped epithelial cells are reported. Eleven were initially misdiagnosed as sexcord stromal tumors, malignant mesodermal mixed tumors, tumors of probable wolffian origin, or metastatic carcinomas. All of the tumors, however, had one or more features establishing them as endometrioid carcinomas, including (a) glands typical of endometrioid adenocarcinoma, (b) foci of squamous differentiation, and (c) an adenofibromatous component. Six cases were examined immunohistochemically, and the epithelial nature of the spindle cells was supported by immunostaining for keratin and epithelial membrane antigen. The patients ranged in age from 42 to 89 years (mean, 61). Four cases were stage I, five stage II, and three stage III. Follow-up information was available in seven cases. Five patients were free of disease at 8, 11, 32, 56, and 103 months, and two patients were alive with disease at 10 and 20 months. The age of the patients, clinical presentation, tumor stage, and gross appearance were similar to those of typical endometrioid carcinomas. It is important that this tumor be distinguished from other ovarian neoplasms with a spindle-cell component because of differences in treatment and prognosis.

Endometrial intraepithelial carcinoma: A distinctive lesion specifically associated with tumors displaying serous differentiation

Endometrial intraepithelial carcinoma (EIC) is a recently described lesion characterized by replacement of endometrial surface epithelium or glands by malignant cells resembling high-grade invasive endometrial carcinoma. EIC has been identified in a high proportion of uteri containing serous carcinoma, but its association with other endometrial tumors is unknown. To determine the strength and specificity of the association of EIC with tumors displaying serous differentiation, the appearance of the endometrium in 38 uteri with serous carcinoma, 113 with endometrioid carcinoma, and 34 with malignant mixed mesodermal tumor (MMMT) were compared. EIC was present in 34 (89%) uteri with serous carcinoma compared with 7 (6%) uteri removed for endometrioid carcinoma ( P = .0001). Hyperplasia without atypia was found in only 2 (5%) of 38 serous carcinomas compared with 38 (34%) of 113 endometrioid carcinomas. Similarly, atypical hyperplasia was not found in any uterus with serous carcinoma, but was present in 14 (12%) uteri with endometrioid carcinoma ( P = .02). The endometrium was inactive or atrophic in 29 (76%) patients with serous carcinoma compared with 33 (29%) with endometrioid carcinoma ( P = .0001). EIC was found in five (56%) of nine MMMTs with a serous epithelial component (serous-MMMT) compared with one (4%) of 25 MMMTs with an endometrioid epithelial component (endometrioid-MMMT). As with endometrioid and serous carcinomas, hyperplasia with and without atypia was more common with endometrioid-MMMTs as compared with serousMMMTs. Hyperplasia was found in 25 (100%) and atypical hyperplasia in 8 (32%) of 25 endometrioid-MMMTs, but in none of the nine serous-MMMTs. This study shows that EIC is frequently and specifically associated with uterine tumors displaying serous differentiation. The findings suggest that EIC represents a form of intraepithelial tumor growth characteristic of serous carcinoma and serous MMMT and that EIC is the likely precursor of these neoplasms. In addition, the findings provide further evidence supporting the view that MMMTs represent variants of carcinoma not sarcoma.

P53 in endometrial cancer and its putative precursors: Evidence for diverse pathways of tumorigenesis

