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Mesodermal mixed tumor primary in the fallopian tube.

Mullerian mixed tumors, as a group, are uncommon. Only 27 cases of this tumor of the fallopian tube have been reported to date. We report the 28th case of mixed mesodermal tumor, originating in the fallopian tube. A 79-year-old woman had mistaken a bloody vaginal discharge for hematuria. Various examinations showed no evidence of malignancy. However, computerized tomography revealed an intrapelvic tumor. Laparotomy was performed, with a suspicion of tubal malignancy. The final pathologic diagnosis was mixed mesodermal tumor, originating in the fallopian tube. Postoperatively, the patient was placed on oral adjuvant chemotherapy for 34 months. At present, she is doing well. Though no definite conclusions regarding the best method of therapy can be reached, an aggressive mode of therapy is recommended. The primary therapy is surgery; however, surgery followed by chemotherapy may have a potential benefit.

Aged↗

Clinical features of advanced ovarian mixed mesodermal tumors and treatment with doxorubicin- and cis-platinum-based chemotherapy.

Records of 15 patients with stage III and IV malignant mixed mesodermal tumors of the ovary treated between 1977 and 1988 were reviewed. All patients had primary surgery; 13 were given postoperative chemotherapy including doxorubicin and cis-platinum. Median survival for patients receiving chemotherapy is 16 months; 62% were alive at 12 months and 31% at 24 months. Progression-free responses were seen in 85% of treated patients and 55% of these recurred. All recurrences involved the pelvis and were predominantly mesenchymal. Serum CA-125 values accurately reflected tumor presence in 82% of tested patients. Cytoreductive surgery followed by treatment including doxorubicin- and cis-platinum-based chemotherapy is effective in treatment of disseminated ovarian mixed mesodermal tumors, but additional components must be added to achieve durable responses and consistently prolonged survivals.

Aged↗

The epithelial origin of a malignant mesodermal mixed tumor of the bladder: report of a case with long-term survival.

Malignant mesodermal mixed tumors of the bladder are complex neoplasms consisting of elements of carcinoma and differentiated sarcoma. They are rare, aggressive and usually rapidly fatal. We report on a patient who remained free of disease 7 years after resection by partial cystectomy of a malignant mesodermal mixed tumor. Only 1 other long-term survivor has been reported. Our case is of particular interest because urothelial carcinoma in situ was found in the bladder epithelium on the surface and at the periphery of the invasive tumor, strongly suggesting an epithelial origin of this and similar tumors of other organs.

Carcinoma in Situ↗

Ovarian malignant mixed mesodermal tumor: the occurrence of hyaline droplets containing alpha 1-antitrypsin.

Twenty-one of 22 cases of malignant mixed mesodermal tumor (including carcinosarcoma) of the ovary were found to contain periodic acid-Schiff(PAS)-positive, diastase-resistant hyaline droplets ranging in diameter from less than 1 micrometer to approximately 50 micrometers. Droplets were located both inside and outside undifferentiated mesenchymal cells, predominantly within myxomatous areas. In 13 cases, droplets also occurred in epithelial structures, including areas mimicking ovarian carcinoma. Immunoperoxidase staining for alpha-fetoprotein was consistently negative, but droplets and cell cytoplasm reacted strongly with anti-alpha 1-antitrypsin. Analysis of the structure of droplet antitrypsin may be necessary to determine the origin of the droplets themselves and the possible usefulness of serum alpha 1- antitrypsin as a tumor marker in ovarian carcinoma and malignant mixed mesodermal tumor.

Adult↗

Histogenesis and tissue reconstruction of mixed mesodermal tumor.

The clonal cell lines designated as HIRS-BMS and HIRS-BMA were established from HIRS-BM (multipotent primitive cells which differentiated into rhabdomyosarcoma and adenocarcinoma cells) by a single cell plating method. The HIRS-BMS was a rhabdomyosarcoma cell line composed of elongated fibrous cells which contained myoglobin. The HIRS-BMA was an adenocarcinoma cell line composed of round cells. The tissue reconstruction of these cell lines was studied in vitro (rotation culture system) and in vivo (transplantation into hamster cheek pouch). The HIRS-BMS cells produced rhabdomyosarcoma, both in vitro and in vivo, and the HIRS-BMA produced poorly differentiated adenocarcinoma, in vitro and in vivo. The mixture of HIRS-BMS and HIRS-BMA produced a mixed mesodermal tumor resembling the original tumor. These results support the theory of a combined tumor as a cause of mixed mesodermal tumor.

