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The prognostic value of the pretreatment serum CA 125, squamous cell carcinoma antigen (SCC), and carcinoembryonic antigen (CEA) levels in relation to tumor type, vascular invasion by tumor cells, and lymph node metastases was investigated in 77 patients with cervical adenocarcinoma. In Stage IB (International Federation of Gynecology and Obstetrics [FIGO]), the five-year actuarial survival of patients with pretreatment serum CA 125 levels greater than 16 U/ml was 52.4% versus 95.6% when normal serum CA 125 levels were determined (P less than 0.01). Pretreatment serum SCC or CEA levels had no substantial prognostic value. In Stage IB (FIGO), 42% of the patients with elevated serum CA 125 levels had lymph node metastases versus 4% when normal levels were found (P = 0.012). The presence of vascular invasion (P = 0.01) or lymph node metastases (P = 0.001) was associated with an increased risk for recurrent disease. Adenosquamous tumors showed a higher incidence of vascular invasion (P = 0.05) and a higher incidence of elevated serum CA 125 levels (P = 0.03). Particularly in Stage II, adenosquamous tumors were found to have a poorer prognosis than adenocarcinomas (P = 0.0566). We conclude that in cervical adenocarcinoma serum CA 125 is an important prognostic factor and an implicit indicator of tumor virulence.

Primary and metastatic tumor tissues of serous papillary adenocarcinoma of the endometrium were examined for the following: (1) amplification of int-2, c-erbB-2 and c-myc proto-oncogenes by Southern blot hybridization; (2) DNA ploidy by flow cytometric study; (3) and expression of specific proteins, such as estrogen and progesterone receptors, keratin, vimentin, and carcinoembryonic antigen (CEA) using immunohistochemical and biochemical techniques. Amplification of c-myc was observed in the specimens from the endometrium (ten-fold) and from omental metastasis (five-fold). Both int-2 and c-erbB-2 amplification were not observed. The tumor showed aneuploidy, with the specimens from the endometrium and omental metastasis exhibiting multiple populations of aneuploid tumor cells. Estrogen and progesterone receptors could not be detected biochemically; however, immunohistochemically, estrogen receptors were observed in tumor cells forming papillary structures but not in the tumor cells of the solid, more poorly differentiated areas. A similar distribution was observed for both low and high molecular weight keratin. The findings of c-myc amplification and aneuploidy in the serous papillary adenocarcinoma of the endometrium are consistent with its aggressive behavior observed clinically and emphasize the importance of distinguishing this lesion from other types of endometrial carcinoma.

We report a case of primary endodermal sinus tumor (EST) of the endometrium in a 42-year-old female. Although numerous extragonadal EST have been reported, primary EST of the endometrium is exceedingly rare. To our knowledge this is the fourth documented case of this nature. The tumor had the typical microscopic features of EST, with papillary, tubular, reticular, and solid growth patterns; occasional Schiller-Duval bodies and many intracellular and extracellular periodic-acid Schiff positive hyaline globules were seen. The neoplastic cells stained positively for alpha-fetoprotein (AFP), alpha-1-antitrypsin (A1AT), cytokeratin, and placental alkaline phosphatase. The globules were positive for AFP, A1AT, albumin, transferrin, and fibronectin. The tumor cells were negative for type IV collagen and the beta subunit of human chorionic gonadotropin (B hcG). Electron microscopic examination showed intracellular and extracellular basement membrane-like material, intracytoplasmic lumina with microvilli, and glycogen. The patient was treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy, followed by four cycles of adjunct chemotherapy (vinblastine, bleomycin, and cisplatinum) repeated every 3 weeks. The serum AFP level was elevated significantly before the surgery and the tumor response was monitored by serial determination of serum AFP level. There was no evidence of recurrence 24 months after surgery.

A 33-year-old woman had a metastasizing leiomyoma in which mitotic figures could not be found. The tumor was composed of well differentiated smooth muscle indistinguishable from uterine leiomyoma or normal myometrium by light and electron microscopy. The S-phase fraction of the tumor, measured by in vitro tritiated thymidine labeling, was near the upper limit of the range seen in seven ordinary uterine leiomyomas and was distinctly lower than that in a uterine leiomyosarcoma. The content of estrogen receptors in the cytosol was within the range seen in uterine leiomyomas. Metastasizing leiomyoma is an actively proliferating neoplasm of mature smooth muscle that appears to be hormonally responsive. The tumor in our patient showed no clear differences from ordinary leiomyomas in findings relating to the rate of cellular proliferation, morphology, or estrogen receptor content.