To elucidate the role of p53 abnormalities in endometrial tumorigenesis, a diverse group of endometrial neoplasms and their putative precursors, atypical endometrial hyperplasia, and endometrial intraepithelial carcinoma (EIC) were studied using a conventional immunohistochemical technique. Immunostaining for p53 protein was detected in 24 (86%) of 28 serous carcinomas compared with nine (20%) of 45 endometrioid carcinomas ( P < .001). Immunoreactivity was also detected in two (100%) of two clear cell carcinomas, five (83%) of six mixed endometrioid/serous carcinomas, and seven (70%) of 10 malignant mixed mesodermal tumors. Benign endometrial tissue and 12 examples of atypical endometrial hyperplasia were nonreactive. In 27 (79%) of 34 tumors containing EIC, both the tumor and EIC were immunoreactive for p53, whereas in 7 (21 %) both were negative. Immunostaining for p53 highlighted small foci of EIC and showed the extent and distribution of the lesions. The strong association and similar p53 immunostaining pattern of EIC and serous carcinoma support the hypothesis that serous carcinomas develop from endometrial surface epithelium that demonstrates abnormal p53 protein expression in conjunction with transformation to EIC. Mutation of p53 seems unrelated to the development of endometrioid carcinoma from atypical endometrial hyperplasia but may be related to dedifferentiation in some of these neoplasms.

Malignant mixed mesodermal tumors of the ovary

To review the experience at Women & Infants Hospital and Hartford Hospital of patients with malignant mixed mesodermal tumors of the ovary, and to review the pertinent literature. Fourteen cases of malignant mixed mesodermal tumors of the ovary at the two hospitals over a 5-year period were identified through their tumor registries. Demographic data, pathology, treatment, and survival rates were reviewed. The median survival of the patients in our series was 7 months, with 64% dead of disease in 1 year. A review of the pertinent literature indicated median survivals of 6-12 months, with more than 70% of the patients dead of disease at 1 year, despite treatment. Further investigation is needed to determine the proper management for malignant mixed mesodermal tumors of the ovary. Meanwhile, current treatment strategies should recognize the present therapeutic limitations, so as not to diminish any further the quality of life for women with this malignancy.

Estrogen and progesterone receptors in malignant mixed mesodermal tumors of the ovary.

Malignant mixed mesodermal tumors of the ovary occur in less than 1% of cases of ovarian cancer. They have a dismal prognosis and the most effective type of therapy is still not known. All cases of malignant mixed mesodermal tumor of the ovary between January 1, 1985 and May 1, 1994 operated on by the gynecologic oncology service are the subject of this report. Data were obtained from the hospital and office records of the patients. Nine patients who had their primary surgery by the gynecologic oncology service were found to have the diagnosis of malignant mixed mesodermal tumor of the ovary. Homologous tumors were found in five patients and heterologous tumors in four. Homologous tumors (mean survival 15.2 months) showed a better survival than heterologous tumors (mean survival 6.5 months; P = 0.001). An elevated estrogen receptor status was shown to correspond to longer survival (P < 0.0001). Six specimens were considered to be estrogen receptor positive and three were receptor negative. The mean survival in those patients who had a positive estrogen receptor status, 13.7 months, with a median of 7.5 months was significantly higher than those who were not positive, 6.7 months (P = 0.019) with a median of 6.25 months. All specimens were progesterone receptor negative. Malignant mixed mesodermal tumors of the ovary have a dismal prognosis, no effective therapy, and controversial prognostic indicators. Increasing estrogen receptor status appeared to correlate with longer mean survival. Larger, multi-institutional studies need to be done to determine the overall significance of these findings.

Ovarian Carcinoma Presenting as Intra-abdominal Hemorrhage

Ovarian carcinoma commonly has an insidious onset. By the time the diagnosis is made, advanced disease is usually present. Rarely does a patient have acute symptoms which require immediate medical attention and lead to the correct diagnosis. A 40-year-old white female presented with lower abdominal pain, nausea, and light-headedness. Physical examination revealed a markedly tender lower abdomen with the right lower quadrant slightly more tender than the left. Hemoglobin level was noted to have decreased 2.6 g/dl over 16 hr. At exploratory laparotomy, 1500 cc of blood and a ruptured right ovarian mass were found. Pathologic analysis revealed a malignant mixed mesodermal tumor of the right ovary and an endometrioma of the left ovary. In conclusion, ovarian carcinoma may present as an acute abdomen because of intra-abdominal hemorrhage. It should be part of the differential diagnosis in a woman with an acute surgical abdomen and a hemoperitoneum.