Adenocarcinoma↗

Secreted noggin protein mimics the Spemann organizer in dorsalizing Xenopus mesoderm.

A dorsalizing signal acts during gastrulation to change the specification of lateral mesodermal tissues from ventral (blood, mesenchyme) to more dorsal fates (muscle, heart, pronephros). This signal, from Spemann's organizer, cannot be mimicked by the mesoderm inducers activin and fibroblast growth factor. The gene noggin is expressed in the organizer, and could be the dorsalizing signal. Here we show that soluble noggin protein added to ventral marginal zones during gastrulation induces muscle, but that activin does not. Dorsal pattern can be partially rescued in ventralized embryos by injection of a plasmid that expresses noggin during gastrulation. The results suggest that the noggin product may be the dorsalizing signal from the organizer.

Activins↗

Maintenance of embryonic stem cell pluripotency by Nanog-mediated reversal of mesoderm specification.

Embryonic stem cells (ESCs) can be propagated indefinitely in culture, while retaining the ability to differentiate into any cell type in the organism. The molecular and cellular mechanisms underlying ESC pluripotency are, however, poorly understood. We characterize a population of early mesoderm-specified (EM) progenitors that is generated from mouse ESCs by bone morphogenetic protein stimulation. We further show that pluripotent ESCs are actively regenerated from EM progenitors by the action of the divergent homeodomain-containing protein Nanog, which, in turn, is upregulated in EM progenitors by the combined action of leukemia inhibitory factor and the early mesoderm transcription factor T/Brachyury. These findings uncover specific roles of leukemia inhibitory factor, Nanog, and bone morphogenetic protein in the self-renewal of ESCs and provide novel insights into the cellular bases of ESC pluripotency.

Animals↗

Extrauterine mesodermal (müllerian) adenosarcoma: a clinicopathologic analysis of five cases.

Five extrauterine examples (three pelvic and two ovarian) of a distinctive mesodermal (müllerian) mixed tumor previously described to occur in the uterus and designated müllerian adenosarcoma are reported. The tumors were diagnosed during the fifth to eight decades of life. They usually formed very large, partly cystic masses, which had occasionally spread to adjacent organs by the time of operation. On microscopic examination the tumors consisted of benign-appearing neoplastic glands lying in a sarcomatous stroma. The glands were lined by a variety of müllerian epithelial cell types, and the stromal element resembled endometrial stromal sarcoma. Three patients had malignant courses manifested by intrabdominal recurrence, distant metastases, or both. This tumor should be clearly distinguished from the more common forms of mesodermal (müllerian) mixed tumor in which the epithilial as well as the stromal component is malignant and the prognosis is much more grave.

Adult↗

Prospective trial of cisplatin, adriamycin, and dacarbazine in metastatic mixed mesodermal sarcomas of the uterus and ovary.

Twenty-four patients with advanced or recurrent uterine (13) and ovarian (11) mixed mesodermal sarcomas received a combination of cisplatin. Adriamycin and dacarbazine (PAD) as initial therapy after surgical debulking. Of the 13 patients with metastatic uterine sarcoma, six (46.1%) remained without evidence of disease (NED) from 8 to 36 months from the start of PAD. The estimated 1-, 2-, and 3-year survivals for these patients were 68%, 68%, and 51%, respectively. Of the 11 ovarian sarcoma patients, five (45.4%) were NED at 5, 7, 32, 56, and 59 months from the start of PAD. The estimated 1-, 2-, and 3-year survivals for these patients were 70%, 35%, and 35%, respectively. The PAD regimen is an active regimen in patients with metastatic uterine and ovarian mixed mesodermal sarcomas and progression-free survival may be improved by maximum debulking surgery prior to the initiation of PAD chemotherapy.

Aged↗

The significance of epithelial differentiation in mixed mesodermal tumors of the uterus. A clinicopathologic and immunohistochemical study.

