George D. Malkasian

Exogenous estrogen and endometrial carcinoma: Case-control and incidence study

Recent independent case-control studies have indicated that treatment with exogenous estrogen is associated with an increase in the risk of endometrial cancer. This question was studied in Olmsted County, Minnesota, by identifying all cases of endometrial cancer among residents over a 30 year period (1945 through 1974) and by matching four controls to each of the 145 patients. The rate of past exposure to any exogenous estrogen for any duration was about the same for patients as for controls. However, the estimated relative risk of endometrial cancer associated with conjugated estrogen treatment of 6 months or longer was 4.9 (P less than 0.01), and this increased to 7.9 (P less than 0.01) with exposure for 3 years or longer. The risk increased with larger doses (1.25 mg. or more) and continuous administration of conjugated estrogens. The incidence of endometrial carcinoma over the three decades of the study, corrected for an increasing rate of hysterectomy, was constant. Thus to this time, the low rate of use of conjugated estrogens in this region over the past 30 years apparently has not had an appreciable impact on the incidence of endometrial cancer.

Preoperative evaluation of serum CA 125 levels in premenopausal and postmenopausal patients with pelvic masses. Discrimination of benign from malignant disease

CA 125 levels were measured in 158 patients with palpable pelvic masses who were about to undergo diagnostic laparotomy. When the 68 patients found to have cancer were compared with the 90 patients with benign disease, those with malignancies were significantly older, were more frequently postmenopausal, and had significantly higher values of serum CA 125. Patients with benign pelvic masses had CA 125 levels greater than 65 U/ml in 8% of cases, whereas those with malignancies had CA 125 levels greater than 65 U/ml in 75% of cases. If only those patients who had frankly malignant, primary, nonmucinous epithelial ovarian carcinomas were considered, CA 125 levels greater than 65 U/ml predicted malignancy with a sensitivity of 91% for all patients. Greater sensitivity and specificity were observed in the postmenopausal subgroup than in the premenopausal subgroup. In the postmenopausal group with a 63% prevalence of ovarian cancer the predictive positive value was 98% and the predictive value negative was 72%. In a premenopausal population with a 15% prevalence of ovarian cancer the predictive value for a positive test was 49%, while the predictive value for a negative test was 93%.

Papillary serous carcinoma of the peritoneum. A review of 33 cases treated with platin-based chemotherapy

Thirty‐three patients were identified who had papillary serous carcinoma of the peritoneum (PSCP). The gross operative specimens, histopathologic condition, and treatment records were reviewed. The median age at presentation was 60 years (age range, 22 to 78 years). Abdominal pain and distention were the most common presenting symptoms. All patients had a total abdominal hysterectomy and bilateral salpingo‐oophorectomy, and all but two had debulking surgery. All patients had disease involving the omentum, the abdominal and pelvic peritoneum, and the surface of the ovaries, but none had intrinsic disease of the ovaries. Eight patients had disease outside of the abdominal cavity. Seven of these patients had malignant pleural effusions. All patients received platin‐based chemotherapy. Sixteen patients underwent second‐look laparotomy, two had no evidence of disease, and one had microscopic disease only. The median survival time for all patients was 17 months. Three patients are alive 6 to 7 years after the initial diagnosis. In conclusion, longterm survival can be achieved in some PSCP patients by debulking surgery and platin‐based chemotherapy.

Evaluation of unfavorable histologic subtypes in endometrial adenocarcinoma

A retrospective review of 388 patients who presented to the Mayo Clinic for treatment of endometrial carcinoma between 1979 and 1983 was performed and the surgical and pathologic observations were documented. An uncommon histologic subtype was detected in 52 patients (13%): 20 adenosquamous, 14 serous papillary, 11 clear cell, 7 undifferentiated. In contrast to the survival of patients with endometrioid lesions (92%), the overall survival in these patients was only 33%. Each of the individual abnormal histologic subtypes exhibited a survival of less than 50%. At the time of surgical staging, 62% of patients with unfavorable histologic subtypes had extrauterine spread of disease. Despite liberal utilization of postoperative adjuvant therapy in 42 of the 52 patients (81%), only 10% of these patients survived 5 years. Fifty-five percent had a component of recurrence outside of the abdominal/pelvic cavity. Subsequent treatment considerations should incorporate regimens addressing systemic and local tissue control.

CA 125 serum levels correlated with second-look operations among ovarian cancer patients

CA 125, which is an antigenic determinant expressed by many epithelial ovarian cancers, is measured in serum using a solid phase immunoradiometric assay. Sera from 55 patients who were in clinical remission and underwent a second-look operation to assess disease status after chemotherapy were studied prospectively. All patients had the CA 125 assay performed within one week before their second-look operation. Twenty-four patients (44%) had no histologic or cytologic evidence of disease, seven patients (13%) had microscopic disease, 13 patients (24%) had disease measuring 1 mm to 1.5 cm, and ten patients (18%) had disease greater than or equal to 1.5 cm in maximum tumor dimension. None of the 24 patients with a negative second-look operation had a positive CA 125 antigen level (greater than or equal to 35 U/mL), compared with six of 20 patients (30%) with less than 1.5 cm disease, and six of ten (60%) with greater than or equal to 1.5 cm disease (P less than .0001). All 12 patients with an elevated CA 125 antigen level (greater than or equal to 35 U/mL) had disease discovered at their second-look operation. Thus, in this setting the predictive value of a positive CA 125 titer (greater than or equal to 35 U/mL) was 100%. The predictive value of a negative CA 125 antigen level (less than 35 U/mL) was 56%, ie, the test did not exclude the presence of disease in 44% of patients with a positive second look. The maximum tumor size associated with at least one prior negative antigen level was 1.9 cm.(ABSTRACT TRUNCATED AT 250 WORDS)