The effect of chemotherapy on the different components of advanced carcinosarcomas (malignant mixed mesodermal tumors) of the female genital tract.

The effect of chemotherapy on the different components of uterine and ovarian carcinosarcoma is largely unknown. This report describes six patients with advanced carcinosarcoma, five of whom received 4 cycles of doxorubicin and ifosfamide (AI) directed at the sarcomatous component of the tumor. Responses in these five patients at second-look laparotomy were: one complete response, two partial responses (persistence of only the carcinomatous component), one stable disease, and one progressive disease (both components still present in both cases). Thereafter 4 cycles of a cisplatin-based regimen were scheduled. Response to the cisplatin-containing regimen was only evaluated clinically. The sixth patient (with no macroscopic disease left after initial surgery) received 6 cycles of a cisplatin-based chemotherapy from the onset and was found to be in complete response at relaparotomy. Median progression-free survival for all patients was 15 months and median survival 21 months. A literature survey showed that carcinosarcoma differs from adult soft tissue sarcomas with respect to responsiveness to chemotherapy. Cisplatin and ifosfamide are active as single agents, whereas the response to single-agent doxorubicin seems to be lower. The data suggest, however, that superior response rates and increased survival times are achieved with cisplatin/doxorubicin-based chemotherapy. The sensitivity of carcinosarcoma to cisplatin supports the recent view that carcinosarcoma of the female genital tract is possibly a high grade carcinoma with metaplastic sarcomatous elements.

Mural Nodules in Common Epithelial Tumors, of the Ovary

The occurrence of mural nodules in cystic common epithelial tumors of the ovary is well established, but differences in terminology and difficulties in histopathologic interpretation have hampered adequate understanding of their differential diagnoses and prognoses. Using immunohistochemistry and ultrastructural analyses supplementally, we studied two cases, one a serous cystadenocarcinoma with nodules of undifferentiated sarcoma, the other a mucinous cystadenocarcinoma with mural nodules of anaplastic carcinoma. Based on these cases and a review of 48 cases in the literature, we propose a standardized terminology. Mural nodules may be either reactive or neoplastic. Neoplastic mural nodules may be composed of benign elements, carcinoma, carcinoma with reactive elements, sarcoma, or an admixture of carcinoma and sarcoma; the latter category has some similarities to malignant mixed mesodermal tumors. The prognosis of patients with malignant mural nodules is poor, with 50% mortality. Strict morphologic criteria supplemented by immunohistochemistry aids in the sometimes difficult differential diagnosis among these types of mural nodules.

Uterine sarcomas: a review of the Edinburgh experience from 1974 to 1992

A retrospective review of patients treated for a uterine sarcoma in Edinburgh from 1974 to 1992 has been performed. Clinical details at presentation, tumour pathology, treatment and the outcome of treatment were all recorded. 82 patients' case notes were reviewed. 54 patients had died and 28 were alive (mean follow-up period 80.3 months). 39 patients had a malignant mixed mesodermal tumour, 12 patients had an endometrial stromal sarcoma, and 27 had a leiomyosarcoma. Using a modified FIGO staging retrospectively, 41 patients had Stage 1 disease, two patients had Stage 2, 16 patients had Stage 3, and 13 patients had Stage 4 disease. Definitive treatment of total abdominal hysterectomy and bilateral salpingo-oophorectomy was used in 69 patients, with 35 of these patients also receiving post-operative radiotherapy to the pelvis. 13 patients did not undergo surgery. Five of these patients received radical radiotherapy, three patients received palliative radiotherapy, and five patients were not treated. The overall median survival is 15 months and the 5-year actuarial survival is 31%. 25 of the 26 surviving patients had Stage 1 disease at presentation. Post-operative pelvic radiotherapy did not influence either survival or local tumour control. 51 of the 54 patients who relapsed had evidence of distant metastases. We conclude that total abdominal hysterectomy and bilateral salpingo-oophorectomy remains the treatment of choice for uterine sarcomas.