Mixed mesodermal tumors and carcinosarcomas of the uterus are classified as sarcomas. However, in other sites, malignant biphasic tumors may be classified as carcinomas, mesotheliomas, or sarcomas. In order to clarify their behavior and patterns of differentiation, we performed a clinicopathologic and immunohistochemical study of 22 cases aimed at analyzing the pattern of spread and histologic appearance of the metastasis, as well as the distribution of intermediate filaments in the primary tumor and the metastasis. Four monoclonal antibodies (Mabs) were used to detect epithelial lineage, three that recognize keratin (AE1/AE3, CAM5.2, MAK6) and one that recognizes epithelial membrane antigen (EMA). A Mab against vimentin was also used. Metastases involved the omentum, pelvic peritoneum, ovaries, fallopian tubes, pelvic or para-aortic lymph nodes, liver parenchyma, and tonsil. These metastases were composed of carcinoma only. Lymphatic/vascular invasion was identified in 11 cases; it consisted exclusively of carcinoma. In all 12 cases evaluated immunohistochemically, keratin and EMA were identified in the majority of the cells in the epithelial component and in a more focal distribution in the spindle cell component in 11 (92%). Vimentin was detected in the majority of spindle cells in nine cases (75%) and in a more focal distribution in the epithelial component in six cases (50%). In the spindle cell component, keratin and EMA were present in widely scattered individual spindle-shaped and rounded cells, within solid clusters of rounded cells, and in nests of cells with small lumens. The distribution of keratin, EMA, and vimentin in the metastases (carcinoma in all instances) was similar to the epithelial component in the primary tumor. Our findings indicate that the epithelial component of these tumors invades lymphatic/vascular spaces and metastasizes, whereas the spindle cell component has limited metastatic potential, if any. Since the behavior of these neoplasms is dictated by the epithelial element, we believe that mixed mesodermal tumors of the uterus should be classified as carcinomas rather than sarcomas.

Aged↗

Differential activation of Xenopus homeo box genes by mesoderm-inducing growth factors and retinoic acid.

What is the nature of positional information during embryogenesis? By using Xenopus homeo box genes as anteroposterior (A-P) markers, we confirm the findings of others that mesoderm-inducing growth factors and retinoic acid (RA) can provide positional information along the axis of the body. Xenopus tissue culture-mesoderm-inducing factor (XTC-MIF) selectively activates an anteriorly expressed homeo box gene (XlHbox 1), while basic fibroblast growth factor (bFGF) activates selectively a posteriorly expressed homeo box gene (XlHbox 6). RA activates expression of the posterior gene XlHbox 6, but not of XlHbox 1. This activation, however, requires exposure to growth factors. The data suggest that growth factors and RA may cooperate with each other to provide positional information in vertebrates.

Animals↗

Anterior boundaries of Hox gene expression in mesoderm-derived structures correlate with the linear gene order along the chromosome.

The developmental expression patterns of four genes, Hox 1.1, Hox 1.2, Hox 1.3 and Hox 3.1, were examined by in situ hybridization to serial embryonic sections. The three genes of the Hox 1 cluster, used in this study, map to adjacent positions along chromosome 6, whereas the Hox 3.1 gene maps to the Hox 3 cluster on chromosome 15. The anterior expression limits in segmented mesoderm varied among the four genes examined. Interestingly, a linear correlation exists between the position of the gene along the chromosome and the extent of anterior expression. Genes that are expressed more posterior are also more restricted in their expression in other mesoderm-derived tissues. The order of expression anterior to posterior was determined as: Hox 1.3, Hox 1.2, Hox 1.1 and Hox 3.1. Similarly, genes of the Drosophila Antennapedia and Bithorax complex specifying segment identity also exhibit anterior expression boundaries that correlate with gene position. The data suggest that Hox genes may specify positional information along the anterior-posterior axis during the formation of the body plan.

Animals↗

Ultrastructure of mesodermal mixed tumor of the uterus.

A case of mesodermal mixed tumor arising in the uterus of a 57-year-old woman is presented. The tumor was a mixture of adenocarcinoma with occasional squamous metaplasia, stromal sarcoma, myxosarcoma and chondrosarcoma. Light and electron microscopic examinations of the tumor revealed close transition between stromal sarcomatous component and each of other sarcomatous and carcinomatous component. The histogenesis of mixed mesodermal tumor was discussed and it was concluded that the tumor might be derived from endometrial stromal cell which possessed the pluripotency to differentiate toward various epithelial and mesenchymal tissues including the heterologous mesenchymal tissue.

Adenocarcinoma↗

Histogenesis of ovarian malignant mixed mesodermal tumours.

The histogenesis of ovarian malignant mixed mesodermal tumours, which includes the concept of metaplastic carcinoma, is controversial. Four such tumours were examined for evidence of metaplastic transition from carcinoma to sarcoma using morphology and reticulin stains. Consecutive sections were stained immunohistochemically using cytokeratin and vimentin to determine whether cells at the interface between carcinoma and sarcoma expressed both cytokeratin and vimentin. There was no evidence of morphological, architectural, or immunohistochemical transitions from carcinoma to sarcoma in the four tumours studied. This suggests that ovarian malignant mixed mesodermal tumours are not metaplastic carcinomas but are composed of histogenetically different elements.