The CA 125 assay as a predictor of clinical recurrence in epithelial ovarian cancer

Abstract Serum CA 125 levels were obtained from 55 women with epithelial ovarian cancer before a second-look surgical procedure and serially thereafter. All patients were clinically and radiographically free of tumor at the time of the second-look operation and were followed to clinical recurrence. Median follow-up was 12 months. CA 125 levels obtained at the second-look operation had a sensitivity and specificity for predicting clinical recurrence of 94% and 88%, respectively. Patients with an elevated CA 125 level (≥35 U/ml) had a 60% chance of clinical recurrence within 4 months, while patients with levels

Prognostic significance of histologic classification and grading of epithelial malignancies of the ovary

Overall survival in 1938 women with epithelial ovarian cancer receiving primary treatment at Mayo Clinic was 35% at 5 years, 28% at 10 years, and 15% at 25 years. For most histologic cell types, observed differences in survival were more apparent than real since the behavior of different cell types was similar when compared stage for stage and grade for grade. Mucinous cystadenocarcinomas tended to be low grade and low stage, while serous cystadenocarcinomas tended to be high grade and high stage. For Stage I disease, factors other than cell type seemed to be more important in determining survival; specifically, Stage IA1 patients did significantly better than all other Stage I patients. In Stage III disease, the amount of residual tumor made a significant difference in survival for all grades. In Stage IV disease, the amount of residual made a highly significant difference in survival for grade 1 disease.

Fracture Risk After Bilateral Oophorectomy in Elderly Women

Elderly women with the lowest serum estrogen levels are at the greatest risk of bone loss and fractures, but it is controversial whether the ovaries contribute to estrogen production after menopause, and therefore, whether bilateral oophorectomy in postmenopausal women might have adverse skeletal effects. To address this potential problem, we estimated long‐term fracture risk among 340 postmenopausal Olmsted County, MN, women who underwent bilateral oophorectomy for a benign ovarian condition in 1950‐1987. In over 5632 person‐years of follow‐up (median, 16 years per subject), 194 women experienced 516 fractures (72% from moderate trauma). Compared with expected rates, there was a significant increase in the risk of any osteoporotic fracture (moderate trauma fractures of the hip, spine, or distal forearm; standardized incidence ratio [SIR], 1.54; 95% CI, 1.29‐1.82) but almost as large an increase in fractures at other sites (SIR, 1.35; 95% CI, 1.13‐1.59). In multivariate analyses, the independent predictors of overall fracture risk were age, anticonvulsant or anticoagulant use for ≥6 months, and a history of alcoholism or prior osteoporotic fracture; obesity was protective. Estrogen replacement therapy was associated with a 10% reduction in overall fracture risk (hazard ratio [HR], 0.90; 95% CI, 0.64‐1.28) and a 20% reduction in osteoporotic fractures (HR, 0.80; 95% CI, 0.52‐1.23), but neither was statistically significant. The increase in fracture risk among women who underwent bilateral oophorectomy after natural menopause is consistent with the hypothesis that androgens produced by the postmenopausal ovary are important for endogenous estrogen production that protects against fractures.

An initial analysis of preoperative serum CA 125 levels in patients with early stage ovarian carcinoma

Preoperative serum CA 125 levels were determined for 36 patients with Stage I and II ovarian carcinoma. Levels ranged from 9 to 1962 U/ml with a mean of 216 U/ml. In Stage I patients, CA 125 levels averaged 133 U/ml and in Stage II patients 382 U/ml. Nine of 24 Stage I (38%) and 9 of 12 Stage II patients (75%) had CA 125 levels in excess of 65 U/ml in a population somewhat overrepresented in mucinous tumors. Patients with non-mucinous neoplasms had CA 125 elevations more often--in 75% of the cases--than those with mucinous tumors. A larger study will be required to more precisely estimate the fraction of early stage patients with elevated preoperative serum CA 125 levels; however, this investigation demonstrates an assay sensitivity minimally adequate to initiate a pilot evaluation of serum CA 125 levels in a population at risk for ovarian carcinoma.

Recurrent disease after negative second-look laparotomy in stages III and IV ovarian carcinoma

Between 1977 and 1984, second-look laparotomy to evaluate disease status after adjuvant chemotherapy was performed in 134 patients originally presenting with advanced epithelial ovarian carcinoma. Surgical and histologic assessment did not detect persistent disease in 50 patients (37%). Recurrent carcinoma was subsequently documented in 15 patients (30%), all failures occurring within the abdominal cavity or the retroperitoneal space. Several patient subgroups at high risk for recurrence after negative second-look laparotomy are identified that might benefit from additional adjunctive therapy. Because of different treatment-associated morbidities, the corresponding sensitivities and specificities of the high-risk groups may assist subsequent treatment selection.