Histological evaluation of endometrium has been the gold standard for clinical diagnosis and management of women with endometrial disorders. However, several recent studies have questioned the accuracy and utility of such evaluation, mainly because of significant intra- and interobserver variations in histological interpretation. To examine the possibility that biochemical or molecular signatures of endometrium may prove to be more useful, we have investigated whole-genome molecular phenotyping (54,600 genes and expressed sequence tags) of this tissue sampled across the cycle in 28 normo-ovulatory women, using high-density oligonucleotide microarrays. Unsupervised principal component analysis of all samples revealed that samples self-cluster into four groups consistent with histological phenotypes of proliferative (PE), early-secretory (ESE), mid-secretory (MSE), and late-secretory (LSE) endometrium. Independent hierarchical clustering analysis revealed equivalent results, with two major dendrogram branches corresponding to PE/ESE and MSE/LSE and sub-branching into the four respective phases with heterogeneity among samples within each sub-branch. K-means clustering of genes revealed four major patterns of gene expression (high in PE, high in ESE, high in MSE, and high in LSE), and gene ontology analysis of these clusters demonstrated cycle-phase-specific biological processes and molecular functions. Six samples with ambiguous histology were identically assignable to a cycle phase by both principal component analysis and hierarchical clustering. Additionally, pairwise comparisons of relative gene expression across the cycle revealed genes/families that clearly distinguish the transitions of PE-->ESE, ESE-->MSE, and MSE-->LSE, including receptomes and signaling pathways. Select genes were validated by quantitative RT-PCR. Overall, the results demonstrate that endometrial samples obtained by two different sampling techniques (biopsy and curetting hysterectomy specimens) from subjects who are as normal as possible in a human study and including those with unknown histology, can be classified by their molecular signatures and correspond to known phases of the menstrual cycle with identical results using two independent analytical methods. Also, the results enable global identification of biological processes and molecular mechanisms that occur dynamically in the endometrium in the changing steroid hormone milieu across the menstrual cycle in normo-ovulatory women. The results underscore the potential of gene expression profiling for developing molecular diagnostics of endometrial normalcy and abnormalities and identifying molecular targets for therapeutic purposes in endometrial disorders.

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Twenty‐nine patients had simultaneous malignant epithelial neoplasms of the uterine corpus and ovary. Three groups were defined on the basis of tumor histology: Group A: those with endometrioid carcinoma in both the uterus and ovary; Group B: those with special variants of corpus carcinoma (papillary, clear cell, mucinous) and identical neoplasms in the ovary; and Group C: those whose uterine and ovarian carcinomas were of dissimilar histologic types. Sixteen women had endometrioid carcinoma in both sites. The median age at diagnosis, 41 years, was younger than is usual for corpus or ovarian cancer. For all 16 patients, the grade of the ovarian endometrioid carcinoma was similar to that of the endometrioid carcinoma of the uterine corpus. Seven patients had bilateral ovarian neoplasms. Only one patient had myometrial invasion by the corpus carcinoma. No patient with simultaneous ovarian and uterine endometrioid carcinoma, regardless of grade, has died of cancer although one vaginal relapse was treated successfully. This excellent survival of patients with simultaneous endometrioid carcinomas is better than would be expected for either Stage III adenocarcinoma of the endometrium or Stage II ovarian carcinoma. These simultaneously occurring endometrioid neoplasms of ovary and endometrium are considered to be separate primary tumors. The morphologic reasons for this view and therapeutic implications are discussed. In contrast to the patients with endometrioid carcinoma, the eleven patients with other histologic types of carcinoma in the ovary and corpus were older (median age, 61 years) and more often post‐menopausal (90%). These neoplasms were more aggressive, with frequent deep myometrial involvement (63%), tubal involvement (27%), and extension to other pelvic tissues (36%) at the time of initial diagnosis. Six of these 11 patients succumbed to their cancer despite surgical therapy and radiation. The distribution of tumor in some of these patients with nonendometrioid types of carcinoma is suggestive of a single primary with metastases. The therapeutic implications of these findings are discussed. Cancer 50:163–170, 1982.

One hundred smooth muscle tumors arising in the gastrointestinal tract and retroperitoneum were reviewed in an attempt to define criteria for the diagnosis of leiomyosarcoma in these sites. On the basis of aggressive behavior, 56 of these neoplasms were diagnosed as leiomyosarcoma. Mitoses were found to be the most useful indicator of malignancy; all of the tumors with five or more mitoses/10 HPF behaved aggressively and smooth muscle tumors with this degree of mitotic activity should be diagnosed as leiomyosarcoma. A paucity of mitoses, however, is no assurance of benignity as nearly 40% of the leiomyosarcomas in this series had fewer than five mitoses/10 HPF. Tumor cell necrosis was closely associated with aggressive behavior even when mitoses were infrequent and it is doubtful that benign smooth muscle tumors develop extensive tumor cell necrosis. In the absence of the requisite number of mitoses or tumor necrosis, it is difficult to distinguish some leiomyosarcomas from leiomyomas, but tumor size, cellularity and cellular atypia may be helpful parameters when assessed together. The importance of these criteria in different anatomical sites is discussed. It is emphasized that the criteria for the diagnosis of leiomyosarcoma of the uterus do not apply to non-uterine smooth muscle tumors. The actuarial 2-year survival rate was as follows: gastric leiomyosarcoma, 40%; small intestinal leiomyosarcoma, 60%; and retroperitoneal leiomyosarcoma, 16%.