Adenocarcinoma↗

Cisplatin therapy for disseminated mixed mesodermal sarcoma of the uterus.

Eighteen patients with metastatic mixed mesodermal sarcoma of the uterus received cisplatin therapy at the University of Texas (UT) M.D. Anderson Hospital and Tumor Institute at Houston. The dose of cisplatin varied from 75 mg/m2 to 100 mg/m2. Previous therapy included surgery in 11 patients, radiotherapy in two patients, and surgery plus radiotherapy in four patients. One patient had no prior therapy. Seven patients had also received prior chemotherapy with doxorubicin. Of 12 patients with measurable disease, one (8%) had a complete response and four (33%) had a partial response for an overall response rate of 42%. The median progression-free survival of patients treated with cisplatin as first- and second-line therapy was 4.5 and 5.5 months, respectively. Cisplatin demonstrated moderate activity with mild toxicity in this group of patients with metastatic mixed mesodermal uterine sarcomas. Further studies including cisplatin-containing combination regimens seem to be warranted.

Aged↗

Cytoplasmic and molecular reconstruction of Xenopus embryos: synergy of dorsalizing and endo-mesodermalizing determinants drives early axial patterning.

Ablation of vegetal cytoplasm from newly fertilized Xenopus eggs results in the development of permanent blastula-type embryos (PBEs). PBEs cleave normally and develop into a very simple tissue consisting only of atypical epidermis. We tried to restore complete embryonic development in PBEs by cytoplasmic transplantation or by mRNA injection. We show a two-step reconstruction of the body plan. In the first step, PBEs injected with either marginal cytoplasm or synthetic VegT RNA restored gastrulation and mesoderm formation, but not axial patterning. Injection of Xwnt8 mRNA (acting upstream of beta-catenin and thus substitutes for the dorsal determinant) did not restore axial development in PBEs. Simultaneous injections of Xwnt8 and VegT into PBEs resulted in dorsal axis development, showing the synergy of these molecules in axial development. These results suggest that the mixing of two cytoplasmic determinants, i.e. the dorsal determinant in the vegetal pole and the endo-mesodermal determinant in the whole vegetal half, triggers the early axial developmental process in Xenopus embryos.

Animals↗

A comparative molecular approach to mesodermal patterning in basal deuterostomes: the expression pattern of Brachyury in the enteropneust hemichordate Ptychodera flava.

This work concerns the formation of mesoderm in the development of an enteropneust hemichordate, Ptychodera flava, and the expression of the Brachyury gene during this process. Brachyury expression occurs in two distinct phases. In the embryo, Brachyury is transcribed during gastrulation in the future oral and anal regions of the gut, but transcripts are no longer detected by 2 weeks of development. Brachyury expression is not detected during the 5 months of larval planktonic existence. During this time, the adult coeloms begin to develop, originating as coalescences of cells that appear to delaminate from the wall of the gut. Brachyury expression cannot be detected again until metamorphosis, when transcripts appear in the mesoderm of the adult proboscis, collar and the very posterior region of the trunk. It is also expressed in the posterior end of the gut. At no time is Brachyury expressed in the stomochord, the putative homologue of the chordate notochord. These observations illuminate the process of maximal indirect development in Ptychodera and, by comparison with patterns of Brachyury expression in the indirect development of echinoderms, their sister group, they reveal the evolutionary history of Brachyury utilization in deuterostomes.

Animals↗

Axial skeletal defects caused by mutation in the spondylocostal dysplasia/pudgy gene Dll3 are associated with disruption of the segmentation clock within the presomitic mesoderm.

A loss-of-function mutation in the mouse delta-like3 (Dll3) gene has been generated following gene targeting, and results in severe axial skeletal defects. These defects, which consist of highly disorganised vertebrae and costal defects, are similar to those associated with the Dll3-dependent pudgy mutant in mouse and with spondylocostal dysplasia (MIM 277300) in humans. This study demonstrates that Dll3(neo) and Dll3(pu) are functionally equivalent alleles with respect to the skeletal dysplasia, and we suggest that the three human DLL3 mutations associated with spondylocostal dysplasia are also functionally equivalent to the Dll3(neo) null allele. Our phenotypic analysis of Dll3(neo)/Dll3(neo) mutants shows that the developmental origins of the skeletal defects lie in delayed and irregular somite formation, which results in the perturbation of anteroposterior somite polarity. As the expression of Lfng, Hes1, Hes5 and Hey1 is disrupted in the presomitic mesoderm, we suggest that the somitic aberrations are founded in the disruption of the segmentation clock that intrinsically oscillates within presomitic mesoderm.

Alleles↗