The immunoperoxidase technique was utilized to study the occurrence and localization of relaxin in malignant and nonmalignant trophoblastic disease and nontrophoblastic gynecologic cancer. Tissue specimens were studied from normal placenta at various weeks of gestation (N = 10), hydatidiform mole (N = 10), invasive mole (N = 10), choriocarcinoma (N = 10), normal endometrium (N = 28), decidua (N = 5), adenocarcinoma of the endocervix (N = 10), of the endometrium (N = 10), corpus luteum (N = 2), ovarian serous papillary cystadenocarcinoma (N = 10), and mucinous cystadenocarcinoma (N = 10). Relaxin was identified in the syncytiotrophoblast of normal placenta at all stages of gestation and also, for the first time, in hydatidiform mole, invasive mole, and choriocarcinoma. No relaxin was found in any nontrophoblastic cancer, including secretory-type adenocarcinoma. The absence of relaxin in the secretory-type endometrial adenocarcinoma is intriguing in light of the finding of relaxin in the normal secretory endometrium. The difference may be due to absence of the relaxin-producing corpus luteum in cancer patients or to loss of relaxin synthesis in the malignant endometrium. The results of this study suggest that relaxin may be synthesized by the normal syncytiotrophoblast and trophoblastic tumors, although differential absorption of relaxin produced in another site cannot be excluded.

Sixty-eight endometrial carcinomas were examined histochemically and immunohistochemically for the presence of amine-containing or neurohormonal peptide-containing cells, particularly in relation to argyrophil cells. Argyrophil cells, detected in 43 of the 68 endometrial carcinomas by the Grimelius method, were subgrouped into two types according to the distribution of argyrophil granules and the shape of the tumor cells. Type I was found in 7 tumors and type II in 39; 3 tumors contained both cell types. The argyrophilia of type II cells was diminished in varying degrees in some tumors by diastase digestion, although it was unchanged in type I argyrophil cells. Indoleamine was detected by the formaldehyde-induced fluorescence method in type I argyrophil cells of four carcinomas. Immunohistochemically, somatostatin-reactive cells were found in two well-differentiated adenocarcinomas with argyrophilia; many of these cells corresponded to some of the type I argyrophil cells, although some were non-argyrophilic. Two adenosquamous cell carcinomas with type II argyrophil cells also contained cells that were immunoreactive with antisera against gastrin; however, they were non-argyrophilic.

Steroid receptor levels were determined in 196 samples of endometrial adenocarcinoma: cytosol estradiol receptors (ERc) were measured in 171 samples, cytosol progesterone receptors (PRc) in all samples; nuclear estradiol receptors (ERn) and nuclear progesterone receptors (PRn) in 68 samples; total estradiol receptors (ERt = ERc plus ERn) and total progesterone receptors (PRt = PRc plus PRn) were measured in 68 samples. The ERc levels were 88.2 +/- 8.9 (mean +/- SEM) and ERn were 94.4 +/- 15.6 fmol/mg protein; PRc levels were 197.9 +/- 25.9 and PRn 178.3 +/- 55.9 fmol/mg protein. The ERt levels were 162.6 +/- 23.2 and PRt 249.8 +/- 75.7 fmol/mg protein. The presence of PRc was related to the ERc levels according to the cut-off used. Estradiol receptors (ER) and progesterone receptors (PR) were present in the cytoplasmic and nuclear fractions in 60.2% and 36.8% of cases, respectively. The simultaneous presence of both ERt and PRt was observed only in 27.9% of cases. In the normal endometrium ERc and PRc were negatively correlated (r = -0.525, P less than 0.005), whereas in endometrial adenocarcinoma the correlation was positive (r = 0.491, P less than 0.001). In contrast with the normal endometrium the correlation between ERc and ERn was positive (r = 0.582, P less than 0.001) in tumor tissue. In neoplastic tissue Scatchard analysis showed a single class of specific ERc sites with a dissociation constant (Kd) of 1.39 +/- 0.8 X 10(-9) mol/l, one tenth of that found in the normal premenopausal endometrium. Qualitative and quantitative analysis of the receptor status showed that in 30% to 40% of cases studied the behavior of the neoplastic cell was similar to that found in the normal endometrial cell. In a 4-year follow-up of patients affected by endometrial adenocarcinoma there is better survival in the groups of patients with a simultaneous presence of ERt and PRt than in the group with their absence.