Uterine Leiomyosarcoma and Endometrial Stromal Sarcoma: Lymph Node Metastases and Sites of Recurrence

This study was undertaken to examine the incidence and conditions under which lymph node metastases are present and patterns of recurrence in women with uterine leiomyosarcoma (LMS) and endometrial stromal sarcoma (ESS), excluding malignant mixed mesodermal tumors. From 1981 through 1991, 21 women with LMS and 10 women with ESS were treated. Retroperitoneal lymph node dissections were performed in 15 women with LMS and 7 women with ESS. In the women with LMS, 4/15 (26.7%) had lymph node metastases; in each there was disseminated intra-abdominal disease. In the 7 women with ESS, there were no lymph node metastases present. Ten women (47%) with LMS developed recurrences, and 3 (14%) had persistent disease. In the 10 women with ESS, 3 (30%) had recurrences, and 1 (10%) had persistent disease. In total, recurrences involved the lung in 84% of cases. Of the 13 women with recurrences, 7 had undergone lymph node sampling, and all were negative; 4 additional women had no evidence of adenopathy on abdominal-pelvic CT scan. Lymph node metastases were found only with extrauterine disease, and in all of these cases there was rapid progression of the sarcoma. Women without extrauterine disease did not have lymph node metastases detected; however, there was still a high rate (40%) of distant failure. Knowledge of lymph node status has minimal impact on the clinical management of women with uterine LMS and ESS.

Role of electron microscopy in metastatic endometrial stromal tumors.

Endometrial stromal tumors may pose a problem in diagnosis when they appear as metastatic lesions without a known primary tumor. To determine the usefulness of electron microscopy in identifying them in these situations, optimally fixed low-grade stromal sarcomas (five), normal endometrial specimens (six), and malignant mesodermal mixed tumors (four) were studied. The endometrial stromal sarcomas had a general resemblance to normal proliferative endometrial stroma, being composed of undifferentiated cells, fibroblasts, and myofibroblasts. One stromal tumor showed evidence of partial epithelial differentiation. One of the four malignant mesodermal mixed tumors had a fibrosarcomalike component, but there was insufficient resemblance to normal endometrial stroma to indicate a relationship between the two. Together with a review of the literature, this study indicates that electron microscopy is useful in the diagnosis of low-grade endometrial stromal tumors by demonstrating characteristic cellular findings as well as a lack of features specific for other round cell and spindle cell neoplasms.

Tissue CA 125 and CA 19-9 in Malignant, Mixed Mesodermal Tumors of the Uterus

Mixed mesodermal tumors of the uterus are biphasic neoplasms composed of both a malignant epithelium and a sarcomatous stromal component. Elevated levels of tumor-associated antigens, such as CA 125, have been reported in some patients with these tumors. The purpose of this study was to determine the frequency and tissue distribution of CA 125 and CA 19-9 in malignant mixed mesodermal tumors of the uterus treated with primary surgery. Consecutive, paraffin-embedded sections from 35 tumors were immunohistochemically evaluated using primary antibodies directed against CA 125 and CA 19-9. CA 125 and CA 19-9 were demonstrated in the neoplastic glandular epithelium and not in the sarcomatous portion of the tumor. The localization of CA 125 and CA 19-9 suggested that both antigens were epithelial secretory products. Positive staining (⩾5% of the glandular epithelium) for CA 125 was present in 46% of the tumors; another 14% of the tumors contained focal staining (<5% of the glandular epithelium) for CA 125. Positive staining for CA 19-9 was demonstrated in 34% of tumors; another 17% contained focal staining for CA 19-9. The markers were concordant in 77% of the tumors examined. Antigen expression was unrelated to the nature of the sarcomatous element (homologous vs heterologous), the extent of disease, and patient survival. However, the epithelial component of these sarcomas frequently expressed these antigens and the degree of expression was related to the cell type and the histologic grade of the glandular element.