Paraffin-embedded tissues from 15 women with breast or endometrial carcinomas were analyzed in a study designed to explore the possible value and validity of an immunoperoxidase method for the detection of estrogen receptor in formalin-fixed paraffin-embedded tissue. Results were compared with biochemical assays for estrogen receptor performed on cytosols of fresh tissue from the same patients. There was complete correlation in nine of 15 (60%) of the tumors analyzed. Four cases (26.7%) were judged positive for estrogen binding sites by immunoperoxidase but were negative for estrogen receptor by biochemical assays; in two cases the converse was observed. The immunohistologic technique is relatively rapid and utilizes fixed paraffin sections of the same tissue that is used for standard histologic diagnosis. The provision of a permanent record that can be kept for future reference provides an advantage over immunofluorescence methods that have been advanced for the detection of estrogen receptors. The excellent morphology achieved permits an assessment of the staining of individual cells in relation to the usual histologic criteria employed in the diagnosis of breast and endometrial cancer. This stands in contrast to biochemical cytosol-based assays that take no account of variations in receptor expression by the tumor cells or variations in the proportion of the assayed material that is in fact neoplastic as distinct from supporting stroma and connective tissue.

The modal DNA value was measured in six patients with simultaneous endometrial and ovarian carcinoma by Feulgen static cytometry. One patient with low-grade endometrial and ovarian carcinoma manifested diploid indices at both sites. Another patient demonstrated aneuploid ovarian carcinoma and diploid endometrial carcinoma, indicating that these were separate neoplasms. The remaining four patients with Stage III disease had aneuploid endometrial and ovarian carcinomas with identical DNA indices. These data support a single neoplastic process with metastasis in the latter four patients. There was good correlation with the clinicopathologic impression on the likelihood of synchronous primaries versus metastatic neoplasms. It was concluded that DNA analysis is a useful adjunct in assessing the probability that spatially separate neoplasms represent metastasis.

A series of 43 patients with endometrial adenocarcinoma were evaluated in order to investigate the relationships of the estrogen receptor (ER) and the progesterone receptor (PR) with the histologic and nuclear grades and the ultrastructural differentiation of these tumors. Twenty-six neoplasms were positive (greater than or equal to 10 fmole/mg protein) for both receptors, 1 was positive for the ER only, 9 were ER-PR+, and 7 were ER-PR-. Twenty carcinomas were histologic Grade I, 12 Grade II, and 11 Grade III. Distribution of nuclear grade was 11 Grade I, 18 Grade II, and 14 Grade III. Both histologic and nuclear grades were found to be significantly related to the presence or absence of both the ER and the PR. Several cytoplasmic structures (cilia, primary lysosomes, intracytoplasmic lumens) were highly specific but of low sensitivity for predicting the receptor status of these tumors. To a limited extent, ultrastructural markers were associated with histologic differentiation.

With endometrial adenocarcinoma, several factors, such as stage and histologic grade, are well recognized as having prognostic significance. Other variables, e.g., nuclear grade, probably are also important clinically. A preliminary investigation of the prognostic value of the ploidy, cell cycle kinetics, and sex steroid receptor contents of these tumors has been conducted and compared with more conventional prognostic factors such as stage, grades, and depth of invasion. As analyzed by flow cytometry, the proliferative activities of the carcinomas were significantly associated with prognosis. Tumors with lower levels of proliferative activity were related to improved survivals. Two thirds of the carcinomas were diploid; ploidy did not carry prognostic weight in the series. Both the estrogen and progesterone receptor status were related to survival. Patients whose tumors were positive for these receptors had a better prognosis than did those in which the receptors were not present in significant quantities.

Similarities between endometrial and mammary tissue as targets for ovarian hormones indicate that measurements of estradiol and progesterone receptor (RE and RP) levels may be as useful in endometrial cancer as they are in breast cancer for the prediction of responses to treatment with steroids and antiestrogens. Receptor levels cannot be inferred from the degree of differentiation of the endometrial tumors, although RP values are lower in poorly differentiated adenocarcinoma. Current studies aim to relate RP levels to objective remissions of metastases after progestin therapy, and attempts are being made to increase RP with tamoxifen before treatment with progestins or assaying for RP. In vitro studies aim to elucidate fundamental problems related to the action of steroids on the tumors, e.g., mechanism by which receptors mediate the effects of pharmacologic doses of drugs, factors that regulate receptor levels, and homogeneity in the distribution of receptors in tumor cell populations.